Abstract
Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study.Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimer's disease (AD) (n = 18), Parkinson's disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of >6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi squared = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement.
NEUROLOGY 1996;47: 1403-1409
The brains from patients with Alzheimer's disease (AD)-type cortical changes reveal the presence of Lewy bodies (LBs) in 10 to 55% of patients. [1-7] Although most dementia patients with LBs also have AD pathology, some patients have multiple cortical LBs and no AD pathology. [8-11] These patients support the claim that LBs alone may produce dementia. Unlike AD pathology, which occurs to some extent in many cognitively intact elderly individuals, [12] LBs have been found in only 2.3% of 131 nondemented elderly. [13] In 273 cognitively intact individuals between 10 and 109 years old, the prevalence of LBs was 5.1%, with a peak in the ninth decade of 12.8%. [14] Although this low reported frequency may increase with exhaustive searches for LBs and the use of more sensitive immunohistochemical techniques in wider populations, the current data suggest that LBs are uncommon in the normal aging brain. The presence of a few LBs in the cortex does not appear to produce dementia; a pathologic review of 100 patients with Parkinson's disease (PD) [15] revealed at least a few cortical LBs in every patient but a dementia syndrome in only 44% of patients (one-third of these patients met pathologic criteria for AD).
Chart review of patients with LBs has provided a clinical profile that may differentiate these patients from others with AD. [5,9,16-27] Interpretation of these studies is difficult because the evolving clinical profile associated with cortical LBs has not been tested against a common pathologic criterion. Pathologic validation of a clinical diagnosis helps refine the clinical criteria of a disease and thereby improves the specificity of antemortem diagnosis. Clinicopathologic correlations require an unequivocal pathologic marker that serves as the gold standard against which clinical criteria are compared. Due to this lack of agreement on both the clinical and pathologic criteria for the disorder, or group of disorders, associated with cortical LBs, a Consortium on dementia with Lewy bodies (CDLB) established guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB). [28] Prior to the CDLB guidelines DLB had at least three different pathologic criteria and two alternate sets of clinical criteria. Proposed pathologic criteria included those of Kosaka, [25] Perry et al., [24] and Hansen et al. [5] Two sets of clinical criteria had also been proposed from which the CDLB criteria were derived (Table 1): the McKeith criteria [26] and the criteria used by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). [29]
Table 1. Clinical criteria for dementia with Lewy bodies (DLB)
To evaluate the evolving clinical and pathologic criteria for DLB we assessed the sensitivity and specificity of these criteria in a sample of patients presenting to our neurobehavior clinic. We conducted two studies: (1) a clinical study to evaluate the interrater reliability of the three sets of clinical criteria; and (2) a pathologic study to determine the diagnostic sensitivity and specificity of the clinical criteria. We have applied the alternate clinical and pathologic criteria in this comparison with the goal of identifying the components of these criteria that require further refinement.
Methods.
Patient.
Twenty-four patients with dementia or movement disorder who presented to the neurobehavior clinic at the University of California, Los Angeles or West Los Angeles Veterans Affairs Medical Center and whose brains were available for subsequent neuropathologic evaluation were studied. The premortem diagnosis of these patients included probable or possible AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) [30] (n = 18), progressive supranuclear palsy (PSP) (n = 1), and PD (n = 5). Inclusion criteria for dementia included an acquired persistent decline involving at least three of the following domains: language, memory, visuospatial skills, cognition (calculation, abstraction, judgment, etc.), and emotion or personality. [31] In the clinical study we included all patients with dementia and movement disorders, to assess the ability of clinicians to detect reliably the signs and symptoms that make up the clinical criteria. In the pathologic study we included only the 18 patients with a premorbid diagnosis of probable of possible AD since it is to this population that the pathologic validity of the clinical criteria are directed.
Neuropathologic evaluation.
