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In practical terms, the lesion responsible for ideomotor apraxia that affects both arms usually resides in the left parietal region. Kertesz and colleagues have provided evidence that the lesions responsible for aphasia and apraxia are different, though the two conditions are frequently associated because of their origin in the left hemisphere. The exact location of the parietal lesion, whether in the supramarginal gyrus or in the superior parietal lobe (areas 5 and 7) and whether subcortical or cortical, is still uncertain. Clinically there is a motor speech disorder, a right hemiparesis, and this type of apraxia of the nonparalyzed hand, which has been termed sympathetic apraxia. If the lesion in the deep white matter separates the language areas from the right motor cortex but not from the left, the patient can write with the right hand but not with the left, or he may write correctly with the right hand and aphasically with the left. That such a syndrome is attributable to interruption of a pathway that traverses the genu of the corpus callosum, as depicted by Geschwind, is questionable, insofar as sympathetic apraxia has not been observed in patients with lesions (or surgical sections) confined to the anterior third of the corpus callosum (see page 395). Perhaps surprisingly, there are but a few cases of apraxia of any type with proven prefrontal lesions. Of a somewhat different nature is a facial-oral apraxia, which is probably the most common of all apraxias in practice. It may occur with lesions that undercut the left supramarginal gyrus or the left motor association cortex and may or may not be associated with the apraxia of the limbs described above. Such patients are unable to carry out facial movements to command (lick the lips, blow out a match, etc. With lesions that are restricted to the facial area of the left motor cortex, the apraxia will be limited to the facial musculature and may be associated with a verbal apraxia or cortical dysarthria (page 418). The terms dressing apraxia and constructional apraxia are used to describe certain manifestations of parietal lobe disease. These abnormalities are not apraxias in the strict sense of a loss of previously learned behavior but are instead symptoms of contralateral extinction or neglect of the body schema and of extrapersonal space (anosognosia, page 401). First, one observes the actions of the patient as he engages in such tasks as dressing, washing, shaving, and using eating utensils. Second, the patient is asked to carry out familiar symbolic acts- wave goodbye, salute the flag, shake a fist as though angry, or blow a kiss. Finally, he is asked to show how he would hammer a nail, brush his teeth, take a comb out of his pocket and comb his hair, cross himself, and so forth, or to execute a more complex act, such as lighting and smoking a cigarette or opening a bottle of soda, pouring some into a glass, and drinking it. These last actions, involving more complex sequences, are said to be tests of ideational apraxia; the simpler and familiar acts are called tests of ideomotor apraxia. To perform these tasks in the absence of the tool or utensil is always more demanding because the patient must mentally formulate a plan of action rather than engage in a habitual motor sequence. One may think of such an ideomotor deficit, if it can be singled out from confusion or a defect in comprehension, as a kind of amnesia for certain learned patterns of movement, analogous to the amnesia for words in aphasia. Children with cerebral diseases that retard mental development are often unable to learn the sequences of movement required in hopping, jumping over a barrier, hitting or kicking a ball, or dancing. It is more helpful to think of the apraxias in an anatomic sense, as disorders of association between different parts of the cerebral cortex, as described above. The patient with a severe ideomotor apraxia nearly always has difficulty at the ideational level and, in any case, similarly situated left parietal lesions give rise to both types. Furthermore, in view of the complexity of the motor system, we are frequently uncertain whether the clumsiness or ineptitude of a hand in performing a motor skill represents a kinetic apraxia or some other fault in the intrinsic organization of hand control. A related but poorly understood disorder of movement has been termed the alien hand. In the absence of volition, the hand and arm undertake complex and seemingly purposeful movements such as reaching into a pocket or handbag, placing the hand behind the head, and tugging on the opposite hand or other body part; these activities may occur even during sleep. Most instances arise as a result of infarction in the territory of the opposite anterior cerebral artery, including the corpus callosum. When the callosum is involved, Feinberg and colleagues find that there frequently appears to be a conflict between the actions of the hands, the normal one sometimes even restraining the alien one. Damage in the left supplementary motor area from any cause as well as in the disease called corticobasal ganglionic degeneration (page 928) are associated with a similar alien hand syndrome. A form that results from a stroke in the posterior cerebral artery territory with associated sensory loss has also been observed by Ay and colleagues. Finally, it should be remarked once again that the complexity of motor activity is almost beyond imagination. Reference was made earlier to the reciprocal innervation involved in an act as simple as making a fist. Over a century ago Hughlings Jackson commented that "There are, we shall say, over thirty muscles in the hand; these are represented in the nervous centers in thousands of different combinations, that is, as very many movements; it is just as many chords, musical expressions and tunes can be made out of a few notes. All are continuously integrated and controlled by feedback mechanisms from the sensory and spinal motor neurons. These points, already touched upon in this chapter, are elaborated in the following three chapters. This term should not be applied to paralysis of isolated muscles or groups of muscles supplied by a single nerve or motor root. Hemiplegia, the commonest form of paralysis, involves the arm, the leg, and sometimes the face on one side of the body. With rare exceptions, mentioned further on, hemiplegia is attributable to a lesion of the corticospinal system on the side opposite to the paralysis. It is most often the result of diseases of the thoracic spinal cord, cauda equina, or peripheral nerves, and rarely, both medial frontal cortices. It may result from disease of the peripheral nerves, muscles, or myoneural junctions; gray matter of the spinal cord; or the upper motor neurons bilaterally in the cervical cord, brainstem, or cerebrum. Diplegia is a special form of quadriplegia in which the legs are affected more than the arms. Triplegia occurs most often as a transitional condition in the development of or partial recovery from tetraplegia. In acute diseases of the lower motor neurons, the tendon reflexes are reduced or abolished, but atrophy may not appear for several weeks. Hence, before reaching an anatomic diagnosis, one must take into account the mode of onset and duration of the disease. Monoplegia with Muscular Atrophy this is more frequent than monoplegia without muscular atrophy. Long-continued disuse of one limb may lead to atrophy, but it is usually of lesser degree than atrophy due to lower motor neuron disease (denervation atrophy). In disuse atrophy, the tendon reflexes are retained and nerve conduction studies are normal. With denervation of muscles, there may be visible fasciculations and reduced or abolished tendon reflexes in addition to paralysis. If the limb is partially denervated, the electromyogram shows reduced numbers of motor unit potentials (often of large size) as well as fasciculations and fibrillations. A complete atrophic brachial monoplegia is uncommon; more often, only parts of a limb are affected. When present in an infant, it should suggest brachial plexus trauma from birth; in a child, poliomyelitis or other viral infection of the spinal cord; and in an adult, poliomyelitis, syringomyelia, amyotrophic lateral sclerosis, or a brachial plexus lesion. Crural (leg) monoplegia is more frequent than brachial monoplegia and may be caused by any lesion of the thoracic or lumbar cord- i. These disorders rarely cause severe atrophy; neither does infarction in the territory of the anterior cerebral artery. A prolapsed intervertebral disc and the several varieties of mononeuropathy almost never paralyze all or most of the muscles of a limb. The effects of a centrally prolapsed disc or other compressive lesion of the cauda equina are rarely confined to one leg. However, a unilateral retroperitoneal tumor or hematoma may paralyze the leg by compressing the lumbosacral plexus. Monoplegia the examination of patients who complain of weakness of one limb often discloses an asymptomatic weakness of another, and the condition is actually a hemiparesis or paraparesis. Or, instead of weakness of all the muscles in a limb, only isolated groups are found to be affected. Ataxia, sensory disturbances, or reluctance to move the limb because of pain must not be misinterpreted as weakness. Parkinsonism may give rise to the same error, as can rigidity or bradykinesia of other causation or a mechanical limitation due to arthritis and bursitis. The presence or absence of atrophy of muscles in a monoplegic limb is of particular diagnostic help, as indicated below. Monoplegia without Muscular Atrophy this is most often due to a lesion of the cerebral cortex. Only infrequently does it result from a subcortical lesion that interrupts the motor pathways.

