The Visual Agnosias and Related Disorders

There are many disorders of higher visual processing that result from damage to specific areas of the cerebral cortex that have a specific role in processing certain aspects (modalities) of vision. These can be grouped into those that affect the ventral, or "what?", pathway (e.g., object agnosia, cerebral achromatopsia, prosopagnosia, topographagnosia, and pure alexia), and those that affect the dorsal, or "where?", pathway (e.g., akinetopsia, simultanagnosia, and optic ataxia). This article reviews pertinent literature, concentrating on recent developments in basic science research and studies of individual patients. An overview of the current understanding of higher cerebral visual processing is followed by a discussion of the various disorders listed above. There has been considerable progress in the understanding of how the extrastriate visual cortex is organized, specifically in relation to functionally specialized visual areas. This permits a better understanding of the individual visual agnosias resulting from damage to these areas.

State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD The Visual Agnosias and Related Disorders Sameen Haque, MBBS, MMed, Michael S. Vaphiades, DO, Christian J. Lueck, PhD, FRACP, FRCP(UK), FAAN Background: There are many disorders of higher visual processing that result from damage to specific areas of the cerebral cortex that have a specific role in processing certain aspects (modalities) of vision. These can be grouped into those that affect the ventral, or "what?", pathway (e.g., object agnosia, cerebral achromatopsia, prosopagnosia, topographagnosia, and pure alexia), and those that affect the dorsal, or "where?", pathway (e.g., akinetopsia, simultanagnosia, and optic ataxia). Evidence Acquisition: This article reviews pertinent literature, concentrating on recent developments in basic science research and studies of individual patients. Results: An overview of the current understanding of higher cerebral visual processing is followed by a discussion of the various disorders listed above. Conclusions: There has been considerable progress in the understanding of how the extrastriate visual cortex is organized, specifically in relation to functionally specialized visual areas. This permits a better understanding of the individual visual agnosias resulting from damage to these areas. Journal of Neuro-Ophthalmology 2018;38:379-392 doi: 10.1097/WNO.0000000000000556 © 2017 by North American Neuro-Ophthalmology Society W hen looking at a visual scene, our brains process many different visual modalities, for example, form, color, location, movement, and identity. This processing occurs simultaneously, giving rise to a unified percept (1). Department of Neurology (SH, CJL), The Canberra Hospital, Canberra, Australia; Departments of Ophthalmology (MV), Neurology, and Neurosurgery, University of Alabama, Birmingham, Alabama; and Australian National University Medical School (CJL), Canberra, Australia. Supported in part by an unrestricted grant from the Research to Prevent Blindness, Inc, New York, NY. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Christian J. Lueck, Department of Neurology, The Canberra Hospital, Canberra, Wooden ACT 2606, Australia; E-mail: [e-mail] Haque et al: J Neuro-Ophthalmol 2018; 38: 379-392 These various modalities have been grouped into 2 broad categories, often labeled "what?" and "where?". "What?" information concerns "fixed" properties of an object, such as size, color, and orientation. "Where?" information refers to spatial information about an object, including position, distance, and movement. How the normal human brain processes these attributes has generated considerable historical debate (2,3). In 1861, Broca described 2 patients with selective language disturbance that he attributed to focal damage of the brain (4), introducing the concept of functional specialization of the cerebral cortex (5). Despite rare reports of patients with isolated loss of color vision (6) or selective preservation of visual motion perception (7), the existence of functional specialization of vision has been debated for over a century (2,3). Evidence from nonhuman primates in the 1970s (8) finally resulted in widespread acceptance that visual processing was functionally specialized (2), and this was demonstrated in humans in 1989 (9). Our understanding of the underlying physiology continues to improve based on both basic science research and detailed studies of individual patients with selective visual disorders. Standard clinical assessment often fails to detect these disorders (10) that are probably more prevalent than currently diagnosed, particularly in the context of stroke (10,11) and neurodegenerative disease (12). OVERVIEW OF ANATOMY AND VISUAL