In this retrospective study of a well-characterized cohort of sCJD and DLB subjects, we found significant clinical overlap between the two conditions as has been reported by others2
. Dementia and parkinsonism were found in nearly all of our subjects in both groups and therefore the presence of these symptoms did not facilitate separation between sCJD and DLB. Similarly, other focal cortical signs were common in both sCJD and DLB. Myoclonus was present in 65% of sCJD subjects, but importantly 35% of DLB subjects also had myoclonus; this finding, a diagnostic feature of sCJD, could lead to diagnostic confusion. Akinetic mutism, another diagnostic feature of sCJD, was found in only one DLB patient; akinetic mutism, however, occurs so late in the course of sCJD that is rarely helps in the differential diagnosis. Hallucinations occur in the majority (70%) of DLB, but many (39%) sCJD subjects also had hallucinations, so this symptom, considered by some to be pathognomonic of DLB, probably lacks specificity in differentiating these two conditions. Furthermore, in both disorders the majority of hallucinations were complex visual hallucinations and so unhelpful for differentiating between DLB and sCJD. Similarly, fluctuation, a core feature of DLB, is also present in sCJD and so it too lacks specificity in differentiating these diseases from each other.
Using the clinical symptom criteria for sCJD and DLB, we found the sensitivity of the UCSF and WHO clinical symptom criteria for probable sCJD to be very high (98% and 93%, respectively). These sCJD symptom criteria alone, however, had low specificity (23% for UCSF and 60% for WHO criteria). As an insufficient number of DLB subjects had EEG or CSF testing, we could not determine in this analysis if these would improve the specificity of sCJD criteria. MRI, however, was very useful in separating sCJD from DLB cases. No DLB subjects had DWI/FLAIR MRI findings consistent with sCJD, whereas 96% of sCJD cases had positive MRIs consistent with sCJD and for the two that did not, one had motion artifact and the other was equivocal, and a second scan in that subject was positive.
The McKeith DLB criteria also performed relatively poorly because of the clinical overlap between sCJD and DLB, resulting in a sensitivity of 87% for probable DLB but a specificity of only 54%. Although generally the rapidity of progression typically separates these two groups, some DLB patients present with a fairly short duration of illness or have periods of rapid decline, making it difficult for clinicians to determine whether the illness is DLB or sCJD.19
Laboratory studies are used to diagnose sCJD and thereby differentiate it from DLB and other conditions, however the EEG and CSF 14-3-3 were of rather limited utility. The periodic EEG changes characteristic of sCJD11
and rare in DLB were present in only 52% of sCJD subjects and usually occurred at late or end-stages of the illness. This sensitivity of EEG in this sCJD cohort is close to that found in the literature of about 65%.11, 17
Whereas there is some disagreement in the Neurology community about the clinical utility of the CSF 14-3-3 protein for sCJD diagnosis, in our experience it lacks both sensitivity and specificity.20
In this cohort of sCJD, it fared poorly, positive in only 33% (negative or inconclusive in 67%) of sCJD subjects.20
By contrast, DWI and FLAIR MRI abnormalities of cortical ribboning and basal ganglia or thalamic hyperintensities were present in 96% of sCJD and none of the DLB cohort. FLAIR and DWI MRI, especially diffusion-weighted imaging, is particularly useful in the diagnosis of sCJD with a sensitivity of 91–96% and a specificity of 93–95% for sCJD.8–10
MRI hyperintensities in sCJD are usually observed in the cerebral cortex (i.e., cortical ribboning), less commonly in the striatum, and least commonly in the thalamus.9, 10
Abnormal hyperintensities often appear early on in the disease course, cortical signal abnormalities often precede basal ganglia changes.8, 9
The DWI signal hyperintensity can increase through the course of disease,21
but may disappear in the last stages of disease.10, 22, 23
The hyperintense cortex and basal ganglia observed on DWI and ADC map in sCJD are thought to reflect pathological involvement of that area, probably due to vacuolation,24–26
and less likely astrocytic gliosis23
or PrPSc deposition.26, 27
In trying to determine which symptom criteria or pattern of symptoms could lead to misdiagnosis of sCJD patients as DLB, we found that among sCJD subjects, those who met probable DLB criteria were more likely to have hallucinations, and there was a trend for them to have more visual symptoms. Interestingly, the radiological analysis portion of this study revealed that hyperintensity on DWI in the occipital lobe was most predictive of a sCJD patient meeting criteria for DLB. Thus this finding could be related to the associated visual findings and possibly hallucinations that can be seen with occipital lobe involvement. Given that hallucinations are part of the McKeith criteria, sCJD patients presenting with these may be labeled as possible or probable DLB. In fact, in the Heidenhain variant of sCJD, visual symptoms are early and predominant.28, 29
Evaluation of the signs/symptoms that are part of the criteria for sCJD and DLB in this sCJD cohort, resulted in only “Other focal cortical signs” (e.g., aphasia, apraxia, acalculia, agnosia, etc…) being associated with involvement of a particular DWI MRI region, in this case the parietal lobe. Lack of an association between other signs/symptoms and brain area involvement might be explained by diffuse pathology as the disease progresses and due to subjects being at different disease stages in this study.
Clinically diagnosed probable DLB is often found to be a pathologically heterogenous disorder; often a combination of DLB mixed with vascular disease or AD.30, 31
This makes accurate diagnosis of DLB even more problematic.
sCJD and DLB are dementing conditions that are associated with degeneration of cortical and basal ganglia structures. This anatomic overlap can lead to overlapping clinical syndromes. The current symptoms/signs in research criteria for both conditions demonstrate a significant overlap, a challenging problem for clinicians, particularly in the early stages of the illnesses. The 14-3-3- protein and periodic EEG both lack sensitivity for sCJD. EEG might only help differentiate sCJD from DLB in the later stages of the illness. This study emphasizes the importance of obtaining a brain MRI with DWI when sCJD is suspected. As we’ve shown previously, an ADC map is also important.10
As the prognosis for these illnesses is very different, it is important to distinguish the two conditions early on to avoid misdiagnosis.