Although the processing of information in the visual pathways relies on multiple channels that interact extensively with each other,^4–6 the notion of separate “what” and “where” pathways (i.e., two visual systems) has proved useful in the monkey model.⁷ Furthermore it provides a convenient framework for interpreting the visual disturbances due to human brain lesions.⁸ The “what” pathway in humans extends from below the calcarine fissure into the visual association cortex in the adjacent medial temporal lobe, which is thought to contain a human homologue of simian areas V4 and IT. Damage to this pathway is associated with impairments in recognition of objects (the agnosias), reading (the alexias), and color perception (cerebral achromatopsia). In humans, the “where” pathway extends from the dorsal bank of the calcarine fissure into visual association cortices over the superior and lateral surfaces of the posterior hemisphere, which is thought to contain a human homologue of the monkey's area MT complex and parieto-occipital areas. Damage to this pathway can alter visuospatial processing, including the control of visually guided eye and hand movements (as in “Balint's syndrome” ), and can impair motion perception (cerebral akinetopsia). We review these deficits below, which differ from the topographic defects caused by lesions of striate cortex. The question of residual vision in a “destriated” field (i.e., “blindsight”) is also addressed.

Figure 1 shows a map of the visual areas and connections in the monkey's brain.^9–15

Inouye¹⁷ and Holmes and Lister¹⁸ found that in area 17 the foveal representation of the retina is located near the occipital pole, and the peripheral visual field is represented anteriorly. These insights came from studying the pattern of visual field defects in soldiers with penetrating wounds of the occiput. Further study has revealed a well-defined and orderly retinotopic arrangement of the visual field in area V1.¹⁹ The superior bank of the calcarine fissure contains cortex corresponding to the superior retina (inferior visual field), while the inferior bank contains the representation of the superior visual field. Most anterior is the representation of the monocular temporal crescent, the region of temporal field in the contralateral eye that lies beyond the limits of the nasal field (60°) of the ipsilateral eye. As is true of most of the visual system, the peripheral field is less represented than central vision. In V1, more than one half of cortex is devoted to the central 10° of vision (“cortical magnification”). Occipital cortex contains a mixture of monocular and binocular cells arranged in ocular dominance columns; however, there is no gross separation of ocular inputs.

VISUAL FIELD DEFECTS FROM STRIATE LESIONS

Focal destruction of the visual cortex produces a scotoma, defined as a region of the visual field within which the patient cannot reliably report the presence of targets of specific size and luminance, tested with either kinetic targets (e.g., Goldmann perimetry²⁰) or static targets (e.g., threshold automated perimetry [Allergan, 1987]). These defects are located in the visual field contralateral to an area V1 lesion and are homonymous, being present in similar regions of the visual fields of both eyes. Their homonymous nature reflects the decussation of the nasal retinal fibers at the optic chiasm. As opposed to visual defects caused by lesions of the optic radiations and especially by lesions of the optic tracts, the hemianopic defects from V1 lesions are highly congruent, meaning that the scotoma or defect in one eye is virtually identical to that in the other eye (Figs. 3 to 7). This reflects the anatomic convergence of the inputs of one eye with that of the other in area V1.

With a complete V1 lesion, the entire contralateral visual hemifield is blind, including one half of foveal vision. This is referred to as a macula-splitting homonymous hemianopia. When vascular in origin, this often represents a posterior cerebral artery infarct in a patient whose entire calcarine cortex was supplied by that artery. Macula-splitting hemianopias, however, also occur with complete lesions of the optic tract or optic radiations and therefore lack localizing value. In contrast, a patient whose macular pole is either supplied by or has abundant collateral circulation from the middle cerebral artery may have a macula-sparing hemianopia (Fig. 3).²¹ Previously it had been argued that macula-sparing results from bilateral representation of a small region surrounding the vertical meridian, which expands to as much as 3° at the fovea²²; however, a recent study of the retinotopy of V1 in the monkey found that the hemi-maculae are not represented bilaterally.²³ In contrast to macula-splitting hemianopias, macula-sparing hemianopias are rarely due to lesions of the optic radiation or optic tract.

Partial lesions of area V1 are not uncommon. Involvement of either the upper or lower bank alone usually results from ischemia, since the banks are supplied by separate branches. Upper bank infarcts cause homonymous contralateral inferior quadrantanopia (Fig. 4), whereas lower bank infarcts cause superior quadrantanopia. Such defects often do not respect the horizontal meridian (see Fig. 4), since the representation of the upper and lower fields is continuous across the meridian in the depths of the calcarine fissure. Similar quadrantanopias can be found with parietal or temporal lobe lesions involving the optic radiations. Partial involvement can also occur along the anteroposterior extent of striate cortex. A lesion of the occipital pole alone can cause a hemianopic central scotoma (Fig. 5),²⁴ whereas a lesion slightly more anterior can cause a hemianopic paracentral scotoma (Fig. 6). These defects are distinguished from ocular causes of central visual loss by their highly congruent and homonymous nature and their respect of the vertical meridian. These central hemianopias sometimes result from watershed infarcts during systemic hypoperfusion. A near-complete lesion that spares only the most anterior portion of V1 may cause a hemianopia that initially appears incongruous (Fig. 7). The hemianopia involves the whole nasal hemifield of the ipsilateral eye, but the temporal hemianopia of the contralateral eye is remarkable for a preserved crescent-shaped island of remnant vision.²⁵ This is the monocular temporal crescent, the sole region of the visual field that is represented only in one eye. This apparent incongruity may be attributed mistakenly to an optic tract lesion; however, the absence of both optic atrophy and relative afferent pupillary defect (RAPD), along with the location of the crescent outside 60° and the high congruity of the homonymous defect inside 60°, indicates a striate lesion. In fact, hemianopia with sparing of the temporal crescent is pathognomonic of a V1 lesion.

Bilateral lesions of striate cortex are not infrequent. Because both the right and left striate cortex face each other on the medial occipital surface, localized pathologic processes such as tumors or traumatic injury may affect both sides concurrently. Also, because the right and left posterior cerebral arteries share a common origin from the basilar artery, vascular disease also can affect both visual areas either simultaneously or sequentially. Distinction from bilateral optic nerve or ocular pathology relies on the high congruity of the visual fields and the demonstration of step defects along the vertical meridian that betray the bilateral homonymous nature of the field loss. With bilateral hemiscotomata from occipital pole lesions, however, such steps may be difficult to demonstrate and require skillful perimetry²⁶ to avoid confusion with macular disease or optic neuropathy.

Cortical Blindness and Anton's Syndrome

Complete bilateral striate lesions lead to cortical blindness. Cortical blindness is easily distinguished from ocular disease by the normal pupillary responses to light and normal funduscopic examination. Some patients with cortical blindness appear unaware of their deficit and deny that they cannot see (Anton's syndrome). The cause of Anton's syndrome remains obscure. Some have suggested that it has a common origin with other anosognosic syndromes,⁸ in which patients deny the presence of hemiplegia or other neurologic problems, and which are thought to arise from right hemispheric dysfunction or disconnections between the thalamus and the right parietal lobe.²⁷ Denial of blindness is not pathognomonic of cortical blindness. It can also occur in subjects with ocular or optic nerve disease; however, in these patients lack of awareness seems to be related to concurrent dementia or confusional states.²⁸ In contrast, denial of blindness with lesions of the visual cortex is not necessarily accompanied by delirium or dementia. Thus it may be better to define Anton's syndrome more specifically as denial of blindness in the absence of dementia or delirium. Even this more restricted definition, however, is not exclusive to lesions of visual cortex, since Anton's syndrome occasionally is mimicked by a combination of bilateral optic neuropathy and bilateral frontal lobe disease.²⁹

Inverse Anton's syndrome is a more unusual condition in which patients with incomplete visual loss deny any ability to see. In contrast to patients with “blindsight,” these patients have small islands of preserved vision that can be demonstrated, and there has been at least one case in which neuroimaging demonstrated residual striate cortex corresponding to the remnant visual field. Hartmann and associates³⁰ suggested that this “meaning stripped of its percept” (contrasting with Teuber's³¹ famous definition of agnosia as a percept stripped of its meaning) resulted from disconnection of visual perception in striate cortex from attentional mechanisms in the parietal lobes. Inverse Anton's syndrome remains a controversial entity, however, and further work is required to verify its existence and elucidate its pathophysiology.

BLINDSIGHT AND RESIDUAL VISION

One of the most interesting questions regarding the visual field defects caused by striate lesions is whether any residual vision exists within the homonymous scotoma. Although there are older investigations of remnant visual function within cortical visual field defects, the modern quantitative study of this phenomenon begins with Pöppel and colleagues,³² who reported some rudimentary localization of targets within hemianopic regions by saccadic eye movements. After this report, Weiskrantz^33,34 performed a series of studies on patient D.B., who had a surgical resection of an occipital lobe.³⁵ D.B. always denied seeing visual stimuli in the hemianopic field, but when forced to guess, he was able to make a variety of visual discriminations at a level better than chance. In other words, D.B. seemed to show visual perception in the absence of acknowledged awareness, a phenomenon that Weiskrantz labeled “blindsight.” Blindsight should be distinguished from “residual vision,” another phenomenon that is sometimes discussed together with blindsight. Patients with residual vision retain some awareness of the presence or absence of visual stimuli within a perimetrically defined visual field defect.^36–38 Thus, their hemianopia is relative even if severe, and the finding of some residual discriminative abilities is less surprising in these patients. Whether blindsight and residual vision share the same mechanisms is unclear.

Measuring Remnant Abilities in Blindsight

Blindsight is not a commonly reported phenomenon, despite heightened awareness of the condition in recent years. It is clear that not all subjects with cortical field defects exhibit blindsight. Weiskrantz³⁹ suggested that this resulted from variable inclusion of extrastriate regions within human lesions. Another possibly important factor is age of onset. Children or infants may be more likely to develop blindsight, since they may be at a stage of greater neural plasticity.^36,40 Demonstrating blindsight also requires special assessment strategies beyond those in common use in the eye clinic.^41,42 These include (1) measurement of eye movements or manual pointing as an index of the spatial localization of visual targets; and (2) forced-choice methods that circumvent the need for subjects to assert, “Yes, I saw it,” the response required in typical perimetric tests. The question raised by these special techniques, however, is whether the improvement observed with forced-choice strategies indicates subconscious vision or merely a relaxation of the criteria used by a subject to respond.⁴³ Indeed, normal subjects shown very brief stimuli exhibit similar patterns of response to those of blindsight patients.⁴⁴ Recent studies have addressed this problem by using signal detection analysis, which calculates a measure of true sensitivity (d') independent of a response criterion.^41,45

Questions have often been raised as to whether blindsight results are due to artifact, such as inadequate fixation, light scatter, nonvisual cues, and nonrandom presentation of targets.⁴³ Inadequate fixation is controlled best by monitoring eye position, although the use of randomly located, very brief stimulus presentations may also minimize this concern. Even so, eye recordings may not detect sustained strategies of eccentric fixation in patients, unless rigorous methods of head stabilization are used.⁴⁶ Light scatter is particularly troublesome, since Campion and co-workers⁴³ showed that blindsight-like performances could be mimicked by light scatter. Some investigators have measured scatter physically^37,47; however, Campion and associates⁴³ argued that psychophysical rather than physical measures are required. Some studies have used anatomic controls for scatter, such as showing that similar stimuli at the physiologic blind spot are not perceived³⁴; other studies have used control patients with pregeniculate lesions, the expectation being that such lesions eliminate the pathways for blindsight.^32,48 All of these issues point to the fact that the demonstration of blindsight requires extreme care in guarding against artifactual results.

The range of visual ability demonstrated in the literature is impressive, including perception of spatial location, form, orientation, color, and motion (Table 1). No clear pattern of preserved versus eradicated visual perception has emerged. In part, this may reflect the idiosyncratic selection of tasks by investigators and the impossibility of testing all aspects of perception with the time-consuming methodologies required in cases of blindsight.