Brains were fixed in 10% buffered formalin for 7 to 10 days. Staining of 6- to 8-micro m paraffin-embedded sections with hematoxylin and eosin (H&E) as well as immunohistochemical analysis, by an immunoperoxidase method previously described, [32] with an antibody against ubiquitin were done on all patients. Sections examined included the neocortex (frontal, parietal, and temporal), hippocampus, entorhinal and cingulate cortex, basal ganglia, and midbrain. The diagnosis of AD was made using the CERAD pathologic criteria [33] in patients who met clinical criteria for AD. [31]
Previously proposed pathologic criteria included those of Kosaka [25]: five or more LBs per 100x field in an H&E-stained section without AD pathology (DLB disease-pure form), or with AD pathology (DLB disease-common form); Perry et al. [24]: "moderate numbers in limbic cortex ... with variable distribution in neocortical lobes" with varying AD pathology (senile dementia of LB type); and Hansen et al. [5]: "the brain must have at least an LB" [34] in the brainstem and cortex with AD pathology (LB variant of AD), this set of criteria requires that brainstem evaluation is done on H&E-stained preparations and that one cortical area, the superior temporal gyrus, is examined using ubiquitin immunohistochemistry. The CDLB pathologic guidelines employ a semiquantitative scale from 0 to 2 where, for a neocortical (temporal, frontal, or parietal) or limbic (transentorhinal or cingulate) area of unspecified field of view, LBs are counted on either H&E- or ubiquitin-stained sections. A score of 0 = no LBs, 1 = up to 5 LBs, and 2 = >5 LBs for each area. Patients with total scores of 0 to 2 are considered brainstem predominant cases, scores of 3 to 6 limbic (or transitional) cases, and neocortical cases if their score is 7 to 10.
To allow a comparison of all pathologic criteria we used a semiquantitative approach. Regarding the occurrence of LBs, the pathologic criteria of Kosaka and Hansen are unambiguous; the criterion of Perry, however, ("moderate numbers in limbic cortex ... with variable distribution in neocortical lobes") leaves some uncertainty as to what constitutes a "moderate" number of LBs. The CDLB scoring is only ambiguous as to the size of the section used to arrive at an area's score; some centers cut large blocks and mount on 38 x 75-mm slides. To control for the size of a field we used a semiquantitative assessment at 250x magnification (25x objective/10x eye piece) where for each patient the presence of few LBs = at least one LB in a field, and many LBs = at least three fields with four or more LBs. To meet the criteria of Perry many LBs (at least three 250x cortical fields with many LBs) were required. To meet a CDLB score of 3 to 6 few LBs needed to be found; to achieve a score >6 many LBs needed to be found. The duration of search of a slide needed to find the single LB is not clear. In patients with few LBs and AD changes, the greatest difficulty is to distinguish a LB from a rounded neurofibrillary tangle (NFT), a structure that is also ubiquitin-immunoreactive. In these patients, we doublelabeled equivocal sections with antibodies against tau, which labels NFTs, as well as ubiquitin using an immunohistochemical system according to methods previously described (Figure 1). [32] This double labeling procedure helped eliminate the occurrence of false positive LB sighting that may occur when only ubiquitin-immunoreactive preparations are studied.
Figure 1. A double-labeled section with antibodies against tau, which labels neurofibrillary tangles (NFTs) blue, and ubiquitin, which labels LBs brown (red arrow), using an immunohistochemical system according to methods previously described. [32] Double labeling procedure is necessary to eliminate the occurrence of false-positive LB sighting that may occur with rounded tangles (blue arrow) when only ubiquitin-immunoreactive preparations are studied. Figure reducedby 35%.)
Statistical analysis.
In the clinical study inter-rater reliability among five neurologists (all with training in geriatric neurology) applying the clinical criteria was determined by a retrospective chart review. Eleven clinical features common to the three clinical criteria were extracted and provided as a checklist to the chart reviewers. These 11 signs and symptoms included major and minor clinical features of the clinical criteria. The chart reviewers were instructed to indicate "yes" or "no" if these features were present or absent or "?" if there was not enough information in the chart. Percent agreement and kappa scores for responses were computed between each reviewer and all others to arrive at the inter-rater reliability scores for each sign or symptom. Inter-rater reliability of the retrospective chart review was analyzed for all 24 patients, regardless of premortem diagnosis, to assess the ability of clinicians to detect the signs and symptoms that make up the criteria. Sensitivity and specificity values were based on a consensus agreement (>or=to3 out of 5 raters) for each sign and symptom scored by the five chart reviewers. The consensus signs and symptoms were then combined according to the three clinical algorithms found in Table 1.
In the second study the pathologic criteria were used to test the validity of the clinical criteria only in the 18 clinically probable or possible AD patients. The patients with movement disorder were not included in this pathologic study since it is known that LBs occur in all PD [15] and some PSP patients. [35-38]
Results.
Clinical reliability study.
The percent agreement and kappa scores for the individual signs and symptoms for the three clinical criteria are shown in Table 2. Fluctuations in test results, activities of daily living (ADLs), and confusion were the most difficult criteria to agree upon. Identifying fluctuations is necessary for a positive diagnosis based upon the McKeith, but not the CERAD or CDLB, criteria.
