Behavioral & Cognitive Disorders
Dementia associated with amyotrophic lateral sclerosis
Aug. 11, 2023
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Unilateral spatial neglect, or “neglect” for short, commonly follows the acute onset of focal hemispheric brain disease, but may also appear in progressive cerebral degeneration. It involves a directional bias of spatial attention that is usually toward the side of brain injury, thus neglect for the opposite side of space, including that side of one’s body. This article indicates that neglect is distinct from other hemibody deficits of movement (hemiparesis) or perception (hemianopia, hemianesthesia) because the spatial deficit can be overcome by cuing or increasing motivation, such as through reward. Nonetheless, the disorder commonly signifies a profound impairment in recovery of self-care abilities. Efficacious treatment has not yet been developed.
• Neglect is a common consequence of focal brain injury.
• Neglect is easily assessed with bedside evaluations.
• Neglect commonly predicts impaired recovery of self-care after brain injury, although it is not yet clear whether functional impairment is primarily from neglect itself or from other, concurrent cognitive deficits.
• Neglect tends to improve in most persons following acute brain injury, but chronically can remain in a small proportion of patients.
• No standard of rehabilitation care has thus far been developed for neglect.
Neglect appears to have not received the same scrutiny in the 19th century as the aphasias, agnosias, and apraxias. Late 19th century experiments in laboratory mammals induced asymmetric behavior that could not be accounted for by hemiblindness or hemiparesis (15; 56; 144). In the 1880s, Loeb obtained asymmetric responses to bilateral simultaneous stimulation (extinction) in animals, which was quickly confirmed in humans by Oppenheim (Benton 1956). In 1865, Prevost reported that Vulpian had found contralesional conjugate eye deviation following brain injury in humans (69), which if not precisely neglect, is closely related. Jackson reported a British patient whose right hemisphere tumor was associated with a right-to-left reading approach to an eye chart, which the patient could not explain (92). In the early part of the 20th century, Zingerle described neglect as a disorder of spatial representations (232). Poppelreuter, and then Brain, emphasized the role of spatial attention in the underlying deficit in neglect (151; 25). In the 1950s, Denny-Brown introduced the notion of "amorphosynthesis," meaning that patients with neglect were unable to synthesize contralateral stimuli into coherent percepts (51). Systematic theoretical approaches to neglect emerged in the 1970s.
• Unilateral spatial neglect, or simply neglect—the reduced awareness of space to 1 side or activity toward that spatial area—commonly follows acute unilateral brain injury.
• Neglect applies to one’s own body, the spatial area within one’s arm reach, or areas beyond reach.
• Neglect can occur in the 3 dimensions of space centered about the patient.
• Patients often are unaware of their neglect, and even when they are aware, commonly lack the ability to overcome the deficit.
Although patients with acquired brain lesions may often be generally inattentive, the term “neglect” is used to describe inattention that is primarily in 1 spatial direction. In the most severe instances, patients with neglect act as though entire regions of space have vanished from existence. They do not orient toward, respond to, or act on meaningful stimuli in 1 direction, usually contralateral to the side of brain injury (84). These patients are often lethargic in the first few days after brain damage and lie in bed with their head and eyes deviated ipsilaterally (Vulpian sign) (143). They may eat food only on ipsilateral parts of their plate. Despite being able to hear sound emanating from contralateral space, they may search only ipsilaterally for its source.
Often unilateral neglect as much involves over-attention to ipsilateral space as under-attention to contralateral space. The removal of prominent objects from ipsilateral space (even when performed by the patient) results in improved exploration of contralateral space (123; 178). When navigating with a wheelchair, patients with unilateral neglect may pay extra attention to ipsilateral obstacles, such that when traversing narrow passageways, they may “cross over” their activities toward the neglected side, thus demonstrating a paradoxical relationship with their surroundings that is not found under other circumstances (155; 202).
In addition, unilateral neglect commonly occurs with nonlateralized inattention (nonspatial attention deficit). Such deficits include reduced alertness and difficulty with maintaining attention to a particular task (187). This was shown by the lag when reacting to the appearance of a central visible symbol on a computer screen, incorrectly counting the number of auditory tones. Such deficits can also occur in the absence of unilateral neglect, thus reflecting general effects of brain damage.
A frequent finding in neglect is the mislocalization of stimuli that are presented on the neglected side of space, but that are reported or demonstrated by the patient to be on the opposite side (129). This phenomenon is termed allochiria (Greek for “other hand”). Allochiria may be seen on copying tasks (76), as well as with unilateral tactile, auditory, or olfactory stimuli (12; 129; 203).
In the early stages, patients may also neglect parts of their own bodies (personal neglect) and deny ownership of their contralateral limbs (somatoparaphrenia). Patients may fail to groom the contralateral side of the body and not comb part of their scalp or shave part of the face. Asymmetries of stance and gait after stroke have been correlated with concurrent spatial neglect (65). Despite being functionally devastated, as well as frequently having accompanying motor and sensory deficits, these patients often appear unaware of or peculiarly unconcerned about their condition; the lack of awareness is called anosognosia, and a lack of concern is called anosodiaphoria. An easily demonstrated finding in acute severe neglect is “one-handed clapping,” which occurs when the hemiplegic neglect patient is asked to clap hands together, but only brings the less-affected hand toward the body’s midline repeatedly, thus showing both neglect for the opposite hemibody as well as anosognosia for hemiplegia (140). Many patients with anosognosia for hemiplegia also have personal neglect for the same side (47). Personal neglect and extrapersonal neglect are not strictly associated with each other (19). Generally, personal neglect appears concurrently with severe extrapersonal neglect, although it is not unusual for extrapersonal neglect to occur without personal neglect (111).
It is surprising that some patients can acknowledge their neglect but they fail to improve on it (28; 87).