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Neurologists often encounter instances of slowly evolving the trigeminal root may be compressed or invaded by intraunilateral or bilateral trigeminal neuropathy in which sensory imcranial meningiomas, acoustic neuromas, trigeminal neuromas pairment is confined to the territory of the trigeminal nerve, some(Fig. Loss of facial sensation can occur as part of a widespread may also implicate the nerve, causing pain and a gradually prosensory neuropathy that occurs as a remote effect of cancer or as gressive sensory loss. The ophthalmic division of the fifth nerve part of Sjogren disease (pages 586 and 1141). Tumors of the spheLecky and colleagues, 9 had either scleroderma or mixed connecnoid bone (myeloma, metastatic carcinoma, squamous cell carcitive tissue disease, and a similar number had either organ- or nonnoma, and lymphoepithelioma of the nasopharynx) may involve organ-specific serum autoantibodies. The symptoms may involve branches of the trigeminal nerve at their foramina of entry or exit. Hughes has also reported cases of triThe mandibular division may be compressed by the roots of an geminal neuropathy with scleroderma, lupus erythematosus, impacted third molar (wisdom) tooth. Pathologic data are limited but point to an inflammatory lesion of the trigeminal ganglion or sensory root. Stilbamidine and trichloroethylene are known to cause sensory loss, tingling, burning, and itching exclusively in the trigeminal sensory territory. Four of their 16 patients had an associated paranasal sinusitis, but subsequent reports have failed to substantiate a causal relationship between sinusitis and cranial neuritis. A recurrent variety of uncertain origin has been reported in the dental literature. We have had experience with two patients whose facial numbness was a component of an upper cervical disc syndrome that included numbness on the same side of the body. Chia has described five patients in whom an aching pain in the cheek and unilateral weakness of mastication were the main features. The function of the nerve may be studied by the electrical recording of blink reflexes. A few laboratories have developed an evoked potential test specifically of the trigeminal nerve. Facial numbness also occurs with diverse conditions affecting the spinal nucleus of the trigeminal nerve, but in these cases there are additional signs of brainstem or upper cervical cord disease. The Seventh, or Facial, Nerve Anatomic Considerations the seventh cranial nerve is mainly a motor nerve supplying all the muscles concerned with facial expression on one side. The sensory component is small (the nervus intermedius of Wrisberg); it conveys taste sensation from the anterior two-thirds of the tongue and, variably, cutaneous sensation from the anterior wall of the external auditory canal. The taste fibers at first traverse the lingual nerve (a branch of the trigeminal mandibular) and then join the chorda tympani, which conveys taste sensation via the facial nerve to the nucleus of the tractus solitarius. Secretomotor fibers innervate the lacrimal gland through the greater superficial petrosal nerve and the sublingual and submaxillary glands through the chorda tympani. The motor nucleus of the seventh nerve lies ventral and lateral to the abducens nucleus, and the intrapontine fibers of the facial nerve partly encircle and pass ventrolaterally to the abducens nucleus before emerging from the pons, just lateral to the corticospinal tract. At their juxtaposition in the floor of the upper fourth ventricle, the sixth and seventh nerves may be affected simultaneously by a vascular or infiltrative lesion. The facial nerve enters the internal auditory meatus with the acoustic nerve and then bends sharply forward and downward around the anterior boundary of the vestibule of the inner ear. The nerve continues in its own bony channel, the facial canal, within which, just distal to the geniculate ganglion, it provides a branch to the pterygopalatine ganglion, i. It makes its exit from the skull at the stylomastoid foramen, then passes through the parotid gland and subdivides into five branches that supply the facial muscles, the stylomastoid muscle, the platysma, and the posterior belly of the digastric muscle. A complete interruption of the facial nerve at the stylomastoid foramen paralyzes all muscles of facial expression. The corner of the mouth droops, the creases and skin folds are effaced, the forehead is unfurrowed, the palpebral fissure is widened, and the eyelids will not close. The lower lid sags also, and the punctum falls away from the conjunctiva, permitting tears to spill over the cheek. Food collects between the teeth and cheek, and saliva may dribble from the corner of the mouth. The patient complains of a heaviness or numbness and sometimes an aching pain in the face, but sensory loss can usually not be demonstrated. Taste, however, is intact because the lesion is beyond the site where the chorda tympani has separated from the main trunk of the facial nerve. If the lesion is in the facial canal above the junction with the chorda tympani but below the geniculate ganglion, all the preceding symptoms occur; in addition, taste is lost over the anterior twothirds of the tongue on the same side. If the nerve to the stapedius muscle is involved, there is hyperacusis (painful sensitivity to loud sounds). If the geniculate ganglion or the motor root proximal to it is involved, lacrimation and salivation may be reduced. Lesions at this point may also affect the adjacent eighth nerve, causing deafness, tinnitus, or dizziness. The disorder affects men and women more or less equally and occurs at all ages and all times of the year. There is controversy regarding an increased incidence in women during the third trimester of pregnancy, particularly in the 2 weeks preceding delivery and in the first 2 weeks postpartum; up to a threefold increase has been cited by some authors, but others have failed to find this disproportionate number of cases. Supporting a proclivity for facial palsy are scattered reports of a recurrence with each pregnancy. Only a handful of such cases are on record, all showing varying degrees of degeneration of nerve fibers. One case was said to show inflammatory changes, but these may have been misinterpreted (see Karnes). Only in the past few years, however, has such a mechanism been established with a reasonable degree of certainty for the majority of cases formerly considered to be idiopathic. Pain behind the ear may precede the paralysis by a day or two and in a few patients is quite intense and persistent. In only a small proportion of patients, a hypesthesia in one or more branches of the trigeminal nerve can be demonstrated. Impairment of taste is present to some degree in most patients but rarely persists beyond the second week of paralysis. As indicated earlier, this indicates that the lesion has extended to or above the point where the chorda tympani fibers join the facial nerve. Hyperacusis or distortion of sound in the ipsilateral ear indicates paralysis of the stapedius muscle. Cases with more pronounced contrast enhancement of the facial nerve have a worse prognosis (Kress). Presumably, the enhancement reflects inflammation and swelling within the course of the facial nerve. Parasympathetic fibers are represented by regular dashes; special visceral afferent (taste) fibers are represented by long dashes and dots. A, B, and C denote lesions of the facial nerve at the stylomastoid foramen, distal to the geniculate ganglion, and proximal to the geniculate ganglion. Disturbances resulting from lesions at each of these sites are described in the text. Early recovery of some motor function in the first 5 to 7 days is the most favorable prognostic sign. Electromyography may be of value in distinguishing temporary conduction defects from a pathologic interruption of nerve fibers; if there is evidence of denervation after 10 days, one may expect a long delay in the onset of recovery, measured in terms of months. Recovery then proceeds by regeneration of nerve, a process that may take 2 years or longer and is often incomplete. Other recurrent forms of facial paralysis occur with Lyme disease and sarcoidosis, and in a familial variety as mentioned below. Treatment Protection of the eye during sleep, massage of the weakened muscles, and a splint to prevent drooping of the lower part of the face are the measures generally employed in the management of such cases. There is no evidence that surgical decompression of the facial nerve is effective, and it may be harmful. The administration of prednisone (40 to 60 mg/day, or an equivalent corticosteroid) during the first week to 10 days after onset has been beneficial in most trials.

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Their clever use of London taxi drivers as subjects for imaging studies has further suggested that the volume of the right hippocampus is larger in subjects who have more experience navigating the arcane streets of London (Maguire et al). This asymmetric representation of certain modalities of memory is in keeping with limited clinicopathologic studies of patients who have undergone temporal lobectomy on one side. These observations in aggregate indicate that integrity of the hippocampal formations and the mediodorsal nuclei of the thalamus are essential for normal memory and learning. Interestingly, there are only sparse direct anatomic connections between these two regions. The importance assigned to the hippocampal formations and medial thalamic nuclei in memory function does not mean that the mechanisms governing this function are confined to these structures or that these parts of the brain form a "memory center. Normal memory function, as emphasized, involves many parts of the brain in addition to diencephalic-hippocampal structures. The aforementioned basal frontal nuclei that project to the hippocampi are an example. It is also clear that extensive lesions of the neocortex may cause impairment of retentive memory and learning and that this effect is probably more dependent upon the size of the lesion than upon its locus. Of particular importance are the circumscribed areas of the cerebral cortex related to special forms of learning and memory (so-called modality-based memory), a subject that is considered in detail in the next chapter. Thus, a lesion of the dominant temporal lobe impairs the ability to remember words (loss of explicit semantic memory), and a lesion of the inferior parietal lobule undermines the recognition of written or printed words as well as the ability to relearn them (alexia). The dominant parietal lobe is related to recollection of geometric figures and numbers; the nondominant parietal lobe, to visuospatial relations; the inferoposterior temporal lobes, to the recognition of faces; and the dominant posterofrontal region, to acquiring and remembering motor skills and their affective associations. Whether these are truly forms of memory or whether these regions of cortex must be entrained in order to retrieve and "experience" the memory is semantic. Taken to its extremes, aphasia from a left temporal perisylvian lesion (Wernicke aphasia) could be viewed as an amnesia for language, and parietal lesions that cause ideomotor apraxia could be taken to represent a loss of memory for these previously learned acts. What remains clear is that the integrity of both the hippocampal-thalamic system and the appropriate cortical region is required for memory as it is commonly understood, but only the former is integrated into all modalities of learning and retrieval. Any hypothesis concerning the anatomic substratum of learning and retentive memory must therefore include not only the diencephalic-hippocampal structures but also special parts of the neocortex and midbrain reticular formation (for maintaining alertness). We would suggest that the diencephalic-hippocampal structures are involved in all active phases of learning and integration of new information, regardless of the sense avenue through which this information reaches the organism or of the final pathway of its expression, and it seems to make little difference whether the newly acquired information involves functions classed as purely cognitive or as emotional. It is a remarkable feature of the Korsakoff amnesic state that no matter how severe the defect in retentive memory may be, it is never complete. Amnesic syndrome of sudden onset- usually with gradual but incomplete recovery A. Bilateral or left (dominant) hippocampal infarction due to atherosclerotic-thrombotic or embolic occlusion of the posterior cerebral arteries or their inferior temporal branches B. Subarachnoid hemorrhage (usually rupture of anterior communicating artery aneurysm) E. Cardiac