Table 2. Inter-rater reliability (% agreement and kappa scores) for components of the three clinical criteria among five raters
Pathologic validity study.
Sixteen of the 18 probable or possible AD patients met pathologic criteria for AD, [33] and two patients did not have the required amount of ageadjusted pathology to meet AD criteria (patients 8 and 18). Reliability of applying the three pathologic criteria was ensured for questionable sections by arriving at a consensus agreement between two reviewers (M.S.M. and H.V.V.); patients with questionable LBs versus rounded NFT were double-labeled and also subjected to a consensus review. The pathologic criterion for the CDLB transitionaltype is met in patients with few LBs, Hansen's criteria can be met in patients with either few or many LBs, while the criteria of Perry and the CDLB neocortical-type would only be achieved in patients with many LBs. No patient met the criteria of Kosaka; we were unable to identify confidently cortical LBs on H&E preparations even when adjacent sections revealed multiple LBs on ubiquitin-immunostained preparations (Figure 2). The CDLB transitional-type occurred in 11 patients, and the CDLB neocortical-type (also consistent with the Perry criteria) occurred in four of the probable or possible AD patients; no LBs were found in three of the probable or possible AD patients. The two dementia patients who did not meet pathologic criteria for AD had no LBs (patient 18) or only a few (patient 8). All six movement disorder patients (PSP = 1, PD = 5) had LBs present in the cortex. Patient demographics, clinical criteria results (based upon the consensus signs and symptoms), and the consensus LB findings (many, few, and none) for the 18 dementia patients are shown in Table 3.
Figure 2. Two adjacent cortical sections stained with H&E (A), and with antibodies against ubiquitin (B), demonstrate the difficulty in identifying cortical LBs on H&E preparations. Figure reducedby 35%.)
Table 3. Clinical and pathologic findings in study patients*
Clinicopathologic correlations.
(Table 4) provides a comparison of the sensitivity and specificity results for the McKeith, CERAD, and the probable CDLB clinical criteria (derived from the consensus signs and symptoms) based on having at least one (few) or four or more (many) LBs in at least three 250x cortical fields. Using the inter-rater reliability results the best operationalized combination of signs and symptoms was extracted. These included: hallucinations, cogwheeling, rigidity, bradykinesia, neuroleptic sensitivity, and evidence of episodic test performance (i.e., fluctuations in cognition); applying the consensus signs and symptoms only three patients had four of these six signs and symptoms. This set of reformulated criteria was tested using a chi square (chi squared) test for linear trend and was shown to predict significantly LB burden in patients with many LBs versus those with few or no LBs (chi squared = 5.48, df = 1, p = 0.02). The specificity of these reformulated clinical criteria (100%) is superior to the other criteria when many LBs are required for the pathologic diagnosis and its sensitivity (75%) is equal to the CERAD and CDLB criteria. Patient 4 had many LBs and concomitant AD pathology but met none of the clinical criteria for DLB. This patient did not meet the CERAD criteria because no EPS or unexplained falls/clouding consciousness were documented-one of which would be needed in addition to his history of delusions (the only primary CERAD symptom present) and his "supported features" of weight loss and depressed mood. The patient did not meet the McKeith criteria because no fluctuations were documented. The patient did not meet the probable CDLB criteria, or our reformulated criteria, because no primary symptom was present. The patient did, however, have dyskinesia of the fingers during stressed gait. One might interpret this finding as evidence of a movement disorder. Another patient in this study with multiple LBs (patient 1) first presented with restless legs syndrome. Meige syndrome has also been reported as the presenting sign in a patient with subcortical LBs. [39]
Table 4. Sensitivity and specificity of the evolving dementia with Lewy bodies clinical criteria based upon a consensus agreement among 5 raters
Discussion.
This study provides a new perspective on the emerging entity of DLB. We compared the reliability, among five neurologists, of identifying the clinical features of DLB. The evolution of the clinical criteria has changed the weighting given to these features but not the features themselves. In a separate pathologic study we determined the sensitivity and specificity of the evolving clinical criteria, based upon the presence of many cortical LBs. We operationalized the CDLB [28] pathologic criteria for both transitional and neocortical DLB by defining a field of view where many (four or more) LBs in at least three cortical 250x fields on ubiquitin-immunoreactive sections would meet the CDLB criteria for neocortical DLB. Although we searched multiple brain regions we never found "many LBs" in neocortical areas when a similar number were not present in limbic cortices. This finding is in agreement with others and supports the CDLB limbic (or transitional) stage as an early manifestation of LB burden. We favor the pathologic diagnosis of DLB being made only when many LBs are found throughout the limbic and neocortex (CDLB neocortical stage).
