© 1990 Raven Press, Ltd.. New York

Disorders of the in Alzheimer's Disease

Mario F. Mendez, M.D., Robert L. Tomsak, M.D., Ph.D., and Bernd Remler, M.D.

Alzheimer's disease (AD) is associated with distur­ Alzheimer's disease (AD) is the most prevalent bances in basic visual, complex visual, and oculomotor form of affecting greater than 2.5 million functions. The broad range of visual system disorders in AD may result from the concentration of neuropathol­ people in the U.S., with the numbers expected to ogy in visual association cortex and optic nerves in this double by the year 2040 (1). Despite the absence of disease. AD patients and their caregivers frequently re­ a clinical test for AD, the recent establishment of port visuospatial difficulties in these patients. Examina­ highly accurate clinical criteria permit a more pre­ tion of the visual system in AD may reveal visual field cise evaluation of the deficits associated with this deficits, prolonged visual evoked potentials, depressed contrast sensitivities, and abnormal eye movement re­ disorder (2-4) (see Table 1). In addition to the cordings. Complex visual disturbances include construc­ usual memory and other cognitive deficits, AD pa­ tional and visuoperceptual abnormalities, spatial agno­ tients have disturbances in basic visual, complex sia and Balint's syndrome, environmental disorienta­ visual, and oculomotor functions, and AD patients tion, visual , facial identification problems, and in greater numbers are undergoing more thorough visual . The purpose of this article is to review the spectrum of visual system disturbances evaluations of their visual systems (4-8). found in AD and, in particular, to describe the methods Physicians are just beginning to understand the used to screen for complex visual abnormalities in these significance of visual system involvement in AD patients. (9,10). Consistent with the clinical heterogeneity of Key Words: Alzheimer's disease-Dementia­ this disorder, individuals with AD vary in the ex­ Visual-Visual -Visuospatial-Balint's syn­ drome---Oculomotor. tent of their visual system pathology and in their visual problems (7,11). The visual system prob­ lems are not simply due to global cognitive impair­ ment and can occur in the absence of other cogni­ tive deficits, increased dementia severity, or pro­ longed duration of dementia (4). However, the visual system abnormalities may contribute greatly to the disability caused by AD and may magnify the effects of other cognitive deficits. For these rea­ sons, any management strategies that improve vi­ sual functions can help alleviate the huge burden of taking care of these patients. Furthermore, there is a need to both identify higher visual tests that could be used for the early diagnosis of AD and to determine the visual physiological mechanisms that are disturbed in dementia. From the Alzheimer Center and the Department of Neurol­ ogy (M.F.M.) and the Division of Neuro-Ophthalmology, De­ NEUROPHYSIOLOGY partment of , and Department of Ophthalmology AND NEUROPATHOLOGY (R. L. T., B.R.), University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio. AD affects the visual association cortex with rel­ Address correspondence and reprint requests to Dr. M. F. ative sparing of primary visual areas (12-14). Se­ H.,· !. f'... I I' Medic,1 C"nter, Jackson University, nile plaques are located throughout the visual cor-

62 VISUAL SYSTEM AND AD 63

TABLE 1. NINCDS-ADRDA criteria for clinically TABLE 2. Visual symptoms in 30 patients with probable Alzheimer's disease (2) Alzheimer's disease (4)