The laterality of neglected stimuli may depend on the kinds of stimuli that are presented. In 1 case study, a patient with an intracerebral hemorrhage neglected right-sided stimuli when he marked nonverbal designs but showed primarily left neglect when reading aloud single words (45). These findings suggest that the spatial attributes of visual stimuli may not be processed all in the same manner, at least in persons who have neglect. In the chronic stages, some patients with neglect may hyperorient toward contralateral space and thus actually manifest ipsilateral neglect (106; 01); however, this phenomenon is specific to line bisection. In a case of acute focal parenchymal hemorrhage, ipsilateral neglect was discovered at 2 weeks into the illness, as reflected by neglect of ipsilateral double simultaneous visual stimuli and a contralateral deviation of the gaze (221). Concurrent brain imaging did not identify a new lesion. Such a case suggests that the regulation of directional spatial attention may not exclusively involve contralateral direction of attention at the level of the cerebral hemisphere.
Even healthy persons may have significant, albeit small, directional biases during certain tests (94), a phenomenon called “pseudoneglect.” This does not appear to affect everyday activities. In addition, persons with acute brain injury that results primarily in hemianopic visual field loss and minimal other disturbance tend to strongly err toward their hemianopic fields during line bisection tests (100). The error is unrelated to the extent of the visual field loss, thus leaving unexplained its precise mechanism (179). The clinical use of the term “neglect,” however, is intended for the pathologic (ie, extreme) occurrence of directional spatial bias, usually when accompanied by several specific nonlateralized cognitive disturbances (eg, generalized inattention, poor initiation of activity, anosognosia, emotional flattening). Because patients with acute, nonprogressive cerebral disease often recover, it is not surprising that their neglect may reduce. Hence, the initially dramatic presentation of neglect often yields to an intermittent, milder disorder that, in some cases, may not be recognized except through specialized testing (77).
Although neglect is more commonly recognized along the horizontal (left-right) axis, it also occurs along the altitudinal (up-down) and radial (near-far) axes. Patients, often with bilateral lesions, may neglect either upper or lower space, as well as either near or far peripersonal space (157; 181; 131). Finally, neglect may appear in 2 dimensions simultaneously, resulting in a “diagonal” skewing of inattention, such as toward the near-left parts of space (121; 122).
Objects in space are anchored to different reference frames. These frames are generally divided by researchers into viewer-centered, object-centered, and environment-centered coordinate systems. Viewer-centered frames refer to the location of stimuli in relation to the viewer: left-right, near-far, or above-below. These coordinates change with movement of the viewer. Environment-centered reference frames refer to an object's relationship to the environment, structured by geographic and gravitational coordinates. Object-centered coordinates refer to an object's intrinsic spatial coordinates of an object. Object-centered reference frames remain stable irrespective of movements of the viewer or object. Neglect may occur in any of these reference frames (107; 30; 54; 33; 130; 53).
Across as well as within patients, the severity of neglect and pattern of recovery can be highly variable (77). Clinically, neglect has been assessed primarily following stroke. Hier and colleagues found that after right hemisphere stroke, visual inattention and neglect recovered much more quickly (median 8 to 9 weeks) than hemianopia (median 32 weeks) or hemiparesis (median 64 weeks). More subtle symptoms associated with neglect, such as extinction (median 19 weeks) and motor impersistence (median 26 weeks), lasted longer (86). Recovery was related to size of lesion, and hemorrhagic strokes recovered more quickly than ischemic strokes. Neglect severity and its recovery are also adversely affected by premorbid cortical atrophy, suggesting that the integrity of undamaged structures plays a role in the recovery from neglect (110). Unfortunately, studies that have evaluated neglect and its recovery have not used consistent methods, subject recruitment, criteria for neglect, or intervals between stroke onset and assessment. Consequently, definitive conclusions concerning the frequency, severity, and recovery from neglect are not available (24). Some studies suggest that the prevalence of neglect following acute stroke markedly reduces to about one third of its incidence by the end of the first year (163; 138). At 7 years, the number declines to about 10%. It is interesting that the patients with chronic neglect at 7 years also had significantly slowed target marking on cancellation tests (described under Diagnostic workup section) in the acute phase (67). The individual’s recovery course from neglect, however, can be inconsistent, showing marked fluctuations over time (93). This suggests that measuring neglect may be influenced by complex factors that change over time.
A lawful relationship has been found for neglect; the severity of neglect at 6 months after stroke is proportional to the initial severity of neglect, based on the cancellation test (226). Generally, the sixth-month severity of neglect is 70% of the initial severity. This relationship, which was found in other post-stroke deficits as well, suggests a biological limit to recovery, at least following usual care. However, this rule does not pertain to the most severe presentations of neglect.
Despite substantial reduction in the prevalence of neglect during stroke recovery, acute neglect is associated with longer hospitalizations and poorer recovery to functional independence in chronic stroke patients (50; 104; 191; 95; 38; 142; 27; 66). Following stroke, patients with neglect are more likely to have spasticity of their paretic limbs than patients without neglect (223). Neglect patients are prone to accidents resulting from collisions on their neglected side (200; 156). Recovery of arm motor function appears to be significantly affected by neglect (105). Neglect severity predicts the extent to which chronic stroke patients are homebound (139). However, other authors suggest that anosognosia, rather than neglect per se, is more often associated with poor functional recovery (145). In addition, the functional correlates of generalized inattention, which commonly accompanies neglect, have been little investigated (170). In 1 study of high-functioning acute stroke patients, a continuous performance test of attention was about as likely as a cancellation test of neglect to predict disability; the nonspatial attentional deficit was more common than neglect (08). Another study, however, found only that the occurrence of neglected targets on the ipsilateral side on a challenging cancellation test predicted disability after acute stroke, unlike contralateral neglect; this suggested that a general degree of inattention rather than unilateral neglect per se was more associated with self-care ability (21). However, these findings were not supported in a later, larger study that used a simpler cancellation test (213). Hence, there is no consensus concerning the relative strength of unilateral neglect versus nonlateralized inattention with regard to functional recovery after stroke at this time.