TABLE ONE. Residual Visual Abilities Shown in Various Blindsight Studies

Saccadic Localization

Spatial localization has been one of the most extensively studied of blindsight abilities, reflecting expectations that functions of the superior colliculus, such as localization, would be the most likely to remain after loss of striate cortex.⁴⁹ Localization has been studied in both saccadic and manual pointing responses. Pöppel and associates³² reported a weak correlation of saccadic size and target position in four patients with incomplete hemianopias, mainly for targets up to 30° in eccentricity. Similarly, patient D.B.^33,35 had only a weak correlation of eye responses between 5° and 25°; for the entire range, the correlation was not significant. Most of the correlation derived from reduced saccadic size for the nearest target at 5°, in a portion of the visual field that later recovered on perimetry.³⁴ Perenin and Jeannerod⁴⁸ found some saccadic localization in two patients with cortical hemianopia, again mainly with targets less than 30°. Lack of correlation at greater eccentricities in these studies perhaps reflects the fact that centrifugal head-fixed saccades of greater than 30° are rare under natural circumstances. In contrast to these reports, Meienberg and colleagues⁵⁰ did not find any localization ability in three subjects with cerebral hemianopia.

Manual Localization

Studies of localization by reaching and pointing allow a greater range of eccentricities to be studied than do studies of head-fixed saccades. Despite the poor saccadic localization of patient D.B., Weiskrantz and associates³³ found near-normal manual localization with large targets beyond 30°, again a region that showed recovery in later perimetry.³⁴ Perenin and Jeannerod⁴⁸ reported some localization ability in six patients with postgeniculate lesions; however, they did not quantify data, and their findings were complicated by the fact that subjects reported seeing a flash, implying either light scatter or conventional vision. Scatter may be particularly important, given that the localization occurred mainly for points of less than 20° eccentricity. In a later study of a cortically blind patient, manual localization was weak and variable.⁴⁷ Corbetta and co-workers⁵¹ found a similar weak correlation of pointing with target location in only one of four patients. Blythe and associates³⁶ reported some manual localization, but only in patients who were aware of the target (i.e., residual vision), which excludes the presence of blindsight by definition.

Manual localization in hemidecorticate patients also has been studied.^49,52 Again, the correlation between pointing and target position in six patients of Perenin and Jeannerod⁴⁹ was variable and appeared to derive mainly from the nearer targets. Ptito and colleagues⁵² found that localization ability was spread over more of the field, although it remained more variable and less accurate than in the normal hemifield. These subjects were aware of targets, suggesting the presence of residual vision, rather than blindsight.

Motion

Some studies of blindsight have tested spatial localization with moving or oscillating targets.^{32,33,37,47,49,52,53} Several of these studies have suggested an advantage of localization for moving over stationary targets.^49,53 Better performance with moving targets is reminiscent of Riddoch's⁵⁴ phenomenon, in which appreciation of movement precedes the appreciation of static targets in recovering hemianopic field defects.

Discriminations of motion speed or direction have also been reported in cases of blindsight. Perenin⁵⁵ found residual direction discrimination in five patients with hemianopia but sparing of the lateral occipitotemporal cortex. Heide and co-workers⁵⁶ found that 2 of 10 subjects discriminated direction and experienced some self-motion from gratings in the blind field. Patient G.Y. (who had residual vision, rather than blindsight) had poor direction discrimination but could detect bright moving targets and discriminate speed differences.^36,37 Ptito and associates⁵² reported that two of three hemidecorticate patients were able to detect motion and had some speed discrimination, but not direction discrimination; however, their results might be explained by response biases of the subjects, rather than blindsight.

Other motion-related abilities have been described. Ter Braak and colleagues⁵⁷ reported on a man who had recovery of optokinetic nystagmus 5 months after a stroke that caused permanent cortical blindness. Pizzamiglio and co-workers⁵⁸ found that rotating stimuli in the blind hemifield exerted an effect on the subject's judgment of the true vertical; however, their stimuli may have inadvertently provided clues that influenced responses. Mestre and associates⁵⁹ studied perception of optic flow in a man with bilateral occipital infarcts. In his completely blind right hemifield, the subject could detect optic flow, discriminate speed differences, and tell the difference between forward and backward flow. However, their display may have abutted an island of preserved vision in the left hemifield, suggesting that scatter or inadvertent stimulation within this island was responsible for his good performance.

Form and Color

Weiskrantz and colleagues³³ first reported that patient D.B. had normal discrimination of the form (X vs O) of large stimuli and later concluded that this was explained by orientation discrimination.³⁴ In contrast, patient G.Y. had poor orientation and pattern discrimination.³⁷ Perenin and Jeannerod's study⁴⁸ of six patients and Blythe and co-workers' study³⁶ of five patients (including G.Y.) with residual vision also found no pattern discrimination with postgeniculate lesions. The patient of Mestre and associates⁵⁹ also could not distinguish X from O. Torjussen⁶⁰ reported that three patients with residual vision could distinguish semicircles from complete circles, despite the fact that the completing half of the circle lay in the blind hemifield. However, all three had hemianopias that spared the macula, suggesting that sufficient clues may have been present in seeing regions.⁴³

Form perception has also been studied in hemidecorticate patients.^40,61 Perenin⁴⁰ suggested some discrimination between triangles and disks in two of six patients, though only one showed consistent results across trials. Performance was better near the vertical meridian, raising the specter of light scatter. Ptito and colleagues⁶¹ found some form discrimination in one of four patients, with some curious features: Discrimination was possible (1) with three-dimensional objects, but not with two-dimensional objects; and (2) only when one stimulus was in a blind hemifield and the other in a seeing hemifield, but not when both stimuli were in the blind hemifield.

The range of residual functions in blindsight now also includes color. Blythe and co-workers³⁶ reported that one of five patients with residual vision after occipital lesions could detect and identify red and green. Stoerig⁴⁵ found that 6 of 10 patients detected red and green targets but not targets of similar wavelength composition to the background (i.e., achromatic). A more recent study of spectral sensitivity in three patients found evidence for color-opponent processes in the blind hemifield.⁴² This contrasts with G.Y.'s spectral sensitivity curves, which were scotopic in shape,³⁷ and the fact that D.B.'s ability to distinguish red from green fell to chance when brightness was varied.³³

Hess and Pointer⁶² tested spatial and temporal contrast sensitivity with forced-choice methods in three hemianopic patients, including G.Y. The rate of correct answers was no better than chance. This contrasts with previous claims of residual vision in G.Y.³⁷ and raises comparisons with the method-of-adjustment techniques used in the prior study.

Interactions between blind and normal hemifields have been suggested. In three hemianopic patients, Rafal and associates⁶³ found that distractor targets in the blind hemifield prolonged the latency of saccades, but not manual reactions to targets in the intact field. Marzi and colleagues⁶⁴ and Corbetta and co-workers⁵¹ studied spatial and temporal summation effects across the vertical meridian. Corbetta and associates⁵¹ found one subject who had evidence of blindsight in all tasks; however, in other subjects in these two studies, the results were inconsistent.

Effects of Training

In six subjects, Zihl and Werth^65–67 found that a visual localization training program improved the accuracy of a series of saccades in a visual search task. It even has been claimed that training actually leads to an expansion of visual fields.^68,69 Improvement in manual localization with training also was found in one case of bilateral blindness.⁵³ Blythe and colleagues, however, did not find a training effect for the accuracy of single saccades.³⁶ Balliet and co-workers⁴⁶ also found no such improvement in 12 patients, and they suggested that positive effects may reflect learned strategies of eccentric fixation.

Anatomy of Blindsight

Initially the favored hypothesis was that blindsight was a “second visual system” involving the superior colliculus. Indeed, in cases of hemidecortication, this must remain the primary hypothesis. The retinotopic arrangement of collicular receptive fields and the discharge of collicular cells with saccades guided early studies of saccadic localization in hemianopic patients.³² The discovery of other remnant visual abilities such as pattern and motion perception, however, are not easily explained by collicular activity alone. These led to suggestions that collicular projections to the pulvinar may provide an indirect input to extrastriate cortex.³³ This would require some adaptation or “plasticity,” since the visual responses in the pulvinar normally originate from the visual cortex and not from the superior colliculus.^70,71 Weiskrantz^34,39 attributed variations in the degree and type of blindsight possessed by subjects to the inevitable variability in naturally occurring human lesions. Most lesions of striate cortex involve some extrastriate regions as well, but the areas affected and the extent of damage are different in each patient. Weiskrantz proposed that the type of blindsight reflects the pattern of extrastriate sparing; however, some studies have not found a correlation between blindsight and lesion extent as depicted on a scan (e.g., MRI).^64,72 More recently the colliculopulvinocortical relay has been further challenged by demonstrations of color perception in blindsight.^42,45 Since collicular neurons lack color opponency, Cowey and Stoerig⁷³ proposed that there is a projection to extrastriate cortex from lateral geniculate neurons that survives the retrograde degeneration occurring after a striate lesion.

The early impetus for human studies on blindsight followed demonstrations of residual vision in primates after striate resection.⁷⁴ These animals retain or relearn the ability to localize targets with saccades.^75–77 They can also detect and discriminate the speed of moving targets,⁷⁶ but there is disagreement over whether they can use motion to guide smooth pursuit and saccades.^77,78 Saccadic localization in destriated monkeys is lost when the striate lesion is combined with a collicular one.⁷⁵ In contrast, little effect is seen when striate lesions are enlarged to include extrastriate areas,⁷⁶ supporting the hypothesis that remnant vision depends on the superior colliculus alone. Single-cell studies, however, do show that some activity remains in extrastriate areas after the occurrence of striate lesions. In particular, responses remain in areas MT and V3A ,^79–82 components of the dorsal pathway of visual processing. This activity is lost after further ablation of the superior colliculus,⁸³ supporting the collicular-relay hypothesis advocated by Weiskrantz.^34,39 However, the activity in components of the ventral pathway, such as V3⁸¹ and inferior temporal cortex,⁷⁹ is abolished by striate lesions. Since perception of color and form are commonly attributed to this ventral stream, these findings appear to conflict with demonstrations of form and color discrimination in human blindsight.

Not all investigators believe, however, that blindsight results from collicular or extrastriate function. The possibility that blindsight depends on remnant striate cortex^32,43 is still viable, given the difficulty of proving complete destruction without performing an autopsy. Fendrich and associates⁸⁴ used highly detailed perimetry in one “blindsight” case to find a small island of preserved vision, which corresponded to spared striate cortex visualized with magnetic resonance imaging (MRI). It is also not clear whether “residual vision” is due to nonstriate function: Celesia and colleagues⁸⁵ found that conscious perception of stimuli requires residual striate cortex, although Ptito and co-workers⁵² claimed that their patients with hemispherectomies retained some awareness of visual targets. Some monkey data also suggest that remnant vision requires intact striate cortex: Merigan and associates^85a found no remnant vision within a scotoma after a V1 lesion, but they did detect some in a V2 scotoma. Thus, at present, the anatomy and physiology of blindsight remain uncertain.^73,86

Given our knowledge of parallel visual processing in the extrastriate cortex of monkeys, an attempt at broadly categorizing the visual dysfunction from human lesions can be made. Lesions of extrastriate cortex fall into two categories: (1) those affecting components of the ventral pathway, which disrupt form and color perception; and (2) those affecting components of the dorsal pathway, which disrupt motion and visuospatial perception.

VENTRAL PATHWAY

Visual Agnosia and Prosopagnosia

The word agnosia, derived from the Greek ( = perception), means “not knowing.” Associative agnosia is an impairment of recognition in which “normal percepts are stripped of their meanings.³¹” Apperceptive agnosia is a failure of recognition due to impaired perceptual abilities.⁸⁷

One of the most striking agnosic disturbances is prosopagnosia (Gr. pros<ovrbaro>pon = face), the inability to recognize familiar faces despite adequate visual abilities. The term was coined by Bodamer^87a in 1947, although the deficit was described much earlier by Quaglino and Borelli in⁸⁸ The difficulty involves recognition of faces familiar before the start of the illness (retrograde prosopagnosia) as well as the ability to learn new faces (anterograde prosopagnosia). Because abnormal facial recognition may be part of more generalized perceptual, cognitive, or memory problems,⁸⁹ the diagnosis of prosopagnosia is best reserved for cases in which the recognition defect appears disproportionately severe.

Prosopagnosic patients usually complain of the embarrassing social consequences of their problem, although those with childhood onset^90,91 and the odd adult case⁹² may be unaware of their defect. To recognize others, they rely on nonvisual cues, such as the context of an encounter or the sound of a voice; or visual cues, such as gait, clothing, or even local facial features, such as hair length, glasses, or facial hair.⁹⁰ Use of these visual cues, however, does not constitute true facial recognition.

