ORIGINAL CONTRIBUTION. Visuoperceptual Impairment in Dementia With Lewy Bodies

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1 ORIGINAL CONTRIBUTION Visuoperceptual Impairment in Dementia With Lewy Bodies Etsuro Mori, MD, PhD; Tatsuo Shimomura, MD; Misato Fujimori, PhD; Nobutsugu Hirono, MD, PhD; Toru Imamura, MD, PhD; Mamoru Hashimoto, MD, PhD; Satoshi Tanimukai, MD, PhD; Hiroaki Kazui, MD, PhD; Tokiji Hanihara, MD, PhD Background: In dementia with Lewy bodies (DLB), vision-related cognitive and behavioral symptoms are common, and involvement of the occipital visual cortices has been demonstrated in functional neuroimaging studies. Objectives: To delineate visuoperceptual disturbance in patients with DLB in comparison with that in patients with Alzheimer disease and to explore the relationship between visuoperceptual disturbance and the vision-related cognitive and behavioral symptoms. Design: Case-control study. Setting: Research-oriented hospital. Patients: Twenty-four patients with probable DLB (based on criteria of the Consortium on DLB International Workshop) and 48 patients with probable Alzheimer disease (based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer s Disease and Related Disorders Association) who were matched to those with DLB :1 by age, sex, education, and Mini-Mental State Examination score. Main Outcome Measures: Four test items to examine visuoperceptual functions, including the object size discrimination, form discrimination, overlapping figure identification, and visual counting tasks. Results: Compared with patients with probable Alzheimer disease, patients with probable DLB scored significantly lower on all the visuoperceptive tasks (P.04 to P.001). In the DLB group, patients with visual hallucinations (n = 18) scored significantly lower on the overlapping figure identification (P =.01) than those without them (n = 6), and patients with television misidentifications (n = 5) scored significantly lower on the size discrimination (P.001), form discrimination (P =.01), and visual counting (P =.007) than those without them (n = 19). Conclusions: Visual perception is defective in probable DLB. The defective visual perception plays a role in development of visual hallucinations, delusional misidentifications, visual agnosias, and visuoconstructive disability charcteristic of DLB. Arch Neurol. 000;57: From the Department of Clinical Neurosciences, Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan. DEMENTIA WITH Lewy bodies (DLB) is increasingly being recognized as a common cause of dementia in elderly people and is the second most common type after Alzheimer disease (AD). 1 In 1996, the Consortium on DLB International Workshop proposed criteria for clinical and pathological diagnosis. 1 In addition to progressive dementia, other criteria specific to the clinical features of DLB are parkinsonism, fluctuating cognitive functions, and complex visual hallucinations. Since publication of the criteria, clinical studies have been conducted to delineate neuropsychiatric, neuropsychological, and neuroimaging features that distinguish DLB from AD. In addition to visual hallucinations, vision-related behavioral symptoms including visual agnosia and delusional misidentification are common in DLB. 1-3 Compared with AD, visuospatial and visuoconstructive disabilities are disproportionately severe. 4-7 Recently, radionuclear studies have demonstrated that glucose metabolism and blood flow are significantly decreased in the occipital lobes, including the primary visual cortex and visual association cortex, in DLB as compared with AD The involvement of the visual cortex may cause dysfunction of elementary visual sensation, which may be involved in development of visual cognitive deficits and vision-related behavioral symptoms. However, only 1 limited study has examined visuoperceptual function in patients with DLB. 1 In the present study, we addressed problems in visual perception in patients with probable DLB, and compared them with patients with probable AD. RESULTS The results of visuoperceptual assessment are summarized in Table 1. The performance was invariably lower in the patients with DLB than in those with AD. 489

2 PATIENTS AND METHODS Patients with probable DLB or AD were recruited from those who were given a short-term admission to the infirmary of the Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan, a research-oriented hospital for dementia, for investigation from April 1, 1997, to March 31, All patients were examined comprehensively by both neurologists (E.M., T.S., N.H., and T.I.) and psychiatrists (M.H., S.T., H.K., and T.H.) and underwent standard neuropsychological examinations, routine laboratory tests, electroencephalography, cranial magnetic resonance imaging, cerebral magnetic resonance angiography, and radionuclear neuroimaging studies. Uncorrected and corrected distant visual acuity testing and Goldmann perimetry were performed by an ophthalmometrician (T.S., T.I., M.H., S.T., H.K., or T.H.). Behavioral and cognitive changes were assessed with a structured interview for a caregiver, the Neuropsychiatric Inventory, 