In addition, the prevailing view that spatial neglect is a leading correlate of poor functional recovery may be an artifact of clinical investigation, due to the ease of assessing neglect compared to other cognitive disorders. Consequently, neglect assessment has been favored over all other cognitive assessments in functional outcomes research after stroke (120). It is also worth noting that chronic unilateral spatial neglect in elderly stroke patients has been associated with previous stroke and deficits in multiple cognitive domains (112). Thus, neglect may be a nonspecific marker for extensive cerebral injury, which may help to indicate its predictive value for impaired functional recovery. The common association between unilateral neglect and nonlateralized attentional disturbances supports this notion (133).
Primate studies implicate interhemispheric and intrahemispheric mechanisms in recovery. Monkeys with neglect from frontal ablations have more severe neglect if the corpus callosum is divided (46; 217), suggesting that compensatory mechanisms are mediated through the contralateral hemisphere. However, the rate of recovery after callosal division remains relatively unchanged, implicating intrahemispheric factors in recovery (217). Consistent with these findings, recovery of severe left-sided neglect in humans is associated with remission of metabolic abnormalities in the left and undamaged right hemisphere on PET studies (146).
A 65-year-old man with left-sided weakness was brought to the hospital by his family. For the first 2 days of his hospitalization he was lethargic but arousable. He lay in bed at an angle, and his eyes and head deviated to the right. As his level of arousal improved, he only shaved on the right side of his face and combed his hair on the right. When approached and talked to from his left, he oriented to the right when replying. At meals, he sometimes neglected the left side of his food tray. Food often collected in the left side of his mouth. The patient seemed unaware of his deficits, but he also seemed unconcerned about being in the hospital. He admitted to being weak but denied any specific left-sided weakness. He omitted left-sided targets on cancellation tasks and neglected left-sided details in copying tasks and in spontaneous drawings, neuroimaging studies revealed a large stroke in the distribution of the right middle cerebral artery.
In the subsequent weeks, he verbally acknowledged his left-sided weakness but had limited insight into the practical limitations imposed by his deficits. Physical therapists observed that he fatigued easily and seemed unmotivated during therapy sessions.
Asymmetries in spatial bias are undoubtedly phylogenetically ancient, even without neurologic disease. Lungfish, a species transitional between fish and amphibians, shows a consistent turning to the left with simulated predator approach and rightward turning during foraging (113). Similarly, humans misplace line bisections to a small but significant degree to the left of center, which is called pseudoneglect and suggests primarily right hemisphere recruitment for such tasks (94). Focal brain disease thus can aggravate natural spatial biases to a point that they are disabling.
Neglect is most often caused by stroke, tumor, or trauma. The etiopathogenesis of neglect involves sensory attentional, premotor intentional, and representational mechanisms.
Sensory attentional theories. These theories try to explain why patients with neglect are selectively aware of rightward stimuli and why neglect is more common and severe after right than left brain damage. Kinsbourne postulated that each hemisphere generates a vector of spatial attention directed toward contralateral space, and this attentional vector is inhibited by the opposite hemisphere (102). Support for this interhemispheric balance hypothesis came from applying of transcranial magnetic stimulation to the posterior parietal cortex in healthy individuals (48). Unilateral stimulation abolished the detection of contralateral visual signals, regardless of which hemisphere was stimulated, whereas bilateral simultaneous transcranial magnetic stimulation to the parietal cortices did not lead to inattention to visual signals. Research on experimental neglect in cats suggests that the interhemispheric imbalance may be related to differential metabolic activity between the superior colliculi, which has been termed the Sprague effect (174). Additional support comes from fMRI examination in recovery from acute left neglect following right hemisphere lesion, which indicates relatively increased left hemisphere activity that gradually subsides as neglect improves (42). The left hemisphere's vector of spatial attention is powerfully directed, whereas the right hemisphere only produces a weak vector. As a consequence of this neural organization of spatially directed attention, after right brain damage, the left hemisphere's unfettered vector of attention is powerfully oriented to the right. Because the right hemisphere's intrinsic vector of attention is only weakly directed, after left brain damage, there is not a similar orientation bias to the left. Thus, right-sided neglect is less common and not as severe as left-sided neglect.
In contrast to Kinsbourne, Heilman and colleagues proposed that the right hemisphere is dominant for arousal and spatial attention (82). Patients with right brain damage have greater electroencephalographic slowing than those with left brain damage. They also demonstrated diminished galvanic skin responses, compared to normal control subjects or patients with left hemisphere damage (80). According to this model, the right hemisphere is capable of directing attention into both hemispaces, whereas the left hemisphere directs attention only into contralateral space. Thus, after right brain damage, the left hemisphere is ill-equipped to direct attention into left hemispace. The more severe the neglect after right hemisphere damage, the more slowed the responses are to visual stimuli, even on the right side of space (11). After left brain damage, however, the right is capable of directing attention into both hemispaces, and neglect does not occur with the same severity as after right brain damage.
Posner and colleagues proposed that spatially directed attention involves elementary operations, such as "engage," "disengage," and "shift" (152). They reported that patients with right parietal damage are selectively impaired at disengaging attention from right-sided stimuli to shift toward and engage left-sided stimuli (154); this may account for some symptoms in neglect. However, some research suggests that voluntary exploration to the left may be intact in left neglect patients, as long as they can attend to closely spaced visual stimuli (117). Instead, the impairment may result from overactive automatic engagement of right-sided stimuli.
Motor intentional theories. Watson and colleagues advanced the idea that neglect patients may have a motor intentional deficit, a disinclination to initiate movements or move toward or into contralateral hemispace (215). Similarly, Rizzolatti and colleagues emphasized that the facilitation of perception by attentional mechanisms is a consequence of activation of circuits responsible for motor preparation (164). In most situations, attention and intention are inextricably linked, because attention is usually directed to objects on which one acts. To dissect intentional from attentional factors, however, Coslett and colleagues had patients bisect lines in right and left hemispace (44). Visual feedback for the task was restricted to a video monitor placed in either right or left hemispace. Thus, by dissociating the locus of attention (location of the monitor) from the locus of intention (location of their movements), they demonstrated that some patients' errors were primarily influenced by the intentional, rather than attentional, demands of the task. Bisiach and colleagues used a set of pulleys to dissociate the direction wherein attention and intention were moved in a line bisection task, and also confirmed the intentional influences on the deficits in some patients (17). Intentional neglect tends to be associated with frontal lesions; however, Mattingley and colleagues reported that slowness in the initiation of leftward movements is associated with right posterior lesions, whereas slowness in the execution of leftward movements is associated with right anterior and subcortical lesions (127).
