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Comparison of clinical DLB DX, SPECT + autopsy (3/07article)
(This post is only for the LBDA Forum. Please don't copy this post elsewhere as I don't want to get in trouble with any attorneys!)
A terrific article was recently published which looks at 20 patients clinically diagnosed with dementia (AD, DLB, or one with CBD), reveals how many core features of DLB they had, shares results of FP-CIT SPECT imaging studies, and compares all this to the neuropathological diagnosis (upon autopsy). A big debt is owed to the 20 patients who donated their brains for this research, and the many health family members that donated their brains as well. Many more studies like this are needed. The researchers are basically asking how accurate is their clinical diagnosis of DLB (using the consensus criteria) and how accurate are imaging studies. The abstract indicates that clinical diagnostic criteria for DLB "can fail to identify up to 50% of cases." Note that the clinical criteria for DLB now includes a certain result in SPECT imaging as a "suggestive feature" for DLB. The citation, abstract, and some excerpts follow. (One of the authors, McKeith, is on the LBDA Scientific Advisory Council.)
J Neurol Neurosurg Psychiatry. 2007 Mar 12; [Epub ahead of print]
Dementia with lewy bodies: A comparison of clinical diagnosis, FP-CIT SPECT imaging and autopsy.
Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, Ince P, Perry R, McKeith I, Katona CL.
University College London, United Kingdom.
BACKGROUND: Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis is available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared to diagnosis by means of clinical criteria alone.
METHODS: A SPECT scan was carried out with a dopaminergic pre-synaptic ligand [123I]-2beta- carbometoxy-3beta- (4-iodophenyl)-N- (3-fluoropropyl) nortropane (FP-CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right + left posterior putamen binding, measured semi-quantitatively, was more than 2 standard deviations below the mean of the controls.
FINDINGS: Over a ten year period it has been possible to collect twenty patients who have been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with co-existing cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and the specificity was 42%. The sensitivity of the FP-CIT scan for the diagnosis of DLB was 88% and the specificity was 100%.
INTERPRETATION: FP-CIT SPET scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.
PubMed ID#: 17353255
Online researcher extraordinaire EricSEA defines "sensitivity" and "specificity" in this way:
Sensitivity: a measure of how good a test is at identifying known positives - so, if you took people with autopsy-confirmed LBD, a test with higher sensitivity would pick them up more often than one with lower sensitivity. In a more understandable way, the higher the sensitivity, the lower the rate of false negatives.
Specificity - a measure of how good a test is at avoiding false positives. A test with high specificity, when the question is "does this subject *not* have (condition x)", will tend to be good at identifying "no, this person does not have this condition". (Robin adds: the higher the specificity, the lower the rate of false positives.)
In terms of the clinical diagnosis of these 20 patients, "Consensus DLB" criteria or NINCDS-ADRDA criteria (for AD) were used. Highlighting the challenge of distinguishing patients with DLB from those with AD, the authors note that many "of the DLB patients fulfilled both sets of criteria." In those cases, the patients were classified as having DLB.
All patients underwent FP-CIT SPECT scans, lasting 30-45 minutes. This scan detects the integrity of the nigrostriatal pathway. In DLB, the function of this pathway is impaired while preserved in AD.
After the FP-CIT scans -- and with knowledge of the results of the scans (but not knowing how reliable the scans might be in diagnosing DLB -- and during the patient follow-up, some of the clinical diagnoses were changed. The researchers also looked at the accuracy of these follow-up clinical diagnoses.
All "the scans were presented randomly and assessed visually by three independent raters experienced in assessing FP-CIT scans, who were blinded to the clinical and autopsy diagnoses. Scans were scored... (Scans) with scores 0 or 1 were combined into a 'normal' group and scans with a score of 2 were declared 'abnormal'."
In a separate exercise, one researcher, "blinded to the clinical and autopsy diagnostic status of all subjects, performed a semi-quantitative analysis of all scans. ...An abnormal scan, signifying a more likely diagnosis of DLB, was defined as a scan with semi-quantitative binding in posterior putamen (right + left), which was more than 2 standard deviations below the mean of the controls."
An "alternative semi-quantitative method" was also used. In this case, an abnormal scan "only needed low posterior putamen binding on one side."
After a patient's death, one pathologist performed the neuropathological exam (brain autopsy). The criteria used by the "Third report of the DLB Consortium." The mean time from "clinical diagnosis and FP-CIT scan to autopsy was 34 months (range 6-94 months)."
"There were no significant difference between the neuropathologically diagnosed DLB and non-DLB groups with regard to any of the demographic or clinical characteristics, including the frequency of parkinsonian signs, visual hallucinations and clinical fluctuation."