This study suggests further refinement of the clinical criteria of DLB. Our inter-rater reliability evaluation of the signs and symptoms of DLB has identified some features needing improvement to maximize their application in a clinical setting. The percent agreement among five neurologists on the presence of the signs and symptoms of DLB reflects the difficulty in identifying these clinical features (see Table 3). The most difficult features to identify are fluctuations. The difficulty in agreeing upon the presence of fluctuations in either ADLs, test performance, or confusion was the main disadvantage of the McKeith criteria. The CDLB criteria respond to this difficulty by not requiring fluctuations for the diagnosis. Fluctuations should not include daily "sun downing" symptoms, as McKeith et al. [26] point out, but well-defined operationalized criteria for distinguishing an abnormal fluctuation-different from the day-to-day variations of the "typical AD" patient-are still lacking. Caregiver reports may be inaccurate. We agree that fluctuations are important in identifying DLB and included fluctuating test performance as an item in our reformulated criteria because test results can be quantified. Since the "typical AD" patient loses about 3 Mini-Mental State Examination [40] (MMSE) points per year, [41,42] we suggest that fluctuations of 5 or more points on the MMSE over three administrations in a 6-month period could meet this criterion. Half of the present patients with a consensus agreement for fluctuating test performance had a 5-point or greater change on the MMSE in 6 months (the other 50% had fluctuations in either attention or word list memory). Future refinement of the clinical criteria will achieve a better standardization of the fluctuation criterion and make its clinical application more reliable.
The CERAD criteria demonstrated poor specificity, in part, by their allowance of delusions as a primary criterion. Delusions are common in AD, affecting 40 to 70% of patients. [43-50] Although delusions are easily detected, showing an inter-rater reliability of 92%, probable CDLB criteria excluded them. Visual hallucinations were included in the CDLB criteria. Less frequent than delusions, hallucinations of any modality affect 3 to 49% [44,47-54] of AD patients and do not always correlate with delusions. [50] McKeith et al. [26] included "visual and/or auditory hallucinations which are usually accompanied by secondary paranoid delusions" as a secondary item in their criteria. In an evaluation of the validity and reliability of their criteria, McKeith et al. [55] allowed the presence of "hallucinations or delusions" to fulfill this criterion in their retrospective chart review. We applied the McKeith criteria as they were originally described and did not allow delusions to satisfy the hallucination criterion. This helped to increase the specificity of the McKeith (71%) and CDLB (79%) criteria over that of the CERAD criteria (50%).
Requiring the presence of extrapyramidal signs (EPS) early in the course of an otherwise "typical AD" patient appears to maximize the sensitivity of detecting DLB. The presence of EPS should be spontaneous, not secondary to neuroleptics, as emphasized by the CDLB. The superior sensitivity of the CDLB (75%) and CERAD criteria (75%) over the McKeith criteria (50%) is due, in part, to the emphasis placed on EPS in their formulation. Four of the six signs and symptoms of our reformulated criteria are EPS (EPS include neuroleptic sensitivity). Patients who met these reformulated criteria will have at least two EPS. This increased emphasis on EPS contributed to the improved specificity of the reformulated criteria (100%) over the CDLB criteria (79%). Chart review of "typical AD" patients with clinical signs of EPS reveals a faster rate of functional decline, [56,57] and earlier neuropsychiatric manifestations such as apathy [53]-features that are also shared by DLB patients. Future studies will determine if EPS, or other movement disorders, should be a requirement for the diagnosis of DLB. Making an early diagnosis of DLB is important because of a possible differential response to treatment that may distinguish the patient with DLB from the patient with pure AD. Patients with DLB appear to have a greater cholinergic decline than patients with AD [58,59] and may have a better response to cholinergic treatments than patients with AD. [60] Patients with DLB also have a more adverse response to dopamine-blocking agents. [61]
We have presented a comparison of the evolving clinical and pathologic criteria for DLB. We have suggested a direction for the refinement of the CDLB criteria by revealing the components of the clinical and pathologic criteria that are difficult to operationalize. This study suffers from a small sample size and its retrospective design. Despite these drawbacks this study supports the conception of DLB as an identifiable clinicopathologic disorder. The relationship of DLB to AD and to PD remains to be further defined.
- Copyright 1996 by Advanstar Communications Inc.
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