'(1) Dementia established by clinical exam and Spatial agnosia: Five patients had prominent difficulties documented by mental status questionnaire or finding objects, looking at them, and reaching for neuropsychological testing them. These patients were unable to walk without (2) Deficits in two or more areas of bumping into things and could not judge distances. (3) Progressive worsening Visual localization problems: Seven additional patients (4) No disturbance of had less severe difficulties visually finding objects. (5) Onset between the ages of 40 and 90 Environmental disorientation: Five patients had an (6) Absence of other potentially causative disorder(s), isolated problem finding their way in familiar such as systemic disorders or brain disease, that surroundings that was not due to a general spatial could account for dementia agnosia. Spatial alexia: Three patients had reading difficulties not due to language disturbances or a general spatial agnosia. On reading, these patients easily lost their tex; however, in early and middle stages of AD, place, neurofibrillary tangles, which are associated with Possible mild optic ataxia: Two patients had difficulties with fine hand-eye coordination tasks that was not the severity of dementia (15), are located in greater due to general spatial agnosia. amounts in higher visual areas (12,13), Neurofibril­ : Three patients had difficulty recognizing lary tangles are rare in area 17, increase 20-fold in common objects when visually presented. Facial identification problems: One patient had area 18, and nearly double again in area 20 (13), . Positron emission tomography scanning studies Visual hallucinations: Three patients had formed also show cerebral hemispheric hypometabolism hallucinations that were not otherwise explainable by medications or confusional states. concentrated in the posterior parietal lobes and ad­ joining areas, with sparing of the primary visual occipital cortex (16-18), This distribution of neuro­ pathological and metabolic changes predicts pre­ without bumping into things), in visual localiza­ dominant deficits in complex visual functions (19), tion (e.g., finding door handles or other common Furthermore, the pattern of complex visual distur­ objects), in environmental orientation (e.g., find­ bances in AD, with prominent visuospatial prob­ ing their way in their surroundings), in reading lems, suggests differential disease of the magno­ (e.g., locating the next word or line of print), and cellular-occipitoparietal visual system, dealing in performing fine hand-eye coordination activi­ with spatial concepts, rather than the parvocellu­ ties (e.g., sewing) (4-9) (see Table 2). AD patients lar-occipitotemporal visual system, dealing with and their caregivers complain less frequently of form and (20-22), difficulties in visually identifying objects, scenes, In addition to the greater disease in visual asso­ or faces (5) and of visual hallucinations (26). ciation areas, there is prominent de­ Examination of the visual system in AD patients generation in AD, with dropout of retinal ganglion reveals a broad range of disturbances. All visual cells and their axons ranging from 15 to 80% (6), functions are not uniformly affected in AD; there One study found decreased retinal M cell degen­ are specific patterns of involvement. Frequently eration in 8 of 10 patients (23). This optic neurop­ impaired basic visual functions include peripheral athy results in minimal clinical evidence of visual vision, visual evoked potentials (VEPs), and con­ impairment (6), and most of the observed visual trast sensitivities (4,6,24,25,27,28). Difficulties with system abnormalities in AD probably result from constructions, figure-ground discrimination, and disease in visual association cortex. However, a visual synthesis are present in the majority of pa­ late decrease in visual acuity and color vision may tients with AD and are the most common findings be consequences of the in AD potentially attributable to complex visual dysfunc­ (4,6,7,24,25). tion in this disorder (4,29). Other common com­ plex visual abnormalities involve visuospatial abil­ ities (4-9) and visual object and face recognition CLINICAL EVALVAnON (4-9). Finally, patients with AD have abnormal oc­ The most common visual complaints in AD are ulomotor functions, such as increased saccadic la­ problems in visuospatial functioning (4-8). In a tency and an inability to inhibit anticipatory sac­ study of 30 community-based patients with clini­ cades (30-35). The rest of this article discusses spe­ cally probable AD, almost half (43%) had visual cific visual system abnormalities in AD and visual symptoms, and these were predominantly visuo­ system testing in demented patients, particularly spatial (4) (see Table 2). Visuospatial difficulties oc­ the screening tests used for complex visual distur­ cur in general spatial orientation (e.g., walking bances (see Table 3).

1Clin Neuro-{)phthalmol, Vol. 10, No. 1, 1990 64 M. F. MENDEZ ET AL.