NEUROPHYSIOLOGY Information from the retina is transmitted to the primary visual cortex (V1, also known as striate cortex or Brodmann area 17). From here, visual information is passed to the surrounding area V2 (prestriate cortex) before being passed to V3 and the rest of the extrastriate cortex; the latter includes almost 40 specialized areas described in the nonhuman primate (1,13,14). These areas are broadly organized in 2 interconnected streams, or pathways, the ventral processing "what?" information and the dorsal processing "where?" information (15). The latter has a major role in 379 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. Lateral (A), medial (B), and inferior (C) views of the brain to show the approximate location of visual functionally specialized areas. FFA, fusiform face area; IPL, inferior parietal lobule; MST, medial superior temporal; MT, middle temporal; OFA, occipital face area; PPA, parahippocampal place area; SPL, superior parietal lobule; STS, superior temporal sulcus; V 1, primary (striate) visual cortex; V2-7, specialized areas (see text); VWFA, visual word form area. 380 Haque et al: J Neuro-Ophthalmol 2018; 38: 379-392 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 2. Diagram of dorsal and ventral pathways and the disorders arising from damage to specific areas in those pathways. visuomotor control and has also been designated the "how?" pathway (16). It is now clear that Ungerleider and Mishkin's original suggestion of separate dorsal ("where?") and ventral ("what?") pathways (17) was too simplistic (15,18,19). For example, some "what?" information is processed in the dorsal pathway (16) and vice versa (20). Space does not permit a detailed overview of extrastriate visual processing (15,21,22) and the precise anatomy of extrastriate processing in humans remains somewhat controversial. A number of issues potentially interfere with interpretation, including variation in interindividual anatomy (23) and the recent suggestion that many functional MRI (fMRI) studies may have overestimated areas of significance (24). As an example, different authors have argued that color processing in humans involves some or all of areas V4, V4a, V4d, V4v, hV4, V8, VO-1, and VO-2 (22,25,26). In fact, color is probably processed by a network of areas rather than a single location (27,28) and similar considerations apply to other visual modalities (18,21,28-30). Nevertheless, the 2-pathway schema remains useful clinically and a number of areas have been defined (Fig. 1). Broadly, the ventral ("what?") pathway runs inferiorly along the occipital and temporal lobes. Area V4 is located in the lingual and fusiform gyri and seems to be essential for processing color and maintaining color constancy, so that objects are perceived as having the same Haque et al: J Neuro-Ophthalmol 2018; 38: 379-392 color despite variations in ambient lighting conditions (8,9,22,31-34). The lateral occipital complex (LOC) is involved in object recognition (35). Some parts of the brain respond to faces more than to other objects. These include the fusiform face area (FFA), just anterior to V4 (36-39), a more posterior "occipital face area" in the inferior occipital cortex (40,41), and an area in the posterior superior temporal sulcus (42). These constitute the "core" facial recognition system (43), but other areas, for example, the ventral anterior temporal lobe and the amygdala, are also involved (40,44). The right hemisphere is dominant for facial recognition (40,41,45). There is ongoing debate regarding whether faces are processed in a location distinct from areas that process other objects (45,46); while the FFA is best activated by faces, it can also be activated by other objects (e.g., birds or cars), especially if the subject previously has acquired expert knowledge in the relevant area (47). Recent fMRI studies suggest that there are distinct areas in the inferior temporal lobe that respond differentially to faces, houses, and objects (48-51). Form and texture also are believed to be processed separately (lateral and inferior occipital cortex, respectively) (52,53). Neurophysiological studies have shown that spatial location is coded for by "place" cells in the hippocampus and "grid" cells in the entorhinal cortex (54). Consistent with this, fMRI has demonstrated a "parahippocampal place area" (PPH) adjacent to 381 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 1. Tests for evaluation of visual agnosias Disorder Object agnosia Cerebral achromatopsia Prosopagnosia Pure alexia Simultanagnosia Cerebral akinetopsia Optic ataxia Diagnostic Test(s) Clinical examination (adequate basic visual function) Naming of visually presented objects (impoverished images: 2-dimensional line drawings, unusual viewpoints) Drawing, copying, and matching of objects