arrest, carbon monoxide poisoning, and other hypoxic states (hippocampal damage) G. Amnesic syndrome of subacute onset with varying degrees of recovery, usually leaving permanent residua A. Tumors involving the floor and walls of the third ventricle and limbic cortical structures B. Alzheimer disease (early stage) and other degenerative disorders with disproportionate affection of the temporal lobes C. Paraneoplastic and other forms of immune "limbic" encephalitis anisms that govern immediate registration, which remains intact in even the most severely damaged patients with the Korsakoff amnesic syndrome. Equally obscure are the anatomic arrangements that enable the patient with virtually no capacity to retain any newly presented factual information to still learn some simple perceptualmotor and cognitive skills, even though there may be no memory of having been taught these skills in the first place. Other psychologic features of human memory that must be accounted for by any model purporting to explain this function are the importance of cueing in eliciting learned material and the imprecision of past memories, allowing for unwitting embellishment and false recollection, to the point of fabrication. The latter aspect has been a topic of considerable importance in children who have (or have not) been subjected to sexual abuse and in adults and children whose memories of past abuse have been suggested by the examiners (see Schacter). Also of interest are the separate roles of the thalamus, the hippocampi, and the frontal lobes in memory and whether the nature of the amnesia resulting from damage at one site differs from the others. That isolated thalamic lesions, without implicating medial temporal areas, can cause a Korsakoff syndrome is evident from the experience with alcoholism. Graff-Radford and colleagues have found that with purely thalamic lesions, as appreciated by imaging studies, anterograde learning is more affected than retrograde recall; but comparing these functions quantitatively seems to us quite difficult. Kopelman, in reviewing his own studies and those of others, concludes that the differences are subtle and pertain mostly to temporal ordering and the modality of information, which is degraded more with diencephalic-temporal lesions than with frontal lobe damage. The cellular mechanisms involved in learning and the formation of memories are only beginning to be understood. Whether physiologic phenomena such as long-term potentiation or anatomic changes in the dendritic structure of neurons are at the center of memory storage is not known; certainly both are likely to be involved. The neurochemical systems that are activated during formation and recall of memory are also obscure. Kandel has provided a detailed review of information on this subject (see the References). Another noteworthy fact is that long-standing social habits, automatic motor skills, and memory for words (language) and visual impressions (visual or pictorial attributes of persons, objects, and places) are unimpaired. Long periods of repetition and usage have made these implicit or procedural memories virtually automatic; they no longer require the participation of the diencephalic-hippocampal structures that were necessary to learn them originally. All of this suggests that these special memories, or coded forms of them, through a process of relearning and habituation, come to be stored or filed in other regions of the brain; i. Not known is how a disease process, acting over a brief period of time, not only impairs all future learning but also wipes out portions of a vast reservoir of past memories that had been firmly established for many years before the onset of the illness. Also unknown are the anatomic and physiologic mech- Classification of Diseases Characterized by an Amnesic Syndrome the amnesic (Korsakoff) syndrome may be a manifestation of several neurologic disorders, identified by their mode of onset and clinical course, the associated neurologic signs, and ancillary findings (Table 21-5). Each of the amnesic states listed in Table 21-5 is considered at an appropriate point in subsequent chapters of this book. The only exception is the striking syndrome of transient global amnesia, the nature of which is not certain. It cannot be included with any assurance with the epilepsies or the cerebrovascular diseases or any other category of disease and is therefore considered here. Transient Global Amnesia this was the name applied by Fisher and Adams to a particular type of memory disorder that they observed in more than 20 middle-aged and elderly persons. The condition was characterized by an episode of amnesia and bewilderment lasting for several hours. During the attack, there was no impairment in the state of consciousness, no other sign of confusion, and no overt seizure activity; personal identification was intact, as are motor, sensory, and reflex functions. Unlike those with psychomotor epilepsy, the patient is alert, in contact with his surroundings, and capable of high-level intellectual activity and language function during the attack. As soon as the attack has ended, no abnormality of mental function is apparent except for a permanent gap in memory for the period of the attack itself and for a brief period (hours or days) preceding the attack. The condition is among the most curious in neurology but is often mistaken for a psychiatric episode. Hodges and Ward have made detailed psychologic observations in five patients during an episode. The psychologic deficit, except for its transience, was much the same as that in the permanent amnesia syndrome. Personality, cognition involving highlevel functioning, semantic language, and visuospatial discrimination were all preserved. The extent of retrograde amnesia was highly variable, but characteristically it shrank after the attack, leaving a permanent retrograde gap of about 1 h. However, some mild impairment of new learning persisted for up to a week after the acute attack. The recurrence of such attacks is not uncommon, having been noted in 66 of 277 patients who were observed for an average period of 80 months (Miller et al) and in 16 of 74 patients followed for 7 to 210 months (Hinge et al). One of our patients had more than 50 attacks, but among all the rest (more than 100 cases), 5 was the maximum. It seems children are not susceptible to the condition; however, a 13-yearold and 16-year-old with migraine were reported to have had similar attacks during participation in sports (Tosi and Righetti). No consistent antecedent events have been identified, but certain ones- such as a highly emotional experience, pain, exposure to cold water, sexual intercourse, and mild head trauma- have been reported in some cases (Haas and Ross; Fisher).

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Supranuclear ophthalmoplegia, ataxia, seizures, myoclonus, nystagmus, and a highly characteristic oculomasticatory movement described as myorhythmia (which looks more 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. Almost always the myorhythmias are accompanied by a supranuclear vertical gaze paresis that sometimes affects horizontal eye movements as well. Presumably, the neurologic complications 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 limb and gait ataxia occurring in middle-aged or older men in whom no cause is uncovered by less invasive means, it is justifiable to perform these tests (see Chap. Rarely, the neurologic symptoms may occur in the absence of gastrointestinal disease (Adams et al). In the extensive review of 84 cases by Louis and colleagues, 71 percent had cognitive changes, half with psychiatric features; 31 percent had myoclonus; 18 percent, ataxia; and 20 percent had the oculomasticatory and skeletal myorhythmias that are virtually pathognomonic of Whipple disease (Schwartz et al). Treatment A course of penicillin and streptomycin followed by trimethoprim-sulfamethoxazole or ceftriaxone and continued for 1 year is one of the currently recommended treatment 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 illness of diverse causes, among them fluid overload and electrolyte imbalance, Reye syndrome (page 969), and, possibly most common, postinfectious encephalitis. 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 these cases, but a careful search for better-characterized causes of febrile coma must be undertaken. The term subdural abscess, among others, has been applied to this condition, but the proper name is empyema, indicating suppuration in a preformed space. It is distinctly more common in males, a feature for which there is no explanation. 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 meningitis, there have been in the last decade 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 spread from a leptomeningitis. Infection gains entry to the subdural space by direct extension through bone and dura or by spread from septic thrombosis of the venous sinuses, particularly the superior longitudinal sinus. Rarely, the subdural infection is metastatic, from infected lungs; hardly ever is it secondary to bacteremia or septicemia. It is again of interest that cases of sinus origin predominate in adolescent and young adult men (Kaufman et al). In such cases, streptococci (nonhemolytic and viridans) are the most common organisms, followed by anaerobic streptococci (often Strep. The factors that lead to a subdural empyema rather than to a cerebral abscess are not fully understood. Pathology A collection of subdural pus, in quantities ranging from a few milliliters 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 posterior 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 depressed, 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 infiltration of the underlying arachnoid with small numbers of neutrophilic leukocytes, lymphocytes, and mononuclear cells. The 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 the unilateral seizures and other signs of disordered cerebral function (Kubik and Adams). Symptomatology and Laboratory 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. They are followed in a few days by drowsiness and increasing stupor, rapidly progressing to coma. At about the same time, focal neurologic 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 in performing a lumbar puncture, and one should proceed first with other diagnostic procedures. Empyema that follows meningitis tends to localize on the undersurface of the temporal lobe and may require coronal views in order 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 (page 638), acute necrotizing hemorrhagic leukoencephalitis (page 792), and septic embolism due to bacterial endocarditis (see further on in this chapter). Treatment Most subdural empyemas, by the time they are recognized clinically, require immediate drainage through multiple enlarged frontal burr holes or through a craniotomy in cases with an interhemispheric, subtemporal, or posterior fossa location. The surgical procedure should be coupled with appropriate antibiotic therapy, which consists in most cases of the intravenous administration of 20 to 24 million units of penicillin per day plus a thirdgeneration cephalosporin and metronidazole. Bacteriologic findings or an unusual presumed source may dictate a change to different drugs, particularly to later-generation cephalosporins. Without such massive antimicrobial therapy and surgery, most 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). 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 inflammatory process: frontal or auricular pain, purulent discharge from sinuses or ear, and fever and local tenderness. Rarely, a focal seizure may occur, or the fifth and sixth cranial nerves may be involved with infections of the petrous part of the temporal bone. Treatment consists of antibiotics aimed at the appropriate pathogen(s)- often Staph. Later, the diseased bone in the frontal sinus or the mastoid, from which the extradural infection had arisen, may have to be removed and the wound packed to ensure adequate drainage. Septic Cavernous Sinus Thrombophlebitis this condition is usually secondary to infections of the ethmoid, sphenoid, or maxillary sinuses or the skin around the eyes and nose, sometimes originating in a seemingly innocuous lesion. In addition to headache, high fluctuating fever, and signs of systemic toxicity, there are characteristic local effects. Obstruction of the ophthalmic veins leads to chemosis, proptosis, and edema of the ipsilateral eyelids, forehead, and nose. The retinal veins become engorged, and this may be followed by retinal hemorrhages and papilledema. More often, however, vision in the affected eye is lost by a yet undefined type of optic neuropathy as noted below, without visible alterations in the fundus.