TABLE 3. Screening test for complex cific verbal answer. Ultimately, clinicians must in­ visual functions terpret critically the results of visual system testing Constructions: Two-dimensional design or cube, in demented patients, as abnormal performance three-dimensional cube or open box, complex design, may be due to a combination of several visual and e.g., clock face cognitive disturbances. Perception: Tests of figure-ground discrimination (overlapping, cross-hatched, or hidden figures) and visual synthesis tasks (completion or visual closure tasks) BASIC VISUAL FUNCTIONS Visuospatial: Tests of inattention or neglect (line bisections), localization (dot circling or picture Investigations of basic visual functions in AD searching), ("linked" versus have found abnormalities particularly in periph­ "unlinked" figures or embedded figures), oculomotor eral vision and in VEPs (6,24,27,28,36). Sadun et (eye movements to visual stimuli), and optic ataxia (hand movements to visual stimuli) a1. (6) reported binasal field loss, inferior field loss, Environmental orientation: Tests of topographic or constriction of the visual fields in 3 of 12 AD amnesia and topographagnosia (follow, describe, draw, and learn route) and geographical orientation patients. Others have also found constriction of (map reading or placing landmarks on map) the visual fields (27) or left homonymous deficits Object recognition: Visual naming, describe or (36). On VEPs, some investigators have found that demonstrate use, tactile naming, and matching (actual objects, pictures of common objects, and flash stimuli, but not pattern reversal stimuli, may drawings of common objects) result in an increased latency and a loss of ampli­ Face identification: Tests of prosopagnosia tude (19,24). This pattern of YEP findings suggests (identification of pictures of famous faces) and facial discrimination (matching unfamiliar faces) that the main problems in the visual system in AD are not in the visual pathways up to the primary , but in the visual association areas There are two special problems involved in the (28). However, late in the course of AD, some pa­ visual evaluation of AD patients. First of all, basic tients have optic nerve pallor, afferent pupillary visual deficits may affect tests of complex visual reflexes, mild diminutions in visual acuity, and dy­ functions. The evaluation of basic visual functions schromatopsia, particularly for blue-yellow must precede the administration of complex visual (6,23,25). tests. Secondly, other cognitive impairments, such The most common basic visual dysfunction in as deficits in general comprehension, language, or AD may be abnormal contrast sensitivity func­ memory, can interfere with performance on visual tions. Several studies show a general depression tasks. The testing methods can partially compen­ across all spatial frequencies in AD (37,38) (see Fig. sate for deficits in other areas of cognition by keep­ I), and a subgroup of AD patients with more ing the task and instructions as simple as possible, prominent visuospatial problems have a greater by allowing as much time as needed for a re­ depression at the lower spatial frequencies (36,38). sponse, and by allowing the patients to respond by Others may have failed to find contrast sensitivity description or demonstration as well as by a spe- difference between dementia and normal aging,

200 ,,+------+-.

100 FIG. 1. Contrast sensitivity function curves for 19 patients with moderately advanced clinically probable Alzhei­ mer's disease and 19 normal age­ matched controls. 40 + NORMAL CONTROLS (n-19) -& AD PATIENTS (n-19) 20 !I:l- ----'- L-_....L..._.i--L----'-----'----'----'- -' 0.6 1.0 2.0 4.0 8.0 SPATIAL FREQUENCY

J elm Nt'urv-ophtfwlnwl. Vol. 11), '\ilI i, 1:14{} VISUAL SYSTEM AND AD 65 possibly because of methodological differences (10). Furthermore, in a recent study of 19 AD pa­ tients compared to 19 normal elderly controls, lower contrast sensitivities at a low spatial fre­ quency (2 cycles per degree [cpd] alternating at 7.5 Hz) correctly predicted the presence of AD in 89.5% of the patients (37). The decrease in contrast sensitivities may be the source of much of the vi­ sual impairment found in AD patients and may be a consequence of the pathology in both the optic nerves and the visual association cortex.

