Behavioral Neurology, 4th Edition

Chapter Four

Disorders of Cognitive Function

The terms organic brain syndrome and dementia are applied to those acquired disorders of thinking and cognitive functions where altered structure or function of the brain can be identified. Generally, neurologists care for patients with these disorders. When no lesion or physiologic change is apparent, cognitive dysfunctions are often labeled functional or psychological disorders. Psychiatrists care for these patients. The inadequacy of this distinction is immediately apparent: any change in behavior must be the result of altered brain activity. In 1994 DSM-IV recognized this arbitrary distinction and did away with the division of behavior disorders into organic and nonorganicconditions. The section called “Organic Disorders” in previous DSM editions is called “Delirium, Dementia, and Amnestic Other Cognitive Disorders” in DSM-IV; this category now stands alongside Affective, Anxiety, Schizophrenic Disorders, etc., removing any implication that there is one group of disorders related to the brain and another group that is just psychological (Tucker et al., 1994). To some degree, cognitive, affective, and behavioral symptoms characterize all disorders of the brain. There are cognitive disturbances in most of the major psychiatric disorders (see Chapters 3 and 5). However, the primary symptoms of delirium, dementia, and amnestic disorders are disturbances of cognition. Cognition comes from the Latin cognitio, which means to think. It refers to how one knows the world, which is achieved by a number of complex functions including orientation to

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time, place and person; memory; arithmetic ability; abstract thought; the ability to focus and to be logical. While disturbances of orientation, memory numerical ability are the hallmarks of dementia and delirium, it is important to note that other types of dysfunction are also variably present, often depending on the location or nature of lesion. Impairment verbal and spatial abilities is common as well personality changes and changes in the level of consciousness. Consequently, to make the diagnosis of a dementia, delirium, or amnestic disorder, the clinician must systematically evaluate: (1) orientation; (2) memory; (3) verbal, spatial, and numerical ability; (4) level of consciousness; (5) perception; (6) executive functions and (7) changes in personality. Only one of these areas may be involved in the disorder, but more often several are disturbed to varying degrees. Disturbances of executive functions tend be the earliest signs of brain dysfunction, and often indicate that the frontal lobes are involved. Executive functions are basically those that one needs to live a normal life: the ability to plan and sequence activities, insight, judgment, social awareness and impulse control (Burgess et al., 1998). When there is a disturbance of higher brain function these abilities are commonly impaired whether the disturbance is caused by a neurological or psychiatric illness. The summary statement of the clinician's observations of cognitive functions is what called formal mental status examination (Taylor, 1981; Trzepacz and Baker, 1993).

Virtually all brain disorders can cause cognitive dysfunction. The site of the lesions may be related to specific symptoms and if these regional symptoms are prominent, the syndrome will often be labeled by the supposed anatomical site of the lesion, e.g., frontal lobe syndrome, or by the cause of the symptom, e.g., stroke. Such syndromes can be described (1) by anatomical site (2) the etiology of the disturbance or (3) by its effect on cognitive function. We feel the weakest descriptor is the anatomical one as most behaviors and symptoms are caused by the interaction of many systems in the brain. Discrete symptoms can always be specified when describing those associated with the dementia or delirium or when citing their etiology. One must remember, however, that even though the patient's main symptoms may be hemiparesis and aphasia, we attribute them to stroke, the patient may also meet diagnostic criteria for dementia. In order to treat such a patient well, it is important recognize both the motor/sensory symptoms caused by the stroke and the problems caused dementia.

The diagnostic process for disorders of higher cortical functioning in both psychiatry and neurology remains clinical. Laboratory tests usually help only to rule out neurological or medical conditions such as thyroid disease brain tumors (Bruckner-Davis et al., 1995). The main diagnostic instrument is the skill and knowledge of the examiner (Chapter 7).

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Regional Syndromes

Three major neurological factors shape the clinical manifestations of brain dysfunction: (1) the amount of tissue destroyed; (2) location the lesion in brain; and (3) the nature of the disease process. With the advent MRI, particularly with the development of dynamic techniques to study human brain as it functions (FMRI, PET, SPECT), we have entered a new era of localization. These powerful techniques based primarily on blood flow have yielded much information on where certain functions take place in the brain but not much on how they are carried out. The brain is a dynamic system of many interacting circuits, which makes it difficult to identify the precise site of a dysfunction. Consider as an example the following brain-behavior correlations: lesions in the dorsolateral premotor cortex have been associated with a loss of executive functions; lesions of the orbitofrontal cortex with disinhibition; and lesions of the anterior cingulate cortex with apathy (Cummings and Coffee, 2000). These same areas, however, have been implicated in such complex behavioral conditions as schizophrenia, mania, depression, OCD, personality disorders, and violence. Though it is clear that anatomical specialization exists in the human brain, the most replicable functional imaging results so far relate to behaviors that are relatively simple and discrete as in dyslexia, whereas the most conflicting findings relate to complex behaviors as in schizophrenia and depression. Even the anatomical localization of discrete functions such as language, however, can vary widely from individual to (Calvin et al., 1973).

Another obstacle to localization is related the complex structure of brain itself. Similar behavioral changes can occur when specific sites are destroyed and when tracts connecting these sites are interrupted. Chapman and Wolff (1959) in their classic study correlated the amount of brain tissue removed during the surgical removal of a tumor with postoperative behavior. When brain damage was not extensive (involving less than 120 gm of cortical tissue), executive functions were found to be impaired even though orientation and memory remained intact. Chapman and Wolff described four areas of dysfunction:

  1. Expression of needs, appetites, and drives. There is less seeking challenges and adventure, less imagination, less desire for human association and sexual activity, along with a passive acceptance of circumstances and a lack of aspiration. When mild, such symptoms mimic depression, and indeed, patients with slight brain damage often are depressed; the depression may be a reaction to or a manifestation of their deficit.
  2. Capacity to adapt for the achievement of goals. Brain-damaged individuals have a decreased ability to anticipate either dangerous or propitious circumstances, to plan, arrange, invent, postpone, modulate, or discriminate in achieving goals. Business failure or unwise sexual liaisons, for example,

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may occur in the course of advancing disease and may cause great distress to the patient's family, especially when he seems normal in other ways.

  1. Socially inappropriate reactions under stress.
  2. Incapacity to recover promptly from the effects of stress.

Deficits in the third and fourth categories can lead to catastrophic reaction first noted in war veterans who had apparently recovered from brain injuries. When confronted with an arithmetic problem they once could have solved easily, patients became “dazed, agitated, anxious, started to fumble; a moment before amiable, they became sullen, evasive, and exhibited temper” (Goldstein, 1948). Although all of the above represent classic loss of executive functions caused by tissue loss almost the same clinical picture can be observed in patients who have had discrete surgical lesions of frontal tracts for lobotomies (Shevitz, 1976).

Clinical Symptoms Associated with Frontal Lobe Dysfunction

Though symptoms of brain dysfunction such as those indicated above may appear regardless of the site lesion, they are often associated with frontal lobe damage. This has led to the formulation of a frontal lobe syndrome. Mesulam (2000) defines two types of frontal syndromes, but notes that they are umbrella terms covering diffuse sets of dysfunctions:

  1. Frontal abulia—loss of creativity, initiative, and curiosity with emotional blunting and apathy.
  2. Frontal disinhibition—impulsivity, loss of judgment, insight and foresight.

The frontal lobes are the largest neocortical region, and much of their tissue, particularly anterior to the motor region, can be removed with little or no disturbance of motor and sensory function. Bilateral frontal lobe damage can cause subtle alterations in the highest integrative functions without causing disorientation or memory disturbance. Lesions of similar extent elsewhere in the neocortex and subcortex, in regions to which frontal fibers project, may produce the same symptom complex but, in addition, are accompanied by disorders of movement, sensory function, speech, and visual motor which often overshadow the disordered thought prominent in frontal lobe lesions.

Though the behavioral changes that are part of the frontal lobe syndrome may not be absolutely specific, it may be worthwhile to describe here those additional changes that characteristically occur when the frontal lobes are damaged. There may be a strong tendency toward inappropriate jocularity (witzelsucht) as well as inappropriate ill humor. Emotional “incontinence” is common, i.e., crying and laughing, which often alternate rapidly. This is provoked by minimal stimuli

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and often is not related to feelings of sadness or mirth. Indeed, a dulling subjective emotionality is also characteristic. Dulled responsiveness may lead to poor self-control and an inability to understand the consequences of actions and to orient actions to the social and ethical standards of community. When lesions are extensive, dulling may give way to torpor and apathy sometimes to a state of akinetic mutism, in which the patient can speak and can move but will often not respond to spoken commands or even painful stimuli but will tend to lie still, speechless, with open eyes. The patient looks awake and therefore is not considered to be in coma yet has little more cognitive function than a comatose person.

Some adverse reactions to antipsychotic medication may be confused with akinetic mutism. These include catatonic and akinetic reactions (Gelenberg and Mandel, 1977; Van Putten and May, 1978) the neuroleptic malignant syndrome (NMS) (Lazarus et al., 1989; Koch et al., 2000). Parkinson-like drug reactions are characterized by a mixture of catatonic symptoms (waxy flexibility, reduced responsiveness, slow responses, incontinence of urine) with stiffness, bradykinesia, rigidity, and tremor. The onset is usually gradual the symptoms may not respond well to anti-Parkinson agents.

The NMS is manifested by the abrupt development of lead-pipe rigidity, “plastic” akinesia, hyperthermia, altered consciousness (mutism, stupor, coma), and autonomic dysfunction (fever, sialorrhea, increased heart rate, incontinence) (Caroff, 1980). The blood creatine phosphokinase (CPK) level is characteristically elevated as a result of muscle breakdown. This can be so severe that renal failure can develop. The incidence of NMS is estimated to occur in 0.5 to 1 percent of those taking neuroleptic medication. Recovery is usually complete within 5 to 10 days after withdrawal of neuroleptics, but there is 20 percent mortality in this condition. It has been reported with all other dopamine receptor blockers and seems to be more frequent in males, especially those over 40 years of age, and in patients with brain damage. The EEG may be indicative of a metabolic encephalopathy. Some patients may appear to be suffering from encephalitis, but the cerebrospinal fluid is normal. The etiology is believed to be similar to that of the hyperthermia noted after the administration some anesthetics. Other than withdrawal of the medication and supportive therapy, there is at present no specific treatment, although dantrolene and bromocriptine are reportedly helpful (Lazarus et al., 1989).