Despite their problems with facial identity, many patients can determine age, gender, and emotional expression from faces^93–96 or can even lip read.⁹⁷ The process by which they do so, however, may differ from normal. For example, one patient could no longer tell age when wrinkles were removed from pictures of faces, whereas a normal subject was still able to judge age accurately.⁹⁰ In some cases involving more pervasive perceptual abnormalities, judgments about age, sex, and expression are also affected.^90,91

An important issue is whether the defect underlying prosopagnosia is specific for faces or extends to other objects. Some patients have difficulty distinguishing among types of an object, such as types of cars, flowers, food, or coins^{90,91,93–95,98–100}; or among unique items, such as buildings, handwriting, personal belongings, and clothing.^90,96,98,100 At a broader level, though, prosopagnosics have no difficulty recognizing a face as a face, a cow as a cow, or a car as a car. Some authors have suggested that this implies difficulty making distinctions within a category of objects, of which faces are merely the most dramatic example, whereas distinctions between object categories are preserved.¹⁰⁰ Others have pointed out, however, that determining what constitutes a category is an arbitrary, somewhat intuitive decision on the part of investigator.¹⁰¹ In any case, there is clearly variability in the degree to which prosopagnosia affects the recognition of other objects. De Renzi's patient¹⁰² recognized his own razor, wallet, glasses, handwriting, and car. The patient of Bruyer and associates⁹³ recognized individual cows, dogs, houses, streets, and cars, and his only difficulty with playing cards involved face cards. McNeil and Warrington¹⁰³ describe a man who learned to distinguish among individual sheep after the onset of his prosopagnosia, a more daunting task than recognizing human faces for normal subjects.

Almost all prosopagnosic patients have other visual problems (Table 2). Visual field defects are frequent, the most common being left homonymous hemianopia, or upper quadrantanopia in the left or both hemifields.^{92,95,104–108} Visual acuity is only sometimes reduced,^90,91,104 and spatial contrast sensitivity may be impaired or normal.^90,91,109 Achromatopsia or hemiachromatopsia^{90,92,93,104–107,110} and topographagnosia^{90–92,95,104,110} form a common triad with prosopagnosia, but there are cases of patients with normal color vision.^{92,94,95,106,108} Visual object agnosia is said to be absent in some,^{95,104,106,108} but present though proportionately milder in others.^90,91,94 More severe generalized apperceptive visual agnosia would preclude a specific diagnosis of prosopagnosia. Another frequent finding is impaired visual memory^{93,94,104,106,107,110}; some subjects also have impaired verbal memory.^92–94,106 Other occasionally associated defects include simultanagnosia,^93,94 palinopsia,⁹² visual hallucinations,⁹² and left-neglect, hemisensory defects or hemiparesis in those with right unilateral lesions.⁹² The determining factor for these last associated defects is likely the extent of the causative brain lesion.

TABLE TWO. Associated Signs in Prosopagnosia

  Major Signs
  Visual field defect

  Left homonymous hemianopia
  Left superior quadrantanopia
  Bilateral superior quadrantanopia

ANATOMY AND PATHOLOGY. The typical lesion in prosopagnosic cases lies in the inferior occipitotemporal cortex, in the fusiform and lingual gyri (Fig. 8).^100,111,112 Opinion has varied as to whether prosopagnosia requires bilateral lesions. The early cases of Wilbrand (1892) and Heidenhain (1927) had bilateral damage.⁸⁹ Reviews by Meadows¹¹² and Damasio and colleagues¹⁰⁰ stressed that all autopsies of prosopagnosic patients revealed bilateral lesions of the inferior occipitotemporal cortex; in some cases, the left-sided lesion was not suspected before the patient died.^98,113 Other evidence for the requirement of bilateral lesions include studies of split-brain subjects showing mechanisms for facial recognition in both hemispheres and the lack of prosopagnosia in patients with right hemispherectomy⁸⁹ (see Sergent and Villemure⁹⁵ for an exception). Modern neuroimaging has also confirmed bilateral lesions in many cases with computerized tomography (CT),^{93,96,104,106,107} MRI,^89,106 and positron-emission tomography (PET).¹¹⁴

Damasio and co-workers¹⁰⁰ stated that the bilateral lesions in prosopagnosia were often symmetric, presumably affecting homologous regions of both hemispheres, whereas Meadows¹¹² believed the position of the left lesion was more variable. Others have argued from this variability that the bilateral nature of the damage is compatible with right-sided lateralization of facial recognition.^102,115 Left-sided lesions may disconnect a right hemispheric locus for facial recognition from visual input of the right hemifield, which would be especially critical in cases with left hemianopia.^99,116,117 More recently, reports of CT scans showing apparently unilateral right occipitotemporal lesions have accumulated.^{92,95,118,119} Although Damasio⁸⁹ suggested that CT scans may miss small lesions in the left hemisphere, there has been at least one case in which a unilateral lesion was documented with an MRI scan.¹²⁰ Moreover, in one autopsy case, Landis and colleagues¹²¹ found only a trivial and probably unimportant lesion on the left. Thus there is mounting evidence that prosopagnosia may develop after the occurrence of right-sided lesions of the fusiform gyrus alone.⁸⁸ Whether the mechanism, severity, or type of prosopagnosia differs between patients with unilateral and bilateral lesions remains to be determined.

The most common lesions causing prosopagnosia arise from head trauma,^{92,94,104,105,110,122} posterior cerebral artery infarctions,^{92,93,100,103,107,118,123,124} and to a lesser extent viral encephalitis.^96,122,123 These conditions all have the potential to cause bilateral damage. Other unilateral lesions, such as primary tumors,⁹² hematomas,^92,108 abscesses,¹²² and surgical resections,^95,104 are reported less frequently. Prosopagnosia may rarely occur with focal bilateral degeneration in the elderly¹¹⁴ and as a developmental disorder in the young,⁹¹ analogous to the reading disorder known as developmental dyslexia.

COVERT VERSUS OVERT RECOGNITION. Although prosopagnosic patients deny being familiar with faces and cannot identify them, it appears that some “knowledge” of faces is retained in some patients. A range of physiologic and behavioral techniques have been used to uncover this “covert recognition.”¹²⁵ The type of retained knowledge shown falls into two categories: (1) distinguishing familiar from unfamiliar faces; and (2) demonstrating knowledge pertaining to an individual face, such as name and occupation.

Covert familiarity was demonstrated with electrodermal skin conductance measurements by Tranel and Damasio.¹²³ They showed two patients a series of familiar and unfamiliar faces and found larger amplitude responses to the familiar faces. Renault and associates¹⁰⁸ used the amplitude of the P300 component of visual evoked potentials to show covert familiarity in one case. Behavioral methods also demonstrate covert familiarity. Rizzo and colleagues¹⁰⁶ studied the eye movements of the two patients reported by Tranel and Damasio.¹²³ When normal subjects scan familiar faces they concentrate on internal facial features (i.e., eyes, nose, mouth) rather than external ones, whereas both external and internal features of unknown faces are examined. This pattern was also shown by the prosopagnosic patients, despite their inability to state which faces were familiar. Normal subjects are quicker at judging whether two faces are from the same person or not when the faces are familiar, and this difference depends on internal facial features. A similar difference between familiar and unfamiliar faces in reaction time and reliance on inner features was shown in one prosopagnosic patient.⁹⁴ Likewise, for both normal subjects and one prosopagnosic subject, Sergent and Poncet⁹⁶ demonstrated that matching the old and young faces of persons across a 30-year gap was also easier with famous faces than with unknown ones.

Both physiologic and behavioral methods have also shown covert knowledge of information about faces. When prosopagnosic patients saw famous faces and were read a list of names, there were more electrodermal skin responses when correct names were heard.^107,110 When forced to choose between a correct and incorrect name for a face, one patient guessed better than chance,⁹⁶ though another did not when the choice concerned occupation.⁹⁴ Several prosopagnosic patients were better at learning to associate a familiar face with a correct name than with an incorrect name.^93,94,96,126

MECHANISMS. In the past, prosopagnosia was attributed to a combination of generalized mental impairment and disturbances of perception and memory.^127,128 It is clear now that it is a specific functional disorder with a specific neuroanatomic basis, as proposed by Hoff and Potzl¹²⁹ and Bodamer.^87a Much of the early debate about its specific nature centered on whether it was a failure of perception or of memory, a dichotomy resembling the apperceptive versus associative distinction for agnosia described by Lissauer.⁸⁷ The fact that many prosopagnosic subjects can make “same or different” judgments about faces, even with different lighting conditions or views (i.e., Benton Facial Recognition Test⁸⁸), led to conclusions that perception was adequate and therefore the defect was one of memory. It is becoming more apparent, however, that prosopagnosia may not be just one disorder but a group of disorders, with varying degrees of perceptual and memory dysfunction.¹²²

The defect (or defects) underlying prosopagnosia have been conceptualized in neuropsychologic terms. Both Damasio⁸⁹ and Bruce and Young¹³⁰ have proposed a staged process of facial recognition:

  Stage 1: Perception or structural encoding of a facial percept. This provides data not only for facial recognition, but also for analysis of facial expression, speech, age, and sex.
  Stage 2: Activation of facial recognition units or templates by sufficiently similar facial percepts from stage 1.
  Stage 3: Activated facial recognition units that access personal identity nodes containing biographic information and multimodal memories about the owner of the face. These memories can also be accessed through other routes besides facial recognition, such as recognition of voice or gait, which are often preserved in prosopagnosic patients.

Tranel and Damasio¹²³ originally suggested that the prosopagnosic defect was faulty activation of memories (i.e., personal identity nodes) by templates (i.e., facial recognition units). This “associative” prosopagnosia would correspond with the memory type of prosopagnosia proposed by de Renzi and co-workers.¹²² Damasio⁸⁹ subsequentlysuggested that prosopagnosia might arise from defects at any level in the process. Thus there may be defects in complex higher order visual analyses of facial features, percept-matching to templates, or template activation of memories. Defects of visual analysis, or structural encoding of faces, would correspond to the “apperceptive” type of prosopagnosia of de Renzi and associates.¹²²

The nature of the defect in apperceptive prosopagnosia has been studied by Sergent and Villemure⁹⁵ and Levine and Calvanio.¹³¹ They have suggested that apperceptive prosopagnosia is caused by abnormal configural processing, meaning an inability to perceive the whole from the component features. Levine and Calvanio's¹³¹ patient performed poorly on “Gestalt completion” tests of visual closure; Sergent and Villemure's⁹⁵ patient with apperceptive prosopagnosia used a feature-by-feature method rather than the whole-form strategy used by both normal subjects and a second patient with associative prosopagnosia in a later study.⁹⁶ In a similar vein, Rentschler and colleagues'¹³² prosopagnosic patient could not perceive texture or Moiré patterns despite having intact perception of textural elements, suggesting a disturbance of “global” visual integration.

Disturbances of Color Processing

CEREBRAL ACHROMATOPSIA. Cerebral achromatopsia is an acquired defect of color perception caused by bilateral lesions of visual cortex or its connections. Patients complain that the world appears colorless, in shades of gray,^133–137 or less bright.^137,138 Daily activities that rely on color discrimination are affected, such as distinguishing coins, stamps, or traffic lights (the experience of an achromatopsic artist has been described by Sacks¹³⁹). A few patients will note other color phenomena, such as abnormal coloration of the world, as if seeing through a colored filter,¹⁴⁰ and illusory spread of residual colors beyond object boundaries.¹³⁵ These latter ancillary phenomena may occur transiently as the achromatopsic syndrome evolves after an acute event.

Achromatopsia is frequently accompanied by other signs (Table 3). Superior quadrantanopia is almost always present, either in both hemifields or in one hemifield with complete hemianopia in the other (for an exception, see Victor and associates¹⁴¹). Prosopagnosia is also almost always present, and topographagnosia is frequent.^135,141,142 Other types of object agnosia also occur.^142,143 Occasionally patients have some memory loss due to extension of lesions into the anterior temporal lobes.^135,143 Alexia without agraphia may be present in achromatopsic patients with right homonymous hemianopias.^135,144

TABLE THREE. Associated Signs of Achromatopsia

  Major Signs
  Visual field defect

  Bilateral superior quadrantanopia
  Unilateral superior quadrantanopia

HEMIACHROMATOPSIA. Unilateral right or left occipital lesions can produce a color defect limited to the contralateral hemifield. The deficit is typically asymptomatic until the defect is demonstrated on a visual examination.^145–147 The remaining color vision in the ipsilateral hemifield allows normal or near-normal performance on standard tests of color vision, such as pseudoisochromatic plates and color sorting tasks such as the Farnsworth Munsell 100-Hue Test. Thus, many such cases may go undetected unless the examiner asks the patient to name or sort colors presented in the peripheral field. When hemiachromatopsia is associated with a superior quadrantanopia, the color defect can be demonstrated only in the remaining inferior quadrant.^145,146,148

ANATOMY AND PATHOLOGY. Achromatopsia is associated with lesions of the lingual and fusiform gyri, in the ventromedial aspect of the occipital lobe. This was shown pathologically by Verrey in 1888 and MacKay and Dunlop in¹⁴⁹ and was confirmed in modern times with CT^144,148,150 and MRI.^137,141,142 Functional imaging with PET also shows color responses in this region.¹⁵¹ Although early reports suggested a possible right-hemispheric dominance,¹⁵² a full-field color defect requires right and left lesions without exception.