Demonstration of improved recognition through tactile or auditory stimuli (282) Specific neuropsychological tests, for example, Efron shape test, Birmingham Object Recognition Battery, Visual Object and Space perception battery, overlapping figures tests (87), pyramid and palm trees test (46) Color-naming tasks: Ishihara charts (26,108) Color discrimination tasks: Farnsworth dichotomous test for color blindness, Farnsworth 100-hue test (FM 100), Lanthony New Color test, Sahlgren saturation test (26,108,283) Color matching: Nagel anomoloscope (45) Spectral sensitivity measurements (284) Tests of color constancy (46) Clinical examination (adequate basic visual function) Exclude general visual object agnosia Tests of facial recognition: Famous-faces test Benton facial recognition test Warrington recognition memory test Cambridge face memory test (46,285) 20-item prosopagnosia index (PI20) (286) Clinical examination (adequate basic visual function) Demonstration of previous ability to read Reading assessment (words, letters, and/or numbers, musical notation, road signs, map symbols) (157,158) Writing assessment-surface dysgraphia (46,287) Clinical examination (exclude cognitive dysfunction, hemineglect, and visual field defects) Tests of attention: Visual search Interpretation of complex scene (e.g. the "cookie theft" picture) (100) Ishihara color plates (288) Navon figure test (232), Arcimboldo paintings (196) Clinical examination (adequate basic visual function; eye movements) Psychophysical testing (45,100,167,174) Computer-animated displays Clinical examination (adequate basic visual and motor function) Misreaching the hippocampus that is active during viewing scenes (37,38). A visual word form area (VWFA), located predominantly in the left inferior temporal sulcus (51,55,56) has been highlighted as an area involved in reading. The dorsal ("where"?) pathway runs upward to the parietal lobes and has strong onward connections with the frontal lobes that control limb and eye movements. Visual motion is processed in area V5 (also known as MT) on the lateral surface of the parieto-occipital junction (30). V5 projects to the medial superior temporal area and the inferior parietal lobule. Other areas involved in processing motion include dorsal V3 and V3A (57). More recently, area V6 has been described on the medial surface of the parietal lobe (58). V3, V3A, and V6 are believed to process global movement while V5 processes motion in the central part of the visual field (59). fMRI studies have suggested that 2D and 3D structure382 from-motion perception is processed independently within the parietal lobes (60), that structure from motion is processed in the LOC (61,62), that motion from stereoscopic depth is processed in and around V5 (63-65) and that biological motion (the perception of a biological entity engaged in a recognizable activity, e.g., walking) is processed in a completely different region, specifically the STS (66-69). Processing depth information is less well localized. Binocular disparity (stereopsis) is an important clue to depth. Stereopsis information is present in V1, but other clues to depth, such as perspective and motion parallax, require post-V1 analysis (70). Depth information is processed in both dorsal and ventral pathways: the dorsal pathway uses it to analyze spatial location (70-75) and direct movement while the ventral pathway uses it to assist with identification (76,77). Depth perception involves area V5 Haque et al: J Neuro-Ophthalmol 2018; 38: 379-392 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review (78), V3a, V7 (75,79), and V6-the latter seems to be particularly involved in the control of reaching (80). DEFINITION OF AGNOSIA The term "agnosia" (from the Greek meaning "absence of knowledge") was coined by Sigmund Freud in 1891 (81). Visual agnosia implies an inability to recognize an object, or a particular aspect of an object, using vision alone, although the basic visual pathways are preserved and function normally. This sort of disorder is occasionally seen as an isolated defect of 1 particular visual modality. More commonly, patients exhibit impaired processing of several modalities, often as part of a more generalized brain disorder. SPECIFIC AGNOSIAS AND RELATED DISORDERS Visual agnosias can affect both "what?" and "where?" pathways. Agnosias affecting the "what?" pathway include object agnosia, cerebral achromatopsia, prosopagnosia, topographagnosia, and pure alexia, whereas those affecting the "where?" pathway include akinetopsia, astereognosis, and simultanagnosia (Fig. 2). Because of damage to neighboring structures, more than 1 abnormality may occur in the same patient and many of these disorders are associated with visual field abnormalities. A number of different causes have been described for each