COMPLEX VISUAL FUNCTIONS Constructional Disturbances Visual system dysfunction contributes to the constructional disturbances in drawing, copying, and block assembly that are common in dementia and widely used to screen for AD (29). However, constructional disturbances are nonspecific and may reflect not only visual disturbances, but also d~~ problems with motor praxis, conceptual abilities, executive functions, or some combination of these (39). Constructional disturbances occur in AD, par­ l- ticularly with decreased metabolism in the poste­ rior right hemisphere (18); however, these distur­ bances may also result from lesions in different Irt-llJ --~ parts of the brain (39). FIG. 2. Example of typical constructional tasks in a Screening tests for constructional difficulties patient with Alzheimer's disease. The patient at· most frequently involve drawing or copying sim­ tempted to copy the drawings on the left. ple two-dimensional objects, such as a simple de­ sign or a cross, and simple three-dimensional ob­ join different parts of a , is frequently jects, such as a cube or an open box (see Fig. 2). present (4). AD patients also have difficulties on Drawings of more complex spatial figures, such as complex visual form discrimination tasks, al­ the face of a clock, are frequently abnormal in AD, though, when administered untimed, they may be but can result from disturbances in several areas of able to successfully perform these tasks in a slow, cognition. Copying or assembling blocks are also serial feature-by-feature fashion (4,7,41). Other ar­ good tests for constructional difficulties (40). Con­ eas of in AD need further explo­ structional errors on these tests include impover­ ration; however, there is some evidence for de­ ishment (omission of essential features), fragmen­ clines in depth perception (6,19,42), the discrimi­ tation (loss of spatial relationships and faulty ori­ nation of line orientation (43), backward pattern entation), cramping (smaller with perseveration masking (10), and possibly, visual memory, visual across items), and, on copying, a "closing-in imagery, and the detection of movement. phenomenon" (the copy overlaps the model) (29). Screening tests for visual perceptual difficulties These elements may reflect a disturbance in both in AD most commonly include tests of figure­ hemispheres, with impoverishment related more ground discrimination (overlapping, cross­ to the left hemisphere and fragmentation more to hatched, or hidden figures) and visual synthesis the right posterior hemisphere (29). (visual completion or closure tasks) (39,44,45) (see Fig. 3). More detailed assessment of visual percep­ tion involves the administration of neuropsycho­ Perceptual Disturbances logical tests (44). Several visuoperceptual processes are com­ Spatial Agnosia and Balint's Syndrome monly disturbed in AD (4). Abnormal figure­ ground discrimination occurs in most AD patients, Patients with AD frequently have difficulties lo­ and abnormal visual synthesis, the ability to con- cating objects in space (4-9). They have lost the

I Gin Neuro-ophthalmol, Vol. 10. No.1. 1990 66 M. F. MENDEZ ET AL.

sia may result in part from a relative weakness of Looo the peripheral fields (49,50) with suppression of ~ I.t-' extrafoveal images (51,52), or from the interfer­ -jill ~ "...... , ences of low spatial frequencies necessary for the ~ spatial integration of images (36). The visuomotor V' ./ disturbances of oculomotor apraxia and optic ataxia may result in an inability to explore the pe­ B I' I , ripheral fields due to disruption of saccadic and fixation in the posterior (53­ 55). Finally, investigators have questioned whether or not demented patients with full-blown Balint's syndrome constitute a separate degenera­ tive disorder; however, it is likely that these pa­ tients are a subpopulation of AD, consistent with the broad spectrum of visual disturbances that oc­ cur in this disorder (4,8,47). Screening tests for spatial agnosia and Balint's syndrome include tests for spatial inattention, spa­ FIG. 3. Examples of tests of visual perception. Figure­ tial localization, simultanagnosia, oculomotor ground discrimination tasks: (A) overlapping figures praxis, and optic ataxia. Line-crossing tasks, where (reproduced from the Southern California Figure various lines on a paper are presented for bisec­ Ground Test with permission from Western Psycho­ tion, are tests for visual heIDi-inattention or neglect logical Services); (B) cross-hatched figures (Luria fig­ of a part of the visual field. Spatial localization tests ures). Visual synthesis tasks: (C) completion (repro­ duced from the Hooper Test of Visual Organization include finding random dots in a visual field or with permission from Western Psychological Ser­ searching for specific items in a picture. Simulta­ vices); (0) visual closure (from the Street figures). nagnosia tests include distinguishing the larger pic­ ture when there are "unlinked" items (e.g., two unconnected circles versus two circles "linked" to of "whereness" (9) and are clumsy in their make a pair of glasses) or when there are smaller attempts to reach for objects or avoid bumping into embedded figures (e.g., smaller letters combined them. This "spatial agnosia" is responsible for the to form a larger letter). Oculomotor praxis tests most common visual complaints in AD, such as involve moving the eyes to visual stimuli, particu­ visual localization difficulties and spatial reading larly into the peripheral fields, and optic ataxia problems ("spatial alexia") (5,6) (see Table 2). Spa­ tests involve moving the hands under visual guid­ tial agnosia is associated with abnormal spatial at­ ance in reaching for objects or through openings in tention or the ability to focus on some spatial lo­ a box (55). cation to the exclusion of others. What little work has been done suggests that AD patients have a Environmental Disorientation decreased capacity of spatial attention, difficulties in moving their focus of attention to a new focus in Disorders of environmental orientation are com­ the periphery, and, even when their visual fields mon in AD and are operationally defined as diffi­ are normal, have a smaller, constricted field of culty with following a route (5,56,57). Patients view (8,45,46). with environmental disorientation are unable to The spatial agnosia may result in abnormalities find their way around unfamiliar surroundings, a in scanning, searching, and hand-eye coordina­ hospital ward, or even their homes, and may have tion severe enough to constitute Balint's syndrome a tendency to wander (56-58). The inability to fol­ in up to 20% of AD patients (4). These patients Iowa route may be due to a primary memory dis­ "see," but may have to be led as if blind because of order for spatial concepts ("topographic amnesia") the degree of visuospatial impairment (8,47). Pa­ or to a primary disorder in the visual recognition of tients with Balint's syndrome can only attend to a landmarks and spatial relationships ("topo­ single visual object at a time ("simultanagnosia"), graphagnosia"). Both of these forms of environ­ have inaccurate eye movements to visuospatiallo­ mental disorientation occur in AD. In addition, a cations (oculomotor apraxia), and cannot accu­ related disturbance that is common in AD is geo­ rately direct hand or other movements by visuo­ graphical disorientation-the inability to read a c;rnr;,J! . ill ·11) (4R) Simultanagno- map.