Motor signs are somewhat more specific for frontal lobe disease. When the motor portions of the frontal lobe are involved, particularly areas 4 and 6 or their many subcortical connections, motor paralysis may develop. In addition, a form of increased muscle tone (gegenhalten, paratonia) may develop. This is also called counterpull and is manifested by the semivoluntary resistance the patient increasingly offers to passive movement of his limbs. When the examiner attempts to extend the patient's elbow, for example, patient will resist, and

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his resistance will increase as the elbow is extended farther. Forced grasping may be seen in response to tactile stimulation of the patient's palm by the examiner's fingers. When the examiner attempts to extend patient's fingers while disengaging his own from the patient's grip, he may encounter counterpull.

Various forms of gait disorder may result from frontal lobe damage. One type that is quite similar to cerebellar ataxia may be seen in frontal lobe lesions and presumably reflects the many connections of the frontal lobe with the pons and cerebellum. Apraxia of gait may lead to loss the ability stand and walk, or even to sit steadily, despite a well-coordinated movement of the limbs. A form of marche a petit pas that superficially may resemble the small stepped gait usually associated with Parkinson's disease may be seen. It is widely based, however, and the patient often seems to be uncertain as to where be is going. A peculiar characteristic is the ability of some patients to step over lines and to climb stairs when they cannot walk on a flat, unmarked surface. Freezing in open doorways also occurs. Difficulty with the initiation of gait can be encountered in parkinsonism as well in gait apraxia, but this symptom of parkinsonism can be treated successfully with L-dopa, whereas frontal gait apraxia does not respond to this medicine. Increased flexor tone caused by frontal lobe damage ultimately may lead to paraplegia in flexion.

Area 8 of the frontal lobes controls voluntary conjugate eye movements. Stimulation of area 8 causes the eyes to deviate conjugately to the opposite side. Destruction of area 8 leads to deviation the eyes conjugately to the side the lesion; but this is a temporary phenomenon, seen mainly in the first days and weeks following acute lesions. During convulsive seizures, the head and eyes characteristically turn away from the lesion, and during postictal phase, they deviate back again toward the lesion. Because frontal regions devoted to eye movements are so extensive, a good screening test for frontal disease is visual tracking. The patient should be able to follow the examiner's smoothly moving finger along a horizontal plane. If the patient's eye movement is jerky, discontinuous, or if it deviates from the examiner's finger, the presumption of frontal disease is justified. The ability to suppress antisaccades, to look up or down (to raise the outer limbus of the iris more than 5 mm, to lower it more than 7 mm), to maintain fixation for 30 seconds and to stop blinking after the third tap on the bridge of the nose are all frontal tests involving the eyes. The frontal battery should also include the two-and three-stepped Luria tests, the face-hand test, limb placement, grasp, snout, and suck reflexes and a test of word fluency (Chapter 7). Abnormalities on three or more of these tests correlate with abnormalities on the Halstead-Reitan battery (Jenkyn et al., 1977, 1985) and the brain MRI (Bae et al., 1998).

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Clinical Symptoms Associated with Parietal Lobe Dysfunction

In general, patients with parietal disease are poor observers, have no awareness of their deficits, and perform variably on psychological tests from day to day. Lesions of the dominant hemisphere usually produce disturbances speech, and lesions of the nondominant hemisphere produce gnostic deficits, faulty corporeal awareness, and defective visuospatial conceptualization. When such deficits are seen in patients who are not grossly disoriented, or dysmnesic, parietal lobe dysfunction should be suspected. Critchley's classic monograph (1953)described the clinical deficits that occur in parietal lobe disease. His categorization of abnormality is summarized in Table 4-1. Table 4-2indicates some of the

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variability in the symptoms of single retro-Rolandic lesions that may give rise to parietal symptoms.

Table 4-1 Some Neurological Deficits Seen with Parietal Lobe Damage

Tacticle Dysfunction
“Primary”: Hemihypalgesia for touch, pain, heat, and cold
“Cortical”: Astereognosis; agraphesthesia, extinction on simultaneous bilateral stimulation, two-point discrimination loss, position sense deficit with pseudoathetosis, sensory ataxia
Motility Disturbance
Apraxia for learned activities (following commands) or automatic acts (walking), gegenhalten, perseveration, echopraxia
Ataxia
Muscular wasting
Constructional Apraxia
Gerstmann Syndrome
Finger agnosia
Dycalculia
Right-left disorientation
Agraphia
Disordered Body Image
Unilateral neglect
Anosognosia
Denial
Visual Defects
Cortical blindness
Anton's syndrome (blindness with confabulation)
Hemianopia
Distortions: Macropsia, micropsia, obliquity, drifting, alexia

Source: Critchley, 1953.

Table 4-2 Origin of Some “Parietal”-Type Deficits in Single Retrorolandic Lesions

DYSFUNCTION

HEMISPHERE

LOBE(S) MAINLY INVOLVED

Apraxia

Constructional

R > L 4:1

Parietal

Dressing

R > L 5:l

Parietal

Agnosia

Somatognosia

   Denial of half of body opposite lesion

R

Parietal

   Finger agnosia (bilateral)

L > R 6:l

Parietal, especially supramarginal and angular gyri

Visual Agnosia

   Neglect of space on side opposite lesion

R > L 10:1

Parietal

   Nonrecognition of faces

R > L 3:l

Parietal

   Nonrecognition of objects, pictures, colors

L

Occipital or post-temporal

   Numbers not correctly placed

L > R 3:l

Parietal

Alexia

L

Temporal-occipital parietal

Agraphia

L

Temporal-parietal occipital

Acalculia

L > R 3:l

Temporal or parietal

Aphasia

Fluent

   Wemicke (poor comprehension, poor repetition)

L

Temporal-parietal

   Conduction (good comprehension, poor repetition)

L

Parietal-temporal

Anomic-amnestic (good comprehension, good repetition)

1. Widespread brain disease

2. Recovery from other forms of aphasia

3. Also L parietal (angular gyrus)

 

L

Posterior-temporal

Nonfluent (motor)

La

Frontal, temporal, parietal, rolandic

Source: Based on Hécaen (1962) and Geshwind (1971).
aR in a minority of sinistrals.

Hecaen (1962) and Hecaen Angelergues (1962) provide a still valid basis for certain generalizations. Dysphasia and dyscalculia are characteristic of posterior left hemisphere lesions but do not occur in all patients. The speech of sinistrals in general is less seriously and permanently affected by single posterior lesions of either hemisphere. Ideomotor apraxia, when it is the result of a single posterior lesion, is seen only with lesions of the left hemisphere and only in a small minority of these cases. Dressing apraxia and spatial agnosia are most characteristic of right hemisphere disease but affect only a minority patients. Delerium can result from an infarct in either parietal lobe but is more commonly encountered in right parietal strokes than left. Sometimes the only clinical clue that indicates focal disease in a delirious patient with a parietal stroke is a field cut to threat on the side opposite the lesion. Like all sensory deficits, this sign is difficult to elicit in a confused patient.

Symptoms characteristic of dementia or frontal disease such as indifference to failure and catastrophic reactions, confusion can be encountered in many patients with unilateral posterior lesions. The most characteristic and striking feature of parietal lobe disease is that patients have agnosognosia—they do not recognize their sometimes obvious and extensive deficits e.g., hemiplegia, hemisensory deficit, hemianopsia, this feature of parietal disease can complicate their rehabilitation.

Clinical Symptoms Associated with Temporal Lobe Dysfunction

When lesions of the temporal lobes produce cognitive deficits, there may be concomitant paranoia, psychosis, depression, sexual dysfunction, and rarely, episodic violence (Tucker et al., 1986). The language deficits that may occur with posterior left temporal lobe lesions are presented below. The also plays a role in memory functions, though the mind's ability to record, store, and recall events cannot be regarded as localized in that region. Recent memory loss is the hallmark of all neurologic disorders that cause severe cognitive dysfunction, whether they are induced by focal or diffuse disease. There is no doubt, however, that the medial temporal lobe and the rest of the limbic system play an especially important role in memory function.

Memory loss (amnesia) has four clinical characteristics) (1) impaired ability to learn new material, (2) normal immediate recall (digit span, etc.), (3) preserved ability to retrieve some old, over-learned material, (4) intact intelligence, naming, and personality (Benson McDaniel, 1991). In humans, limited bilateral lesions in regions of the limbic system can produce a severe, permanent disturbance of recent memory. This has been repeatedly noted after bilateral hippocampal destruction or after unilateral lesions in patients whose other hippocampus

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was impaired. That both of the hippocampuses are important for recent memory has been further emphasized by the observation that bilateral destruction of the amygdala, another limbic structure, does not cause any memory deficit. The fornix, however, must play some role in memory, given that its bilateral destruction makes the mental recording of ongoing events and their subsequent recall difficult, but the extent of memory deficit after sectioning the fornices is not as great as that caused by hippocampal lesions (Ojemann, 1966).

Lesions in other areas of the brain can also disrupt memory function. Destruction of both the dorsomedian thalamic (DMT) and medial pulvinar nuclei produces severe recent memory deficits even when the hippocampus is intact. Dorsomedian thalamic lesions have been identified as the major anatomical correlate of recent memory loss in Wernicke-Korsakoff encephalopathy. Lesions the mammilary bodies had previously been regarded as the locus of amnesia in that condition (Victor et al., 1971). Stimulation of the lateral surface temporal lobes, especially the superior temporal gyrus, in neurosurgical patients under local anesthesia, evokes remote memories, chiefly auditory and visual, apparently of long forgotten events. Usually these events were trivial and not of obvious psychodynamic significance (Penfield and Perot, 1963). Removal of the stimulated regions has not obliterated such memories, however, so it would be incorrect to conceive of the temporal cortex as a unique memory storage center.