The bilateral occipital lesions in achromatopsia are most commonly caused by a stroke, given the common origin of both posterior cerebral arteries from the basilar artery. Bilateral strokes can occur either simultaneously or sequentially. Achromatopsia may be the presenting symptom, or it may evolve from an initial cortical blindness. Other lesions causing achromatopsia are due to herpes simplex encephalitis,¹⁴² presumed cerebral metastases,¹⁴⁴ repeated focal seizures,¹⁵³ and focal dementia.¹⁵⁴ Transient achromatopsia has also been described in cases of migraine aura.¹⁵⁵

THE NATURE OF THE COLOR DEFECT. Normal perceptual color space can be conceived as a threedimensional solid with two chromatic axes and one achromatic axis:

  First chromatic axis (tritan axis): The activity of the short-wavelength-sensitive cone (the blue or S cone) varies, whereas the ratio of the activity of the long-wavelength-sensitive cone (the red or L cone) to that of the medium-wavelength- sensitive cone (the green or M cone) remains constant.
  Second chromatic axis (deutan axis): The ratio of L-cone to M-cone activity varies, whereas S-cone activity remains constant.
  Third (achromatic) axis: The activity of all three cones varies synchronously, such that their activity relative to each other remains constant. The value of light along the achromatic axis is termed brightness. The term luminance is reserved for light sources and reflectance for objects that reflect light.

Conventional color diagrams such as the Committee Internationale de l'Eclairage diagram depict the colors contained within a plane defined by the two chromatic axes. Variations in hue and saturation (the amount to which a color is mixed with white) are contained within such a plane. In cerebral achromatopsia, processing along the two chromatic axes is altered, manifest by abnormal perception of hue and saturation.¹³⁷ In contrast, discrimination of brightness (tested with sorting of shades of gray) is intact.^137,141,156

It should be recognized that color is a property of the appearance of surfaces, and is not inherent to objects.¹⁵⁷ Important factors in determining color appearance are the nature of the illuminant (light source), the wavelength composition of the light reflected by the colored object, and the reflectant properties of the scene surrounding the object.¹⁵⁸ Color is not equivalent to the wavelengths reflected to the eye. In fact, the colors of objects appear remarkably stable under very different lighting conditions, even though the wavelengths reaching the eye vary widely between those conditions.¹⁵⁹ Thus, an apple looks red whether viewed under fluorescent light or sunlight, a phenomenon known as color constancy. To achieve color constancy, it seems likely that the nervous system averages the spectral luminance across large regions of the scene to determine what kind of lighting is present, and then “discounts the illuminant” from the wavelengths reflected by a given object.^159,160 Several investigators suggest that area V4 in monkeys may be the site at which color constancy is generated.^161–163 Although it has been suggested that human achromatopsia may result from damage to a homologue of monkey V4,¹⁴⁹ clinical studies suggest that achromatopsic subjects suffer from a severe defect of hue discrimination at a more elementary level than the generation of color constancy.^137,156 Furthermore, lesions of V4 in macaques only mildly impair hue discrimination, if at all.^10,164–167 Thus the degree to which the putative human color area involved in achromatopsia can be equated with monkey V4 is unclear.

Not all color information is lost in achromatopsia. Some patients can use chromatic differences to define boundaries between areas of different color but similar brightness,^141,142,165 although they do not know what the colors are and cannot order them correctly by hue. This ability may reflect intact opponent color processing in striate cortex.¹⁴¹ Photopic spectral sensitivity curves also have shown preserved trichromacy and color opponency, indicating intact function of the three cones and retinal ganglion cells of the parvocellular pathway.¹⁴²

TESTING ACHROMATOPSIA. Patients with cerebral achromatopsia affecting the central portions of the visual fields can be tested with the standard procedures used to probe more common disorders such as inherited or acquired achromatopsia of retinal origin. These include anomaloscopic procedures,^137,150 in which the subject has to adjust a mixture of color lights (670-nm “red” and 545-nm “green”) to find the unique proportion to match a monochromatic (589-nm “yellow”) target, as on the Nagel Anomaloscope. Tests of color matching and sorting are also useful. The Farnsworth-Munsell 100-Hue Test (Fig. 9) provides a detailed assessment of patients who have failed a screening task such as the Farnsworth D-15. It requires observers to sort isoluminant colors chips along four different axes in color space. The deficits in cerebral achromatopsia affect all hue discriminations,^{135,137,141,156} unlike common congenital retinal cone defects, although the relative severity of the defect along the red-green and blue-yellow axes may vary.¹³⁷ Patients with full-field achromatopsia can sometimes discriminate figures on pseudoisochromatic plates. ^135,141,142 Zeki¹⁴⁹ has argued that performance on pseudoisochromatic plates separates patients into two achromatopsia groups: those with complete achromatopsia and those with incomplete achromatopsia. Heywood and colleagues,¹⁴² however, showed that reading of such plates may improve with increased viewing distance, when the individual color dots are no longer resolvable. The ability to read pseudoisochromatic plates at further distances may be due to the retained detection of the chromatic borders of the dots by striate color mechanisms.^141,142

Testing of color field defects in hemiachromatopsia offers a special challenge because most of the tests described above are designed for viewing in the fovea. In hemiachromatopsia, color vision in at least part of the fovea is spared, so affected patients can achieve normal scores despite having a true color defect.¹³⁷ Testing color in the peripheral visual field requires (1) monitoring of eye movements to ensure that subjects do not glimpse the target with their fovea or (2) a rapid enough random presentation of targets so that the test is no longer visible if subjects attempt a saccade to the target area. It is also necessary to use larger targets (to compensate for decreased photoreceptor density and concomitant decreased spatial and chromatic discrimination) and to suppress rod activity, which alters color discrimination.

COLOR ANOMIA AND AGNOSIA. Perceiving colors is different from knowing and naming them. Thus achromatopsia must be distinguished from color anomia and agnosia (Table 4). Patients with color anomia or agnosia can still discriminate among different colors, although they have difficulty naming or recognizing them. They do not complain of impaired color perception and may not even be aware that they have a color-naming problem. In contrast, achromatopsics have no particular difficulty producing the name of colors associated with familiar objects, even if they can no longer perceive the differences between colors.

TABLE FOUR. Test Results in Various Cerebral Color Defects

Color anomia is often part of a general anomia in aphasic patients who have no color perception deficits, but it can occur as an isolated entity. Several types of specific color anomia have been described, all in patients with left occipital lesions:

1. Interhemispheric visual-verbal disconnection syndrome: This is associated with right homonymous hemianopia and alexia without agraphia.^168–171 The lesions of patients with this syndrome disrupt callosal connections from the remaining right striate cortex to the language areas of the left hemisphere.^169,171 These subjects can see words but cannot read and can see colors but cannot name them. In some, naming of objects is normal,¹⁶⁹ suggesting that not all visual information is disconnected.
   
2. Color dysphasia¹⁷⁰: In addition to having difficulty naming colors of objects they see (visual-verbal task), patients with color dysphasia also have difficulty naming the colors of familiar objects named to them (verbal-verbal task). They cannot complete a sentence like, “A rose is … ”—a task that poses no difficulty for achromatopsic patients.
   
3. Short-term color memory deficit: In a study by Davidoff and Ostergaard,¹⁷² a patient could not name seen colors but could point accurately to colors named by the examiner. Verbal memory for color names was normal, but visual short-term memory for colors was impaired, which they held to be the primary defect underlying their patient's anomia.
   

Kinsbourne and Warrington¹⁷³ described a case of color agnosia, although Oxbury and associates¹⁷⁰ considered it color dysphasia. In addition to impaired naming of colors for either visually presented or verbally named objects, their patient could not color line drawings of objects correctly or learn paired associations between seen objects and seen colors (visual-visual task). The defect went beyond anomia because the patient could not associate the appropriate color with objects, despite normal performance on color-matching and color-sorting tasks. The exact site of the lesion was unknown, but the patient also had object anomia and alexia without agraphia.

The Alexias

Acquired alexia is the loss of efficient comprehension of reading material despite adequate visual acuity. Reading is a complex process that involves form perception, spatial attention, scanning saccadic eye movements, and linguistic processing; thus it is not surprising that disturbed reading is a component of many types of cerebral or visual dysfunction. In most of these conditions, alexia is overshadowed by other clinical signs. In most patients, however, impaired reading can also be either the sole or the most dramatic complaint, and these patients may present to the ophthalmologist. The severity of alexia can range from a complete inability to read numbers and individual letters, to mildly slowed reading with occasional errors, confirmed only by comparing reading speed with normal controls matched for educational level.¹⁷⁴ The latter type of subtle error is more frequently encountered in developmental dyslexia, a very different condition that Galaburda and co-workers¹⁷⁵ and Livingstone and associates¹⁷⁶ have attributed to a congenital paucity of neurons in the magnocellular layers of the lateral geniculate nucleus. Table 5 provides a classification of acquired alexic syndromes.

TABLE FIVE. Classification of Alexia

  Secondary Alexia
  Alexia due to visual problems

  Hemifield slide
  Hemianopic dyslexia

  Simultanagnosia
  Neglect dyslexia

  Surface dyslexia
  Phonologic dyslexia
  Deep dyslexia

The landmark studies of alexia were made by Dejerine.^177,178 He first described a patient with alexia and agraphia, but no other linguistic or visual defect, due to a lesion of the left angular gyrus.¹⁷⁷ The next year he described a patient with alexia without agraphia (i.e., pure alexia or “word blindness”), associated with an incomplete right homonymous hemianopia, due to a lesion of the left fusiform and lingual gyri.¹⁷⁸ This patient subsequently developed agraphia after a second infarct of the left angular gyrus, confirming the findings from the first patient. Dejerine inferred that (1) the left angular gyrus stores the visual representation of words, needed for reading and writing; and (2) alexia without agraphia results if the left angular gyrus is spared, but its visual inputs from both hemispheres are removed (Fig. 10). Dejerine's basic concepts of alexia have survived in Geschwind's²⁸ disconnection theory, and his description of the anatomy of pure alexia remains consistent with the data from modern neuroimaging.¹⁷⁹

PURE ALEXIA. The hallmark of this syndrome is a striking dissociation between reading and writing. In extreme cases, patients are unable to read what they have just written. Some alexics can decipher words one letter at a time (i.e., letter-by-letter reading, or spelling dyslexia), whereas others cannot read letters, numbers, words, or other symbols (global dyslexia).¹⁸⁰ In patients who use letter-by-letter reading, the time required to read a word characteristically increases with the number of letters in the word.^181,182

Pure alexia is frequently associated with a right visual field defect, usually a complete homonymous hemianopia, sometimes a superior quadrantanopia, with or without hemiachromatopsia (Table 6).¹⁷⁹ Although field defects can impair reading efficiency, they do not account for pure alexia. Pure alexia can occur without hemianopia,^183–186 and many subjects with complete right hemianopia can still read. Other associated defects include color anomia,^169,179 anomia for visual objects and photographs, defects of verbal memory, and other types of visual agnosia, including prosopagnosia.^179,187

TABLE SIX. Associated Defects of Pure Alexia

  Major Signs
  Visual field defect

  Right homonymous hemianopia
  Right superior quadrantanopia

Covert Reading in Pure Alexia. Several studies have suggested that some covert reading ability is retained in some patients with pure alexia, analogous to the covert abilities in blindsight and prosopagnosia. Some patients with pure alexia can indicate whether a string of letters forms a word (lexical decision task).^182,188,189 Another patient was able to indicate which letters in a string of letters formed a word and also could point to a written word named by the examiner, even though she was unable to read the word aloud.¹⁹⁰ In another study, a patient was able to identify rapidly presented letters better if the letters were part of words than if they were parts of random letter strings.¹⁸¹ Not all patients with pure alexia, however, possess covert abilities.^191,192 As with blindsight, the factors that determine whether such covert reading ability is retained by a given patient with pure alexia remain to be elucidated.