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Environmental orientation is tested by follow­ exclude global recognition difficulties, patients ing, describing, drawing, or learning a route. With must identify visually missed objects, unseen, by topographic amnesia, the patients are unable to touch or sound. Finally, in order to assess the ap­ describe or draw a previously familiar route and perceptive-associative dichotomy, patients must are unable to learn a new route. When topograph­ identify missed objects by visual matching with a agnosia, patients may be able to describe or draw a second series of identical objects (or, alternatively, previously familiar route or even learn the map of correctly copy unrecognized drawings). a new route, but they cannot recognize the route itself or its landmarks. Geographical disorientation tests involve placing well-known cities or land­ Facial Identification Problems marks on a map. There are several forms of facial identification problems in AD. Prosopagnosia, the inability to Visual Agnosia recognize famous faces, is a perceptual distur­ bance usually associated with other perceptual dis­ Visual object recognition problems or "agnosia" crimination difficulties (62) and occurs to some de­ are present in almost half of AD patients and can gree in most moderately advanced AD patients (5). be a major source of disability from the dementia True prosopagnosia is distinct from an inability to (4,6). Visual are deficits in the recognition remember the specific faces tested and, when ex­ of visually presented material in the absence of treme, demented patients may not recognize basic visual or general cognitive deficits suffi­ themselves in the mirror (the "mirror sign"). Test­ ciently severe to otherwise account for the recog­ ing involves the presentation of photographs of nition problems (41,45,59). There are traditionally famous individuals that cannot otherwise be dis­ two forms of visual agnosia: an "apperceptive" tinguished on the basis of salient features, such as form, where the inability to recognize an object is beards or glasses. Patients with AD also have dif­ associated with significant impairments in visual ficulty discriminating unfamiliar faces, as tested by perception, and an "associative" form, where per­ the Benton Facial Recognition Test (40). Finally, ception is sufficiently intact, as indicated by the many AD patients suffer from Capgras syndrome, ability to visually match objects, but the object's a related form of misidentification of others (26). In visual representation is isolated from its other cog­ Capgras syndrome, the AD patient denies the nitive associations. The existence of a true visual identity of a person and claims that the person has agnosia in AD has been controversial, as de­ been replaced by a look-alike, often with a malev­ mented patients may fail to recognize an object olent intent. The Capgras syndrome appears to be from failure to understand or cognitively interpret tied to paranoid thinking, but complex visual pro­ the visual representation, especially if it was al­ cessing may contribute to this phenomena. tered by an abnormality in basic visual functions (52,60). However, some AD patients have had vi­ Hallucinations sual recognition difficulties in the presence of nor­ mal basic visual functions and only mildly im­ Hallucinations may occur in up to 20% of pa­ paired general cognition (4,6,61). In sum, the vi­ tients with AD, and 80-90% are in the visual sual recognition problems in AD represent a true sphere (26). Visual hallucinations in AD are usu­ visual agnosia and may be either of the "ap­ ally formed, animate, changing, and often in color, perceptive" or of the "associative" form. lilliputian, and frightening (26). The hallucinations Screening tests for visual agnosia in AD involve are not associated with clear evidence of eye pa­ the identification of actual common objects, simple thology or basic ; however, the photographs of common objects, and simple draw­ combination of visual perceptual disturbances and ings of common objects. Actual objects are less dif­ paranoid thinking in AD may predispose to para­ ficult to recognize than photographs or line draw­ noid hallucinatory experiences. Other positive ings. Testing for agnosia involves excluding lan­ phenomena, such as or , are guage difficulty, causing inability to name the much rarer in AD. objects, excluding global recognition difficulties not restricted to the visual sphere, and assessing OCULOMOTOR FUNCTIONS the apperceptive-associative dichotomy. In order to exclude the effects of language difficulties, pa­ Eye movement recordings in AD patients show tients must identify incorrectly named objects by saccadic pursuit (33), increased latency and hypo­ description or demonstration of use. In order to metric saccades (30,32), fixation instability (30,35),