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Although difficult to appreciate, it may be detected (using pupillometry) by noting a lag in the redilation of the initially small pupils when light is withdrawn (Smith and Smith). Use is made of this phenomenon in the testing of the ciliospinal pupillary reflex, which is evoked by pinching the neck (afferent, C2, C3) and is effected through the efferent sympathetic fibers. Extreme constriction of the pupils (miosis) is commonly observed with pontine lesions, presumably because of bilateral interruption of the pupillodilator fibers. Interruption of the parasympathetic fibers causes an abnormal dilatation of the pupils (mydriasis), often with loss of pupillary light reflexes; this is frequently the result of midbrain lesions and is a common finding in cases of deep coma (the "blown" or Hutchinson pupil, described in Chap. As an ancillary test to determine the cause of changes in the size of the pupils, the functional integrity of the sympathetic and parasympathetic nerve endings in the iris may also be determined by the use of certain drugs. Atropinics dilate the pupils by paralyzing the parasympathetic nerve endings; physostigmine and pilocarpine constrict the pupils, the former by inhibiting cholinesterase activity at the neuromuscular junction and the latter by direct stimulation of the sphincter muscle of the iris. Epinephrine and phenylephrine dilate the pupils by direct stimulation of the dilator muscle. Cocaine dilates the pupils by preventing the reabsorption of norepinephrine into the nerve endings. In diabetes mellitus, where autonomic spinal and cranial nerves are often involved, the pupils are affected in the majority of cases. They are smaller than would be expected for age due to involvement of pupillodilator sympathetic fibers, and mydriasis is excessive upon instillation of sympathomimetic drugs. The light reflex, mediated by parasympathetic fibers (which are also damaged), is reduced, usually to a greater degree than constriction on accommodation (Smith and Smith). Some of these abnormalities require special methods of pupillometry for their demonstration. Argyll-Robertson Pupil In the forms of late syphilis, particularly tabes dorsalis, the pupils are usually small, irregular, and unequal; they fail to react to light, although they do constrict on accommodation (light-near dissociation) and do not dilate properly in response to mydriatic drugs. The exact locality of the lesion is not certain; it is generally believed to be in the tectum of the midbrain proximal to the oculomotor nuclei where the descending pupillodilator fibers are in close proximity to the light reflex fibers. The possibility of a partial third nerve lesion extending to the ciliary ganglion seems more plausible to us. A similar pupillary abnormality has been observed in the meningoradiculitis of Lyme disease and in diabetes. A dissociation of the light reflex from the accommodation-convergence reaction is also sometimes observed with a variety of midbrain lesions-. Adie Tonic Pupil (Holmes-Adie Syndrome) Another interesting pupillary abnormality is the tonic reaction, also referred to as the Adie pupil. This syndrome is due to a degeneration of the ciliary ganglia and the postganglionic parasympathetic fibers that normally constrict the pupil and effect accommodation. The patient may complain of unilateral blurring of vision or may have noticed that one pupil is larger than the other. The affected pupil is slightly enlarged in ambient light and the reaction to light is absent or greatly reduced if tested in the customary manner, although the size of the pupil will change slowly with prolonged light stimulation. Once the pupil has constricted, it tends to remain tonically constricted and redilates very slowly. Once dilated, the pupil remains in this state for many seconds, up to a minute or longer. Light and near paralysis of a segment or segments of the pupillary sphincter is also characteristic of the syndrome; this segmental irregularity can be seen with the high plus lenses of an ophthalmoscope. The affected pupil constricts promptly in response to the common miotic drugs and is unusually sensitive to a 0. The tonic pupil usually appears during the third or fourth decade of life and is much more common in women than in men; it may be associated with absence of knee or ankle jerks (Holmes-Adie syndrome) and hence be mistaken for tabes dorsalis. From all available data, it represents a special form of mild inherited polyneuropathy. An acquired type of tonic pupil has also been attributed, sometimes on uncertain grounds to diabetes, viral infection, and trauma. Springing Pupil Finally, mention should be made of a rare pupillary phenomenon characterized by transient episodes of unilateral mydriasis for which no cause can be found (the "springing pupil"). These episodes of mydriasis, which are more common in women, last for minutes to days and may recur at random intervals. Oculomotor palsies and ptosis are notably lacking, but sometimes the pupil is distorted during the attack. Some patients complain of blurred vision and head pain on the side of the mydriasis, suggesting an atypical form of ophthalmoplegic migraine. In children, following a minor or major seizure, one pupil may remain dilated for a protracted period of time. The main consideration in an awake patient is that the cornea has inadvertently (or purposefully) been exposed to mydriatic solutions, among them vasopressor agents used in cardiac resuscitation. As stated above, in dealing with anisocoria, it is worth noting that at any given examination, 20 percent of normal persons show an inequality of 0. This is "simple" or physiologic anisocoria, and it may be a source of confusion in patients with small pupils. Its main characteristic is that the same degree of asymmetry in size is maintained in low, ambient, and bright light conditions. It is also variable from day to day and even from hour to hour and often will have disappeared at the time of the second examination (Loewenfeld; Lam et al). In first dealing with the problem of pupillary asymmetry, one has to determine which of the pupils is abnormal. If it is the larger one, the light reaction will be muted on that side; if it is the smaller pupil, it will fail to enlarge in response to shading both eyes. More simply stated, light exaggerates the anisocoria due to a third-nerve lesion, and darkness accentuates the anisocoria in the case of a Horner syndrome. A persistently small pupil always raises the question of a Horner syndrome, a diagnosis that may be difficult if the ptosis is slight and facial anhidrosis undetectable. In darkness, the Horner pupil dilates more slowly and to a lesser degree than the normal one because it lacks the pull of the dilator muscle (dilation lag). The diagnosis can be confirmed by placing 1 or 2 drops of 2 to 10% cocaine in each eye; the Horner pupil dilates not at all or much less than the normal one- a response that can be documented by photos taken after 5 and 15 s of darkness. Such a response to cocaine will occur with a defect at any point along the sympathetic pathway (page 461) because lesions of the first- or second-order sympathetic neurons eventually deplete norepinephrine at the synapses with third-order neurons. The reduction of neurotransmitter at the nerve endings in the ciliary dilator muscle greatly reduces the reuptake blocking effects of cocaine. If the subsequent (24 h after cocaine) application of the adrenergic mydriatic hydroxyamphetamine (1%) has no effect, the lesion can be localized to the postganglionic portion of the pathway since this drug releases any norepinephrine that may remain in the third-order neuron. Localization of the lesion to the central or preganglionic parts of the sympathetic pathway depends upon the associated symptoms and signs (Chap. A variety of lesions, some of them purely ocular, such as uveitis, may give rise to a dilated pupil. Neurologically, there are three main diagnostic considerations: An interruption of the parasympathetic preganglionic pupilloconstrictor fibers in the third nerve. It is a safe clinical rule that the interruption of these fibers is practically always associated with ptosis, palsy of the extraocular muscles, or signs of other brainstem or cerebral disease. The importance of unilateral pupillary enlargements in the diagnosis of coma is discussed in Chap. Often in this circumstance the pupil goes through an early phase of miosis followed by irregularly shaped enlargement. Here one requires that the pupillary abnormalities conform to the diagnostic criteria for this disorder, enumerated above. Not infrequently, particularly among nurses and pharmacists, a mydriatic fixed pupil is the result of accidental or deliberate application of an atropinic or sympathomimetic drug. Failure of 1% pilocarpine drops to contract the pupil provides proof that the iris sphincter has 1. Differential Diagnosis of Anisocoria In regard to pupillary disorders, there are two main issues with which the neurologist has to contend. One is the problem of unequal pupils (anisocoria) and determining whether this abnormality is derived from sympathetic or parasympathetic denervation. Completely Sector palsy immobile of iris Test for cholinergic sphincter Impaired No dilation lag ``Dilation lag' supersensitivity with light reaction of smaller Mecholyl 2. As a rule, bilateral smallness of pupils does not pose a difficult diagnostic problem.