13 and with monitoring during the patient s hospital stay by staff physicians. Staff physicians also closely monitored significant fluctuation of cognitive function during a 1-month admission by means of repeated Mini-Mental State Examination (MMSE) 14 (significant change, 5 points), activities of daily living, and episodic or periodic confusion. Parkinsonism was rated as present when 1 or more of the following features were found: resting tremor, cogwheel or lead-pipe rigidity detectable without facilitation, bradykinesia, and loss of postural reflexes. The whole procedure followed the clinical study guidelines of the Ethics Committee of Hyogo Institute for Aging Brain and Cognitive Disorders and was approved by the institutional review board. Written consent was obtained from both patients and caregivers after they were provided with a complete description of the study. We adopted the clinical criteria of the Consortium on DLB International Workshop 1 for selection of patients with DLB and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer s Disease and Related Disorders Association for probable AD 15 for selection of patients with AD. Patients who had defective visual acuity (best-corrected visual acuity in either eye, 0/70), defective visual field, defective ocular movement of either eye, complication of other neurological diseases, or evidence of focal brain lesions on magnetic resonance images were excluded from the study. The consortium criteria for DLB include 3 core features (fluctuating cognitive functions, recurrent visual hallucinations, and spontaneous parkinsonism), and any of them are necessary for a diagnosis of probable DLB. We excluded patients with a clinical history of parkinsonism longer than 1 months before dementia developed ( Parkinson disease with dementia as designated by the consortium criteria). A sensitivity of 75% and a specificity of 79% have been documented in a preliminary validation study of the DLB International Workshop criteria. 16 In the present study, patients with AD who fulfilled any 1 of the 3 DLB criteria were excluded. The DLB group consisted of 4 patients. The mean (± SD) age was 74.0 ± 5.8 years for the 11 women and 13 men. The mean educational attainment was 9.1 ±.3 years. The mean duration of illness (the interval from the moment of the nearest caregiver s awareness of the patient s cognitive abnormality to the assessment) was 4.7 ± 0.4 months, and the mean score (the best performance in repeated measures) on the MMSE was 19.1 ± 4.1. Of the 4 patients, 6 had fluctuating cognition and parkinsonism, 4 had fluctuating cognition and visual hallucinations, had visual hallucinations and parkinsonism, and 1 had all 3 features. The AD group consisted of 48 patients ( sets of 4 patients) with probable AD who were matched :1 to the patients with DLB on the basis of sex, age, and severity of cognitive disturbances represented by their MMSE score. The mean age was 74.0 ± 7. years for the women and 6 men. The mean educational attainment was 8.8 ±.0 years. The mean duration of dementing illness was 31.9 ± 1.5 months, and the mean MMSE score was 19.1 ± 3.5. Corrected visual acuity was comparable between the DLB and AD groups (range, 0/70 to 0/0; median, 0/30 in the worse eye; r = 1.37; P =.50, Friedman -way analysis of variance [ANOVA]). There was no significant difference in the scores for the Alzheimer s Disease Assessment Scale 17 between the DLB and AD groups ( r = 3.10; P =.1, Friedman -way ANOVA); the mean total scores were 8. ± 10.8 in the patients with DLB and 3.9 ± 8.4 in the patients with AD. Global severity of dementia as demonstrated by the Clinical Dementia Rating 18 was comparable between the DLB and AD groups ( r =.94; P =.3, Friedman -way ANOVA); Clinical Dementia Rating scales of 0.5, 1,, and 3 were obtained by, 8, 11, and 3 patients, respectively, in the probable DLB group, and by 6, 3, 16, and 3 patients, respectively, in the probable AD group. ASSESSMENT OF VISUAL PERCEPTION We used 4 test items to examine various aspects of the patients visual perception, a subset of the object and spacial vision test battery. 19 The discrimination of object size task was used to examine elementary visual perception, the form In the DLB group, scores on the size discrimination, form discrimination, overlapping figure identification, and visual counting tasks were correlated with each other ( = 0.39 to 0.64; P =.008 to.001). The score on the overlapping figure identification was lower in those with visual hallucinations (n = 6) than in those without them (n = 18) (Table ), while no significant difference was noted in background characteristics except sex (most of the patients with visual hallucination were women). The delusional misidentification syndrome was present in 1 patients. The Capgras type, phantom boarder, house, and television misidentifications were noted in, 19, 11, and 5 patients, respectively. There was no significant difference in the visuoperceptual task scores between those with and those without house misidentifications or between those with and those without phantom boarder misidentifications. The number of patients with Capgras-type misidentifications and the number of patients without delusional misidentification syndrome were too small to perform a statistical analysis on them. Scores on the size discrimination, form discrimination, and visual counting tasks were significantly lower in those with television misidentification (n = 5) than in those without it (n = 19) (Table 3). The Wechsler Adult Intelligence Scale Revised block design subtest score was significantly correlated with scores on form discrimination ( = 0.53; 490