Other Symptoms of Cortical Dysfunction

Aphasia

The division of the aphasia into anterior (Broca or expressive) and posterior (Wernicke or receptive) types has prevailed for over 100 years. Geshwind (1971) proposed dividing aphasias into nonfluent and fluent. He considered pathology around the Sylvian fissure to be the primary source of most aphasia and identified nonfluent aphasia with precentral lesions and fluent postcentral pathology. Benson (1979) agreed with this but said that this division characterized only approximately one-third of aphasic patients. He stressed that repetition is impaired in patients with perisylvian lesions, whereas repetition normal or superior in patients whose aphasia derives from zones adjacent to the perisylvian language areas. One of Benson's greatest contributions is his delineation of extrasylvian (transcortical) aphasias (Benson and Ardila, 1996).

New methods are available for determining the site and extent of brain lesions that cause aphasia. Computed tomography and MRI using T-l and T-2 sequences started the modern era of brain localization. To these have been added the fluid attenuated inversion recovery (FLAIR) MRI technique and diffusion weighted images (DWI). Functional MR, SPECT, and PET have shown much

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more extensive deficits in some patients than static imaging tests such as CT and MRI (Mettler et al., 1981). In general, the classical concepts regarding cerebral sources of aphasia based on gross pathology have been confirmed (Kreisler et al., 2000), but there is considerable variation among individuals. Some of the variation is related to the freshness and type of damage some premorbid factors such as handedness, asymmetries in the size of the anterior and posterior halves of the two hemispheres (Bear et al., 1986), and individual variations in brain organization, some of which may have experiential roots (Rapin and Allen, 1988). Subcortical structures (thalamus basal ganglia) white matter tracts that connect portions of the cortex that support speech can all cause aphasic disorders when they are damaged.

Either hemisphere can support language despite the genetic program that normally establishes speech in the left hemisphere of most individuals. Unilateral lesions sustained early in life do not prevent the development of language (Annett, 1973). Even left hemispherectomy in children for control of epilepsy does not permanently prevent the development of language (Basser, 1962). Unilateral lesions on either side in children cause transient but not permanent aphasia. On the basis of intracarotid amytal injections in epileptics prior to surgery,Milner (1974) reported that if left-sided lesions are perisylvian, the right hemisphere is likely to have become dominant for language, whereas if lesions are extrasylvian, dominance remains in the left hemisphere.

The secondary, pathological lateralization of language to the right hemisphere in left hemisphere damaged children is evidence of the interhemispheric plasticity in the organization of a child's brain with respect to language. Recovery of speech in left hemisphere-damaged adults may also derive from a reorganization of language sources in the right hemisphere as well within the left hemisphere (Kinsbourne, 1971; Knopman et al., 1984; Ohyama et al., 1996). Impressive evidence of right hemispheric participation in adult language function has been presented by Kinsbourne (1971); he studied three right-handed men who suffered left hemispheric strokes that caused aphasia and found all three were able to speak a little at the time of testing and that one had shown considerable improvement. The speech in all three, however, was markedly impaired. Intracarotid injections of amytal caused complete speech arrest when the right carotid was injected but not when the left injected. It thus appears that whatever speech these patients retained or recovered after they sustained left hemispheric damage originated not in the remaining undamaged portion of the left hemisphere but in the right

The dysphasic language in adults with left hemispheric lesions supposedly originates in the remaining intact portions of left hemisphere. On the basis of the Kinsbourne study, it appears likely that dysphasic language is largely right hemispheric and that recovery from aphasia depends largely on how completely the right hemisphere can redevelop language skills. The participation of

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the right hemisphere in dysphasic speech may well be the reason why various forms of aphasia correlate incompletely with the anatomical locus the lesion (Mazzocchi and Vignolo, 1979).

The contribution of the minor hemisphere to speech has been investigated by Gazzaniga and Sperry (1967) in patients whose cerebral hemispheres were functionally separated by commissural section. Testing each hemisphere independently, they found that information perceived by the minor (right) hemisphere could not be communicated in speech or writing and that complex calculation likewise appeared to be solely a function of the major (left) hemisphere. None-theless, the minor hemisphere showed considerable ability to comprehend written and spoken language, though less than the major hemisphere. These experiments suggest that in individuals with intact left hemispheric speech function, the right hemisphere may make some contribution to the understanding of language but is incapable of producing language.

Two opposing theories about aphasia had arisen by the beginning of the twentieth century, and they are still maintained. According to one theory, language is a property of cortical centers that have particular functional significance. Destruction of these centers, the association fibers between them, or the projection fibers from them, it is believed, will produce predictable forms of aphasia. According to the other theory, the locus of lesion is less important in determining the speech deficit than adequacy of the remaining circuits.

The classic work of Penfield and Roberts (1959) provides evidence that supports the second theory. During operations on epileptic patients whose seizures had been impossible to control with medication alone, they stimulated and excised virtually all areas of the cortex thought to have a role in speech. Stimulation in either hemisphere produced vocalization and arrest of speech. It never resulted in actual speech or even words, but only grunts the enunciation of syllables. In these and other studies that followed, such “speech areas” as the temporal and parietal regions, the supplementary motor area, Broca's area have been removed. Excision of each area produced only temporary aphasic disturbances as long the rest of brain was intact.

What leads to the dominance of one hemisphere, how is maintained, and how recovery from aphasia occurs are not known. Nor is it known whether the change in the language potential of minor hemisphere that is thought to occur in childhood is the result of inactivity of that hemisphere or whether the dominant zone has some active role in the change. The mechanism of dominance may be analogous to the one demonstrated by Wiesel and Hubel (1965) for the visual cortex. If one eye of a newborn kitten is occluded 2 to 3 months, the visual cortex becomes unresponsive to impulses from that eye permanently, but it is normally responsive to impulses from the unoccluded eye. When both eyes are occluded for 2 or 3 months and then tested, most of the visual cortical cells that still respond register visual impulses from both eyes.

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Thus, it appears that the seeing eye of the monocularly occluded cat either preempts all the dendritic connections of visual cortex or inhibits (suppresses) impulses that come from the occluded eye.

The development of right-handedness is part the process by which the left hemisphere becomes dominant for speech and other functions. The fact that major speech functions reside in the left hemisphere of most sinistrals indicates that the two functions—handedness and speech—are independent. Yet the state of left-handedness implies that the right hemisphere is not completely subordinate to the left. In sinistrals, hemispheric speech dominance is less complete than in dextrals. This is manifested by the less serious and permanent nature of speech deficits that result from either left or right hemispheric lesions in sinistrals. This is because the speech potential of the right hemisphere sinistrals has not been permanently rendered ineffective by the dominant left hemisphere. Thus, both hemispheres are closer to being equipotential for language function in sinistrals. The time-course of recovery from aphasia after a destructive lesion has been sustained reflects the time necessary for the reorganization of remaining circuits for the development of speech functions, not just the recovery time for cells damaged but not destroyed. If reorganization supports restoration of speech, theoretically, it is conceivable that learning and practice can aid the redevelopment of language skills in previously underused circuits and that speech therapy could have a positive impact. This expectation has been realized in several group studies (Basso et al., 1979; Wertz 1986).

Some remission in the symptoms of acquired aphasia is typically seen patients with nonprogressive brain diseases, such as cerebrovascular disorders. Significant spontaneous recovery is often thought to occur even 3 to 6 months after onset. Available data suggest that most spontaneous recovery occurs mainly in the first month after onset of aphasia (Pashek and Holland, 1988). Some improvement may continue for the next few months. The most important factors in recovery are early age of onset, left-handedness, and lack of bilateral or widespread brain damage. A variety of systematic rehabilitation procedures for aphasia have been developed. These have summarized and discussed byBenson and Ardila (1996).

Progressive aphasia is a manifestation of dementia various types that starts as aphasia without other signs of dementia and evolves over several years to a more general decline in cognitive capacity. It has been seen Alzheimer's, Pick's, and Creutzfeld-Jakob diseases. Other neurobehavioral symptoms can be the presenting ones in these disorders with alexia, visual agnosia, or apraxia preceeding general dementia by several years. Progressive aphasia is therefore not a disease but a manifestation of any one of several dementing diseases (Benson and Ardila, 1996).

Like speech, there are other cortical functions that unequally represented in various brain regions. Apraxia, agnosia, acalculia, agraphia, and alexia may

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result from retrorolandic lesions. Like aphasia, apraxia, and agnosia in sinistrals are generally less severe and less permanent than in dextrals (Hecaen and Angelergues, 1962).

Apraxia

Apraxia can be defined as an inability to carry out a voluntary act that the patient should know how to do, the nature of which the patient understands, in the absence of paralysis, sensory loss, or ataxia. In dextrals, apraxia both sides of the body is likely to result from lesions in the posterior left hemisphere, especially the supramarginal gyrus of the parietal lobe. Certain forms apraxia are more likely to result from right parietal lesions; these include dressing apraxia and constructional apraxia (loss of the ability to copy a two-dimensional figure).

Agnosia

Agnosia is the failure to perceive the nature and meaning of a sensory stimulus when the sensory pathways conveying it are intact. Visual agnosia is present, for example, when a patient is unable to recognize an object he clearly sees. The inability to recognize objects, pictures, and colors is almost always the result of a lesion in the posterior temporal—parietal regions but lesions these regions do not always give rise to this form of agnosia. When present, visual agnosia is usually associated with other deficits of mental and cognitive function including the nonrecognition of faces (prosopagnosia) and hemianopsia (Benson and Greenberg, 1969; Rubens and Benson, 1971; Bender and Feldman, 1972). It is likely to be associated with a right parietal lesion, though only minority of patients with right parietal lesions manifest this sign (Hecaen, 1962; Meadows, 1974). Probably some patients with left hemisphere disease would have this symptom but language disturbance prevents its detection.