Representational theories. Representational theories propose that the inability to form adequate contralateral mental representations of space underlies the behavioral deficits in neglect (16). Bisiach and Luzzatti asked 2 patients to imagine the Piazza del Duomo in Milan, Italy, from 2 perspectives: looking into the square toward the cathedral and looking from the cathedral door into the square (18). The patients only reported structures to the right of their imaginal space, resulting (in both conditions) in the reporting of different structures. Rapid eye movements in sleeping neglect patients are also restricted ipsilaterally (52), raising the possibility that these patients' dreams are spatially restricted.
Cortical lesions. Neglect is more commonly associated with right than left hemisphere damage (61). The technique of lesion-symptom mapping in stroke patients has identified the following loci important to the manifestations of neglect: the inferior parietal lobule for perceptual aspects of neglect, the dorsolateral prefrontal cortex for the motor-exploratory aspects of neglect, and the deep temporal lobe for object-centered neglect (211). The cortical areas associated with neglect are supramodal or polymodal, areas into which unimodal association cortices project. This observation underscores the idea of neglect as a spatial disorder, not one of primary sensory processing (such as a visual field defect).
Subcortical lesions. Subcortical lesions in the thalamus, basal ganglia, and midbrain may also produce neglect. Neglect in humans is associated with decreased arousal (80). Interruptions of ascending monoaminergic or cholinergic projections may, in part, mediate this clinical observation. The thalamic extension of the reticular system (nucleus reticularis) is a thin shell of neurons encasing much of the thalamus. These neurons inhibit sensory thalamic relays to the cortex. Both ascending mesencephalic reticular systems and polymodal association cortices project to and inhibit the nucleus reticularis. Therefore, damage to these systems may result in a release of the inhibitory action of the nucleus reticularis on thalamic relay nuclei, with the resultant impairment of sensory processing (216). Damage to the pulvinar, having reciprocal connections with the posterior parietal lobule, may also produce neglect. Lesions of the basal ganglia, being tightly linked to prefrontal and cingulate cortices, may also produce neglect (85) and particularly are associated with a motor disturbance of neglect, directional hypokinesia (175).
Distributed neural networks. The clinical observations that lesions to disparate cortical and subcortical structures produce neglect led Heilman and colleagues to propose that an anatomically distributed network mediates spatially directed attention (81; 216; 83). The limbic connections to the anterior cingulate may provide an anatomic basis for the abnormal alerting (214) or poor motivation in neglect patients. Mesulam also proposed a similar model, and suggested that different regions within a large-scale network implement different aspects of an individual's interaction with the spatial environment (134), thus emphasizing the interconnectivity of the different brain regions associated with neglect. Support for this model was found by a tract-based spatial statistics imaging evaluation of patients with post-stroke neglect (116). In the subacute phase, neglect was associated primarily with reduced white matter integrity along the superior longitudinal fasciculus of the damaged hemisphere, which links intrahemispheric frontal and parietal cortical regions. In contrast, in the chronic phase, neglect was primarily associated with structural disruption of the posterior portion of the corpus callosum, which links interhemispheric posterior brain regions. Primate studies indicate that neurons within frontal and parietal cortices are selectively sensitive to stimuli encoded in distinct spatial reference frames (41).
Functional MRI has been used to evaluate the coherence of oxygen-dependent metabolic changes in disparate brain areas in response to particular attentional tasks. He and colleagues have postulated that neglect commonly results from disruption of 2 systems: a bihemispheric dorsal attentional network linking the dorsal parietal cortex with the ipsilateral frontal eye field, which is involved with allocating attention to contralateral visual targets; and a ventral attentional network that, in contrast, is in the right hemisphere and mediates attention to unexpected events from either side (79). This ventral system links the temporoparietal junction with ipsilateral ventral frontal cortex. Functional MRI research supports these metabolically linked systems. Neglect tends to result from lesions that overlap more the ventral than dorsal networks, even though functional connectivity within both systems may be acutely disrupted. However, He and colleagues found that in neglect patients the dorsal network tends to recover more than the ventral network. This account suggests why patients who have recovered from unilateral spatial neglect may nonetheless have impaired functional recovery long after stroke onset, owing perhaps to reduced recovery of the ventral attentional system (104).
Motor neglect. This term applies to the patient’s lack of initiating use of parts of the body contralateral to the brain lesion, specifically the limbs, unless cued to move (31). In contrast to the perceptual and intentional aspects of neglect, as of now no pathophysiological model for motor neglect has been developed (10).
Spatial neglect may follow focal brain injury on either side, but it is more commonly recognized following right hemisphere injury (163). However, within the first week of stroke onset, neglect has been found to occur with nearly equal frequency following right versus left hemisphere injury (192). Another study using a different method of assessment found reduced neglect incidence following left hemispheric stroke in the first week of onset, but with about the same severity as following right hemispheric stroke (194). Spatial neglect is most commonly associated with acute stroke; as many as two thirds of acute right hemisphere stroke patients may show neglect (143). Neglect after stroke is more common with older age, cortical rather than subcortical lesions, and larger lesions (163; 70). Neglect may occur in as many as 30% to 40% of patients with traumatic brain injury who are admitted for acute neurologic rehabilitation (128; 37); this disorder is commonly overlooked in this population. The disorder has also been identified in many persons with posterior cortical atrophy, an uncommon neurodegenerative disease of older age (04). Early in Parkinson disease, when motor symptoms are biased to 1 side, a modest amount of unilateral neglect has been found in patients with predominantly left motor deficits, unlike patients with right-sided motor deficits (212). Effects of such spatial bias on everyday activities in Parkinson disease have not so far been evaluated. Rare reports have also observed neglect in Alzheimer disease and Huntington disease, in association with asymmetric cerebral atrophy or metabolism (210; 88).