3 discrimination task was used to examine more complex visuoperceptual function that requires analysis of -dimensional visual stimuli, the overlapping figure identification task was used to examine the abilities to actively extract concrete shapes and to recognize objects, and the visual counting task was used to examine the ability to explore and identify the spatial relation of visual stimuli to count targets without duplication or omission. Specific brain regions have been assumed to be involved in the performance of these tests: the occipital visual association cortex for size discrimination, the occipitotemporal visual association cortex for form discrimination, and the occipitoparietal cortex for visual counting. 19 The assessments were performed while subjects were free of neuroleptic and neurotropic agents and not in a state of confusion or with active hallucinations. Subjects were allowed to wear their own glasses when requested. Test instructions were given repeatedly as needed to ensure the patients comprehension. Furthermore, no time limits were given for the tasks to exclude the influence of psychomotor slowing resulting from parkinsonism on the performance in the visuocognitive tests. In a previous study, cognitively healthy subjects (8 women and men; age, 7.6 ± 5.1 years; education, 8.5 ± 0.8 years) achieved almost full scores in all these tasks. 19 DISCRIMINATION OF SIZE The task stimuli consisted of 6 sets of lines and 6 sets of circles printed on separate sheets of paper (1 sheets). Three of the sets of lines consisted of parallel (horizontal) lines with lengths of 5.5 and 14.5 cm; 5.5, 14.5, and 1.5 cm; and 6, 10, 16, and 1.5 cm. The other 3 sets consisted of nonparallel lines with lengths of 5.5 and 14.5 cm; 5.5, 14.5, and 1.5 cm; and 6, 10, 15, and 0.5 cm. Three of the sets of circles were arranged in rows, and the other 3 sets were arranged randomly. The diameters of the circles in both sets were 4 and 7 cm; 3.5, 6, and 8 cm; and 3.5, 6, 7, and 9 cm. For each of the 1 sheets of paper, the subject was asked to point out the longer (in the sets of lines), the longest and shortest (in the sets of 3 or 4 lines), the larger (in the sets of figures), or the largest and the smallest (in the sets of 3 or 4 figures). One point was given for each correct answer, and the total score ranged from 0 to 0. DISCRIMINATION OF FORM The task stimuli consisted of 0 sheets, each with 4 linedrawn geometric figures. Three of the figures were the same and the fourth was distorted or rotated. The subjects were instructed to point to the odd figure. The maximum score was 0. OVERLAPPING FIGURE IDENTIFICATION The subjects were shown 3 sets of overlapping line drawings individually. The first set contained 3 simple geometric figures, the second contained 4 man-made objects, and the third contained 5 fruits (a total of 1 objects). The subjects were asked to identify each figure; in the first and second sets, to either name, describe, or trace the object by finger; and in the third set, to match each fruit with one of 8 nonoverlapping drawings printed on another sheet. The maximum score was 1. VISUAL COUNTING The task stimuli consisted of 14 sheets, each with 5 to 1 figures (circles, triangles, or both) of 1 or colors (red or blue). Patients were shown the sheets one at a time, and were asked to count the number of figures with a specified color (red or blue) or form (circle or triangle), or to count the total number of objects. The score was the number of attributes identified correctly. The maximum score was 38. VISUAL HALLUCINATIONS, MISIDENTIFICATIONS, AND CONSTRUCTIONAL ABILITY IN DLB In the DLB group, visual hallucinations and delusional misidentifications were assessed during an interview with the caregiver by means of the Neuropsychiatric Inventory and were monitored during the patient s hospital stay by staff physicians. The Capgras type, phantom boarder, house misidentifications (the patient s belief that the house is not his or her own house), and television misidentifications (the belief that television figures are actually present in the home) were included in delusional misidentifications. 3 Constructional ability was assessed by the Wechsler Adult Intelligence Scale Revised block design subtest. 