Anatomy and Mechanisms of Pure Alexia. Lesions causing pure alexia are most commonly located in the medial and inferior occipitotemporal region.^179,180 The most commonly invoked explanatory mechanism of pure alexia remains the visual-verbal disconnection proposed by Dejerine¹⁷⁸ and Geschwind.²⁸ Callosal pathways transmitting visual information from visual association cortex of the right hemisphere to language centers in the left hemisphere are interrupted by a lesion in the splenium, forceps major, or paraventricular white matter surrounding the occipital horn of the lateral ventricle.¹⁷⁹ Visual information from the right hemifield is either absent in cases with right hemianopia, or also interrupted in its course to the left language centers. In fact, right hemianopia from lesions elsewhere in the visual pathways, such as the left geniculate nucleus, can lead to pure alexia when combined with a splenial lesion.^193,194 Cases of pure alexia without hemianopia have been found in patients with lesions of the white matter underlying the angular gyrus. Such “subangular” lesions presumably interrupt the input to angular gyrus from both hemispheres at a very distal site.^183–185 Although some cases of pure alexia without hemianopia suggest that the callosal fibers from the right hemisphere travel in white matter tracts inferior to the occipital horn,^184,185 Binder and Mohr¹⁸⁰ proposed that some fibers may travel dorsal to the occipital horn. They also hypothesized that preservation of these dorsal callosal fibers is critical to retained letter-by-letter reading in spelling dyslexia, which they consider a partial form of pure alexia, compared with global pure alexia, which they consider the complete form.

Although disconnection theory dominates the discussion of pure alexia, other interpretations of the defect also exist. Some argue that it represents a form of simultanagnosia (see Balint's syndrome).¹⁰¹ Others have argued that letter-by-letter readers are unable to access information about the visual word-form: that is, pure alexia may be a specific type of visual agnosia.^191,195 In keeping with this, a recent investigation found that a patient with pure alexia had difficulty perceiving complex textures, suggesting a problem with local pattern analysis.¹³² It was suggested that alexia and prosopagnosia are hallmarks of two different types of visual agnosia, stemming from basic differences in right and left hemispheric visual processing.

HEMIALEXIAS. The disconnection hypothesis advanced by Dejerine¹⁷⁸ and Geschwind²⁸ involves two deafferentions of the left hemisphere reading process: the disconnection of right-hemisphere visual information and the disconnection or destruction of left-hemisphere visual information. Each of these two disconnections have been described in isolation, both causing hemialexias. Greenblatt¹⁹⁶ reported left hemialexia, in which reading was impaired in the left but not the right visual hemifield because of isolated damage to callosal fibers. A similar left hemialexia follows surgical section of the posterior corpus callosum.¹⁹⁷ Right hemialexia due to a lesion of the left medial and ventral occipital lobe that spared other visual functions in the right field also has been reported.¹⁹⁸ Left hemiparalexia is yet another rare disconnection syndrome attributed to splenial damage.¹⁹⁹ The reading pattern in this disorder is similar to that in left hemineglect dyslexia (see later in chapter) in that substitution and omission errors occur for the first letter of words. Patients with left hemiparalexia, however, do not have any evidence of hemineglect and have right rather than left hemianopia.

ALEXIA WITH AGRAPHIA, LETTER BLINDNESS, AND CENTRAL DYSLEXIAS. Alexia with agraphia is characterized by relatively intact oral and auditory linguistic function, but deficits in reading and writing skills. Dejerine^177,178 and others²⁰⁰ showed that lesions of the left angular gyrus caused alexia with agraphia, although lesions of the temporoparietal junction also have been implicated.²⁰¹ In Gerstmann's syndrome, alexia with agraphia is also accompanied by acalculia, right-left disorientation, and finger agnosia.

Another form of alexia and agraphia is described as an accompaniment of Broca's aphasia (nonfluent aphasia), due to lesions of the left inferior frontal operculum.^202,203 The difficulty these patients have with reading aloud and writing is understandable given their nonfluent aphasia; however, their ability to comprehend written material is also impaired. These patients are better at occasionally grasping a whole word, without being able to name the letters of the word. For this reason it has sometimes been called “literal alexia” or “letter blindness,” as opposed to word blindness in pure alexia. These patients also have impaired comprehension of syntactic structure of sentences (grammar), just as their speech output often demonstrates agrammatism.

Central dyslexias are unusual reading problems that have been described more recently. Many of these occur in association with other aphasic features, but they can occur as isolated dyslexias also. They are labeled central dyslexias because they reflect dysfunction of central reading processes rather than “peripheral” attentional or visual processes. Central dyslexias are formulated in terms of reading models derived from cognitive neuropsychology. A review of central dyslexia is beyond the scope of this chapter, but can be found in Black and Behrmann.¹⁷⁴

SECONDARY ALEXIA: VISION AND ATTENTION. Patients with normal acuity but visual field defects can have reading problems secondary to visual loss. Complete bitemporal hemianopia from lesions affecting the optic chiasm can cause “hemifield slide,” in which the absence of overlapping regions of visual field between the two eyes leads to a breakdown of binocular alignment.²⁰⁴ This in turn causes episodic horizontal deviation, which is manifest by transient diplopia or disappearance of objects along the vertical meridian, and episodic vertical deviation, which is manifest by a vertical step in objects crossing the vertical meridian. Thus, when reading, letters may disappear or duplicate and lines of words may be confused as they cross from one hemifield into the other (Fig. 11). Patients with complete homonymous hemianopia may also complain of reading problems. With languages written from left to right, patients with left hemianopia may have difficulty returning to the beginning of the next line because the left margin disappears into their scotoma as they scan rightward. Marking their place with an L-shaped ruler may reduce this frustration, but may be futile if hemianopia is compounded by left hemineglect.

Attentional problems can also affect reading. In attentional dyslexia, the perception of single items is adequate, but perception of several objects simultaneously is impaired.^205,206 These patients can identify single words normally but have difficulty with several words together; similarly, they can identify single letters but cannot name the letters in a visually presented word. They may demonstrate literal migration errors, in which a letter from another word is substituted at the same place in another word (e.g., BONE TURN becomes TONE TURN). Letters may be mistaken for others similar in appearance (e.g., O for C, but not T for C).²⁰⁶ Attentional dyslexia has been associated with lesions in the left parietal lobe²⁰⁵ or temporo-occipital junction.²⁰⁶

Neglect dyslexia is another attentional reading problem, most often associated with right parietal lobe lesions. The hemineglect for the left side of space is reflected in left-sided reading errors.²⁰⁷ Such patients may omit reading the left side of a line, of a page, or of individual words (Fig. 12). With the latter, they may make omissions (e.g., PLANE becomes LANE), additions (e.g., ART becomes CART) or substitutions (e.g., TURN becomes BURN). These defects appear specific for the left side of space rather than the beginning of words because such errors do not occur for vertically printed words.²⁰⁷

DORSAL PATHWAY

“Balint's Syndrome” and Associated Visuospatial Disorders

In 1909, Balint²⁰⁸ reported an unusual triad of visual behavior defects in a man with bilateral cerebrovascular lesions:

1. “Spatial disorder of attention”: Wolpert²⁰⁹ later called this simultanagnosia and defined it as “an inability to interpret the totality of a picture scene despite preservation of ability to apprehend individual portions of the whole.”
   
2. “Optic ataxia”: A defect of hand movements under visual guidance despite normal limb strength and position sense.
   
3. “Psychic paralysis of gaze”: Also known as “spasm of fixation”or ocular apraxia,⁴ this is defined as the inability to move the eyes voluntarily despite unrestricted ocular rotations.
   

The visual fields in Balint's patient were reportedly normal for white objects and colors, and visual acuity was 20/40 or better; however, the man's attention appeared to quickly wane, producing a “concentric constriction” of the useful field of view. Balint believed his subject could see only one object at a time, no matter what its size. He reported that the man's focal point of attention was displaced 35° to 40° into the right hemifield and that he would read the letters only at the right ends of lines of text, a finding compatible with a left hemineglect syndrome (see Fig. 12). Defective reaching was worse with the right hand, and Balint believed both hands should have been affected equally if the problem was just visual. Also, when Balint positioned the left hand, the man could imitate the same position with his right hand, showing that position sense was normal. The patient died of cerebrovascular complications, and an autopsy was performed (Fig. 13). Balint emphasized that the subject had bilateral lesions of the angular gyri and that the calcarine cortex was preserved; however, there was also extensive damage to other visual areas and connections, including damage to the posterior corpus callosum and white matter bilaterally as well as the pulvinar of the thalamus.

Holmes's 1918 report²¹⁰ on disturbances of visual orientation is often compared with Balint's. Holmes studied six soldiers with missile wounds of the occiput causing “an affection of the power of localizing the position in space and the distance of objects by sight alone.” The men had “moderately good” visual acuity and stereoacuity, and Holmes doubted that their various visual field defects (including homonymous hemianopia, quadrantanopia, paracentral scotomata, and extensive loss of peripheral vision) could account for their visual disorientation (i.e., errors in judging the relative location and distance of objects). The soldiers failed to detect objects presented in their “normal” visual fields if they were otherwise occupied, but Holmes distinguished this from “the unilateral ‘disturbance of visual attention;” that occurs “as a result of parietal and lateral occipital lesions.” He believed that his subjects' difficulty counting coins and navigating were due to multiple defects, including the spatial localization defect, failure to attend to objects in the periphery, and defective fixation and search. Altogether, their abilities “contrasted unfavorably with a blind man.” Two soldiers (cases 2 and 5) died, and autopsies were performed. The soldier in case 2 had an entry wound in the lateral surface of the right occipital lobe, with exit in the area of the left angular gyrus affecting the “dorsal portions of the sagittal bundles” in both hemispheres, “posterior to the splenium and dorsal to the calcarine fissures,” in the region of the parieto-occipital sulci. In case 5, the soldier had an entry wound in the left hemisphere destroying the supramarginal gyrus, with softening toward the central fissure. The missile tract lay above the splenium, and the exit wound affected the right angular gyrus. Craniometric assessments of the entry and exit wounds in the skulls of the survivors also suggested similar bilateral dorsolateral lesions.

Hécaen and Ajuriaguerra^210a are credited with coining the term Balint's syndrome. They reported on four patients with “minor forms of Balint's syndrome” who showed sluggish exploration of the visual environment, which they attributed to “sticky fixation,” or restriction of fixation to a single point. They also recognized a “motor component” of their patients' defects, relating it to possible damage in posterior parietal and occipital association cortices concerned with ocular pursuit. Precise anatomic localization was not possible, as in most cases that antedate the era of modern neuroimaging procedures. Luria²¹¹ reported on “disorders of simultaneous perception” in a Polish officer, shot in the head in the waning days of World War II. The brain damage resulted in “vestibular giddiness,” “fits,” and severe constriction of the visual fields on a perimetric examination. The patient could perceive objects “in an essentially normal manner,” but “moved his eyes from one object to another in a confused and inadequate manner” leading to “failure to fixate one or more of the objects present.” The patient tended to neglect objects on the left, as did the patients of Balint, Holmes, and Hécaen and Ajuriaguerra. Luria's²¹² subject also showed defective hand movements under visual guidance, and “his gaze manifest the same helplessness as his arm.” He believed that his patient had “limitation of visual attention,” “incapacity to combine details into a coherent whole,” and “piecemeal perception” due to a “weakness in cortical tonus” within the visual cortex causing each “focus of excitation” within that area to “inhibit the remainder of the visual cortex by negative induction.”

There have been several objections to the need for the designation “Balint's syndrome.²¹³” The full syndrome is generally associated with a wide variety of behavioral disturbances, which raises questions as to the existence of a specific underlying mechanism. These disturbances include cortical blindness, Anton's syndrome (denial of cortical blindness), bilateral visual field defects including central or paracentral scotomata, bilateral upper quadrantanopia, metamorphopsia, palinopsia, monocular polyopia, poor visual acuity, cerebral akinetopsia, and dementia (Table 7).²¹³ Many aspects of the disorder are indistinguishable from the hemineglect (right parietal lobe) syndrome, violating the principle of autonomy for a syndrome.