Individuals of any age may be affected by neglect following focal brain injury. Although uncommon, neglect has been reported in children as young as age 7 months (108; 23).
Spatial neglect most commonly follows acute focal unilateral brain injury and is, therefore, not specifically preventable.
Neglect needs to be differentiated from lateralized sensory deficits such as hemianopic visual field defects, hemisensory loss, or unilateral hearing loss. Such deficits may coexist with neglect but are neither necessary nor sufficient to produce neglect. Patients with hemianopias and without neglect who are evaluated on other assessments can successfully explore contralateral portions of space (91). Patients with a “pure” hemianopia who lack other evidence of contralesional hemispatial neglect may significantly err when bisecting horizontal lines, but the errors tend to be negligible. The error on horizontal lines toward the side of hemianopia may represent a substantial behavioral compensation to adapt to the loss of vision to 1 side (188). Tactile neglect may be differentiated from somatosensory loss by the improvement of awareness of stimuli in the former condition by explicitly requiring the patient to focus attention on the deficient side of the body (148). Neglect is also distinguished from integrative visual disorders such as visual agnosias, in that in the former, processing of the same stimulus varies along a spatial axis. In agnosias, recognition is not affected by the spatial location of the stimuli.
Similarly, neglect must be differentiated from unilateral weakness. “Motor neglect” is recognized when patients are disinclined to move their contralateral limbs spontaneously but improve when prompted (31). Often, depending on the social environment and motivation, hemiparetic stroke patients vary in the extent of spontaneous use of the more affected limb (05). Evidence indirectly supports the existence in humans of conditioned inhibition of limb use on the hemiparetic side (“learned nonuse”), in contrast to an unlearned mechanism that can be ascribed to spatial neglect (197). A possibly valid distinction between motor neglect and learned nonuse is that only patients with the latter disorder will complain of motor failure (124). It has also been suggested that because motor neglect is 1 form of acute attentional disorder, it should, in most instances, gradually improve, whereas learned nonuse, which becomes conditioned by unsuccessful movement attempts, should not ordinarily improve without the intervention of a specific rehabilitation program (197).
Numerous studies have drawn attention to “neglect-like phenomena” that are associated with acutely acquired unilateral limb pain, most often following trauma to the limb. This distinct disorder, termed complex regional pain syndrome (CRPS), has been associated with reduced spontaneous movement of the limb and increased effort to move the limb, independent of the occurrence or severity of the pain itself (62; 63; 60). Further research has found that persons with CRPS involving 1 limb can demonstrate unilateral neglect specifically for one’s own body (and not always with respect to the painful limb), but not for other aspects of the environment (160). If a subcategory of unilateral neglect, termed somatospatial inattention, were confirmed in CRPS, this could represent a form of pathological unilateral bodily neglect that somehow results as a reaction to injury located outside of the brain.
Disorders that commonly occur with unilateral neglect include hemiparesis (ie, deficit in voluntary limb movement unrelated to inattention) and hemianopia (lack of visual perception to 1 side that is not modified by attention). In addition, particularly in acute presentation, neglect often occurs with anosognosia for hemiparesis as well as the neglect itself, emotional aprosodia (diminished modulation of vocal tone in relation to emotion), and anosodiaphoria (diminished emotional reaction to one’s own impairment, while acknowledging it). In addition, patients with unilateral neglect generally also have nonspatial inattention (208). Among such deficits are reduced arousal and limited sustained attention, which can be assessed by the elevator tone counting task from the Test of Everyday Attention (169).
Several bedside tasks are used by neuropsychologists or other clinicians to detect neglect and assess its severity. These are simple enough for any clinician to perform.
Line bisection. Patients are asked to place a mark at the midpoint of lines (which are usually horizontal). The task is generally administered without restricting head or eye movements, and without time limitations. Patients with left-sided neglect typically place their mark to the right of the true midposition (177).
Cancellation. In cancellation tasks, sheets with arrays of targets are placed before patients. Patients are asked to place a mark on, or "cancel," each of the targets. Similar to line bisection tasks, cancellation tasks are usually administered without restricting head or eye movements and without time limitations. Patients with left-sided neglect cancel targets on the right side of arrays and neglect targets on the left (02).
Increasing the number of targets may uncover neglect not evident on arrays with fewer targets (35). Although there can be variation of neglect on repeated administration of a cancellation test, generally the test reliably discriminates between patients with mild and more severe neglect over repeated administrations (118).
The sensitivity of cancellation tasks may be increased by presenting arrays wherein targets are difficult to discriminate from distracter stimuli (158). In addition, requiring the patient to cognitively manipulate the stimuli can aggravate neglect, such as, for example, requiring cancellation only of multiples of a specific number (such as 5) in an array of diverse numerals (132). Thus, the most sensitive cancellation tasks would contain a large number of stimuli (greater than 50), with distracters that are difficult to discriminate embedded in the array, and require identifying targets based on mental manipulations. However, the clinician can provide a simple cancellation test by drawing a patternless array of 20 lines 2 cm long, oriented in different directions across a sheet of hospital chart paper. The omission of 2 or more lines to 1 side will identify neglect in the more severe instances.
Although unilateral spatial neglect on cancellation tests has usually been graded by the number of omissions remaining after the patient has signaled test completion, this method is insensitive to the extent to which the omissions were located to 1 side. As an alternative, some authors have recommended calculating (or allowing a computer to calculate) the “center of cancellation” (see this Online CoC measure tool for freely available software), that is, the geographic center of all of the canceled targets in relation to the width of the display (172). This method, thus, directly indicates the severity of the lateral spatial bias on the test.
Drawing. When asked to copy stimulus arrays with multiple objects, or complex objects with multiple parts, patients may omit left-sided objects in the array or omit the left side of individual objects, regardless of where they appear in the array (126; 180). Occasionally, patients may draw left-sided features of target items with less detail or even on the right side of their drawings (76).