0 Scaled score was calculated according to the manual. STATISTICAL ANALYSIS Statistical analyses were carried out with the Statistica version 4.1 software package (StatSoft Inc, Tulsa, Okla) with a significance level set at P.05. The nonparametric Friedman -way ANOVA was used for the matched group comparison (1 set of AD and sets of DLB). The -tailed Mann- Whitney test was used for analyses of group difference, and the Kendall test was used for correlational analyses. P.001), overlapping figure identification ( = 0.44; P =.003), and visual counting ( = 0.38; P =.010). COMMENT The DLB and AD groups in the present study were comparable in age, educational attainment, visual acuity, and composite assessments of cognitive functions. We found that the patients with probable DLB performed significantly worseonbothelementaryandcomplexvisuoperceptualtasks than did those with probable AD. These results indicate that not only higher-order visual perceptual functions but also elementary visual perception are defective in DLB. The differences in visuoperceptual dysfunction between the diseases probably represent the different distributions of vulnerable regions. The visuoperceptual dysfunction in DLB can be attributed to accentuated damage in the occipital lobes. Albin et al 8 demonstrated that regional glucose metabolism was decreased in the occipital association cortex and primary visual area in 6 patients with autopsy-proved DLB. In recent studies by Imamura 9 and Ishii 10 and their colleagues, using fludeoxyglucose F 18 and positron emission tomography, the glucose metabolic rate in the occipital cortices was found to be significantly lower in patients with probable DLB than in controls with probable AD matched for age, sex, disease 491

4 Table 1. Results of Visuoperceptual Tasks Mean ± SD* DLB (n = 4) AD (n = 48) r P Size discrimination (0-0) 19.5 ± ± Form discrimination (0-0) 13.0 ± ± ± ± indentification (0-1) Visual counting (0-38) 7.9 ± ± *DLB indicates dementia with Lewy bodies; AD, Alzheimer disease. Friedman -way analysis of variance. The range of possible scores is shown in parentheses. Table. Difference in Visuoperceptual Performance Between Patients With Dementia With Lewy Bodies With and Without Visual Hallucinations Visual Hallucinations, Mean ± SD Present (n = 18) Absent (n=6) U * P * Size discrimination (0-0) 19.4 ± ± Form discrimination (0-0) 1.8 ± ± identification (0-1) 7.4 ± ± Visual counting (0-38) 7.5 ± ± *Mann-Whitney test. The range of possible scores is shown in parentheses. Table 3. Difference in Visuoperceptual Performance Between Patients With Dementia With Lewy Bodies With and Without Television Misidentification Television Misidentification, Mean ± SD Present (n=5) Absent (n = 19) U * P * Size discrimination (0-0) 18.0 ± ± Form discrimination (0-0) 7.0 ± ± ± ± identification (0-1) Visual counting (0-38) 15. ± ± *Mann-Whitney test. The range of possible scores is shown in parentheses. duration, and MMSE score despite similar decreases in the parietotemporal lobe in the patients with DLB and AD. Similarly, a single photon emission tomographic study demonstrated that occipital blood flow was significantly lower in patients with DLB than in those with AD. 11 Therefore, in DLB, not only does the parietotemporal damage provoke visuocognitive dysfunctions, but also occipital damage causes disturbance of visual sensation and intensifies the higher-order visuocognitive dysfunctions. Defective visual perception, resulting in illusions including distortions of form, size, movement, or color, in combination with general defects such as confusion and mental deterioration may cause a sense of strangeness or inexplicable familiarity. 1 Defective visual input caused by visual system lesions may result in hallucinations from defective visual processing or an abnormal cortical release phenomenon. The finding in a study by McShane et al 1 that poor eyesight is correlated with the severity of the visual hallucinations in DLB supports this hypothesis. The association between visual hallucinations and the score on the overlapping figure identification task demonstrated in the present study is interesting, because interpreting blurred images with top-down visual processing would be involved both in overlapping figure identification and in generation of visual hallucinations. Similarly, defective visual perception would contribute partially to the delusional misidentification syndrome. In particular, television misidentifications are likely to link to the patients difficulty in visually recognizing size and form, as television images are spatially and dimensionally distinct from real-world images. Defective visual perception and visual illusions reportedly occur after lesions of the occipital, occipitoparietal, or occipitotemporal regions. 