TABLE SEVEN. Balint's Syndrome and Other Disorders of Visuospatial Processing

  Balint's syndrome

  Simultanagnosia (visual disorientation)
  Optic ataxia
  Ocular apraxia

  Inability to perceive a directional motion signal
  Reduced dynamic visual acuity
  Inability to perceive 2-D and 3-D structure from motion cues
  Defective flicker perception

Indeed, each of Balint's original triad of defects, particularly simultanagnosia, may represent relatively broad categories that subsume other combinations of defects of widely different degrees of severity. Moreover, the main proposed mechanism, an inability to see more than one object at a time, no matter what its size, is not sound. The first half of this assertion was an exaggeration. True, Balint's patient performed worse in the detection, description, or identification of visual stimuli when several were present, which is compatible with constriction of the fields of attention. Yet it is clear from Balint's own observations that his subject could process more than a single object at once, as when he successfully read whole sections of text (comprising several words). The second half of Balint's assertion, that his subject could see any single object, no matter what its size, is erroneous. This claim was based on the patient's ability to recognize relatively large targets, such as a person, by vision alone. Yet, the recognition of persons or their faces can be accomplished with economy, based on just a few features. Normal subjects can recognize degraded representations of persons as in caricatures of famous faces, or they can identify familiar persons from glimpses, silhouettes, or partial views. Recognizing a person or object, as Balint claimed his subject could do, can never prove that all of the object is being seen simultaneously. (See Ball and colleagues²¹⁴ for more modern insights on reductions in the the useful field of view in conditions of attentional load or impairment.)

Nevertheless, Balint's report is valuable because it suggested that the dorsolateral visual association cortices are critical for processing visuospatial information and for visual attention.²¹³ It also provided preliminary clues as to the neural substrates of visually guided reaching and grasping behavior. Subsequent studies have supported the presence of attention-related neurons in the visual association cortex of primates and humans.^215–217 These later studies have also confirmed the role of structures in the parietal lobe and occipitoparietal regions, including Brodmann's areas 5, 7, superior 19, 37, and 39 in the neural control of visually guided reaching and grasping of objects in extrapersonal space (Fig. 14).²¹⁸ Damage in these areas is now also reported to impair motion perception²¹⁹ (see Disorders of Motion Perception).

The many causes of “Balint's syndrome” and related disorders of visuospatial processing include cerebrovascular disease (especially watershed infarctions),^8,220,221 tumor, trauma, “slow virus” or prion infections such as Creutzfeldt-Jakob disease, HIV infections,²²² and degenerative conditions such as Alzheimer's disease.^223,224

In these cases, as in the other disorders of cerebral integration outlined in this chapter, a basic ophthalmologic examination is crucial to rule out disorders of the retina or ocular media. Perimetry may be difficult because of attentional difficulties, fixational lapses, and easy fatigue. The use of neuropsychologic probes, as summarized by Tranel,²²⁵ is most helpful.

Disorders of Motion Perception

MOTION PERCEPTION IN NONHUMAN PRIMATES. Initial evidence for motion-sensitivity in extrastriate visual cortex came from studies of monkeys. These studies have revealed several motion-sensitive regions. Neurons in the MT area of the superior temporal sulcus were first found to be selective for the direction and speed of motion,^226–230 but not for shape or color.^227,230,231 MT projects to the adjacent MST and ventral intraparietal (VIP) areas.²³² MST has two distinct regions: a ventral portion responds best to the relative motion of small objects, and a dorsal portion responds best to motion over large regions of the visual field.²³³ Dorsal MST also has neurons that respond to large complex motion patterns, such as expanding or contracting radial patterns and rotating motion.^234–237 The VIP area has not been extensively investigated, but it is reported to contain cells that discharge in the presence of a moving object that would collide with the monkey's face.²³⁸

The anterior superior temporal polysensory (STPa) area contains cells responsive to form²³⁹ and others responsive to motion.²⁴⁰ Some STPa cells discharge selectively for complex body movements, such as hand actions, gait, and head movement,^239,241 and may represent an integration of visual input from both dorsal and ventral pathways. Some regions in the ventral (form) pathway also respond to moving stimuli. For example, form- and orientation-selective neurons in the IT cortex respond to their preferred stimulus regardless of whether the defining visual attribute is luminance, texture, or motion.^242,243

Considering that there are already direction-selective neurons in striate cortex, several studies have asked what specific contribution MT makes to motion perception. Experiments with transparent motion^244–246 and moving plaids^247,248 show that some MT neurons may reduce motion noise by averaging motion vectors over large regions to derive a judgment of common global motion. In contrast, V1 neurons respond whenever motion in their preferred direction is present, without regard for the presence of other moving stimuli. Noise reduction within MT is restricted to motion at the same stereoscopic depth, while motion at different depths and presumably from different objects continues to be represented, allowing the perception of transparent moving surfaces.²⁴⁹

Motion can also be differentiated into first- and second-order types. First-order motion involves displacement of luminant object borders, whereas second-order motion is defined solely by movement of features such as texture and stereo disparity, without changes in mean luminance. Most MT cells respond to both first- and second-order motion, suggesting that MT functions as a general motion detector.^229,250 Another possible role of some MT neurons is the analysis of relative motion. The direction-selective responses of some MT neurons are inhibited by motion in a similar direction in the surrounding visual field.^251–253 This surround inhibition may play a role in figure-ground discrimination, perceptual constancy, and motion cues to depth perception. It may also aid in accurate judgment of object trajectory during eye movements by comparing object motion to the movement of the background across the retina as the eye moves.

Lesions of MT or MST cause pursuit and saccades to targets in areas of the contralateral visual field to underestimate target velocity (retinotopic motion defects).^254–257 This is thought to represent abnormal motion analysis rather than an oculomotor defect because the defect is restricted to a contralateral area of visual space, is specific for moving targets, and affects both pursuit and saccades. Deficient motion perception in the contralateral hemifield has been confirmed with random dot cinematograms that require subjects to judge motion direction from a background of motion noise.²⁵⁸ Schiller¹⁰ also found mild-to-moderate contralateral retinotopic impairments in motion detection, motion direction discrimination, and speed discrimination, though all defects were less severe than those caused by geniculate lesions, suggesting that other cortical areas participate in motion processing. Recovery of pursuit and perceptual defects after small MT or MST lesions usually occurs within 2 weeks and likely depends on surviving portions of MT or MST.^{254,255,258,259} Recovery after complete lesions of both MT and MST also occurs but is slower and incomplete and likely involves other cortical areas.²⁵⁹ Large bilateral lesions of MT and MST create enduring impairments in a range of motion tasks.^260,261

Lesions of either monkey MT/MST²⁶¹ or IT cortex²⁶² impair perception of motion-defined form, implying that elements of both the ventral and dorsal streams participate in the perception of form-from-motion. In support of this concept, Schiller¹⁰ found that lesions of either V4 or MT alone produced only mild defects in the discrimination of rectangular shapes defined by moving dots against a background of stationary dots, but that concurrent lesions caused a moderate defect.

In monkeys viewing random-dot cinematograms, microstimulation in the MT area was found to affect judgment of direction.^263–265 Small currents biased the decision in the preferred direction of the stimulated neurons, whereas large currents impaired discrimination, presumably by increasing motion noise from current spread into adjacent neuronal columns.

Psychophysical and physiologic performance have been assessed simultaneously in monkeys viewing coherence-based random dot cinematograms.²⁶⁶ “Neurometric” thresholds based on the firing rates of MT neurons were similar to the psychophysical performance of the monkey for direction discrimination. In a similar experiment with MST neurons, Celebrini and Newsome²⁶⁷ found similar results, and showed that neuronal and psychophysical thresholds were both affected by changes in stimulus size and speed. Thus it is possible that motion direction discrimination in monkeys is supported sufficiently by a small number of neurons in either MT or MST.

TESTING MOTION PERCEPTION. Motion perception can play many roles in vision.²⁶⁸ One role is the perception of moving objects in the environment. Since such objects usually occupy only a small portion of the visual field, one can obtain a sense of their relative motion by comparing their motion with that of the background. Perception of object motion is used to guide reaching movements of the limbs and tracking eye movements, such as saccades and smooth pursuit. Information about the movement of the observer can also be derived from motion perception. As the observer moves or turns his or her head or eyes, the image of the entire visual environment moves in the opposite direction. Thus, motion occurring over large portions of the visual field usually implies that the observer rather than an external object is moving. This large field of motion generates optokinetic responses that complement the vestibulo-ocular reflex in stabilizing the line of sight during head- or self-motion. It is also possible to derive information about object identity from visual motion: The difference in motion between a figure and its background aids in segmenting its two-dimensional form, and the pattern of velocity gradients within an object encodes the object's three-dimensional form.

Tests for these different aspects of motion perception exist. Studies of eye movements have long revealed abnormalities of smooth pursuit and optokinetic nystagmus with cerebral lesions, but whether these represent motor or perceptual defects cannot be determined definitively from eye movements alone. Animated displays with random dots or moving gratings have come into use more recently. Displays can be designed to probe whether subjects can discriminate motion direction, motion speed, the presence of a motion boundary, and forms defined by motion (Fig. 15). Most of these are still experimental.

HUMAN CEREBRAL AKINETOPSIA. Lesions of extrastriate cortex can produce a defect in motion perception, which Zeki²⁶⁹ called cerebral akinetopsia. The cases of two such patients, who had bilateral lesions of lateral temporo-occipital cortex, have been well-described in the literature. The most well known is the case of L.M., a patient who suffered a sagittal sinus thrombosis with cerebral infarction of lateral aspects of Brodmann's areas 18, 19, and 39 bilaterally.^{219,270–273} Patient A.F. had bilateral lesions of lateral occipitotemporal cortex caused by an acute hypertensive hemorrhage.¹⁹⁵ In both patients, spatial and temporal aspects of contrast sensitivity, shape, orientation, and color discrimination, as well as complex tasks such as matching forms and recognizing faces and objects, were relatively normal. In L.M., detection of motion was relatively preserved both centrally and in the peripheral field for moderate velocities (up to 8°/sec), but greater impairments were evident on more complex motion tasks. Her ability to predict the trajectory of moving objects and her ocular smooth pursuit were abnormal, and there was dramatic impairment of discrimination of temporal frequency and drift velocity of gratings. Small amounts of random motion or even stationary noise degraded her discrimination of motion direction and identification of three-dimensional shapes from motion cues. Similarly, A.F. was severely impaired in discriminating speed differences, direction in the presence of motion noise, and two-dimensional forms on the basis of regions with relative differences in motion speed.

Some impairments on nonmotion tasks were also evident in these two patients. L.M. also could not perceive form on the basis of texture, dynamic stereo, and static density cues. A.F. was poor at recognizing objects from unusual viewpoints and in incomplete outline drawings. The patient also showed impairment on tests of spatial vision (e.g., hyperacuity, line orientation, line bisection, spatial location) and stereopsis.

Unilateral lesions of extrastriate cortex cause more subtle abnormalities of motion perception. Motion defects restricted to the contralateral hemifield have been described. These include speed discrimination,^274,275 detecting boundaries between regions with different motion,¹⁹⁵ and discriminating direction from backgrounds of motion noise.²⁷⁶ In these studies, motion detection and contrast thresholds for motion direction^274,275 were normal. Lesions were located in the lateral occipitotemporal cortex or in the inferior parietal lobule. As with hemiachromatopsia, such hemiakinetopic defects may not be common because hemianopia caused by damage to optic radiations or striate cortex frequently accompanies natural lateral occipitotemporal lesions.

Abnormalities demonstrated by centrally viewed motion tests also can occur in patients with unilateral lesions, circumventing the problem of hemianopia. Vaina²⁷⁷ found that patients with right occipitotemporal lesions could not identify two-dimensional structures from motion cues, whereas patients with right occipitoparietal lesions could not discriminate velocity or detect three-dimensional structures from motion cues. Regan and associates²⁷⁸ reported difficulty in detecting or recognizing motion-defined letters in patients with white-matter lesions underlying the lateral temporo-occipital cortex of either hemisphere. Nawrot and colleagues²⁷⁹ found abnormal direction discrimination in seven subjects with right hemisphere lesions. Five had a lesion in the occipitotemperoparietal area, and two had other lesions: a ventromedial occipital in one and an insular lesion in the other. Impaired direction discrimination of motion toward the side of the lesion has been found in cases of lesions of the lateral occipitotemporal area.²⁷⁶

These lesion studies suggest that, in humans, a variety of complex motion tasks involve the lateral occipitotemporal or occipitoparietal cortex. These tasks include discrimination of the speed of motion vectors, integration of vectors for discrimination of global direction and three-dimensional structure, and segregation of motion vectors to discriminate the two-dimensional structure of shapes and letters. Simpler tasks of motion perception, however (e.g., detection of motion, discrimination of motion in the absence of noise), are not impaired. This implies that more elementary motion signals are processed at other, possibly earlier, cortical sites. The role of lateral occipitotemporal cortex may be to use these simpler motion signals to derive a higher order representation of motion. Therefore its destruction may not leave a patient truly motion-blind, but impaired at complex analyses of motion. Furthermore, other aspects of spatial analysis may be impaired,^195,270 as might be expected of a lesion affecting the dorsal pathway.