JClin Neuro-ophlhalmol, Vol. 10, No. I, 1990 68 M. F. MENDEZ ET AL.

inability to inhibit anticipatory saccades (30,31), contribute disproportionately to the disability from disorganized scanpaths (34), and, as previously AD. Finally, some demented patients develop spa­ discussed, oculomotor apraxia (8) (see Table 4). In tial agnosia sufficiently to constitute Balint's syn­ addition to nonspecific disturbances in pursuit drome. The prevalence of these visual changes in eye-tracking, patients with AD show a prolonga­ moderately advanced AD patients suggests over­ tion of saccadic latency, are likely to undershoot a lapping subpopulations with abnormalities in con­ small target displacement by 10-30%, and may trast sensitivity functions, constructions, figure­ have a decreased peak velocity for large amplitude ground discrimination, and saccadic latency in saccades (40°) but not for small ones (30,31). The nearly 100%, visuospatial difficulties in about two­ cortical neuronal loss in AD may also impair the thirds, abnormalities in visual recognition in about ability to maintain or release fixation, and saccadic one-half, visual hallucinations in about 20%, and intrusions, such as large square-wave jerks, may the full triad of Balint's syndrome also in as many intrude into fixation (30-35). There are difficulties as 20%. in suppressing anticipatory saccades, which, in the Further research in AD should establish man­ extreme, may constitute a "visual grasp reflex" agement strategies, such as the use of color coding with inability to inhibit a saccade to an extraneous and card-hole and other visuospatial guidance visual stimuli (30,31). Patients with AD also have tools (6), and the relationship of these visual sys­ abnormal scanpaths with inability to concentrate tem disturbances to the concentration of neuropa­ on high information areas of a picture or scene thology in visual association cortex and the optic (34). In sum, the prolonged saccadic latency and neuropathy found in AD. the inability to suppress anticipatory saccades may be the most characteristic oculomotor findings in AD (31). REFERENCES 1. Evans DA, Scherr PA, Cook NR, et al. Impact of Alz­ heimer's disease in the United States population. In: Suz­ CONCLUSIONS man R, Willis DP, eds. The oldest old. London: Oxford Uni­ versity Press. A range of disturbances of the visual system is 2. McKhann G, Drachman 0, Folstein M, Katzman R, Price 0, common in AD. The most common complaints in­ Stadlan EM. 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