1 Complex or formed visual hallucinations are indicative of lesions in the visual association areas or their connections with the temporal lobe. In a recent study by Imamura et al 3 using positron emission tomography, where regional cerebral glucose metabolism was compared among patients who had DLB with visual hallucinations, DLB without visual hallucinations, and AD without visual hallucinations, they found that visual hallucinations were associated with a relatively preserved metabolism in the right temporoparietal association cortices and severe hypometabolism in the primary and secondary visual cortices in DLB. In addition to defective visual processing, brainstem lesions that appear to affect ascending cholinergic and serotonergic pathways may underlie visual hallucinations. Retrospective studies of patients with DLB have demonstrated that these patients have greater impairment on visuoconstructive and visuospatial tests than patients with AD. 4-6 In a previous case-control study by Shimomura et al, 7 where patients with DLB were compared with patients with probable AD who had comparable global dementia severity, disproportionately severe visuoconstructive and visuospatialdysfunctionindlbwasfound.walkeretal 6 demonstratedthatpatientswithdlbperformedworsethanthose with AD who were similar in overall degree of cognitive impairment on the praxis subtest of the Cambridge Cognitive Examination, including visuoconstructive tasks. Furthermore, Gnanalingham et al 4,5 pointed out the usefulness of the clock face test that assesses executive and visuospatial functioning in differentiating DLB from AD: patients with ADdowellonthe copy partofthetestdespitedoingpoorly onthe draw part, whilepatientswithdlbdoequallypoorly on both parts of the test. However, the defective visuoperceptual ability should be taken into consideration when visuoconstructive and visuospatial deficits in DLB are interpreted. Since a relationship between visuoperceptual performance and constructive performance was demonstrated in this study, visuoperceptual deficits underlie the severe visuocognitive deficits in DLB or explain a part of them. The mechanism of occipital involvement and visuoperceptual deficits in DLB is highly speculative. In a recent postmortem study, occipital and inferotemporal cortical degeneration was found in a patient with DLB and 49

5 a left homonymous hemianopia. 7 The degeneration was characterized by a disproportionately large number of neurofibrillary tangles and likely was the cause of the patient s visual field defect. However, in general, the pathologic features of DLB (including the Lewy bodies) hardly affect the occipital lobes. 8,9 Psychomotor slowing accompanied by parkinsonism is unlikely to explain the low performance on the visuoperceptual tasks, since the tests were untimed measures. Because spontaneous motor features of parkinsonism in DLB are generally mild, 1 poor performance on the tasks would not be attributable to other motor components of parkinsonism. Nonmotor components of parkinsonism would be more involved. Occipital glucose hypometabolism has also been reported in patients with Parkinson disease both with and without dementia Bodis-Wollner 33 speculated that dysfunction of the occipital visual cortices was attributed to dopaminergic systems in the visual pathway, and abnormal visual input from the retina, caused by a retinal dopamine deficiency, might explain the dysfunction. Degeneration of dopaminergic cells in the retina of patients with Parkinson disease was indicated, and dopaminergic treatment improved abnormal visual contrast sensitivity. 34,35 On the other hand, Bohnen et al 3 found that patients with Parkinson disease showed glucose metabolic reduction in the occipital lobe, which correlated with motor dysfunction, and suggested a pathophysiological association between nigrostriatal dysfunction and occipital glucose hypometabolism. In either case, a common pathologic process in the dopaminergic system among Lewy body diseases would be conceivable. On the other hand, involvement of the occipital cholinergic system also has been assumed. The activity of a cholinergic enzyme, choline acetyltransferase, is reportedly lower in the temporoparietal and occipital neocortex in DLB compared with AD. 36,37 Kuhl et al, 38 using single photon emission computed tomography and iodine 13 labeled iodobenzovesamicol, an in vivo marker of the vesicular acetylcholine transporter, found that the presynaptic cholinergic terminal density was reduced in the parietal and occipital cortices in Parkinson disease without dementia. In conclusion, both elementary and higher-order visuoperceptual functions are affected in patients with probable DLB as compared with patients with probable AD. Our results suggest that these deficits reflect dysfunction of the visual cortices and play a role in development of the vision-related behavioral and cognitive symptoms in DLB. Accepted for publication October 9, This work was supported in part by a Comprehensive Research on Aging and Health research grant, Ministry of Health and Welfare, Tokyo, Japan. Reprints: Etsuro Mori, MD, PhD, Department of Clinical Neurosciences, Hyogo Institute for Aging Brain and Cognitive Disorders, Saisho-ko 50, Himeji , Japan ( mori@hiabcd.go.jp). REFERENCES 1. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. Neurology. 1996;47: Ballard C, Harrison RWS, Lowery K, McKeith IG. Noncognitive symptoms in Lewy body dementia. In: Perry RH, McKeith IG, Perry EK, eds. Dementia With Lewy Bodies. New York, NY: Cambridge University Press; 1996: Hirono N, Mori E, Tanimukai S, et al. Distinctive neurobehavioral features among degenerative dementias. J Neuropsychiatry Clin Neurosci. 1999;11: Gnanalingham KK, Byrne EJ, Thornton A. 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