syndrome, and these are listed in Supplemental Digital Content 1 (see Table E1, http:// links.lww.com/WNO/A243) (234-270,271-281). Object (or "Visual") Agnosia Charcot is credited with documenting the first case of "visual object agnosia" in 1883 (82,83). A few years later, Lissauer defined the syndrome as an inability to name or demonstrate the use of visually presented objects despite 1) adequate visual acuity and general intelligence and 2) retention of the ability to name or describe the use of objects when touched (84- 86). He proposed that impaired visual recognition could occur at 2 levels: apperceptive (i.e., impairment in basic visual processing) and associative (i.e., impairment in accessing stored visual memories or access to meaning) (82,87). It has subsequently become clear that detailed testing may reveal an overlap between these 2 levels (88,89). The classification of object agnosia has become much more complicated. For example, apperceptive agnosia has been divided up into local (or form) agnosia and more global (or integrative) agnosia. Integrative visual agnosia describes inability to derive shape information at a global level despite obtaining accurate local information about an object or a scene's component parts (87,89-93). Similarly, other very specific forms of object agnosia are now recognized, for example, impaired perception of fragmented pictorial material, inability to recognize objects shown from unusual viewpoints ("transformational agnosia"), and agnosia for mirror images Haque et al: J Neuro-Ophthalmol 2018; 38: 379-392 (94-96). Patients with form agnosia are well-described, but this is usually seen in combination with other abnormalities (87). Isolated, complete loss of form vision with preservation of other modalities has not been described (2). Details of the clinical tests involved in making a diagnosis of the various agnosias are given in Table 1. Cerebral Achromatopsia Cerebral achromatopsia is a disorder of color perception arising from impaired cortical processing rather than from damage to the retina or optic nerves. It is distinct from "color agnosia"-an inability to recognize colors-and "color anomia"-an inability to name colors (26,97,98). Patients see the world as "drained of color," "dirty," or in shades of black and white (45,99,100). They may have difficulties with tests of hue, saturation, and color constancy (101-103). Achromatopsia can involve the entire visual field or just 1 hemifield, and loss of color vision may be partial ("dyschromatopsia") or complete (100,104). The rare cases of "pure" achromatopsia typically have a lesion affecting the lingual and/or fusiform gyri on the inferior occipital surface (6,31,99,105). The suggestion that this represents the human homolog of V4 in the monkey has been supported by imaging (105-107) and functional imaging studies (9,22,26,33,34,108,109). Most cases involve bilateral lesions, but unilateral lesions (often associated with hemiachromatopsia) are well described (110). Clinically, patients are often relatively asymptomatic, particularly if their problem is dyschromatopsia or only 1 hemifield is involved (100,111,112). They may have difficulty in distinguishing traffic lights and in dealing with tasks such as sorting paper money. Achromatopsia is often not detected clinically unless specifically sought. Diagnosis requires objective demonstration of impairment on more than 1 test because many achromatopsic patients perform normally on colornaming tasks, and about one-third perform normally on Ishihara charts (108). Performance on the Farnsworth-Munsell 100-hue test is typically poorer than on the Ishihara test (99,108). Other tests include the Lanthony new color test, Sahlgren saturation test, and the Nagel anomaloscope (45,100). Prosopagnosia The term "prosopagnosia" was first coined in 1947 (113). It refers to an inability to recognize faces, either those previously known to the patient or those learned recently as part of a neuropsychological test (114-116). The patient must have adequate visual acuity and sufficient visual field to permit correct recognition of other objects. Again, accurate diagnosis requires detailed cognitive testing (117). Like object agnosia, there are 2 broad categories: apperceptive (difficulty discriminating specific features of a face) (118), and associative (patients can identify, compare, and match individual features of a face but cannot link their percept with their own database of known faces) (117,119). Patients often find prosopagnosia 383 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review very distressing and have to rely on other features such as voice, hairstyle, clothes, or movement to identify people. Defects in recognition of other specific objects-for example, cars and dogs-may occur, often associated with