Reading. Patients with left-sided neglect may have trouble bringing their gaze to the left margin of the page when reading text. As a consequence, they may read lines starting in the middle of the page, resulting in sequences of words or sentences that do not make sense. When reading single words, they may either omit left-sided letters or substitute them with confabulated letters (34). Thus, the word "walnut" might be read as either "nut" or "peanut." This reading disorder is called neglect dyslexia (103).
Orientation to one’s own body: tests of personal neglect. A couple of assessments for examining the patient’s self-awareness of the body’s spatial extent have been popular. The Zoccolotti and Judica scale involves grading the extent to which the limb crosses over to the neglected side during requested use of a comb, razor for men, and facial powder for women (233). The Fluff Test, in contrast, examines whether patients can find lint (or “fluff”) on the contralesional arm and leg, following applying cardboard circles with Velcro on them; patients are required to find the circles with eyes closed (40). Personal neglect recovers to a different extent than extrapersonal neglect, which suggests that these are different processes that are involved with neglect (90).
Orientation to the environment. The patient’s spatial navigation can be assessed by placing target squares on both sides of hallways, and then to have the patient to either walk or propel a wheelchair through the hallways, and then find the targets (137). Alternatively, course collisions can be measured (156; 202). Although these assessments can indicate spatial neglect during self-operated navigation in hallways, the generalization of these findings to other test sites has not been evaluated. Moreover, measuring neglect in hallways may be complicated by the occurrence of patients or staff in the hallway, or arranging the exclusion of such individuals during testing.
Spontaneous visual exploration of pictures presented to the front of patients can be measured with infrared eye tracking. An advantage of this approach is that it can be used for individuals with severe aphasia, who might not comprehend other forms of testing (98). Whether this approach excels over simple clinical evaluation of patients at the bedside by inspection needs to be determined.
Double simultaneous stimulation. Many patients with neglect also demonstrate extinction to double, bilateral simultaneous stimulation. Extinction refers to the unawareness of stimuli that can be perceived alone but are lost when competing stimuli are simultaneously presented to the side that commands greater attention (13). Extinction may occur in visual, auditory, or tactile modalities. At the bedside, extinction may be tested by asking patients to count fingers presented to 1 or both hemifields, snapping fingers at 1 and both ears, and touching 1 and both hands. When presented with stimuli on both sides, patients with neglect preferentially report the stimulus ipsilateral to the brain lesion. Extinction for contralateral stimuli cannot be tested in the presence of a primary contralateral sensory disorder such as a visual field defect, unilateral hearing loss, or lateralized somatosensory loss. However, extinction of stimuli may be observed with double strictly ipsilateral visual or tactile stimuli (159; 55).
Neglect test batteries. The Behavioural Inattention Test is a standardized neuropsychological battery to assess neglect (224). This test incorporates many of the conventional bedside tests above and provides scores that can be used to monitor change, recovery, or response to treatment. The test also simulates several spatial daily living activities, such as clock reading or recognizing objects from a familiar indoor scene.
The Catherine Bergego Scale (CBS) was developed as a structured method for assessing neglect on activities of daily living (07). The test battery is reliable, valid, and sensitive to change during rehabilitation (06). Although the CBS has gained popularity for assessing neglect on functionally-related activities under test conditions in the clinic, it has also been shown to predict the extent of home-bound behavior in chronic patients (139). However, whether neglect per se is primarily responsible for home confinement among patients is not yet clear. Academic occupational therapists have suggested that the CBS should be revised to accommodate more complex, instrumental activities to improve sensitivity to unilateral spatial neglect on real-world daily living activities (71).
Simulated driving. Generally, neglect is assessed with static stimuli, for example, the cancellation test, in which the stimuli are immobile. Double simultaneous stimulation presents stimuli that although they flicker, they are situated in a relatively restricted area of space and are simple. Although more elaborate presentation of dynamic stimuli can uncover neglect, the methods at present are not standard or readily affordable. Spreij and colleagues found that a subset of acute stroke patients could show unilateral neglect on a simulated road test when they had appeared to have recovered on static neglect tests (190). It is surprising that other patients in their study showed the opposite dissociation, in which they showed neglect on static tests but normal performance on the driving simulation. There is at present no model that can account for these dissociations, other than to conclude that neglect is not all the same from 1 person to the next. Such findings underline the importance of providing a variety of assessments of directed spatial attention that may indicate the vulnerability of patients toward dependency or injury in different real-world tasks and conditions.
Neglect patients may be distinguished by highly variable performance toward contralateral space, rather than a fixed deficiency of contralateral exploration (03). Hence, there is hope for improving contralateral inattention. Numerous promising rehabilitation approaches have been evaluated to date; a comprehensive overview of these methods as well as their historical development is available (101). However, most of these studies have assessed laboratory-based measures of neglect rather than measures from actual daily living activities, thus limiting the rehabilitation implications of the findings (162). Moreover, long-term follow-up in these studies is generally lacking, and small sample sizes have limited statistical power (230). Although many of the more encouraging forms of treatment are reviewed below, presently there is insufficient evidence of treatments for real-world functional activities (225), and therefore, there is no recommend routine use of these in clinical practice (184).
Scanning. Weinberg and Diller developed an extensive rehabilitation program wherein patients with neglect are trained to systematically scan and explore the left side of space (219). This program is labor intensive, requiring 20 to 35 hours of training. Patients with severe neglect are most likely to improve. Benefit beyond the specific tasks being trained seems limited (165). This technique has been modified to train trunk rotation toward the neglected side in patients who can stand without assistance (222). Smooth pursuit scanning training of moving stimuli on a computer screen has preliminarily been reported to show a benefit over more basic visual scanning training of stationary stimuli (99). A computer-assisted scanning training program can improve wheelchair maneuvering in patients with neglect (218). The benefit on home activities in these approaches has, thus far, not been evaluated.
In a novel variant of scanning training, patients with left neglect had to practice musical scales and familiar melodies in a largely right to left manner on a xylophone (22). Excursions toward the left were furthermore shaped by spacing apart the chime bars with practice. This approach shows improved neglect on standard tests and suggests a motivationally-based enhancement of spatial training.