Auditory agnosia, pure word deafness, describes the inability to understand words that can be heard. The pathology involves the primary auditory cortex (Heschel's gyrus) and/or its connection to the thalamus (Benson and Ardila, 1996).

Alexia and Agraphia

Rare syndromes like alexia without agraphia attest to the specialization of some cortical functions within specified brain regions. In this syndrome, patients can write—their names, for example—and then cannot read what they have written. There is usually a lesion in the splenium of corpus callosum and a right hemianopsia-producing lesion in the left occiput. Even more rarely, hemianopsia

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is not present but the lesion in the splenium and adjacent white matter interrupts the connections of the visual cortex with the dominant angular gyrus (parietal lobe) so that the information that reaches visual cortex cannot be transmitted to where it is interpreted and from which writing originates. If there is a lesion in the left angular gyrus there is alexia with agraphia (and usually a hemianopsia). Agraphia is an element of the Gerstmann syndrome.

The Gerstmann syndrome (1940) has four components, right-left disorientation, finger agnosia (the inability to name the fingers), acalculia, and agraphia. When all four components co-occur, there is usually a lesion in the left angular gyrus (Benson and Ardila, 1996). Each of the individual components alone or in combination with one or two of the others can be encountered pathology elsewhere in the brain. The left angular gyrus is not a center for these functions, though it is an important component in the circuitry that supports them. Agraphia and acalculia may result from left temporal lobe lesions from right hemispheric lesions (Hecaen, 1962). This information is summarized in Table 4-2.

Dysfunctions Associated with Severing the Corpus Callosum—Split Brains

The theory that supple widespread neuronal circuits exist for all the higher functions is supported by the innovative experiments on commissurotomized patients. The nature of the functional differences between the left and right hemispheres has been explored by psychological testing of epileptic patients in whom commissuretomy was performed as a reasonable measure of last resort to control their seizures. In the initial postoperative period, such patients characteristically appear somewhat dull; there is temporal confusion, but orientation and speech are intact. Patients restrict their physical activity and have to be urged to perform the simplest body functions. As they begin move about, a degree of spatial disorganization becomes apparent. The patient often settles into a repetitive pattern of behavior, such as closing a door with the right hand and opening it with the left, which stops only when he is distracted from activity (Wilson et al., 1977). By flashing pictures, objects, written material, and numbers in a single visual field or by presenting objects for touch by one hand, the examiner can test each hemisphere independently. Material presented to the subject's right visual field or hand registers in the left hemisphere. A picture of an orange, for example, can be flashed to the right visual field. The patient can then correctly retrieve by touching with his right hand an orange from a series of test objects. The subject would say in a normal fashion that the stimulus had been an orange.

If another object, such as a key, were projected to the left visual field, it

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would register in the right hemisphere. This information could not be conveyed to the left hemisphere because of the callosotomy. The patient claims that he has seen nothing (in other words, the left hemisphere “is talking”). The patient would be unable to use his right hand retrieve the key from a group of test objects but with his left hand, the patient could retrieve key. If the were asked what has been retrieved with his left hand, he would reply that be didn't know. Once again, this represents the “left hemisphere talking.” The left hemisphere neither “saw” the visual stimulus nor had direct access to the tactile information. Because the right hemisphere performs consistently and well in such tests over a longer period of time, one assumes that it “knows” and is “aware” of the test stimulus but isn't able to “talk” about it (Gazzaniga and Smylie, 1984).

Anterior section of the corpus callosum frequently results in transient hemiparesis of the nondominant leg and temporary difficulties in initiating speech. Posterior section is followed by disconnection symptoms such as those in the example above. Visual and tactile stimuli presented to the nondominant hemisphere cannot be verbally identified because of disconnection from the language-dominant hemisphere. Total callosotomy additionally interrupts interhemispheric communication between the motor regions. This results in deficits bimanual coordination and apraxia of the nondominant hand to verbal commands. Some of the symptoms subside, probably because of increased use of ipsilateral sensory and motor pathways. The residual symptoms are not disabling given that unrestricted visual scanning of the environment ensures bilateral representation of sensory experience. Cognitive functions are frequently improved by callosotomy (perhaps by lowering AED requirements), although preexisting lateralized deficits may be exacerbated. Language are observed mainly in patients with crossed dominance. Studies in children reveal that callosotomy performed before puberty is not followed by permanent disconnection deficits. This may be attributable to the greater neural plasticity of immature brain (Sauerwein and Lassonde, 1997).

In many ways the right hemisphere is identical in function to the left; reaction times are the same, intermodal transfers from vision to touch and vision are as efficient in both, and the ability to respond emotionally provocative stimuli is equal in both but not the same. The right hemisphere a bit disinhibited, more amused by earthy humor, for example. The left hemisphere is more proper and respectful of social conventions. The right hemisphere can “learn” any of a number of visual and tactile problems with the same rapidity as the left hemisphere. In short-term memory experiments, the right hemisphere functions as well the left and its ability to control the half of body is equal to that of the left hemisphere in controlling the right. Stereognostic recognition for the left hand is present and intact in the right hemisphere, as it is for the right hand in the left hemisphere.

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The major differences between the right and left hemispheres are seen in the analysis of language, speech, arithmetic, and morality. The left hemisphere is capable of speech but the adult right hemisphere is not. The left hemisphere has the capacity for complicated mathematical computations, but the right hemisphere is very poor at arithmetic. In some tasks, mainly those involving spatial patterns, relations, and transformations, the right hemisphere is superior to the left. For example, the right hemisphere has a greater capacity than left for drawing block designs and for copying test figures. In addition, the right hemisphere apparently processes information by direct perceptual processing and does not depend on verbal reasoning processes for solving problems. It solves spatial problems directly and rapidly. In contrast, the left hemisphere solves similar problems slowly; the process is accompanied by a great deal of talking about the problem. It has been suggested that left and right hemispheric modes of reasoning might interfere with each other if they were both located in the same hemisphere. If so, this would give an evolutionary rationale for the development of cerebral dominance in human beings (Sperry, 1974).

In young patients who have had commissurotomies and in patients were born with the congenital absence of the corpus callosum, interhemispheric differences noted in commissurized adults have disappeared. The functions normally associated with either the left or the right hemisphere may become established in both hemispheres. In independent tests of each hemisphere such patients, it has been determined that the right hemisphere can produce spoken language, writing, and calculations as well the left, the left can perform spatial tasks as well the right. In both young commissurotomized patients and patients with congenital agenesis of the corpus callosum, there is a tendency for language facility to develop normally but for nonverbal functions be some-what impaired (Sperry, 1974). This indicates plasticity of the nervous system and argues against the identification of a cerebral structure, even a hemisphere, with a particular function. It supports the view that specific tasks of the “dual processor,” language and nonverbal tasks, can be subserved by more than one neuronal circuit (Gazzaniga, 2000).

There is much less evidence relating lateralized hemispheric dysfunction to psychiatric illness, despite what might be called a clinical renaissance of cerebral localization in psychiatry. There have been approximately 40 studies of schizophrenia alone, most of which advance the hypothesis that some form left hemisphere hyperor hypoactivity is present. These theories have little factual basis and often depend on unreliable or untested indicators of cerebral dominance and cerebral activity. For example, lateralized amplitude of EEG activity or initial eye movements to the right or left are proposed as indicators of hemispheric dominance, but their correlation with other standards of dominance or with normal functioning has not been established (Marin and Tucker, 1981; Taylor and Abrams, 1984). Current evidence suggests that the major psychoses

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are characterized by bilateral rather than lateralized dysfunction and that they possibly involve certain amine pathways.

Diffuse Disorders of Cognitive Function—Delirium and Dementia

Delirium is an excellent example of how the primary cognitive disorders differ from regional syndromes. Delirium demonstrates how the nature of the disease process is critical to the character of brain syndrome rather than the anatomical site or size of the lesion. Brain syndromes acute onset are often characterized by delirium. Delirium (Table 4-3) is a cognitive disorder of acute onset most often caused by toxic or metabolic causes. In delirium one can see all the symptoms of cognitive dysfunction, especially disorientation and alterations in level of consciousness, but also fear, irritability, and visual/tactile hallucinations.

The mechanisms underlying delirium are unclear. There is some indication that it is a disturbance of subcortical function affecting the ascending reticular formation. This pathway is intimately related to the ability focus attention (Trzepacz et al., 1989; Figel et al., 1990,1991).

There are two kinds of delirium (Meagher et al., 2000): an agitated or hyperactive type and a hypoactive or somnolent type. The agitated is characteristically seen in such conditions as delirium tremens (alcohol withdrawal), fever, and anticholinergic overdose. The patient is overactive, often difficult to restrain, and tremulous. Hepatic coma often provides a good example of a somnolent delirium; the patient is difficult to arouse and when aroused seems quite confused and may often have myoclonus or asterixis. No clear neurotransmitter system has been implicated in either type of delirium, although anticholinergic agents will certainly make most delirious states worse. Flumazeil, a benzodiazepine antagonist, has been reported as being effective in temporarily reducing delirium in hepatic coma and in other delirious states, which may implicate the GABA system in some types of delirium (Bostwick and Masterson, 1998).

Delirium is the brain's acute or subacute response to a significant somatic stress. Other names that have been used for the condition areacute brain failure,

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acute confusional state, and toxic-metabolic encephalopathy, they imply the cataclysmic nature of the stress. Toxic and metabolic disturbances can clearly cause delirium, but in other cases it may simply reflect the severity of illness. There are distinct risk factors for delirium; it is more common in the very young and the old, (particularly when febrile or overmedicated); when there is evidence of brain damage particularly dementia; and with the use of medications, particularly anticholinergics, meperidine, and benzodiazepines (Schor et al., 1992; Marcantonia et al., 1994a, b). In the elderly, delirium is a poor prognostic sign. Francis et al. (1990) studied 229 patients 70 years of age or older who had been admitted to a general hospital. Twenty-two percent became delirious during the hospital stay; risk factors for the development of delirium were abnormal sodium levels, severity of illness, dementia, fever or hypothermia, psychoactive drug use, and azotemia. Patients with three or more of these risk factors had a 60 percent chance of developing delirium. The patients with delirium had a higher mortality rate, stayed longer in the hospital, and were more likely to be transferred to chronic care facilities. Even those who do not meet the full diagnostic criteria for delirium but develop, during hospitalization, some of the symptoms, such as disorientation, clouding of consciousness, or perceptual disturbances (illusions or delusions), are as much at risk for a poor outcome as if they met the full diagnostic criteria (Levkoff et al., 1996).