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Tumors of the foramen magnum should be differentiated from spinal or brainstem-cerebellar multiple sclerosis, Chiari malformation with syrinx, and chronic adhesive arachnoiditis. Treatment is surgical excision (see Hakuba et al) followed by focused radiation if the resection has been incomplete and the tumor is known to be radiosensitive. These so-called paraneoplastic disorders are not specific or confined to cancer, but the two conditions are linked far more frequently than could be accounted for by chance. They assume special importance because the neurologic syndrome in many cases becomes apparent before the underlying tumor is found. Some of the paraneoplastic disorders that involve nerve and muscle- namely, polyneuropathy, polymyositis, and the myasthenic-myopathic syndrome of Lambert-Eaton- are described on pages 1194 and 1259, respectively. Here we present several other paraneoplastic processes that involve the spinal cord, cerebellum, brainstem, and cerebral hemispheres. Comprehensive accounts of the paraneoplastic disorders may be found in the writings of Posner, Darnell and Posner, and of Dropcho. Some of these disorders are associated with IgG autoantibodies (Table 31-5), but it should be remarked that although certain antibodies are associated with specific syndromes, they are not invariably linked to particular cancers. Small-cell cancer of the lung, adenocarcinoma of the breast and ovary, and Hodgkin disease are the tumors most often associated with these disorders, but the paraneoplastic neurologic syndromes occur in only a very small proportion of these cases. The mechanism(s) by which carcinomas produce their remote effects are poorly understood. Perhaps the most plausible theory, as intimated above, is that they have an autoimmune basis. According to this theory, antigenic molecules are shared by certain tumors and central or peripheral neurons. The immune response is then directed to the shared antigen in both the tumor and the nervous system. The evidence for such an autoimmune mechanism is most clearly exemplified by the Lambert-Eaton syndrome, in which an antibody derived from a tumor binds to voltage-gated calcium channels at neuromuscular junctions (Chap. Furthermore, in some types of paraneoplastic disorders, there is provocative evidence that the inciting tumor has receptors for the antibody on its surface and the self-binding of the antibody may inhibit tumor growth. This is said to account for the difficulty in detecting diminutive small-cell lung cancers that underlie some of the paraneoplastic syndromes. It should be noted, however, that there is no evidence that suppressing or removing the antibody leads to growth of the tumor. Paraneoplastic Cerebellar Degeneration For many years, this disorder was considered to be quite uncommon, but it is perhaps the most characteristic of the paraneoplastic syndromes. In reviewing this subject in 1970, we were able to find only 41 pathologically verified cases; in a subsequent review (Henson and Urich), only a few more cases were added. At the Cleveland Metropolitan General Hospital, in a series of 1700 con- secutive autopsies in adults, there were 5 instances of cerebellar degeneration associated with neoplasm. In the experience of Henson and Urich, about half of all patients with nonfamilial, late-onset cerebellar degeneration proved sooner or later to be harboring a neoplasm. Large series of cases have been reported from the Mayo Clinic and the Memorial Sloan-Kettering Cancer Center (Hammock et al; Anderson et al). We see three or more cases yearly but have also encountered numerous instances of an identical syndrome with no cancer evident and no antibodies (Ropper). In approximately one-third of the cases, the underlying neoplasm has been in the lung (most often a small-cell carcinoma)- a figure reflecting the high incidence of this tumor. However, the association of ovarian carcinoma and lymphoma, particularly Hodgkin disease, accounting for approximately 25 and 15 percent, respectively, is considerably higher than would be expected on the basis of the frequency of these malignancies. Carcinomas of the breast, bowel, uterus, and other viscera have accounted for most of the remaining cases (Posner). Characteristically, the cerebellar symptoms have a subacute onset and steady progression over a period of weeks to months; in more than half the cases, the cerebellar signs are recognized before those of the associated neoplasm. Symmetrical ataxia of gait and limbs- affecting arms and legs more or less equally- dysarthria, and nystagmus are the usual manifestations. Striking in fully developed cases has been the severity of the ataxia, matched by few other diseases. In addition, there are quite often symptoms and signs not cerebellar in nature, notably diplopia, vertigo, Babinski signs (common in our cases), sensorineural hearing loss, disorders of ocular motility, and alteration of affect and mentation- findings that serve to distinguish paraneoplastic from alcoholic and other varieties of cerebellar degeneration. Pathologically, there are diffuse degenerative changes of the cerebellar cortex and deep cerebellar nuclei. Purkinje cells are affected prominently and all parts of the cerebellar cortex are involved. Rarely, there are associated degenerative changes in the spinal cord, involving the posterior columns and spinocerebellar tracts. The cerebellar degeneration is frequently associated with perivascular and meningeal clusters of inflammatory cells. Henson and Urich regard the inflammatory changes as an independent process, part of a subacute paraneoplastic encephalomyelitis (see below). This view is supported by the finding that the specific antibodies that are linked to cerebellar degeneration differ from those that are found in paraneoplastic inflammatory lesions in other parts of the nervous system. Anderson and colleagues report a similar proportion but point out that several anti-Purkinje antibodies besides the highly characteristic one may be found by special techniques. In an equal number of cases without antibodies, half are men with lung cancer and a few have circulating antibodies of another type ("anti-Hu") that are more closely linked to the paraneoplastic encephalomyelitis discussed further on. This leaves a proportion who have no circulating antibody but nonetheless are found to have a concealed tumor that must be sought by other ancillary tests. In another small group, it must be conceded that no underlying tumor can be found despite extensive examinations and even at autopsy (Ropper). The death rate in these cases has varied widely from 6 months to several years and depends on the behavior of the underlying tumor. Whether the anti-Yo antibodies are merely markers of an underlying tumor or the agents of destruction of the Purkinje cells is not known. They have been found to bind to a C-myc protein that initiates a degeneration of Purkinje cells. Regardless of the pathogenic significance of the antibodies, finding them in a patient with the typical neurologic disorder has considerable diagnostic significance. As mentioned above, their presence strongly suggests that there is an underlying breast or ovarian cancer, which may be asymptomatic and small enough to be resected successfully. Other antibodies besides anti-Yo and anti-Hu are found on occasion, such as those against a glutamate receptor in patients with Hodgkin disease (Smitt et al). The main considerations are a variant of CreutzfeldtJakob disease, postinfectious cerebellitis, and various intoxications. Treatment Little can be done to modify the cerebellar symptoms, although there are on record several cases in which there was a partial or complete remission of symptoms after removal of the primary tumor (Paone and Jeyasingham). Further, in some cases associated with Hodgkin disease, there has been spontaneous improvement of the cerebellar symptoms. Preliminary reports of aggressive plasma exchange or intravenous immunoglobulin treatment early in the course suggest some benefit, but it should not be assumed that this approach will succeed in most patients, and our own experience in over 10 cases has been discouraging. Opsoclonus-Myoclonus-Ataxia Syndrome In children, this syndrome is usually a manifestation of neuroblastoma, but it is more common and occurs in adults in relation to breast cancer and small-cell lung cancer. This antibody is not found in the opsoclonus-ataxic syndrome of neuroblastoma and is present only rarely with small-cell lung cancer. There have also been a limited number of positive serologic tests in children with opsoclonus, apparently without an underlying tumor. More complex syndromes have been reported with the antiRi antibody, manifest by rigidity and intense stimulus-sensitive myoclonus in addition to the core features of opsoclonus and ataxia. Besides breast cancer, we have observed the opsoclonusmyoclonus syndrome in a middle-aged woman with bronchial carcinoma and also in a man with gastric carcinoma.


  • Reduced emotion
  • To reduce the risk of choking accidents, make sure infants and small children cannot reach buttons, watch batteries, popcorn, coins, grapes, or nuts.
  • Limit processed and red meat in the diet
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  • Have major depression
  • Chest x-ray
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A small but uncertain number are associated with adjacent venous malformations, visualized by imaging studies. The lack of formation of a mass over a long period of time separates this lesion from a malignant tumor that has bled. In one of the families we have followed of ItalianAmerican origin, there were 29 affected members in three generations. The inheritance followed an autosomal dominant pattern; Marchuk and coworkers have localized the abnormal gene in other kindreds to the long arm of chromosome 7. One interesting characteristic of this group, as pointed out by Labauge and colleagues, is the appearance over time of new lesions in one-third of patients. Treatment Cavernous angiomas on the surface of the brain, within reach of the neurosurgeon, even those in the brainstem, can be plucked out, like clusters of grapes, with low morbidity and mortality. Kjellberg and colleagues have treated 89 deeply situated cavernous angiomas with low-dose proton radiation. Our impression is that these vascular malformations, like the hemangioblastoma, respond poorly to radiation and are not amenable to treatment by endovascular techniques. Lesions that cause recurrent bleeding and are surgically accessible with little risk are often removed, but incidentally discovered angiomas and those that are inaccessible may be left alone. Although this is the approach usually taken, there is not adequate data on the rate and risk of bleeding to determine the proper approach. Most cavernous angiomas are much smaller and sometimes mulitple but have the same signal characteristics. Other Causes of Intracranial Bleeding Next to hypertension, anticoagulant therapy is currently the most common cause of cerebral hemorrhage. The hemorrhages that develop, though sometimes situated in the sites of predilection of hypertensive hemorrhage, are more likely to occur elsewhere, mainly in the lobes of the brain. When the bleeding is precipitated by warfarin therapy, treatment with fresh-frozen plasma and vitamin K is recommended; when bleeding is associated with aspirin therapy or other agents that affect platelet function, fresh platelet infusion, often in massive amounts, is required to control the hemorrhage. The use of thrombolytics in the treatment of stroke is complicated by intracranial hemorrhage in 6 to 20 percent of cases, depending on the dose and timing of drug administration after the onset of symptoms, as discussed on page 694. In the elderly, amyloid angiopathy appears to be a major cause of lobar hemorrhages, especially if they appear in succession or are multiple. In our own material, only severe impregnation of vessels with amyloid and fibrinoid change in the vessel wall were associated with hemorrhage (Vonsattel et al). Greenberg and colleagues have found that apolipoprotein E4, the same marker that is overrepresented in Alzheimer disease, is associated with severe amyloid angiopathy and intracerebral hemorrhage, but others have found an association with the E2 allele. Contrary to previous notions, there is probably no greater risk in evacuating these clots surgically than in the case of other cerebral hemorrhages, but most of them are of a size that allows conservative management. Several primary hematologic disorders are also complicated by hemorrhage into the brain. The most frequent of these are leukemia, aplastic anemia, and thrombocytopenic purpura. Often they give rise to multiple intracranial hemorrhages, some in the subdural and subarachnoid spaces. Other, less common causes of intracerebral bleeding are advanced liver disease, uremia being treated with dialysis, and lymphoma. Usually several factors are operative in these hematologic cases: reduction in prothrombin or other clotting elements (fibrinogen, factor V), bone marrow suppression by antineoplastic drugs, and disseminated intravascular coagulation. Any part of the brain may be involved, and the hemorrhagic lesions are usually multiple. Frequently there is also evidence of abnormal bleeding elsewhere (skin, mucous membranes, kidney) by the time cerebral hemorrhage occurs. The use of anticoagulant drugs and intrinsic coagulopathies of all types are risks for these extracerebral hemorrhages. In chronic subdural hemorrhage, which can occur without remembered trauma, the indefinite picture of drowsiness, headache, confusion, and mild hemiparesis may erroneously be attributed to a stroke, especially in elderly persons. Occasionally the origin of intracranial hemorrhage cannot be determined clinically or pathologically. In some postmortem cases, a careful search under the dissecting microscope discloses a small arteriovenous malformation; this is the basis for suspecting that an overlooked lesion of this type may be the cause of cerebral hemorrhage in other cases. Primary intraventricular hemorrhage, a rare event in adults, can sometimes be traced to a vascular malformation or neoplasm of the choroid plexus; more often, such a hemorrhage is the result of periventricular bleeding, in which blood enters the ventricle without