Sensory cueing. Butter and colleagues postulated that dynamic visual stimulation would activate collicular neurons and serve as an attentional cue prompting patients to orient to the left side. They created a line bisection task on a computer screen wherein small squares on the top and bottom of the left end of lines appeared to jump back and forth (26). Patients' performances improved when patients were required to point to the middle of line with the dynamic visual stimulation at the left. Following this lead, they placed light-emitting diodes on the left edge of patients' spectacles. Unfortunately, the improvements on task performance did not generalize to everyday activities. Findings suggest that improved neglect under these circumstances does not result from nonspecifically improved arousal (150).
Motor cueing. Patients perform better on line bisection tasks if they use their left hand (75). These improvements can be matched if the right hand is first brought to the left end of the line (motor cueing) before patients bisect the lines. Robertson and colleagues similarly showed that some patients with neglect improve after being trained to use their left hand by placing it at the left margin of the area wherein an activity is to take place. Further analysis suggests that it is the movement of the arm, or the motor activation, rather than perceptual anchoring of the limb, that contributes to the improvement. These improvements may generalize to activities of daily living (167), and they may be specific to neglect in peripersonal space (166). Passive movement to the left arm may also benefit neglect on standard neuropsychologic tests (59).
Mirror training. In a variant of motor cueing, Pandian and colleagues observed that left neglect patients who practiced flexion-extension movements of their left hands (which were paretic) while their view of their left hands was blocked by an upright mirror, which overlay the image of their right hands practicing the same maneuvers, experienced significant and prolonged improvement on spatial tests (141). Moreover, the patients who had undergone such training were significantly less likely to be dependent for basic activities of daily living at 6 months follow-up compared to patients who had not undergone such training. The basis for this benefit is unclear. Pandian and colleagues suggested that observing the illusion of paretic hand movement may have stimulated premotor neurons in the damaged hemisphere and, thus, in some manner secondarily improved mechanisms of contralateral spatial exploration (141). Replication will be required with tighter control over lesion location before this simple but encouraging intervention can be accepted as treatment for neglect.
Eye patching. Posner and Rafal suggested that patching the right eye in left-sided neglect would decrease left superior collicular activation and mitigate the leftward orientational bias by altering the balance of activation between the colliculi (153). Each colliculus receives input from the contralateral eye and also inhibits the contralateral colliculus. In animal models, neglect is reduced by damaging the ipsilesional superior colliculus or by transecting the intracollicular commissure (189). Despite some encouraging findings, research to date has not identified a consistent benefit from eye patching in neglect (185).
Prism adaptation. Investigations into the use of spatially distorting lenses that bring the field of view toward the right have shown improved spatial attention and gaze in patients with left neglect (183). The training involves pointing to targets across a table without viewing the arm while wearing the lenses. After the lenses are removed, there is improved attention to the left as an after-effect. Results, however, have been inconsistent (193). One study identified significant improvements on real-world behaviors in a small group of persons with neglect after prism adaptation training, in comparison to neglect patients who received less-specific cognitive training (206). Treatment benefits were maintained at 5 weeks follow-up. However, the psychometrics of the real-world assessment were not indicated. In contrast, a trial of 69 neglect patients randomized either to prism adaptation or placebo treatment did not have a differential benefit on the CBS (198). Possibly the location of brain lesion affects the success of prism adaptation training. In 1 clinical trial, stroke patients with frontal lesions improved on the CBS after prism adaptation training whereas patients with lesions outside of the frontal lobe did not benefit (68). It is unfortunate that the patients were followed only for 6 weeks, and so it is not clear whether the benefits may be retained for longer extents of time. In the largest randomized clinical trial of prism adaptation for stroke patients with neglect, involving 1720 patients and 16 study sites, the treatment was more beneficial for quantitating self-care neglect on tasks that are performed on command, than without such treatment (36). However, there was no assessment of retention of such training effects or transfer to activities in the home. Thus, the ultimate benefit of prism adaptation has thus far not been established.
Optokinetic stimulation. Despite numerous efforts to introduce optokinetic stimulation toward treating neglect, which continue to the present, research has not yet established that this intervention has any benefit over other interventions for neglect (149).
Vestibular stimulation. Injecting cold water into the ear contralateral to the lesion stimulates the vestibular system and temporarily ameliorates neglect (173). Interestingly, hemiparesis in neglect patients may also temporarily improve with cold water irrigation, unlike hemiparetic patients without neglect (171). Side-effects of vestibular stimulation, such as nausea, are not reported in neglect patients. It is not clear if improvement from vestibular stimulation is mediated through modality-specific (vestibular) mechanisms, or through increases in general arousal. Simply shifting orientation by driving the eyes to the left cannot be the only factor. Reported transient resolution of somatosensory inattention and anosognosia (29; 20) are not easily explained by the shift in gaze.
Cutaneous electrical stimulation. Contralateral electric stimulation of the neck has been examined in neglect patients, with various levels of success. Conflicting results have been reported regarding the effect of transcutaneous electric nerve stimulation to the neck on standard paper-and-pen assessments of neglect (copying, cancellation) (96; 204). In contrast, transcutaneous electric nerve stimulation seems to benefit the spatial completion of object drawings from memory and spatial orientation in environments devoid of distinguishing features (74; 73). Furthermore, transcutaneous electric nerve stimulation has also benefited sitting posture control in patients with neglect (147). These findings suggest that transcutaneous electric nerve stimulation may serve as a “sensory prosthesis” to compensate for some of the functional impairments of neglect. However, as with vestibular stimulation, the improvement is transient. It is, therefore, not yet clear whether transcutaneous electric nerve stimulation may be chronically effective in ameliorating neglect.
In related research, 1 study found benefit of electrical stimulation to the contralateral arm in most patients with neglect who were studied, with measurable benefits as long as 6 months after treatment and with apparent carryover to real-world activities, as reflected by improvement on the Barthel Index (78). The investigators suggested that an improved weighting of proprioception in the contralateral arm may have fostered these improvements.