Table 4-3 Summary of Diagnostic Criteria for Delirium Based on DSM-IV

Disturbance of consciousness (defined as reduced ability to focus, sustain, or shift attention)
A change of cognition or the development a perceptual disturbance that is not accounted for by a preexisting, established, or evolving dementia
Develops over a short period time (usually hours to days) and tends fluctuate
Evidence that the disturbance is caused by a medical disorder or drug

Delirium can be mistaken for depression in hospitalized patients because of the patient's often slowed, disorganized responses and inattentive manner. Psychiatric consultation services often find that 25%–40% of the referrals for depression turn out to be delirious reactions (Nicholas and Lindsey, 1995; Armstrong et al., 1997). Another factor that makes the diagnosis easy to miss is delirium's fluctuating course; a patient can perform quite well on formal mental status testing in the morning and be quite confused at night. As delirium is often a response to another condition, the accurate recognition of delirium is the first critical step in the effective care of patient. Infection, often urinary tract, can cause delirium especially in mildly to moderately demented patients. Delirium clears in such cases when the infection resolves.

Delirium is almost the only disorder in DSM-IV that consistently associated with a laboratory abnormality. The EEG in delirium is usually abnormal and this abnormality usually ceases when the delirium ceases. In most cases of delirium the EEG will show a diffuse bilateral slowing. At times there may be evidence of fast-wave activity superimposed on the basic slowing. The pathophysiology of the EEG changes is unclear although they are generally felt to reflect some change in metabolic activity, perhaps related to the cholinergic system. Anticholinergic agents can produce both delirium and EEG changes (Tune and Bylsma, 1991).

The treatment of delirium should be directed at the underlying causal condition but symptomatic measures can help too. These involve attempts to orient

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the patient, keep the room lighted at night, and, as a last resort, restrain him or her. Benzodiazepines and haloperidol in sedating regular dose schedules (oral, IM, or IV) have all been useful in the acute management of delirious patients. Often these medications are used in heroic doses, particularly intensive care units where the agitated delirious patient can interfere with treatment of the primary condition by pulling out IVs or trying to get out of bed (Frye et al., 1995).

Dementia is a disorder of varied etiologies that consists multiple cognitive deficits and often motor speech disturbances without a disruption of attention as in delirium (Table 4-4). Delirium is an acute disorder of the brain and dementia is most often a chronic disorder. When the term acute used with dementia,

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it implies a reversible cognitive disturbance, but in general the term dementia means stasis or inexorable progression. Until recently, almost all dementias were attributed to Alzheimer's or cerebrovascular diseases (multi-infarct dementia [MID]). With increased research on aging, many other forms of dementia have been recognized and some are fairly common. Pick's or frontotemporal atrophy (FTA) and Lewy body dementia (LBD) are two common types of dementia. The risk dementia is approximately 1 percent at the age of 60 years and reaches 30 to50 percent by the age of 85. With increased standardization of diagnostic criteria (Table 4-5) it has become clear that approximately 70 percent of dementia is caused by Alzheimer's disease; MID accounts for approximately 15 percent; FTA for 5 percent (Eldmacher and Whitehouse, 1996). We expect the rates of MID, FTA, LBD to rise as diagnostic sophistication increases and the comorbidity of these conditions becomes clearer.

Table 4-4 The Differential Diagnosis of Dementia

Degenerative

Neoplastic

Alzheimer's disease

Gliomasa

Pick's disease

Meningiomasa

Huntington's chorea

Secondary tumorsa

Mechanical

Infectious

Traumaa

Luesa

Occult hydrocephalusa

Abscessa

Subdural hematomaa

Chronic meningitisa
Subacute sclerosing panencephalitis

Metabolic

Creutzfeldt-Jacob disease

Hypothyroidisma
Hyponatremiaa

Exogenous Poisoning

Hypercalcemiaa

Metalsa

Hypoglycemiaa

Bromidesd

Porphyriaa

Alcohola

Hypoxiaa

Barbituratesa

Wilson's diseasea

Belladonna alkaloidsa

Uremiaa

Organic phosphatesa

Hepatic comaa

Hallucinogensa

Carbon dioxide narcosisa

Psychotropicsa

Vascular

Vitamin Deficiencya especially:

Arteriosclerosis

B1a

Collagen diseasea

B6a

B12a

Niacina

Folatea

aPotentially reversible by medical or surgical means.

As the population ages, clinicians will be confronted with disorders of cognition with increasing frequency. Recently, the American Academy of Neurology has published comprehensive practice guidelines, supported by extensive data, for the diagnosis and management of cognitive disorders. The first guideline refers to patients with symptoms of mild cognitive impairment, e.g., isolated memory impairments, without any other symptoms of dementia (Petersen et al., 2001). These patients are at high risk for dementia and should be followed regularly with standardized neuropsychological tests. The guideline for the diagnosis of dementia notes that in addition to neuropsychological testing, screening for treatable causes of dementia such as depression, hypothyroidism, and vitamin deficiencies is critical (Knopman et al., 2001). The evidence-based review of the management and treatment dementia showed only a small benefit for the use of cholinesterase inhibitors, primarily in mild to moderate dementia, and indicated that vitamin E might delay worsening of symptoms. Good support was found for the active treatment of both depression (SSRIs) and agitation psychosis (atypical antipsychotics) in patients with dementia. Psychoeducational

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efforts for the families of cognitively impaired patients delayed nursing home placements (Doody et al., 2001).

Table 4-5 Summary of DSM-IV Criteria for Dementia of the Alzheimer's Type

Multiple cognitive deficits manifested by both memory impairment (impaired ability to learn new information or to recall previously learned information) and one (or more) of the following:
   aphasia
   apraxia
   agnosia
Disturbance of executive functions
Significant impairment of in social or occupational functioning
Gradual onset and continuing decline

Alzheimer's Disease

Alzheimer's disease (AD) is a progressive, partly treatable condition of unknown etiology that is often fatal within seven years of diagnosis. Described 100 years ago, it is surprising there is still controversy as to whether a genetic condition and what is the nature of the basic defect. Neurofibrillary tangles neuritic plaques in the cerebral cortex characterize the neuropathology. It is probably familial in approximately 10 percent of cases (Heston, 1979). It is common knowledge that the brain shrinks in the course of aging and it is commonly assumed that the loss of cortical neurons is even greater in AD. Using a computerized method of image analysis that permits the high speed counting of large numbers of cells, Terry (1979) compared the brains 20 clinically and histologically diagnosed cases of AD with brains from 20 normal individuals who died between the ages of 70 and 90 years. He found that AD brains showed no significant loss of small neurons, increase in glia, and no significant shrinking of neuronal or neuropil size. However, subsequent studies showed a 40 percent decrease in the number of large neurons throughout the neocortex (Terry and Katzman, 1983). The qualitative changes in neurons are as significant as the quantitative loss of cells. The microscopic hallmarks of AD are neuritic plaques (often containing amyloid), masses of ring-shaped silverstaining material in the cortex, and neurofibrillary tangles, intraneuronal fibers that stain with silver. A correlation exists between the numbers of these lesions and the psychometric deficiency (Blessed et al., 1968). Some cases of AD, especially familial ones, show “lawless” secondary growth of dendrites with bizarre clusters of spine-rich dendrites (Scheibel, 1979). Other signs dendritic abnormality in AD have been reported (Buell and Coleman, 1979).

These neuropathologic changes appear to be quite relevant to the pathogenesis of Alzheimer's disease. Patients with Down syndrome, almost all of whom will develop dementia, also develop the same plaques, neurofibrillary tangles and amyloid deposits that are found in Alzheimer's disease if they live to be 30 years old (Schupf et al., 2001). The gene for amyloid production is located on chromosome 21, which has also been implicated as one of the chromosomes associated with early-onset Alzheimer's disease and Down syndrome (van Duijn et al., 1995; Blacker and Tanzi, 1998). Although the role of amyloid deposits is unclear, some have suggested that in both conditions the disease progression may relate to continued deposition and degradation of amyloid (Hyman et al., 1993). Other chromosomes that have been implicated in early onset Alzheimer's disease are 14 and 1; but all of these currently identified chromosomes can only

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account for approximately 50 percent of the cases early onset Alzheimer's disease.

Every person has two genes that produce a certain type of apolipoprotein (APOE) and there are four types of such genes (1,2,3,4). One gene comes from each parent. Most people who have APOE-4 from both parents will develop Alzheimer's disease by the age of 70. With two APOE-3 genes the risk of Alzheimer's disease is much less. With one APOE-3 and one APOE-4, the risk is intermediate (Roses, 1997; Blacker and Tanzi, 1998). The presence of APOE-4 also lowers the age of onset of Alzheimer's disease. It is clear that there are other genetic factors not yet understood in the majority of Alzheimer's disease cases.

The new imaging techniques, though not being diagnostic of Alzheimer's disease have helped us understand the disease process. As people age, MRIs have shown an increased likelihood of white matter and perivascular hyperin-tensities called leukoaraiosis. These hyperintensities are some of the MRI manifestations of small vessel disease and correlate with increased ventricular volume, higher systolic blood pressures, lower frontal lobe metabolism, lower scores on neuropsychological tests of frontal lobe functions (DeCarli et al., 1995) and “frontal” signs on neurological examination (Blake et al., 1995; Bae and Pincus, 1998). Similar correlations of leukoaraiosis on MRI have been noted in patients with late-life onset of depression (Cahn et al., 1996; Salloway et al., 1996). Many of these changes are at subcortical locations that support the premotor frontal cortex, reflecting their role in lobe function.