prosopagnosia (120). Like prosopagnosia, these disorders necessitate a high level of premorbid expertise (120). Face processing seems to be localized to the right hemisphere so lesions tend to be either on the right (121-125) or bilateral (114,115,121). Diagnosis requires demonstrating that the patient does not have object agnosia, can still recognize people based on nonvisual cues (e.g., voice), but is unable to recognize faces on tests such as the famous-faces test, the Warrington Recognition Memory Test, or the Cambridge Face Memory Test (45). Prosopagnosia can also be seen as a developmental condition. This is surprisingly common with a prevalence of 2.5% (126). Conventional neuroimaging is often normal. The mechanism and underlying pathophysiology are distinct from acquired prosopagnosia (117,127,128) and this condition will not be discussed further. There is a suggestion that disordered face processing may contribute to certain neuropsychiatric syndromes such as Capgras syndrome (a familiar person has been replaced by an impostor), reduplicative paramnesia (the patient has been replaced by a near-identical person), or Fregoli syndrome (an unfamiliar individual is actually a familiar person in disguise) (39,129,130). Similarly, there is a suggestion that face processing is abnormal in Asperger syndrome and autism (39). Topographagnosia This refers to loss of environmental familiarity despite relatively intact verbal memory, cognition, and perception. It typically manifests as getting lost in familiar surroundings (131). There are several possible reasons, but the 2 principal ones are impaired identification or recognition of spatial landmarks ("landmark agnosia") and difficulty in constructing a mental spatial map on which to base navigation (132). Landmark agnosia is believed to arise from damage to the PPH (37,38). Difficulties with constructing mental maps may arise from damage to the hippocampus and retrosplenial cortex (133,134); alternatively, damage to the parietal lobes may give rise to egocentric disorientation (135,136). Like prosopagnosia, topographagnosia can be developmental (137). Pure Alexia There are many disorders of reading which are beyond the scope of this article (100,138). Pure alexia or alexia without agraphia, falls well within this article's scope. Pure alexia, also known as alexia without agraphia, represents an inability to read while maintaining the ability to write (5,139). There are varying degrees of severity ranging from global alexia to "letter-by-letter reading," that is, patients recognize letters but have difficulty assembling them to form words, longer words being progressively more difficult (140-142). Comprehension 384 remains intact if words can be accessed through nonvisual routes (143). By definition, there are no deficits in aural comprehension or spontaneous speech (5,144). Patients typically read words slowly and exhibit more fixations than normal (55,145,146). They can write to dictation but cannot read back the words they have written. The classic lesion causing pure alexia was described by Dejerine in 1892 (5,147,148), that is, damage to both the left occipital lobe and the splenium of the corpus callosum, thereby generating a right homonymous hemianopia and preventing information from the right occipital lobe (left homonymous visual fields) to enter the left hemisphere. This deprives the left hemispheric language centers of all visual input (5,139,147,149). However, not all lesions involve the corpus callosum (150,151), and more recently, it has been suggested that letter-by-letter reading is caused by damage to the VWFA in the inferior temporal sulcus (55,56,145,147,149,152,153), although there is still some debate about this (154). Patients may have difficulty reading music, numbers, road signs, or map symbols (5,148,155-157). The severity of impairment may correlate with the size of the associated visual field defect (158), but pure alexia has been reported to persist in a patient whose visual field defect had resolved (159). Right occipital lobe lesions have occasionally been reported in right-handed patients, presumably explained by right-sided cerebral dominance (160,161). Cerebral Akinetopsia Akinetopsia, or "motion blindness," refers to impairment in detecting visual motion after damage to the cerebral cortex (32). Like achromatopsia, it can be seen as an isolated entity or as part of a more widespread disturbance of visual processing. Profound akinetopsia is very rare and is only seen following bilateral hemispheric damage (162,163). Patients complain that moving images "jump" and they have difficulty in performing tasks such as pouring water (100). They also have impaired smooth pursuit eye movements (164) and show errors in reaching for moving targets (165). Milder forms are seen with unilateral