producing a visible parenchymal clot. Hemorrhage into primary and secondary brain tumors is not rare; when this is the first clinical manifestation of the neoplasm, diagnosis may be difficult. Choriocarcinoma, melanoma, renal cell and bronchogenic carcinoma, pituitary adenoma, thyroid cancer, glioblastoma multiforme, intravascular lymphoma, and medullo- blastoma may present in this way. Careful inquiry will usually disclose that neurologic symptoms compatible with intracranial tumor growth had preceded the onset of hemorrhage. Needless to say, a thorough search should be made in these circumstances for evidence of intracranial tumor or of secondary tumor deposits in other organs, particularly the lungs. The term mycotic aneurysm designates an aneurysm caused by a localized bacterial or fungal inflammation of an artery (Osler introduced the term mycotic to describe endocarditis, but its proper current use is to describe fungal infection). With the introduction of antibiotics, mycotic aneurysms have become less frequent, but they are still being seen in patients with bacterial endocarditis and in intravenous drug abusers. Peripheral arteries are involved more often than intracranial ones; about two-thirds of the latter are associated with subacute bacterial endocarditis due to streptococcal infections. In recent years, the number of mycotic aneurysms due to staphylococcal infections and acute endocarditis appears to have increased. Later, or as the first manifestation, the weakened vessel wall gives way and causes a subarachnoid or brain hemorrhage. The mycotic aneurysm may appear on only one artery or several arteries, and the hemorrhage may recur. The underlying endocarditis or septicemia mandates appropriate antibiotic therapy and, in at least 30 percent of cases, healing of the aneurysm can be observed in successive arteriograms with this approach alone. Some neurosurgeons believe in excising an accessible aneurysm if it is solitary and the systemic infection is under control. Some mycotic aneurysms do not bleed, and in our view medical therapy takes precedence over surgical therapy. The pathologic entity called brain purpura (pericapillary encephalorrhagia), incorrectly referred to as "hemorrhagic encephalitis," consists of multiple petechial hemorrhages scattered throughout the white matter of the brain. The clinical picture is that of a diffuse encephalopathy, but diagnosis is essentially pathologic. It is virtually impossible to establish the diagnosis during life, but the pathologic appearance is unique and highly characteristic. In this para-adventitial area, both the myelin and axis cylinders are destroyed, and the lesion is usually though not always hemorrhagic. Fibrin exudation, perivascular and meningeal infiltrates of inflammatory cells, and widespread necrosis of tissue are not observed. In these respects brain purpura differs fundamentally from acute necrotizing hemorrhagic leukoencephalitis. It may complicate viral pneumonia, uremia, arsenical intoxication, and, rarely, metabolic encephalopathy and sepsis, or there may be no associated disease. A degree of hemorrhage is to be expected in acute hemorrhagic leukoencephalitis (Hurst type), which represents an extreme form of acute disseminated encephalomyelitis (Chap. Rupture of a vessel in these circumstances may be on the basis of hypertension or local vascular disease, and bleeding nearly always occurs into brain tissue rather than into the subarachnoid space. Rarely, intracranial dissection of an artery (usually the vertebral) may allow some blood to escape into the subarachnoid space. Angiographic study of the radicular spinal vessels and the origins of the anterior spinal arteries from the vertebral arteries may disclose the source of bleeding. Extradural and subdural spinal extravasations may be spontaneous (sometimes in relation to rheumatoid arthritis) but are far more often due to trauma, anticoagulants, or both. Extradural spinal hemorrhage causes the rapid evolution of paraplegia or quadriplegia; diagnosis must be prompt if function is to be salvaged by surgical drainage of the hematoma.

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Acute Blood Loss Acute hemorrhage, usually within the gastrointestinal tract, is a cause of weakness, faintness, or even unconsciousness when the patient stands suddenly. The cause (gastric or duodenal ulcer is the most common) may remain obscure until the passage of black stools. Transient Cerebral Ischemic Attacks the many symptoms comprised by these attacks in the carotid system are fully described in Chap. In the case of attacks in the vertebrobasilar territory, an impairment of consciousness is a rare manifestation, but almost always in the context of additional signs of upper brainstem dysfunction. Drop Attacks this term is generally applied to falling spells that occur without warning and without loss of consciousness or postictal symptoms. The patient, usually elderly and more often female, suddenly falls down while walking or standing, rarely while stooping. There is no dizziness or impairment of consciousness, and the fall is usually forward, with scuffing of the knees and sometimes the nose. The patient, unless obese, is able to right herself and to rise immediately and go her way, quite embarrassed. One potential mechanism is a lapse of tone in leg muscles during the silent phase of an unnoticed myoclonic jerk. Drop attacks also occur in hydrocephalics, and these patients, though conscious, may not be able to arise for several hours. Drop attacks as defined above are usually without an identifiable mechanism, requiring no treatment if cardiologic studies are normal. In only about one-quarter of such cases, according to Meissner and coworkers, can an association be made with cardiovascular or cerebrovascular disease, to which treatment should be directed. Seizures and Syncope In the final analysis, the loss of consciousness in the different types of syncope must be caused by impaired function of the neural elements in those parts of the brain subserving consciousness, i. In this respect syncope and primary generalized (so-called centrencephalic) epilepsy have a common ground; yet there is, of course, a fundamental difference. The difference relates to the essential pathophysiology- the rapid spread of an electrical discharge in epilepsy and a more gradual failure of cerebral circulation in syncope. There are also a number of important clinical distinctions between epileptic and syncopal attacks. The epileptic attack may oc- cur day or night, regardless of the position of the patient; syncope rarely appears when the patient is recumbent, the only common exception being the Stokes-Adams attack. An epileptic attack, as indicated above, is more sudden in onset; if an aura is present, it rarely lasts longer than a few seconds before consciousness is abolished. The onset of syncope is usually more gradual, and the prodromal symptoms are quite distinctive and different from those of seizures. In general, injury from falling is more frequent in epilepsy than in syncope, because protective reflexes are instantaneously abolished in the former. Urinary incontinence is a frequent occurrence in epilepsy, but it need not occur during an epileptic attack and may occasionally occur with syncope, so that it cannot be used as a means of excluding entirely the latter disorder. The return of consciousness is slow in epilepsy, prompt in syncope; mental confusion, headache, and drowsiness are common sequelae of seizures, and physical weakness with clear sensorium of syncope (a brief period of grogginess may follow vasodepressor syncope). Repeated spells of unconsciousness in a young person at a rate of several per day or month are much more suggestive of epilepsy than of syncope. Elevated prolactin levels have not proved discriminating enough for routine use in separating seizure from syncope but remain useful in distinguishing both of these from other causes of loss of consciousness, particularly hysteria, in which such elevations do not occur. Here it is important to recall that normal persons can faint if made to squat and overbreathe and then to stand erect and hold their breath (Valsalva maneuver). This test may also be of therapeutic value, because the underlying anxiety tends to be lessened when the patient learns that the symptoms can be produced and alleviated at will simply by controlling breathing. Most patients with tussive syncope cannot reproduce an attack by the Valsalva maneuver but can sometimes do so by voluntary coughing if severe enough. Another useful procedure is to have the patient perform the Valsalva maneuver for more than 10 s (thus trapping blood behind closed valves in the veins) while the pulse and blood pressure are measured (see "Tests for Abnormalities of the Autonomic Nervous System," Chap. In each of the aforementioned instances, the crucial point is not whether symptoms are produced but whether they reproduce the exact pattern of symptoms that occurs in the spontaneous attacks. Other conditions in which the diagnosis is clarified by reproducing the attacks are carotid sinus hypersensitivity (massage of one or the other carotid sinus) and orthostatic hypotension (observations of pulse rate, blood pressure, and symptoms in the recumbent and standing positions or, even better, with the patient on a tilt table). There is a distinct difference in the cardiovascular challenge imposed by a tilt table and that created by the simple act of standing up from a sitting or recumbent position, as discussed below. It should be re-emphasized that, from the perspective of detecting an underlying autonomic failure, having the patient stand abruptly from a lying position and then recording the blood pressure every 30 to 60 s for up to 3 min is more informative than interposing a period of sitting between the lying and standing positions. Patients with sympathetic failure of central or peripheral type, and those with hypovolemia will show a drop in blood pressure within 30 s; those with a propensity to reflex fainting may take much longer, or show no drop at all. The measurement of beat-to-beat variation in heart rate is a simple but sensitive means of detecting vagal dysfunction, as described in Chap. The diagnostic yield from loop recording is much greater than that from Holter monitoring (Linzer et al). Tilt-Table Testing There are two types of abnormal response to upright tilting: early hypotension (occurring within moments of tilting), which signifies inadequate sympathetic tone and baroreceptor function; and a delayed (several minutes) hypotension and syncope, which indicates a neurocardiogenic mechanism. The normal response to an 60- to 80-degree head-up tilt for 10 min is a transient drop in systolic blood pressure (5 to 15 mmHg), a rise in diastolic pressure (5 to 10 mmHg), and a rise in heart rate (10 to 15 beats per minute). Abrupt and persistent declines in blood pres- sure of greater than 20 to 30 mmHg systolic and 10 mmHg diastolic and a drop (or failure to rise) of the heart rate are considered abnormal; often these findings are associated with faintness and sometimes with syncope. Although controversial, in some circumstances the infusion of the catecholamine isoproterenol (1 to 5 mg/ min for 30 min during head-up tilt) may be a more effective means of producing hypotension (and syncope) than the standard tilt test alone (Almquist et al; Waxman et al). It should be repeated that the presence of a delayed faint with tilting only demonstrates a proclivity to neurocardiogenic fainting, since it occurs in a proportion of individuals who have never fainted; it is not to be taken as incontrovertible evidence that a recent spell is explained by this mechanism. All tight clothing and other constrictions should be loosened and the head and body positioned so that the tongue does not fall back into the throat and the possible aspiration of vomitus is avoided. The patient should not be permitted to rise until the sense of physical weakness has passed and he should be watched carefully for a few minutes after arising. As a rule, the physician sees the patient after recovery from the faint and is asked to explain why it happened and how it can be prevented in the future. One should think first of those causes of fainting that constitute a therapeutic emergency. Among them are massive internal hemorrhage and myocardial infarction, which may be painless, and cardiac arrhythmias. In an elderly person, a sudden faint without obvious cause must always arouse the suspicion of a complete heart block or other cardiac arrhythmia. In the usual vasodepressor faint of adolescents- which tends to occur in circumstances favoring vasodilatation (warm environment, hunger, fatigue, alcohol intoxication) and periods of emotional excitement- it is enough to advise the patient to avoid such circumstances. In postural hypotension, patients should be cautioned against arising suddenly from bed. Instead, they should first exercise the legs for a few seconds, then sit on the edge of the bed and make sure they are not light-headed or dizzy before starting to walk. Standing for prolonged periods can sometimes be tolerated without fainting by crossing the legs forcefully. Alternatives should be found for medications that are conceivable causes of orthostasis. Beta-adrenergic blocking agents, diuretics, antidepressants, and sympatholytic antihypertensive drugs are the common culprits. In the syndrome of chronic orthostatic hypotension, special corticosteroid preparations- such as fludrocortisone acetate (Florinef) 0. These and other approaches that have proved useful in treating orthostatic hypotension are reviewed by Mathias and Kimber. Neurally mediated syncope (neurocardiogenic or vasodepressor syncope), identified largely by the clinical circumstances and by upright tilt-table testing, may be prevented by the use of betaadrenergic blocking agents. Our colleagues in cardiology have favored, and we endorse from experience, acebutolol 400 mg daily, in part because of its partial alpha-adrenergic activity, which raises baseline blood pressure, but atenolol 50 mg may be as effective. The treatment of carotid sinus syncope involves, first of all, instructing the patient in measures that minimize the hazards of a fall (see below). A loose collar should be worn, and the patient should learn to turn his whole body, rather than the head alone, when looking to one side.