VISUAL PERSEVERATION

The persistence, recurrence, or duplication of a visual image is a rare complaint. The term palinopsia (or paliopsia) refers to the perseveration of a visual image in time.²⁸⁰ It is distinguished from visual hallucinations by the fact that the palinopsic illusion is determined by the elements of a previously or currently viewed scene, whereas the content of visual hallucinations lacks a relation to current or recent visual experience. Nevertheless, the distinction is sometimes difficult, and some patients have both perseverative and hallucinatory phenomena.^280,281 Perseveration of a visual image in space has been termed cerebral diplopia or cerebral polyopia: these phenomena describe the perception of one or more duplicates of a seen object simultaneously.^282,283 Another type of spatial perseveration occurs when the contents or surface of an object appear to spread beyond the true spatial boundaries of the object, a phenomenon termed illusory visual spread.²⁸⁰ Thus a wallpaper pattern may appear to spread beyond the true borders of the wall, and the pattern of a garment may spread over the wearer's face.²⁸⁰ Some patients experience perseveration in both space and time, resulting for example in palinopsic polyopia.²⁸³ A form of this occurs in patients who report that as an object moves they see multiple copies of the object in its trail, although this may not be true polyopia. Bender and associates²⁸¹ argued that because palinopsic images were often larger than the original images, this represented an illusory visual spread concomitant with palinopsia; however, Critchley²⁸⁰ considered this combination exceptional.

Palinopsia, the abnormal persistence of a visual image in time, may take two forms:

  Immediate type: An image continues to be seen long after the actual scene has disappeared, eventually fading after a period of several minutes usually. This type of palinopsia thus has some similarity to the normal afterimage experienced after prolonged viewing of a bright object. Indeed, detailed investigations of some palinopsic patients have suggested that the differences between normal afterimages and palinopsic images are primarily quantitative²⁸⁴; however, other studies disagree.²⁸¹
  Delayed type: An image of a previously seen object may reappear after an interval of minutes to hours, sometimes repeatedly for days or even weeks.²⁸⁴ Some patients have both immediate and delayed types of palinopsia.²⁸⁴

The location of the perseverated image in the visual field can vary. In some patients, it persists in the same location as the original image (usually foveal) and moves as the eyes move, much like a normal afterimage.²⁸⁵ In other patients, the image reappears in a coexistent visual field defect²⁸⁰; indeed, Bender and colleagues²⁸¹ considered palinopsia to be a transient feature in the evolution of homonymous field defects. In other patients, the perseverated image is multiplied across otherwise intact visual fields.²⁸³ The location of palinopsic images is sometimes quite contextually specific. For example, some patients report that after they view a face on television, everyone else in the room appears to have the same face as the person on television; others report that the print on a sign over one shop reappears on the signs over other shops.^280,283,286 Although some of these visual descriptions may represent a sophisticated form of palinopsic polyopia, others may actually be consistent with a constant foveal or perifoveal location of a perseverative image that manifests itself repeatedly when the context is appropriate.

Visual perseveration can be accompanied by a wide variety of other symptoms. Almost always there is an associated homonymous visual field defect. Both upper^92,286 and lower²⁸⁴ quadrantanopias have been reported. Other illusions of spatial aspects of stimuli can accompany visual perseveration, such as metamorphopsia (the distortion of objects), macropsia (the illusion that objects are larger than in reality), and micropsia (the illusion that objects are smaller than in reality).^{280,281,284,287} Less frequently, signs of a “ventral stream” lesion have been reported, such as topographagnosia, prosopagnosia, and achromatopsia.^92,281 Visual perseveration within other sensory modalities may also occur: Cummings and co-workers²⁸⁵ reported on a patient with both visual and somatosensory perseveration.

The prognosis for visual perseveration varies. Bender and associates²⁸¹ considered palinopsia to be a rare but transient phase in the resolution or progression of a visual field defect, usually lasting days to months. Others, however, have described palinopsia persisting for months to years.^{284,285,288,289} Anticonvulsant treatment may help some types of palinopsia,²⁸⁸ but not others.²⁸⁵

Mechanisms

The pathophysiology of palinopsia remains obscure. Four main hypotheses have been advanced, as summarized by Bender and colleagues.²⁸¹ These include a pathologic exaggeration of the normal afterimage, a seizure disorder, hallucinations, and psychogenic origin.

EXAGGERATION OF THE NORMAL AFTERIMAGE. This hypothesis was suggested by Kinsbourne and Warrington's study²⁸⁴ of two patients with shared palinopsic features. These features included a dependence of the prominence of the palinopsic image on the intensity and duration of the initial stimulus, a negative (i.e., complementary color) afterimage when visualized against a light background, a binocular afterimage after monocular viewing of an object, and motion of the afterimage in the same direction as active eye movements but in the opposite direction when the eyes are moved passively. However, not all cases of immediate palinopsia exhibit these features.²⁸¹ In particular, the color of palinopsic images tends not to depend strongly on the colors of the original stimulus.^281,289

SEIZURE DISORDER. The hypothesis that palinopsia is a manifestation of epilepsy is supported circumstantially by the fact that several patients in early series^280,281 had other features that suggested seizures, such as episodic loss of consciousness, tongue biting, and confusion. Epileptiform abnormalities seen on electroencephalograms and improvement of palinopsia with anticonvulsants have been reported in some cases of patients with the immediate type of palinopsia,^287,288 although it should be stressed that improvement with anticonvulsants does not prove ictal origin.

HALLUCINATIONS. The third hypothesis is that palinopsia may be a nonictal hallucinatory state. Some patients with palinopsia have coexistent nonpalinopsic visual hallucinations, and the location of perseverative images within visual field defects is reminiscent of the release hallucinations of the Charles Bonnet syndrome. Hallucinogenic drugs have been known to cause palinopsic illusions as well.²⁸⁴ Cummings and co-workers²⁸⁵ suggested that delayed palinopsia with concurrent hemianopia was a release hallucination, whereas immediate palinopsia was more likely ictal in origin, especially in the absence of a visual field defect. The value of such a distinction remains to be proved.

PSYCHOGENIC DISORDER. The possibility of a psychogenic basis was considered by Critchley,²⁸⁰ who postulated that palinopsic reports may be a confabulatory response to other visual dysfunction.

Anatomy and Pathology

In investigating visual perseveration, intoxication with hallucinogens such as mescaline and lysergide (LSD) must be excluded. There are also isolated reports of palinopsia and other visual illusions caused by prescribed medication, such as clomiphene,²⁹⁰ interleukin 2,²⁹¹ and trazodone.²⁹² Rarely, palinopsia occurs in psychiatric conditions such as schizophrenia²⁹³ and psychotic depression,²⁹⁴ but as with visual hallucinations in such patients, the visual symptom is always accompanied by other signs of mental illness.

Once these conditions are excluded, however, visual perseveration virtually always indicates a cerebral lesion. One possible exception was a case of immediate palinopsia whose only known visual pathway lesions were bilateral optic neuritis²⁹⁵; however, this patient had clinically definite multiple sclerosis with prior brainstem symptoms, so without MRI one cannot exclude subclinical cerebral hemispheric lesions. The value of palinopsia in localizing cerebral lesions more precisely, however, is uncertain. Bender and associates²⁸¹ found a predominance of right parieto-occipital lesions, although they stated that left hemispheric lesions may have been underrepresented because of coexisting aphasia. Critchley²⁸⁰ documented right, left, and bilateral lesions with palinopsia. Bender's parieto-occipital location is contested by the demonstration of medial occipital and occipitotemporal lesions in some patients' CT and autopsy specimens.^283,286 In a rare case, no lesion was found with neuroimaging.²⁸⁹

VISUAL HALLUCINATIONS

Hallucinations are defined as perceptions without external stimulation of the relevant sensory organ. They are not uncommon in patients with abnormal mental states due to dementia or confusional states secondary to metabolic or toxic insults. Visual hallucinations also occur in cases of psychiatric illness, but they usually are accompanied by other signs of mental illness and hallucinations in other sensory modalities, especially auditory. In persons with intact cognition and mental function, however, isolated visual hallucinations can occur. In these cases, the hallucinations are often a sign of underlying neurologic or ophthalmologic disease.

Isolated visual hallucinations can be categorized into three pathophysiologic groups: “release” hallucinations, visual seizures, and migraine.

“Release” Hallucinations (Charles Bonnet Syndrome)

It is increasingly recognized that visual loss of any origin can result in visual hallucinations. These are called release hallucinations because it is thought that they somehow arise or are released in visual cortex by the absence of incoming sensory impulses. Patients with release hallucinations are characterized as having a clear mental state, associated central or peripheral visual field defects (usually binocular), awareness that the visions are not real, lack of distress, and lack of hallucinations in other sensory modalities. One series reported release hallucinations occurring in up to 57% of patients with a variety of causes of visual loss.²⁹⁶ Hallucinations are often classified as simple or complex: Unformed lights, colors, and shapes are seen in the former; recognizable objects and figures are seen in the latter. Lepore²⁹⁶ estimates that the simple type of hallucination is at least twice as common as the complex type. Several series have suggested an incidence of 10% to 30% for complex hallucinations in visual loss,^296–299 so even these more dramatic forms are not unusual. It has been suggested that the true incidence of these is often underestimated because of a reluctance on the part of patients to mention hallucinations, for fear of being labeled “crazy.”

The content of hallucinations ranges from brief flashes of points of light and colored lines, shapes, and patterns in simple hallucinations (phosphenes),^300–302 to complex scenes of humans and animals moving,^{296,303–305} with a potential for bizarre, dream-like imagery of considerable detail and clarity.²⁹⁸ Some authors reserve the diagnosis of Charles Bonnet syndrome for patients with complex, formed hallucinations.^298,299 It is clear, however, that some patients who initially have simple hallucinations eventually experience complex ones,^303,305,306 as is reported in visual hallucinations in normal people subject to sensory deprivation.³⁰⁷ Also, because the type of release hallucination does not correlate with the site of visual loss,³⁰³ the value of such a distinction is questionable. In patients with complex hallucinations, the vision is sometimes a recognizable image from the patient's past.^303,305,308

Not all patients with visual loss experience release hallucinations, so it appears that there must be other contributing factors in those patients who do have them. Increased age is one that is often cited. Indeed, in the review by Schultz and Melzack,²⁹⁸ 80% of patients with hallucinations were more than 60 years old. However, even subjects as young as age 10 can have release hallucinations.²⁹⁸ Social isolation has also been mentioned as a potential factor exacerbating the sensory deprivation inherent to visual loss.³⁰⁹ The prospective study of Teunisse and colleagues²⁹⁹ found a trend toward hallucinatory patients living alone or being widowed. Although it is often stated that release hallucinations occur in persons with an otherwise sound mind, Cole³⁰⁹ found that cognitive impairment was a feature in 9 of his 13 patients. Schultz and Melzack,³¹⁰ however, administered a psychologic test battery to 14 patients and found no evidence of cognitive dysfunction or depression. This suggests that cognitive decline is not a necessary precondition for visual release hallucinations.