Biochemical studies of AD have indicated that there are no major deficits in several neurotransmitters, including norepinephrine, 5-hydroxytryptamine, dopamine, and gamma-aminobutyric acid (GABA), but that acetylcholine is seriously impaired. The major enzymes responsible for acetylcholine synthesis and hydrolysis, choline acetyltransferase, and actylcholinesterase, are markedly reduced. A presynaptic acetylcholine deficiency in AD is thought to exist, as there is no loss of postsynaptic acetylcholine receptors in the brains AD patients (Davies, 1979). The loss of cholinergic neurons is specific rather than generalized; those of the basal nucleus Meynert are heavily affected whereas those of the candate, putamen, and anterior horn cells are not. Cohen et al. (1995) has also shown that older adults have decreased choline uptake from the blood stream into the brain. The cholinergic system role in Alzheimer's disease is as yet unclear. Medications that inhibit acetylcholinesterase, (tacrine, donepezil, metrifonate, galantamine), all induce minor improvement in the cognitive symptoms of Alzheimer's disease, but do not alter the course the illness (Knapp et al., 1994; Morris et al., 1998; Rogers, et al., 1998;Wilcock et al., 2000).

One of the major changes in the DSM-IV classification of Alzheimer's disease was the recognition that Alzheimer's disease involves not only memory loss but

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significant behavioral symptoms as well. Along with the primary symptoms, AD patients can have depression, delusions, and other conditions. Mega et al. (1996) studied a group of 50 Alzheimer's disease patients with mild, moderate, and severe cognitive impairments and compared them to age-matched controls. Eighty percent of the Alzheimer's disease patients had behavioral changes; the most common behavioral changes were apathy (72%), agitation (60%), anxiety (48%), irritability (42%), dysphoria and aberrant motor behavior (38%), disinhibition (36%), delusions (22%), and hallucinations (10%). Agitation, dysphoria, apathy, and aberrant motor behavior were significantly correlated with increasing cognitive impairment. Aggressive behavior has also been found to be more common in the Alzheimer's disease patients who are psychotic (Aarsland et al., 1996). Incontinence and aggression are the most common reasons for institutionalization of AD patients. One of the remarkable phenomena observed in patients is that the personality often preserved even when cognitive processes are quite impaired. Many patients can carry on very appropriate conversations in social situations but when questioned about things that require memory functions, one suddenly becomes aware of how impaired they are. There is no way to predict the rate of progression the dementing process Alzheimer's disease. Clinically the Alzheimer's disease patient can remain relatively stable for years, but when cognitive functions begin to slip, the rate of change usually accelerates. The development of extrapyramidal symptoms, psychosis, or myoclonus signal deterioration (Chen et al., 1991; Stern 1996).

Problems with memory often begin several years before the family consults a physician. There is often a disparity between the family assessment and the patient's self-assessment. When a patient complains of memory loss and the family does not agree, the patient's complaints are usually benign. If the patient does not acknowledge a problem but the family does, it is very likely that the patient is ill. From that point on the usual survival approximately 8 to 10 years. Once the Alzheimer's patient is placed in an institution, average survival time for men is approximately 2.1 years and for women approximately 4.5 years (Heyman et al., 1997). In general, dementia severity, general debility, vascular disease, sensory impairments, and aphasia seem to predict increased mortality (Bracco et al., 1994; Bowen et al., 1996).

Factors that may reduce the risk of Alzheimer's disease or slow rate decline are just beginning to emerge. Groups of patients who have used medications such as estrogen (Tang et al., 1996), anti-inflammatory agents (McGeer et al., 1996), and selegiline or alpha-tocopherol (Sano et al., 1997), all have had a lower prevalence of AD than comparable groups that have not. Ginko biloba is comparable to cholinesterase inhibitors in salutary effect (Wettstein, 2000). Many studies now show that patients with greater cognitive reserve (higher education levels and occupations that require more cognitive effort) seem to develop Alzheimer's disease less frequently and even when they do the cognitive

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impairments for the same amount of tissue damage are not as great (Stern et al., 1994, 1996; De Ronchi et al., 1998). Conversely, a history of learning disabilities has been associated with higher rates of dementia (Cooper, 1997).

Vascular Dementia

Vascular dementia (formerly called multi-infarct dementia) can result from discrete, small infarcts, caused by hyalinization of vessels and from more severe strokes, intracerebral hemorrhages, emboli, and varied types of vasculitis. Although the course has been classically described as fluctuating with a stepwise progression, it can also be insidious; consequently the history of other medical conditions and the evaluation of the cardiovascular system, especially blood pressure is crucial. Sultzer et al. (1993) studied 28 pairs of patients (1 with vascular dementia and 1 with Alzheimer's disease) found that the patients with vascular dementia had more severe motor retardation, depression, and anxiety when the levels of cognitive impairment were similar, but in spite these research findings the clinical differentiation of the individual patient is still difficult. Risse et al. (1990) highlighted the difficulty of the clinical differential diagnosis of dementia in a study 25 patients who met antemortem criteria for the diagnosis of Alzheimer's disease. At autopsy only 68 percent met neuropathological criteria for the diagnosis of Alzheimer's disease. Those that did not meet criteria at autopsy had dementias of diverse etiologies, e.g., corticostriatal degeneration, Parkinson's disease with Lewy bodies, and Pick's disease. The now-famous “Nuns Study” in which serial psychological tests were performed in life and an autopsy after death showed that AD patients without vascular disease had better cognitive function than those with AD alone and infarcts alone (Snowden et al., 1997).

Pick's Disease and Dementia of the Lewy Body Type

Current histopathologic techniques and imaging methods have delineated two seemingly distinct types of dementia: Pick's disease or frontotemporal atrophy and Lewy body dementia (LBD). Pick's disease produces prominent degeneration in the frontotemporal areas and at times there is also degeneration of anterior spinal neurons, the basal ganglia, or both. Inclusion bodies that have biochemical similarity are found in both of these frontotemporal degenerations, however it is more the localization of the degenerations that unites these syndromes. Both of these frontotemporal dementias have been linked to a genetic abnormality on chromosome 17 (Kertesz and Munoz, 1998).

It has been found recently that 15%–25% of demented elderly patients have Lewy bodies in their brain stems and cortexes. In most of the neuropathological studies of patients with Lewy body dementia there are some neuropathological

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findings that are similar to the neuropathologic findings in vascular and Alzheimer's dementia, but there are some dementia cases that have just Lewy bodies. As Lewy bodies have been found primarily in patients with Parkinson's disease the relationship of Lewy bodies to all of these conditions is as yet unclear (Klatka et al., 1996; McKeith et al., 1996). The clinical course of Lewy body dementia is interesting as there are prominent psychiatric symptoms in additon to cognitive changes. In Lewy body dementia there is rapid fluctuation in cognitive functions, particularly attention and alertness; recurrent well formed detailed visual hallucinations; delusions and depression motor features of parkinsonism (Klatka et al., 1996).

Human Immunodeficiency Virus-1 Dementia

Another recently described but fairly common cause of dementia is that associated with acquired immunodeficiency syndrome (AIDS) infections. In the course of human immunodeficiency virus-1 (HIV-1) infections, dementia is quite common, particularly late in the course of illness, but when the dementia symptoms occur early in the course of HIV-1 infection it seems to be a bad prognostic sign and often heralds a rapidly deteriorating course (Martin, 1994; Wilkie, et al., 1998).

Occult Hydrocephalus

Of the chronic conditions causing dementia, one of the most difficult to diagnose is occult hydrocephalus. Accuracy of diagnosis is important because this condition can be reversed by a relatively simple neurosurgical procedure, the placement of a ventriculoperitoneal shunt. Occult hydrocephalus is usually confused with one of the nontreatable causes of chronic dementia, such as AD or vascular dementia. The classical patient is a middle-aged or elderly person with gait disturbances, incontinence, and dementia whose ventricles are large whose cerebrospinal fluid pressure, measured at lumbar puncture, is normal (Adams, 1975). In some patients, a previous history of head trauma, subarachnoid hemorrhage, meningeal inflammation, or tumor suggests the possibility of a deficit in the absorption or circulation of cerebrospinal fluid. But in most cases where the diagnosis of occult hydrocephalus is considered, the patient has become progressively demented over a period of months or years without any such history. At an early stage these patients sometimes consult a psychiatrist for symptoms like apathy, psychomotor retardation, and forgetfulness, which may easily be mistaken for a depressive reaction (Price and Tucker, 1977). Characteristically, a gait disturbance (apraxia) appears first and is more severe than the accompanying mental changes. This contrasts with Alzheimer's disease, which begins with dementia and does not impair gait until a relatively late stage of

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illness. Urinary incontinence and personality change have led us, heuristically, to describe such patients as “wobbly, wet, and weird.” Magnetic resonance imaging and CT scanning have not been very useful tools for distinguishing hydrocephalus ex vacuo (in which brain cell loss has resulted in large ventricles) from hydrocephalic dementia. Enlarged ventricles and atrophy of the cortical gyri may be seen in both conditions. Evidence of enlarged ventricles, when unassociated with widening of the cortical sulci, as demonstrated by computerized axial tomography and when the cerebrospinal fluid pressure is normal, may suggest occult hydrocephalus (Gawler et al., 1976). But this too is not likely to avoid misdiagnosis.

Direct continuous monitoring of the intraventricular pressure via a catheter placed in one of the lateral ventricles for periods of 24 to 72 hours patients suspected of being hydrocephalic has revealed intermittent increases above the normal range in some patients, particularly during REM sleep when the cerebral blood flow is increased. Some of these patients have subsequently benefited dramatically from shunting. Transient improvement after removal of 15 to 20 ml of cerebrospinal fluid may predict improvement with shunting (Fisher, 1982), but this test is unreliable. The time between lumbar puncture and improvement, if any, and the period of time needed for observation have not been established. The choice of patients for shunting relies on the art of medicine, which is to say that no firm criteria have been established. In general, the patients who have most consistently benefited from shunting have been those with demonstrable pathology whose symptoms have developed subacutely. Examples are patients with parasellar or posterior fossa tumors malformations, and those who have had meningitis, subarachnoid hemorrhage, or head trauma. The shunting procedure, which sounds simple, is fraught with hazards and failures. Blocked shunts, subdural hematomas, and infection justify a conservative approach to this condition, which is not easily diagnosed (Clarfield, 1989).