Virtual reality training. Preliminary findings suggest that neglect patients can benefit from a gaming environment for 5 weeks’ intervention (58). Although the patients’ benefits on standard laboratory tests were maintained 6 months later, and the patients reported maintained improvement on the CBS, caregivers’ responses did not show any benefit from training. Further investigation of this intervention will require a randomized controlled trial.
Noninvasive cerebral stimulation. Nearly a decade of research has consistently indicated that repetitive transcranial magnetic stimulation (rTMS) over the left scalp among persons with left neglect can ameliorate the disorder, most likely as a result of reducing the amount of interhemispheric inhibition from the left hemisphere upon the right by way of the corpus callosum (32). The extension of improvement on laboratory tests to the real world has not so far been evaluated. Because treatment effects have not so far been shown to extend beyond a few weeks, it is doubtful that rTMS will advance to becoming a standard treatment for neglect. Similarly, some benefits of transcranial direct current stimulation (tDCS) have been reported for neglect (195; 49), but thus far without indicating improvement for daily living activities. A trial that combined rTMS with sensory cuing (in this case, a buzzer episodically stimulating the left arm) benefited neglect on formal tests, and yet had no benefit on self-care skills (229).
Pharmacological treatment. Lesions to ascending dopaminergic pathways in rats produce behavioral abnormalities that resemble neglect. The dopaminergic agonist, apomorphine, ameliorates these deficits, and this improvement can be blocked by pretreatment with spiroperidol, a dopamine receptor blocking agents (43). These observations led to a small open trial of the dopamine agonist bromocriptine in 2 patients with neglect (57). Both patients' performances improved on neuropsychologic testing. One patient had noted improvement in her activities of daily living as reported by her husband. Bromocriptine may produce greater improvement than methylphenidate (89). Levodopa with carbidopa (like bromocriptine, a standard treatment for Parkinson disease) at a dose of 25 to 100 mg 3 times a day has been associated with improved neuropsychologic test performance and functional activities in stroke (136). However, a control group was not assessed and, therefore, it was not clear how much benefit the medication had over spontaneous recovery. In a related study, levodopa 100 mg every morning was associated with significantly improved neglect dyslexia, which persisted after discontinuation of the drug (176). Dopamine agonists may be more effective in treating perceptuomotor behaviors than strictly perceptual ones (64). Methylphenidate has been reported to improve line bisection error in children with attention deficit hyperactivity disorder (182). The reinstatement of recovered unilateral neglect by a gamma aminobutyric acid agonist (midazolam) suggests that GABA antagonists may benefit recovery from neglect (109). A preliminary study has associated the improvement of arousal and unilateral right neglect with modafinil (227). Similarly, a noradrenergic agonist that is generally used to treat hypertension, guanfacine, has been shown to improve spatial inattention after stroke on computerized cancellation assessment (119), but the benefit to daily living activities was not evaluated. A trial of transdermal nicotine in stroke benefited arousal but had only limited effect on neglect (115).
These reports of pharmacologic efficacy in neglect are single-case or small-case series. Side effects may ensue (64), and treatment may even exacerbate inattention or search inefficiency (72; 09). Although the value of pharmacologic treatment in the neglect syndrome deserves improved understanding, one must consider the potential for such treatment to interfere with neurologic rehabilitation (161).
Constraint-induced movement therapy (CI therapy). Constraint-induced movement therapy for chronic mild-moderate hemiparesis involves restricting use of the less-affected arm while promoting use and repetitive task practice with the more-affected arm. In 1 study of an infant with congenital hemiparesis and unilateral spatial neglect (23), 1 year of training (without actually restraining the less-affected arm) was associated with improvement in both impairments. In a study of 3 children, constraint-induced movement therapy was reported to have limited benefit for spatial neglect (39). Whether such extended training would be practical in most clinical settings remains unclear. However, 1 trial of 3 weeks of constraint-induced movement therapy for post-stroke adults observed a significant improvement on the Catherine Bergego Scale of neglect assessments of everyday activities (228). Another study observed neglect patients to benefit in their use of the more paretic arm after constraint-induced movement therapy, although without indicating whether real-world neglect tasks had themselves improved (220). Encouraging as these findings are, it is important to note that preliminary studies have found that cognitive impairment may limit the treatment gains from constraint-induced movement therapy for adults (205; 125), and so the generalizability of constraint-induced movement therapy for patients with spatial neglect at present is uncertain. On the other hand, it may be possible to adapt the constraint-induced movement therapy method to systematically improve unilateral inattention without motor training; an outline of such an approach has been published (196).
Improving motivation. Providing a pleasant setting or rewards for spatial task completion can benefit neglect. For example, paying a patient for each canceled stimulus can improve neglect during formal testing (135). Neglect during cancellation can also improve when music that is preferred by the patient is played (186) or when classical music is played (201). In a variant of this approach, the lateral source of the favorite music of neglect patients was gradually shifted toward the neglected side over 10 minutes (97). The benefits were shown on a cancellation test and self-selected visual exploration of pictures. However, such interventions have not been shown to carry over to real-world activities.
General attention training. Patients with unilateral neglect commonly have disturbances of general (ie, nondirectional) attention (133). Attempts to improve neglect through training alertness or general attention has had limited success thus far (168; 199; 209).
Numerous clinical trials for unilateral neglect have not been found to improve everyday activity for any personally relevant extended periods (114). For example, although a trial to improve general attention in neglect patients initially improved the Catherine Bergego test and the Barthel scale, the gains receded to baseline by 3 months (207). In a review of clinical trials of mirror therapy for unilateral neglect (231), one study in the Chinese literature reported improvements on the Barthel activities scale at 1 month follow-up but no further follow-up was reported.
In short, there is yet to be demonstrated a form of neglect therapy that can yield to sustained gains in functional improvement after discharge from the program.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Victor W Mark MD
Dr. Mark of the University of Alabama at Birmingham has no relevant financial relationships to disclose.See Profile
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