Hallucinations often start in close relation to the time of visual loss. Often they follow visual loss by a period of several days or weeks, but they may be even more delayed.^304,305 In cases of asymmetric binocular ophthalmic pathology, it often is not until visual loss develops in the second eye that hallucinations develop.^304,306 Hallucinations and visual loss may also occur simultaneously; in such cases, it is the complaint of visual hallucinations that leads to the discovery of a visual field defect. On rare occasions, it has been documented that the hallucinations actually preceded hemianopia by a few days.³⁰⁰

The time during which hallucinations occur is often short, lasting a few days to a few months, although hallucinations persisting for years have also been reported.^304,305 In Kölmel's series,³⁰⁰ the mean duration of complex hallucinations was 11.5 days. Kölmel²⁹⁷ also believed that the occurrence of colored patterns in hemianopic fields correlated with temporary damage to optic radiations rather than permanent destruction of striate cortex, and that these patterns were a good prognostic sign for recovery of hemianopia. The hallucinatory episode can be brief, each episode lasting a few seconds or minutes, or virtually continuous.²⁹⁸ Although many subjects are not troubled by their hallucinations and may even enjoy them,²⁹⁸ some find them annoying. Thus, although most subjects do not require treatment for hallucinations, a therapeutic trial is sometimes warranted. Unfortunately, there is no agreement on effective treatment. Good responses to anticonvulsants have been reported in some cases,^305,311 but not others,^304,305 and positive and negative results have also been reported with the use of haloperidol.^306,309 Moving socially isolated patients into a more stimulating environment has helped on occasion.³⁰⁹

ANATOMY AND PATHOLOGY. Visual loss of any type can lead to release hallucinations.³⁰⁴ The most common site of damage in Lepore's series²⁹⁶ of 104 patients was cerebral, and most of these patients had had infarctions. Among ocular causes of visual loss, cataracts were most frequent. Retinal disease³⁰⁶ and pathology of the optic nerves and chiasm³⁰³ also have been reported. It is generally agreed that no other pathology is required for the production of release hallucinations than the disorder causing visual loss. That is, release hallucinations are not a manifestation of an underlying cerebral abnormality, but a physiologic reaction to loss of vision. It then remains to be determined, however, why not all subjects with binocular visual loss have hallucinations. Besides the influence of age and social isolation mentioned above, one report suggests that patients with hallucinations from ocular disease have a higher incidence of posterior periventricular white matter lesions seen on MRI,³¹² an interesting finding that needs verification.

Most series consist of patients with some degree of bilateral visual loss.^303,304 The need for binocular pathology, however, has been questioned,²⁹⁶ and it would appear that occasionally patients who have no or minimal demonstrable visual loss have similar visual hallucinations.^296,304,309 Release hallucinations can occur in normal subjects in sensory deprivation experiments,³⁰⁷ and it is possible that some subjects with hallucinations but without visual loss are experiencing a similar deprivation in conditions of social isolation, especially since their hallucinations can resolve with a change in surroundings.³⁰⁹

MECHANISMS. Schultz and Melzack²⁹⁸ have summarized the various theories concerning release hallucinations. In cases of intracranial pathology, hallucinations have sometimes been considered visual seizures,³⁰⁵ although Cogan³⁰⁴ suggested that release hallucinations differed from seizures by their longer duration and variability in content, as well as their association with visual loss rather than secondary motor or sensory epileptic events.²⁹⁸

Earlier reports of optic nerve pathology causing visual hallucinations suggested an analogous “irritation” occurring at the optic nerve.³⁰³ Others suggested that hallucinations associated with ocular pathology such as cataracts were a type of entoptic phenomenon, being the subject's interpretation of the image of retinal blood vessels, the retinal ganglion network, and other ocular structures. This theory is clearly untenable in those with enucleations. Most authors today believe that release hallucinations originate within the brain rather than in ocular structures. Visual experience is represented by patterns of coordinated impulses within the vast neural network of visual cortex. These patterns represent individual experience and normally are generated by sensory stimuli; however, it is proposed that the brain has an inherent capacity to generate such patterns spontaneously, and does so in conditions of sensory deprivation through imposed isolation or pathologic denervation.²⁹⁸ These patterns then correspond to hallucinations. A similar explanation has been invoked for the “phantom limb” phenomenon that sometimes follows amputation, and presumably also underlies other release phenomena such as musical hallucinations in cases of decreased hearing.³¹³

Visual Seizures

Visual seizures are not common among the epileptic population, but they do occur and can cause confusion with migraine and release hallucinations. Indeed, much of the confusion regarding the localizing value of the content of epileptic hallucinations stems from failure to distinguish between release hallucinations and visual seizures. Weinberger and Grant's influential statement³⁰³ that “the complexity of the hallucinations has no localizing value” occurred in the context of a discussion of release hallucinations associated with optic nerve disease, not visual seizures. Clearly, release hallucinations can take on an impressive variety of manifestations, and it is the associated field defect, rather than the hallucinatory content, that holds the key to localization. The same may not be true, however, of visual hallucinations due to seizures, as Cogan³⁰⁴ indicated. The stimulation experiments of Penfield and Perot³¹⁴ and Foerster³¹⁵ suggested that simple, unformed flashes of light and colors resulted from electrical activity in primary visual cortex, whereas stimulation of visual association cortex in area 19 and temporal regions resulted in complex, formed images. A similar distinction may hold for epileptic visual hallucinations. For example, a left parietotemporal lesion was reported to cause hallucinations of objects and written words followed by post-ictal aphasia,³¹⁶ and a right temporal hemorrhage caused hallucinations of a familiar face,³¹⁷ whereas occipital lobe seizures were found to cause hallucinations of colored circles and spheres.³¹⁸ Nevertheless, occipital lesions have also been associated with complex hallucinations.³¹⁹ In such cases, spread of ictal activity into extrastriate cortex may be responsible for the formed visions.

The distinction between visual seizures and release hallucinations can be difficult when the underlying lesion is intracerebral. Cogan³⁰⁴ believed that release hallucinations were continuous and nonstereotyped in their content, whereas visual seizures were brief episodes with the same visual content in all seizures. Schultz and Melzack,²⁹⁸ however, point out that release hallucinations can sometimes be episodic rather than continuous and that their content may be repetitive. They suggest that the association with other ictal phenomena or a visual field defect is more helpful. We would add that although accompanying confusion, dysphasia, or head and eye deviation strongly support an epileptic origin, homonymous field defects indicate only the possibility of release hallucinations, since lesions that cause epilepsy may also damage the optic radiations or striate cortex. Indeed, Kölmel³⁰⁰ believed that complex hallucinations in hemianopia might represent a combination of ictal and release phenomena.

Although a variety of structural pathology in visual cortex may cause visual seizures, one syndrome that deserves emphasis is “benign childhood epilepsy with occipital spike-waves.”³²⁰ This idiopathic epilepsy syndrome often begins between ages 5 and 9 and ceases spontaneously in the teen-age years. Seizures are characterized by blindness or both simple and formed hallucinations, and may progress to motor or partial complex seizures. Some children develop nausea and headache after the visual seizure, creating diagnostic confusion with migraine. Electroencephalographic demonstration of occipital spike-waves during eye closure establishes the diagnosis.

Migrainous Hallucinations

Persons with migraine headaches can experience a variety of visual phenomena. These often precede the migraine headache (classic migraine) or may occur without the headache (migraine equivalent). Photopsic images are the most common, variably described as heat-wave-like shimmering, spots, or wavy lines.³²¹ The scintillating scotoma phenomenon is a slowly enlarging blind region surrounded by a margin of sparkling lights. In some persons, the form of this hallucinatory margin can be distinctly discerned as a zig-zag pattern of lines oriented at 60° to each other,³⁰¹ usually restricted to one hemifield, and on the leading edge of a C-shaped scotoma. Other terms for this pattern are “fortification spectrum” and teichopsia (Gr. teichos = town wall), derived from the resemblance of the zig-zag margin to the ground plan of town fortifications in Europe.³²² Several sets of zig-zag lines may be visible and often appear to shimmer or oscillate in brightness.³²³ They may be black and white³¹⁸ or vividly colored.^322,323

The lines begin near central vision and expand toward the periphery at an accelerating rate over a period of about 20 minutes, the size of the lines also increasing with retinal eccentricity. The speed and size of these lines are predicted by the cortical magnification factor, which is a measure of the area of visual field represented in a given amount of striate cortex as a function of retinal eccentricity.^301,324 This suggests that these visual hallucinations are generated by a wave of neuronal excitation spreading anteriorly through striate cortex at a constant speed, leaving in its wake a transient neuronal depression that is responsible for the temporary scotoma.³²³ It is also hypothesized that the zig-zag nature of the lines reflects the sensitivity to line orientation and the pattern of inhibitory interconnections within and between columns in striate cortex.^323,324 Although both migraine and visual seizures can feature abnormal visions followed by headache and vomiting, Panayiotopoulos³¹⁸ has suggested that the two disorders can be distinguished by the content of the hallucination, with black and white zig-zag lines dominating the former and colored circular patterns typifying the latter. This observation requires further corroboration.

Studies using functional MRI provide a source of data that is complementary to PET data and have shown motion-selective responses in the lateral occipitotemporal cortex, V2, and superior and inferior parietal lobules.^333,334 Signal changes in lateral occipitotemporal cortex also correlate with the motion aftereffect illusion that persists after cessation of the moving display.³³⁵ Probst and co-workers³³⁶ used visual evoked potential dipole analysis to show motion responses localized to the contralateral occipitotemporoparietal border (junction of areas 19, 37, and 39). Magnetic stimulation has been employed to create temporary dysfunction within cortical areas. Stimulation over lateral occipitotemporal cortex impairs motion direction discrimination but not form discrimination in the contralateral hemifield^337,338 and to a lesser degree in the ipsilateral hemifield.³³⁹

Comparative anatomic studies have provided yet another type of evidence on the organization of the human visual pathways to complement the data from functional neuroimaging and lesions studies. For example, some have inferred the location and size of a putative human area MT by comparing the histologic patterns of staining found in human brain material with the patterns observed in monkeys. Area MT is identifiable in monkeys by a pattern of dense myelination in the lower cortical laminae,^226,231,232 by dense cytochrome oxidase staining,^340,341 and by labeling with a monoclonal antibody (CAT-301) in Old World monkeys.³⁴² In human lateral temporo-occipital cortex, there are similar patterns of myelin staining,^341,343 cytochrome oxidase activity,^341,344 and CAT-301 immunoreactivity.³⁴¹

For color perception, most PET studies confirm the localization elicited from patients with cerebral achromatopsia, with increased blood flow in the lingual and fusiform gyri bilaterally,^{329,345–347} though some studies show changes in additional cortical regions that may vary according to the specific task used.^346,347 Associating colors with line drawings of objects activated regions in the ventral temporal lobe just anterior to the region activated during color perception.³⁴⁸ An evoked potential study³⁴⁹ with implanted electrodes in epileptic patients localized responses related to color perception to the posterior fusiform gyri, but also found activity over the dorsolateral surface of the brain, which they postulated were related to selective attention to color in their task. Stimulation of electrodes near the lingual and fusiform gyri produced alterations in color perception in some of these patients.

Face perception and recognition has been the subject of numerous functional imaging experiments. Sergent and associates,³⁵⁰ found that identifying faces was associated with activity in the fusiform gyri and anterior temporal lobe bilaterally, whereas merely noting the gender of a face activated only ventral occipital cortex, more on the right side than on the left side. Also, object recognition activated left occipitotemporal cortex but not right, implying an anatomic dissociation between face and object perception. A ventromedial temporal focus related to face perception has been found by others as well,^351–354 including a functional MRI study.³⁵⁵ An asymmetry in favor of right hemispheric dominance for face perception is suggested by some studies, although some left-sided activation does occur in most studies.^{350–352,354} Thus, functional imaging provides some circumstantial support for the claim that right hemispheric lesions alone can cause prosopagnosia.^92,95,118 The hypothesized sequence of events involved in facial recognition¹³⁰ has also been investigated with PET studies. One study that focused on the hippocampi concluded that the right hippocampus was involved in “primary visual processing” of faces, whereas the left was involved when explicit memory was required.³⁵⁴ Another study found that, although encoding of faces was associated with activity in the right medial temporal lobe, face recognition activated a large bilateral network of regions, including prefrontal, anterior cingulate, inferior parietal, ventral occipital, and even cerebellar cortex.³⁵²

In addition to these investigations of regional responses to specific perceptual stimuli, PET studies have also been used to study the basic concept of “two visual pathways.” Most of these studies have compared form and spatial vision by using tasks that require subjects to match objects either by their identity (e.g., form vision) or their location (e.g., spatial vision). These studies are in agreement, with greater activity occurring in occipitoparietal areas during spatial tasks and greater activity in occipitotemporal areas during object identification tasks.^353,356,357 Other studies of activation during spatial shifts of attention confirm the role of parietal cortex in this aspect of vision.^358,359

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