damage (166-171); these patients are relatively asymptomatic, their disordered motion processing being detectable only with the help of specific psychophysical tests (45,100,167). If they are symptomatic, the symptoms are often vague, such as difficulty in judging the speed of moving cars or dealing with "cluttered moving scenes" (100). Clinical studies pointing to a common area of cortical damage in the lateral parieto-occipital region (162,163,166-168,170,172) have been supported by studies using functional imaging (30,109,173,174) and electromagnetic stimulation (175,176). This area is believed to be the human homolog of area V5 (MT) in the monkey (177). Our understanding of visual motion processing has become more complex. There are different types of "low-level" motion perception (first- and second-order motion) and a structural percept can be derived from motion in both 2 and 3 Haque et al: J Neuro-Ophthalmol 2018; 38: 379-392 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review dimensions; these different perceptual processes can be affected separately or in combination (178,179). For example, some patients cannot perceive first-order motion but can detect structure from motion (180,181). Other patients cannot perceive structure from motion, although they are only mildly affected (182). Astereognosis Clinicians are familiar with the impaired depth perception (astereognosis) that arises from impaired binocular input to the brain. However, a small number of patients have been reported with abnormal depth perception secondary to unilateral or bilateral occipitoparietal lesions. These patients often describe the world as "flat" (183). Early suggestions that impaired stereoscopic depth perception arose predominantly from right-sided lesions (184,185) have not been confirmed (186-188). As above, much of the extrastriate visual cortex processes depth information. Impaired global stereopsis after anterior temporal lobectomy (189) suggests involvement of the "what?" pathway, but most authors have found that parietal lesions are more likely to interfere with depth perception placing it in the "where?" pathway (190,191). One important confounding factor is that many studies have not controlled for impaired convergence (192). Perception of depth probably contributes to both personal and extrapersonal perception of space. Disordered depth perception may therefore contribute to visual neglect, particularly personal neglect, and this is consistent with functional imaging studies (193,194). Simultanagnosia, Optic Ataxia, and Ocular Motor Apraxia This triad of abnormalities was originally described by Bálint in 1909 (195), and together they constitute the syndrome that bears his name (196). Bálint syndrome is, however, only a description, not a diagnosis. It is often accompanied by other features such as astereognosis and smooth pursuit deficits, and its individual components are more often seen separately (45). Simultanagnosia refers to a failure to generate a global percept of a complex visual scene despite an intact ability to perceive the individual elements that make up that scene (197). Essentially, it represents a restricted window of attention (198,199). Patients are usually very symptomatic, often rendered functionally blind (200). It is most commonly seen in the context of stroke affecting the parietal lobes (196,201-203), but the frontal lobes may be involved (204). It is also seen in neurodegenerative conditions such as posterior cortical atrophy (PCA), Alzheimer disease, or Lewy body dementia (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A243) (199,205). Accurate diagnosis requires exclusion of general cognitive dysfunction, hemineglect, cerebellar ataxia, and extensive visual field defects (100,206). Relevant clinical tests are discussed in Table 1. Haque et al: J Neuro-Ophthalmol 2018; 38: 379-392 Optic ataxia refers to impaired reaching under visual guidance despite normal limb strength and normal joint position sense. Clinicians may be alerted to it by impaired accuracy of reaching to shake hands when the patient first walks into the consulting room. Errors in reaching are less obvious for foveated targets and progressively greater for targets further away from fixation (207). It is not clear whether optic ataxia represents a disorder of perception, a disorder of motor control, or both (198,202,208,209), but it is believed to imply damage to the "where?" pathway. It can be seen in isolation or in the context of Bálint syndrome and is typically associated with lesions at the parieto-occipital junction. Many studies have suggested that the responsible lesion must include the superior parietal lobule (210) although others have suggested a slightly lower area (211). Ocular motor apraxia is a disturbance of eye movements. It is also