Cerebral White Matter Dysfunction and Cognitive Changes

The primary symptoms of grey matter diseases, memory loss, and seizures, are not as common in white matter diseases where motor-sensory functions are more prominent than cognitive loss. Although patients with multiple sclerosis often have significant depression and cognitive impairment it is primarily a disorder of the white matter of the brain and as such represents another interesting model of the commonality, complexity, and ubiquity of behavioral symptoms associated with neurological disorders. Almost half the volume of the cerebral hemisphere is white matter (Filley, 1998). Cerebral white matter is mostly comprised of the tracts that connect the nerve cell bodies or gray matter. Each axon that traverses

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the brain and comprises part of the white matter is an extension a nerve cell, the body of which is in the gray matter. Consequently it is often difficult to speak of a pure white matter disorder, because the cell bodies which white matter are extensions may also be dysfunctional when their axons or the myelin that covers the axons is dysfunctional. The major white matter tracts are those that connect and transmit sensory motor information, commissure fibers that connect the two cerebral hemispheres, and short long association fibers that connect portions of the cerebral hemispheres. The most common disease white matter is multiple sclerosis. Multiple sclerosis an inflammatory disorder of the myelin sheaths that causes waxing and waning sensory motor symp toms. Associated with multiple sclerosis (MS) are frequent mood and cognitive changes (Klonoff et al., 1990; Nyenhuis et al., 1995; Sadovnick et al., 1996). As one would expect from a disorder that affects pathways, almost half of which connect with the frontal lobes, cognitive changes are primarily in the area of poor concentration and inattention with consequent secondary problems in memory and learning. These cognitive changes are similar to those demonstrated by Parkinson's and Huntington's disease patients. They represent changes more in the efficiency of mental functioning than actual loss function (Caine et al., 1986). There is little loss of language function in MS. Depression and lability of affect are common in MS. Patients also have significant elevations cortisol and CRF, just as has been noted in depressed patients who do not have MS (Fassbinder et al., 1998). The cognitive symptoms of white matter, frontal, and subcortical dementias can be very similar.

Depression in Dementia

Demented patients often appear to be depressed. Depressed patients can also appear to be demented. Confusion, psychomotor retardation, and general apathy are commonly observed in depressed patients. These symptoms often connote brain damage, but clinicians have been reluctant to regard them as symptoms of brain dysfunction because they are reversible. With the increasing use of neuropsychological tests in psychiatry, however, it has become clear that most psychiatric syndromes, particularly schizophrenia and affective disorders, have manifestations that are characteristic of neurological impairment. To explain these reversible symptoms of dementia in psychiatric patients, the term pseudodementia has been used. (McAllister, 1983). There are no validated diagnostic criteria for pseudo-dementia, but Caine (1981) has stipulated the following characteristics: (1) A patient with a primary psychiatric diagnosis is intellectually impaired. (2) The features resemble, at least in part, a clear cognitive deficit. (3) The intellectual disorder is reversible. (4) The patient does not appear to have any significant neuropathology. Some have added various other discriminating

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features such as: the patient often acts as a caricature of demented patient and frequently answers, “I don't know,” to many of the questions that one would think he should be able to answer (Wells, 1979). Also, the EEG is usually normal in pseudodementia. Neuropsychologists can help to differentiate dementia from depression (Lezak, 1995).

The cognitive symptoms associated with depression may be a bad prognostic sign both for the future development of dementia and the irreversibility the cognitive symptoms noted during the depression (Emery and Oxman, 1992; Alexopoulus et al., 1993). The often high levels of cortisol secretion in depressive disorders suggest a possible pathophysiologic mechanism (Nelson and Davis, 1997); in animals, prolonged elevated glucocorticoid secretion causes hippocampal damage. Thus, the prolonged stress of a depressive illness with its concomitant stimulation of glucocorticoids could lead to some the cognitive changes associated with the illness. Another possible mechanism is suggested by animal studies showing that stress can increase dopaminergic (D1) activity in the premotor frontal cortex and also affect cognitive function (Arnsten Goldman-Rakic, 1998). Methylphenidate is an underused remedy for the negative symptoms: inactivity, social withdrawal, inattentiveness, daytime somnolence, and loss of initiative depression with dementia (Galynker et al., 1997).

Neuropsychological Testing

When dementia is moderate or severe, neuropsychological testing usually serves to confirm the physician's clinical impression, but in cases of mild or minimal dementia, psychological tests can provide clinical information that is not readily apparent to a careful interviewer (Lezak, 1995; Chen et al., 2000). Neuropsychological testing can give information about the localization of a lesion and, when repeated at intervals, can provide precise information as to the progression or regression of a disease process. This can be quite useful for treatment planning (Report Academy of Neurology, 1996). It is not easy to differentiate depression in the elderly from Alzheimer's or other dementias by neuropsychological tests. The response of deficits to successful antidepressant treatment is the only certain way (Robbins et al., 1996).

Cognitive Syndromes in Childhood

Children have a different response to brain damage than adults, especially at an early age. Lateralization and dominance with regard to speech, reading, writing, and praxis are not fully established until several years after birth. After early unilateral injury to either hemisphere, these functions become established on the

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healthy side and surgical removal of the damaged tissue produces no further deficit. Thus, unilateral brain damage in children is less likely to cause permanent loss of speech or the other lateralized functions. Large unilateral injuries in infants, however, tend to produce a more widespread deficit in intellectual abilities than do similar injuries in adults. It is not clear why this is so. The older a child at the time of injury, the more likely he is to suffer impairment resembling that of an adult with a similar lesion. The classical cortical dysfunctions that may result from single lesions in adults are seen only young children who have sustained bilateral cortical damage because these functions not yet become lateralized. These dysfunctions include dyscalculia, right-left confusion, finger agnosia, constructional apraxia (Hansen, 1963), and aphasia (Landau et al., 1960).

In infancy there is an exuberant development of synaptic connections that peaks around age two. This probably underlies the greater reorganizational capacity of the immature brain to recover functionally after focal injury.

Early Childhood Autism

Disorders of speech are the hallmark early childhood autism, a behavioral syndrome first described by Kanner (1957) and often in the past mislabeled “childhood schizophrenia.” The diagnostic criteria for schizophrenia in children are the same as criteria for adult schizophrenia, with emphasis on hallucinations and delusions. In children schizophrenia is referred to as early-onset schizophrenia. DSM-IV has placed autism within a group of disorders that represent serious developmental problems, called pervasive developmental disorders (PDD); all the disorders involve severe social and communicative impairments and often stereotyped behaviors, interests, and activities.

Although almost all the pervasive developmental disorders entail impaired speech functions, one does not. Asperger's syndrome can include all the symptoms of autism but without the speech delays or mental retardation. Another PDD is disintegrative disorder (Heller's syndrome), development is normal from between 2 and 10 years but then the child undergoes a severe regression and develops autism. All of this suggests a spectrum of autistic conditions rather than a single entity. Autism still remains the most common PDD. Using DSM-IV diagnostic criteria for autism, its prevalence is approximately 1 per 1000 (Rapin, 1997).

The syndrome of autism includes speechlessness and an inability to make meaningful patterns out of auditory or visual stimuli. Typically, it begins in the first few years of life. Characteristically, feeding difficulties and excessive screaming mark the first year of life. Motor developmental milestones are usually somewhat delayed but within the normal range. Social withdrawal, odd behavior, and peculiar affect are usually quite noticeable by the second or third year of

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life. Autistic children have a marked inability to form human relationships and give a sharp impression of extreme solitariness. The severity these symptoms varies, and those children who develop speech by 5 years of age have a fair chance of achieving independence in later life. Nearly all those who do not speak by this age require permanent care. Autism is often seen in children who also show strong evidence of neurological abnormality; it may be associated with phenylketonuria, tuberous sclerosis, and infantile spasms during the first year of life. Many autistic children have multiple cognitive deficits and perhaps half have electroencephalographic abnormalities or a history of seizures both (Rutter, 1966; Rapin, 1998).

About the only feature that childhood autism shares with schizophrenia is the term “autism,” itself one of Bleuler's fundamental symptoms. Otherwise, the two conditions are very different in age of onset, symptomatology, sex distribution (1:1 schizophrenia; 4 boys: 1 girl in childhood autism, PDD, Asperger's), and the social and intellectual status of the patient's family (high in autism tending toward low in schizophrenia) (Kolvin et al., 1971). The only autistic syndrome that is more common in girls Rett's disorder (stereotyped hand movements, poor coordination, language delay, social isolation, onset 6-48 months after normal development).

The prevalence rate of autism is 4 per 10,000 population. Only 9.7 percent of 207 families with one autistic child had more than (Ritvo et al., 1989). There is no increase in the prevalence of schizophrenia families autistic children, though anxiety and depression are more prevalent than in the general population.

The bulk of evidence seems to suggest that autism is not a disease entity itself but rather a behavioral syndrome of childhood that can result from many different disorders of the central nervous system that cause bilateral dysfunction and defective speech. In these terms, it is not difficult to understand why autistic children often have varying deficits in comprehension, symbolic thinking, and the formation of abstract concepts that reflect varying degrees central nervous system dysfunction and the diseases that cause it. This could easily explain why the pattern of cognitive functioning is often uneven, with “islets intelligence.”