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Attempts to treat the mucopolysaccharidoses by enzyme replacement therapy, bone marrow transplantation, and gene transfer are in progress. Mucolipidoses and Other Diseases of Complex Carbohydrates (Sialidoses; Oligosaccharidoses - Table 37-3) In recent years several new diseases have been described in which there is an abnormal accumulation of mucopolysaccharides, sphingolipids, and glycolipids in visceral, mesenchymal, and neural tissues, due to an -N-acetylneuraminidase defect. All are autosomal recessive diseases that manifest many of the clinical features of Hurler disease, but- in contrast to the mucopolysaccharidoses- normal amounts of mucopolysaccharides are excreted in the urine. Mucolipidoses At least three and possibly four closely related forms have been described. Cherry-red spots in the maculae, corneal opacities, and ataxia have been noted in some patients. Vacuolation of lymphocytes, marrow cells, hepatocytes, and Kupffer cells in the liver and metachromatic changes in the sural nerve have been described. Gingival hyperplasia is prominent, and the liver and spleen are enlarged; but deafness is not found and corneal opacities are slower to develop. There is a typical vacuolation of lymphocytes, Kupffer cells, and cells of the renal glomeruli. Bone marrow cells are also vacuolated and contain refractile cytoplasmic granules (hence the designation inclusion-cell, or I-cell, disease). A deficiency of several lysosomal enzymes required for the catabolism of mucopolysaccharides, glycolipids, and glycoproteins have been found. In the pseudo-Hurler type, symptoms do not appear until 2 years of age or later and are relatively mild. Retardation of growth, fine corneal opacities, and valvular heart disease are the major manifestations. Here, clouding of the corneas is noticed soon after birth, and profound developmental retardation is evident by 1 year of age. Skeletal deformities, enlargement of liver and spleen, seizures, or other neurologic abnormalities are notably lacking. Ultrastructural examination of conjunctival and skin fibroblasts has demonstrated lysosomal inclusions of material similar to lipids and mucopolysaccharides that remain to be further characterized. Mannosidosis this is another rare hereditary disorder with poorly differentiated symptomatology. The onset is in the first 2 years, with Hurler-like facial and skeletal deformities, mental retardation, and slight motor disability. Corticospinal signs, loss of hearing, variable degrees of gingival hyperplasia, and spoke-like opacities of the lens (but no diffuse corneal clouding) may be present. Radiographs show beaking of the vertebral bodies and poor trabeculation of long bones. Vacuolated lymphocytes and granulated leukocytes are present and aid in diagnosis. Mannose-containing oligosaccharides accumulate in nerve cells, spleen, liver, and leukocytes (see Kistler et al). Fucosidosis this also is a rare autosomal recessive disorder, with neurologic deterioration beginning usually at 12 to 15 months and progressing to spastic quadriplegia, decerebrate rigidity, severe psychomotor regression, and death within 4 to 6 years. Hepatomegaly, splenomegaly, enlarged salivary glands, thickened skin, excessive sweating, normal or typical gargoyle facies, beaking of the vertebral bodies, and vacuolated lymphocytes are the main features. A variant of this disease has been described with slower progression and survival into late childhood and adolescence and even into adult life (Ikeda et al). The latter type is characterized by mental and motor retardation, along with the corneal opacities, coarse facial features, skeletal deformities of gargoylism, and dermatologic changes of Fabry disease (angiokeratoma corporis diffusum), but no hepatosplenomegaly. The basic abnormality in both types is a lack of lysosomal L-fucosidase, resulting in accumulation of fucose-rich sphingolipids, glycoproteins, and oligosaccharides in cells of the skin, conjunctivae, and rectal mucosa. Aspartylglycosaminuria this disease is characterized by the early onset of psychomotor regression; delayed, inadequate speech; severe behavioral abnormalities (bouts of hyperactivity mixed with apathy and hypoactivity or psychotic manifestations); progressive dementia; clumsy movements; corticospinal signs; corneal clouding (rare); retinal abnormalities and cataracts; coarse facies including low bridge of the nose, epicanthi, thickening of the lips and skin; enlarged liver; and abdominal hernias in some. Radiographs show minimal beaking of the vertebral bodies, and the blood lymphocytes are vacuolated. The pattern of inheritance in this entire group of diseases, as already stated, is probably autosomal recessive. Diagnostic methods applicable to amniotic fluid and cells are being developed so that prenatal diagnosis will be possible, prompted often by the occurrence of the disease in an earlier child. Neurons are vacuolated rather than stuffed with granules, much like the lymphocytes and liver cells. The specific biochemical abnormalities, as far as they are known, are listed in Table 37-3. Cockayne Syndrome this disorder is probably inherited as an autosomal recessive trait. The main clinical findings are stunting of growth, evident by the second and third years; photosensitivity of the skin; microcephaly; retinitis pigmentosa, cataracts, blindness, and pendular nystagmus; nerve deafness; delayed psychomotor and speech development; spastic weakness and ataxia of limbs and gait; occasionally athetosis; amyotrophy with abolished reflexes and reduced nerve conduction velocities; wizened face, sunken eyes, prominent nose, prognathism, anhydrosis, and poor lacrimation (resembling progeria and bird-headed dwarfism). Pathologic examination reveals a small brain, striatal and cerebellar calcifications, leukodystrophy like that of Pelizaeus-Merzbacher disease, and a severe cerebellar cortical atrophy. At least three different forms of Cockayne syndrome have been identified, each with a different underlying gene defect. Rett Syndrome this syndrome is mentioned here because for many years, on the basis of psychomotor regression after a period of normal development, it was presumed to have a metabolic basis (urea cycle defect). Familial striatocerebellar calcification (Fahr disease) and Lesch-Nyhan disease may also become manifest in this age period, but they usually have a later onset and are therefore described with the diseases of later childhood in the section that follows. Diagnosis of Metabolic Diseases of Late Infancy and Early Childhood this group of metabolic disorders presents many of the same diagnostic problems as those of early infancy. The flow chart in Figure 37-4, which divides these disorders into dysmorphic, visceromegalic, and purely neurologic groups, is equally serviceable in the differential diagnosis of both age groups. As with the early infantile diseases, certain clusters of neurologic, skeletal, dermal, ophthalmic, and laboratory findings are highly distinctive and often permit the identification of a particular disease. Corneal clouding- several of the mucopolysaccharidoses (Hurler, Scheie, Morquio, Maroteaux-Lamy), mucolipidoses, tyrosinemia, aspartylglycosaminuria (rare) b. Optic atrophy and blindness- metachromatic leukodystrophy, neuroaxonal dystrophy. Impairment of vertical eye movements- late infantile Niemann-Pick disease, juvenile dystonic lipidosis, seablue histiocyte syndrome, Wilson disease h. Extrapyramidal signs- late-onset Niemann-Pick disease (rigidity, abnormal postures), juvenile dystonic lipidosis (dystonia, choreoathetosis), Rett, ataxia-telangiectasia (athetosis), Sanfilippo mucopolysaccharidosis, type I glutaric acidemia, Wilson disease, Segawa dopa-responsive dystonia 5. Dwarfism, spine deformities, arthropathies- Hurler, Morquio, and other mucopolysaccharidoses, Cockayne syndrome 7. Beaked thoracolumbar vertebrae- all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis; aspartylglycosaminuria, multiple sulfatase deficiencies 10. Vacuolated lymphocytes- all mucopolysaccharidoses, mucolipidoses, mannosidosis, fucosidosis 13. Leigh disease may begin at the same age, with hypotonia and optic atrophy, but abnormalities of ocular movement and respiration appear early; in many cases the lactic acidosis and pyruvate decarboxylase defect will corroborate the diagnosis. Sequencing tests of the mitochondrial genome now allow definitive diagnosis in most cases, as described in a later section. Lipofuscinosis cannot always be diagnosed accurately; curvilinear bodies in nerve twigs and in the endothelial cells in skin biopsies and the recently discovered gene mutations are the most informative laboratory tests. There is a tendency for them to be less severe and less rapidly progressive, an attribute shared by many diseases with a dominant mode of inheritance. Nonetheless, there are diseases, such as Wilson disease, in which the onset of neurologic symptoms occurs after the 10th year and in rare instances after the 30th year, and the mode of inheritance is recessive in type. However, in the latter instance, the basic abnormality has existed since early childhood in the form of a ceruloplasmin deficiency with early cirrhosis and splenomegaly; only the neurologic disorder is of late onset. This brings us to another principle- that the pathogenesis of the cerebral lesion may involve a factor or factors once removed from the underlying biologic abnormality. Genetic heterogeneity poses another problem with respect to both the clinical and biochemical findings. It is well established that a single clinical phenotype such as the one seen in Hurler disease can be the expression of a number of different alleles of a given gene mutation. Conversely, a number of different clinical phenotypes may be based on different degrees of the same enzyme deficiency.