known as "spasm of fixation" or "psychic paralysis of gaze" and refers to an inability to disengage from what is being looked at to initiate a saccade to a new target. Some patients find that this can be overcome by blinking. While initiation of voluntary saccades is impaired, patients are usually able to execute reflexive (or pro-) saccades to novel targets (212,213). Isolated ocular motor apraxia is typically seen with bilateral frontoparietal lesions (214,215), but is more commonly seen with bilateral occipitoparietal lesions in the context of Bálint syndrome. INVOLVEMENT OF MULTIPLE MODALITIES There have been many isolated case reports of patients with disturbance restricted to 1 modality. However, most patients have disturbance of several modalities, presumably because of damage to adjacent cortical areas (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A243). Involvement of multiple modalities is also seen in the context of neurodegenerative disease affecting the occipital lobes and adjacent regions. A good example of this would be disturbance of higher visual function in patients with Alzheimer disease (12,216-218). Similarly, as in Supplemental Digital Content (see Table E1, http://links.lww.com/WNO/A243) patients with stroke frequently experience disturbance of more than 1 modality (11). Most recently, PCA has been described as a degenerative disorder with distinct clinical features relating to focal involvement of the occipital and parietal lobes (219-222). The pathology is usually similar to that of Alzheimer disease, but the distinguishing feature is that the pathology is concentrated in the occipital lobes. Patients with Lewy body and corticobasal degeneration pathology also have been described (223,224). Patients may exhibit a number of agnosias related to both "what?" and "where?" pathways and accompanying visual field loss is not uncommon. Some patients may have a preponderance of parietal lobe (and hence "where?" pathway) involvement (199,205,221,223). A recent study found occipitotemporal region atrophy in patients with PCA with 385 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review visuoperceptual ("what?" pathway) defects but occipitoparietal region atrophy in those with visuospatial ("where?" pathway) deficits (221). Topographagnosia and prosopagnosia can be prominent features of the semantic dementia variant of frontotemporal dementia (225) and visual disturbance is well recognized in other degenerative disorders such as Creutzfeldt-Jakob disease (226,227), particularly the Heidenhain variant (226,228,229). However, most of these patients present with "diffuse" disturbance of vision rather than a specific, testable, disorder of 1 particular modality (230,231). As mentioned above, these visual disorders are not routinely screened for in clinical practice and testing patients with dementia is often difficult (12), meaning that the prevalence may be greater than currently recognized. SUMMARY AND CONCLUSION We have outlined the anatomy and neurophysiology underlying the visual agnosias and briefly described the clinical conditions themselves. Space has not allowed detailed clinical descriptions of the various syndromes, and the interested reader is referred elsewhere (45,100,102,232). The disorders are more likely to be unearthed if they are specifically looked for, particularly in the context of stroke and degenerative disease. Every new case has the potential to add insight into the brain's processing of vision, and this is reflected in the increasing number of related publications in visual physiology, neuropsychology, and neuroimaging. There is currently little that can be offered by way of specific treatment for most cases of visual agnosia, but an increase in our understanding has the potential to change this. Several disorders of higher visual function have not been covered here owing to limitation of space, including congenital prosopagnosia, congenital topographagnosia, blindsight, hemispatial neglect, various forms of specific anomia and amnesia, and the different types of alexia. Again, the reader is referred to the many excellent reviews that cover these topics in more detail (45,100,102,151,206,232,233). STATEMENT OF AUTHORSHIP Sameen Haque, Michael Vaphiades, and Christian Lueck: Category 1: a. conception and design, b. acquisition of data, and c. analysis and interpretation of data; Category 2: a. drafting the manuscript and b. revising it for intellectual content; and Category 3: a. final approval of the completed manuscript. ACKNOWLEDGMENTS The authors are grateful to David Fisher for his help in producing Figures 1 and 2. 386 REFERENCES 1. Zeki S. The Ferrier lecture 1995. Behind the seen: the functional specialization of the brain in space and time. 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