One strange aspect of autism is the occasional appearance an isolated, unusual, and highly developed skill in an autistic child. Such is the case of the idiot-savant, who can tell on what day of the week any date will fall, though he is otherwise incapable of doing simple arithmetic and generally functions at a grossly retarded level. Similarly isolated and abnormally developed skills relating to music, memory, factual knowledge of history or science, ability read have been described in children who lack any developmental delay but have features of autism: eccentric, mirthless, flat personalities, unable to adapt socially. This is Asperger's syndrome. The abilities demonstrated are especially striking because they contrast so vividly with the individuals' low social capabilities.

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Recent studies have shown that approximately 75 percent of the patients with autism are mentally retarded. By adulthood at least one-third of those with autism will have at least two unprovoked seizures (Rapin, 1997).

Little is known about the etiology of autism though there seems to be a very high concordance in monozygotic twins (90%), but only 5–10% concordance dizygotic twins (Bailey et al., 1995). The cerebellar cortex, the parietal lobes, and the corpus callosum have been implicated in a number of studies using MRI but not confirmed in others (Courchesne et al., 1988; Garber et al., 1989; Egaas et al., 1995; Hendrew et al., 1997; Piven et al., 1997). The neuropathologic studies of the brains of autistic children also point to the cerebellum, describing a paucity Purkinje and granular cells. The brains also tend to be larger (Rapin, 1997).

The identification of the cerebellum as site abnormality in autism, about as clear a disorder of cerebral gray matter as exists (seizures and cognitive deficits), reveals much about the deficiency of the investigative tools available to us. The light microscope and MRI miss the neuropil, site of synapses. We have no information about the number and quality of synapses in autism and we have every right to expect that they are abnormal. The cerebellum has no cognitive role, or a very minor one (Fiez, 1996). It is difficult to believe that it is truly the source of the behavioral abnormalities autism presents.

There is a little evidence that disturbed serotonin metabolism may play a role in autism. Increased levels of whole-blood and platelet serotonin as well increased serotonin transporter levels have been reported (Marazziti et al., 2000). Tryptophan depletion and the use of agents that block serotonin uptake seem to improve many of the symptoms autism (Longhurst et al., 1997); however, these effects may be related to nonspecific actions of medication rather than indicating a causal role for serotonin. These disparate findings would suggest that autism results from some generalized developmental process that affects information processing and language function. Some cases may have genetic determinants, others may be acquired, the result perhaps of prenatal influences that cannot be identified.

Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is the latest name to be applied to this condition; other terms have been minimal brain damage (MBD), attentiondeficit disorder (ADD), hyperkinetic syndrome, and hyperkinesis. In part the names keep changing because the classification changes, and in part because theories about etiology change. Minimal brain damage was dropped because the relation to brain damage was unclear, although the World Health Organization (ICD-10) retains the diagnostic requirement of a history perinatal or traumatic neonatal events. DSM-IV requires that the symptoms must appear before age of 7 years and that the impairments must be significant in two or more

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settings (e.g., home and school). The symptoms must be present for at least 6 months. They are divided into two categories. The first isinattention: the subject fails to give close attention details (makes careless mistakes); has difficulty sustaining attention; does not seem to listen when spoken directly; does follow through; has organizational difficulties; avoids or dislikes tasks requiring attention; often loses things; is easily distracted; or forgetful (six more of the above symptoms are necessary). The second type is hyperactivity-impulsivity symptoms: fidgets and squirms; often unexpectedly leaves his seat; runs and climbs excessively; has trouble playing quietly; is constantly “on the go”; blurts out answers before questions are completed; has trouble awaiting turn; often interrupts and intrudes (six or more of the above symptoms are necessary). This division leads to three types of ADHD, an inattentive type, a hyperactive-impulsive type and a mixed type. Using the criteria in DSM-IV, prevalence in this country runs approximately 3%-5% (3:1 greater in males), which is much higher than the prevalence in Europe (Arnold and Jensen, 1995). As diagnostic criteria have become clearer, it has also become evident there are significant comorbid conditions; 25%–30% of children with ADHD have learning disabilities; conduct and/or oppositional disorder, mood, anxiety disorders, or Tourette's syndrome. There is also increasing evidence that ADHD persists into adolescence (50%-80%) and adulthood (30%-50%) with significant psychiatric comorbidity of substance abuse, antisocial personality, mood and anxiety disorders (Zametkin, 1995;Murphy and Barkley, 1996; McCann and Roy-Byrne, 2000; Pliszka, 2000). The diagnosis of comorbid conditions is essential to effective treatment.

Many neurological conditions such as head trauma, seizures, and infection can manifest symptoms similar to ADHD (Zametkin and Ernst, 1999). Most children with ADHD show no signs of major neurological deficit, but many have minor signs. These include clumsiness; impaired succession movements; excessive synkinesis; motor impersistence; mild involuntary movements of a choreiform nature; inability to perform tandem gait, stand on either foot, hop, or in children more than 7 years of age, to skip. Stereognosis, graphesthesia, and two-point discrimination may also be impaired.

Other forms of childhood psychopathology can be mistaken for ADHD (Zametkin and Ernst, 1999). Depression, especially in the agitated form, could interfere with attentiveness and cause a child to be moody, irritable, hostile, overactive, unable to concentrate at home or school, and contribute awkward socialization. Such a child could be forgetful and distractible. Mania expressed at age 6 could also produce the picture of a driven, hyperactive child, with poor concentration and easily distracted, who says does unwelcome things. Obessive-compulsive disorder and other anxiety disorders (see pp. 203–205, 231–232) often cause poor concentration (Spencer et al., 1998), as may schizophrenia.

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It is clear that the diagnosis of ADHD requires a careful evaluation. Many questions have been raised about the over diagnosis of this condition in both children and adults. This is based on the increased prescriptions for stimulants (Klein, 1995; Safer et al., 1996). Whether this represents an increasing awareness of the condition or an overuse of medication is still not clear (Elia et al., 1999; Zametkin and Ernst, 1999). This increased awareness is also apparent in the general population and it is a frequent self-diagnosis that brings parents and adults to consult physicians. Careful monitoring of the effectiveness medication can help in diagnosis, as in the correctly diagnosed patient the results of treatment are often dramatic (Elia et al., 1999).

Significant evidence has accumulated to show that there is a genetic element in some cases of ADHD. The relative risk for ADHD in the relatives patients is 2%–10%. Although estimates from twin studies demonstrate that there is an 80 percent heritability of ADHD (Farone et al., 1998, 1999). There is some data to indicate familial subtypes where Attention-deficit hyperactivity disorder is comorbid with bipolar disorder and in others there comorbidity with antisocial behavior (Farone et al., 1998). Molecular genetic studies have begun to focus on polymorphisms of the dopamine transporter gene (which inactivates dopamine) in ADHD patients (McCraken et al., 2000).

Magnetic resonance imaging studies of ADHD have found changes in the caudate, the corpus callosum, and the cerebellar regions; leading to postulations of a subcortical-cerebello-thalamo-premotor frontal circuit causing the motor and executive deficits noted in ADHD (Matochik et al., 1994; Baumgardner et al., 1996; Castellanos et al., 1996; Filipek et al., 1997; Mataro et al., 1997; Berquin et al., 1998). Functional imaging studies of ADHD have indicated frontal and striatal dysfunction (Zametkin et al., 1990; Ernst et al., 1994; Lou et al., 1998;Gustafsson et al., 2000; Krause et al., 2000).

Treatment

Over the years stimulants, dextroamphetamine and methylphenidate, have become the standard treatment, each achieving efficacy rates of 70 percent for the symptoms of ADHD (Elia et al., 1999; Vitiello et al., 2001). In children with ADHD these drugs do not cause euphoria and rarely cause addiction. Transient tics have been noted with their use. Desipramine, imipramine, and bupropion have been tried, but the therapeutic effect was not sustained in long-term use (Biederman et al., 1989; Singer et al., 1995; Connors et al., 1996). The anticholinergic and cardiac effects of the TCAs limit their use in children. Sudden deaths have been reported with the use of TCAs, and they should be considered only if the stimulants do not work (Elia et al., 1999). Clonidine has also been found to be effective in ADHD (Elia et al., 1999). Psychoeducational efforts, behavior modification and social skills training are important components of the treatment ADHD (Zametkin and Ernst, 1999).

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Attention-deficit hyperactivity disorder in adults

Adult ADHD has received much attention in the media and it has become a popular self-diagnosis. One study (Roy-Byrne et al., 1997) of 143 adult patients referred to a specialty clinic for evaluation of ADHD found that only 32 percent met the diagnostic criteria, although another 36 percent had some ADHD symptoms without meeting the diagnostic criteria. The patients who did not meet the diagnostic criteria for adult ADHD usually had no documented history of childhood ADHD and often had severe comorbid substance abuse disorder (Biederman et al., 1995; Roy-Byrne et. al., 1997; Mannuzza and Klein, 2000). Mannuzza et al. (1991) followed up 91 white males with a childhood diagnosis of ADHD at a mean age of 25 years and found that although 30%–50% continued to have some symptoms, only approximately 10 percent had clinical symptoms that interfered with their ability to function. Comorbid substance abuse is a significant factor in the cause of adult ADHD (Biederman et al., 1993; Murphy and Barkely, 1996). Although there are many fewer controlled studies of the treatment adult ADHD, the same drugs as used for children, seem effective in adults (Cox et al., 2001; Wilens et al., 2001).

Conclusion

In this chapter we discuss what appear to be a diverse group of disorders. But what defines them primarily is that they all represent disturbances of cognition. Certainly any disturbance of the brain will cause cognitive changes. Seizure disorders manifest cognitive changes; in fact the postictal state is an excellent example of delirium, but seizure disorders are episodic disturbances brain function and the cognitive changes are usually transient not the prominent clinical features. Depression can have cognitive changes but what defines a depression is the alteration of mood. Schizophrenia also shows cognitive disturbances but again this is not the defining diagnostic characteristic. The disorders discussed in this chapter, e.g., Alzheimer's disease, delirium, autism, etc. have distinct natural histories but they all have as their most prominent characteristic a disturbance of cognition, e.g., difficulties in orientation, attending to stimuli, executive functions, etc.

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