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Needles, glassware, needle electrodes, and other instruments should be handled with great care and immersed in appropriate disinfectants and autoclaved or incinerated. The performance of a brain biopsy or autopsy requires that a set of special precautions be followed, as outlined by Brown (see References). Obviously such patients or any others known to have been demented should not be donors of organs for transplantation or blood for transfusion. It begins insidiously in midlife and runs a chronic course (mean duration, 5 years). The main characteristics are a progressive cerebellar ataxia, corticospinal tract signs, dysarthria, and nystagmus. Brain tissue from patients with this disease, when inoculated into chimpanzees, has produced a spongiform encephalopathy (Masters et al). Molecular genetic studies of affected members demonstrate a mutation of the prion protein gene. Fatal Familial Insomnia this is another very rare familial disease; it is characterized by intractable insomnia, sympathetic overactivity, and dementia, leading to death in 7 to 15 months (see also page 340). The pathologic changes, consisting of neuronal loss and gliosis, are found mainly in the medial thalamic nuclei. Studies of a few families have shown a mutation of the prion protein gene, and brain material was found to contain a protease-resistant form of the gene. Transmission of the disease by inoculation of infected brain material has not been accomplished (Medori et al). Kuru this disease, which occurs exclusively among the Fore linguistic group of natives of the New Guinea highlands, was the first slow infection due to a nonconventional transmissible agent to be documented in human beings. Clinically the disease takes the form of an afebrile, progressive cerebellar ataxia, with abnormalities of extraocular movements, weakness progressing to immobility, incontinence in the late stages, and death within 3 to 6 months of onset. In some ways it is similar to the ataxic (Brownell-Oppenheimer) variant of Creutzfeldt-Jakob disease. The remarkable epidemiologic and pathologic similarities between kuru and scrapie were pointed out by Hadlow (1959), who suggested that it might be possible to transmit kuru to subhuman primates. This was accomplished in 1966 by Gajdusek and coworkers; inoculation of chimpanzees with brain material from affected humans produced a kuru-like syndrome in chimpanzees after a latency of 18 to 36 months. Since then the disease has been transmitted from one chimpanzee to another and to other primates by using both neural and nonneural tissues. Kuru has gradually disappeared, apparently because of the cessation of ritual cannibalism by which the disease had been transmitted. At least 50 percent of the neurologic disorders in a general hospital are of this type. At some time or other, every physician will be required to examine patients with cerebrovascular disease and should at least know something of the common types- particularly those in which there is a reasonable prospect of successful medical or surgical intervention or the prevention of recurrence. There is another advantage to be gained from the study of this group of diseases- namely, that they have traditionally provided one of the most instructive approaches to neurology. Fisher has aptly remarked, house officers and students learn neurology literally "stroke by stroke. It must also be noted that, in the last two decades, new and extraordinary types of imaging technology have been introduced that allow the physician to make physiologic distinctions between normal, ischemic, and infarcted brain tissue. This biopathologic approach to stroke will likely guide the next generation of treatments and has already had a pronounced impact on the direction of research in the field. Salvageable brain tissue to be protected in the acute phase of stroke can be delineated by these methods. To identify this ischemic but not yet infarcted tissue virtually defines the goal of modern stroke treatment. Which of the sophisticated imaging techniques will contribute to improved clinical outcome is still to be determined, but certain ones, such as diffusionweighted imaging, have already proved invaluable in stroke work. First, all physicians have a role to play in the prevention of stroke by encouraging the reduction in risk factors such as hypertension and the identification of signs of potential stroke, such as transient ischemic attacks, atrial fibrillation, and carotid artery stenosis. Second, careful bedside clinical evaluation integrated with the newer testing methods mentioned above still provide the most promising approach to this category of disease. Finally, the last decade or two have witnessed a departure from the methodical clinicopathologic studies that have been the foundation of our understanding of cerebrovascular disease. Increasingly, randomized studies involving several hundred and even thousands of patients and conducted simultaneously in dozens of institutions have come to dominate investigative activity in this field. These multicenter trials have yielded highly valuable information about the natural history of a variety of cerebrovascular disorders, both symptomatic and asymptomatic. However, this approach suffers from a number of inherent weaknesses, the most important of which is that the homogenized data derived from an aggregate of patients may not be applicable to a specific case at hand. Moreover, many large studies show only marginal differences between treated and control groups. Each of these multicenter studies will therefore be critically appraised at appropriate points in the ensuing discussion. Since 1950, coincident with the introduction of effective treatment for hypertension, there has been a substantial reduction in the frequency of stroke. This was most apparent three decades ago, as treatment for high blood pressure became a public health focus. During this period, the incidence of coronary artery disease and malignant hypertension also fell significantly. In the last decade, according to the American Heart Association, the mortality rate from stroke has declined by 12 percent, but the total number of strokes may again be rising. Definition of Terms As discussed below, the term stroke is applied to a sudden focal neurologic syndrome, specifically the type due to cerebrovascular disease. The term cerebrovascular disease designates any abnormality of the brain resulting from a pathologic process of the blood vessels. Pathologic process is given an inclusive meaning- namely, occlusion of the lumen by embolus or thrombus, rupture of a vessel, an altered permeability of the vessel wall, or increased viscosity or other change in the quality of the blood flowing through the cerebral vessels. The vascular pathologic process may be considered not only in its grosser aspects- embolism, thrombosis, dissection, or rupture of a vessel- but also in terms of the more basic or primary disorder, i. Equal importance attaches to the secondary parenchymal changes in the brain resulting from the vascular lesion. These are of two main types- ischemia, with or without infarction, and hemorrhage- and unless one or the other occurs, the vascular lesion usually remains silent. The only exceptions to this statement are the local pressure effects of an aneurysm, vascular headache (migraine, hypertension, temporal arteritis), multiple small vessel disease with progressive encephalopathy (as in malignant hypertension or cerebral arteritis), and increased intracranial pressure (as occurs in hypertensive encephalopathy and venous sinus thrombosis). Also, persistent acute hypotension may cause ischemic necrosis in regions of brain between the vascular territories of cortical vessels, even without vascular occlusion. The many types of cerebrovascular diseases are listed in Table 34-1, and the predominant types during each period of life, in Table 34-2. Meningovascular syphilis, arteritis secondary to pyogenic and tuberculous meningitis, rare infective types (typhus, schistosomiasis, malaria, mucormycosis, etc. Connective tissue diseases (polyarteritis nodosa, lupus erythematosus), necrotizing arteritis. Wegener arteritis, temporal arteritis, Takayasu disease, granulomatous or giantcell arteritis of the aorta, and giant-cell granulomatous angiitis of cerebral arteries Cerebral thrombophlebitis: secondary to infection of ear, paranasal sinus, face, etc. Trauma and dissection of carotid and basilar arteries Amyloid angiopathy Dissecting aortic aneurysm Complications of arteriography Neurologic migraine with persistent deficit With tentorial, foramen magnum, and subfalcial herniations Miscellaneous types: fibromuscular dysplasia, with local dissection of carotid, middle cerebral, or vertebrobasilar artery, x-irradiation, unexplained middle cerebral infarction in closed head injury, pressure of unruptured saccular aneurysm, complication of oral contraceptives Undetermined cause in children and young adults: moyamoya disease and others Table 34-2 Cerebrovascular diseases characteristic of each age period 1. Antiphospholipid arteriopathy, plasma C-protein deficiency and other coagulopathies j. More than any other organ, the brain depends from moment to moment on an adequate supply of oxygenated blood. Constancy of the cerebral circulation is assured by a series of baroreceptors and vasomotor reflexes under the control of centers in the lower brainstem. In Stokes-Adams attacks, for example, unconsciousness occurs within 10 s of the beginning of asystole. In animal experiments and probably in humans, the complete stoppage of blood flow for longer than 5 min produces irreversible damage. Brain tissue deprived of blood undergoes ischemic necrosis or infarction (also referred to as a zone of softening or encephalomalacia).