Table 3 is fascinating. It lists, for all 20 participants, their clinical diagnosis (AD, DLB, or one with CBD), the number of core features of DLB each had, the visual rating diagnosis (three independent raters looking at the FP-CIT scans), the semi-quantitative diagnosis (one researcher made these), and the final neuropathological diagnosis. In case #1, the clinical diagnosis was AD, the participant had no core DLB features, the visual rating was abnormal, the semi-quant diagnosis was abnormal, and the neuropathological diagnosis was DLB + AD. In case #5, the clinical diagnosis with CBD, there was one core DLB feature, the visual rating was abnormal, the semi-quant diagnosis was normal, and the neuropathological diagnosis was DLB + AD. There were 8 cases of confirmed DLB; in four of these cases DLB occurred concurrently with another disorder (in two cases with AD, in one case with cerebrovascular disease, and in one case with both AD and CVD).
Here's how accurate the various diagnostic methods were:
Initial clinical diagnosis
75% sensitivity 42% specificity
Follow-up clinical diagnosis
88% sensitivity 58% specificity
Visual rating of scans (3 raters)
88% sensitivity 83% specificity
Semi-quant analysis of scans (1 rater)
88% sensitivity 100% specificity
Alternative semi-quant analysis
100% sensitivity 92% specificity
"The results of this study indicate that FP-CIT SPECT scans have good sensitivity and very good specificity for diagnosing DLB. In this series, 'dementia not otherwise specified plus abnormal scan' performs considerably better than clinical criteria alone as a means of making the diagnosis of DLB."
The "sensitivity and particularly the specificity of our clinical diagnosis was poor. There are several possible explanations for this. The clinical diagnosis was made using the Consensus criteria but usually by only one clinician... The clinical diagnosis was made at baseline, before patients were scanned... A high proportion of the non-DLB patients were thought to have symptoms and signs characteristic of DLB patients, namely persistent hallucinations, fluctuations and parkinsonian symptoms. On the other hand one of the DLB patients did not have any core features of DLB at baseline (case #1) and two DLB patients did not have any parkinsonian symptoms (cases #1 and #6). In cases like this the scan could be particularly helpful. A high proportion of the non-DLB cases had one or more core features of DLB. This illustrates the difficulty that clinicians face when making a diagnosis of DLB as all the characteristic features of DLB can be present in possible AD cases."
"The majority of the non-DLB cases had AD and it might appear surprising that there was no significant difference between the DLB and non-DLB groups with regard to hallucinations and signs of parkinsonism. We think there are three explanations. Firstly this is a small series. Secondly the non-DLB group included a case of CBD and a case of FTD, both of which, unsurprisingly, had rigidity. Thirdly many of the cases were recruited from a diagnostic Memory clinic to which they had been referred because of diagnostic difficulty, so they were possibly not typical cases. This may also account for the relatively low accuracy of the clinical diagnosis of AD in this series."
"Case #5 is the only DLB patient whose FP-CIT scan (semi-quantitative assessment) was in the normal range. The patient was...55 years. The presenting symptom was strikingly unilateral...leading to an initial clinical diagnosis of CBD... Thus the semi-quantitatively assessed scan result represents a false negative. (Using the alternative semi-quantitative method, based on a unilateral analysis, the scan was abnormal.)"
"Assessing scans on the basis of abnormality on one side (whichever side is more abnormal) increased sensitivity but reduced specificity. The typical abnormality in DLB is bilateral loss of binding... Generally there is less asymmetry than in Parkinson's disease."
The authors reviewed reports from two other groups that have "correlated functional imaging and autopsy findings in DLB. In one, PET scans of patients with an autopsy diagnosis of DLB or AD were examined retrospectively. Glucost hypometabolism of the occipital cortex, particularly of the primary visual cortex, distinguished DLB from AD" with:
90% sensitivity 80% specificity
"On this evidence FP-CIT has comparable sensitivity but better specificity than occipital cortex metabolism measured by PET."
An abnormal FP-CIT SPECT scan is not "specific for Lewy body pathology. How reliably it identifies patients with DLB will depend on the population of patients tested. For instance, PD and multiple systems atrophy (MSA) cannot be distinguished by FP-CIT SPECT... There are...some neurological disorders which might be expected to give 'false positive' results, reducing the specificity of the test. These might include...CBD (and PSP)..."
"Multiple pathologies represent another important possible cause of false-positive scan results... It must be possible for patients to have, for instance, AD and also have PD or incidental nigral Lewy body disease without having diffuse Lewy body disease... Widespread use of FP-CIT scans in very large numbers of patients with unselected dementia would be expected to generate a number of false positive results."
"(Our) conclusion from this study is taht FP-CIT SPECT scanning performed considerably better than clinical criteria as a means of supporting the diagnosis of DLB in patients with dementia. It correlates very well with the presence of LB pathology at autopsy, even with a gap of nearly three years on average between scan and autopsy. It clearly supports the recent change made in the 'Revised Clinical Criteria for the diagnosis of DLB' which now includes 'low dopamine transporter uptake in the basal ganglia demonstrated by SPECT imaging' as a 'suggestive feature' for DLB."