In this study, we show that the pattern of MRI involvement can differentiate sCJD from npRPD. Using FLAIR and DWI MRI, we found that after consensus review, MRI sensitivity and specificity for sCJD were 98% and 93%, respectively, higher than any other diagnostic test.4,16–18
We identified 4 distinguishing MRI features:
- In sCJD, hyperintensity on DWI was greater than on FLAIR, but in npRPD, hyperintensity on FLAIR was greater than on DWI.
- In subjects with sCJD with subcortical DWI hyperintensity, ADC in these regions was always hypointense (i.e., restricted diffusion).
- Isolated limbic involvement was not found in sCJD, but often seen in npRPD.
- sCJD has characteristic DWI patterns of gray matter involvement.
Regarding the first 2 features, the prevalence of DWI over FLAIR hyperintensities suggests diffusion restriction is a crucial feature of MRI in sCJD; diffusion restriction and T2 prolongation both contribute to DWI hyperintensity, but only T2 prolongation causes FLAIR hyperintensity. Only sCJD cases had ADC hypointensity correlating with DWI subcortical hyperintensity and this finding had high specificity for sCJD. The diffusion restriction is probably related to vacuolation.19
This study used the first MRI scan obtained at our institution, but we and others have observed that diffusion restriction might decline in late stages of sCJD, particularly in patients with very prolonged courses and significant atrophy.20,21
Nevertheless, we believe that the prevalence of DWI over T2 abnormalities is one of the most important MRI criteria for diagnosing sCJD, which is supported by other studies.18,21
Furthermore, DWI is often bright very early in CJD when T2-weighted images are not.20,21
Many studies have confirmed the sensitivity of DWI in sCJD, some gPrDs, and vCJD.3,13,18,21
In this study we show the high specificity of diffusion restriction (with DWI and ADC map) in the basal ganglia in sCJD compared to npRPDs. A recent large study examined the sensitivity and specificity of FLAIR, and in some cases DWI, MRI in sCJD compared to subjects initially suspected of CJD, but in whom other diagnoses were found.18
This article proposed new MRI criteria for sCJD, but had several problems. First, the authors did not look at true diffusion restriction (ADC map), which is critical for differentiating CJD from npRPD. Secondly, they do not include cingulate, hippocampal, insular, and frontal cortical involvement because of a high rate of false-positive FLAIR or DWI MRI readings in these regions. These regions, however, are among the most common areas affected in CJD () and false positivity due to artifact can be avoided by performing sequences in multiple planes and examining for restricted diffusion (ADC map).
Other npRPD conditions (many of which were not included in this cohort) might present with subcortical or cortical DWI hyperintensity—sometimes with decreased ADC—and might mimic CJD MRI findings. For example, subcortical diffusion restriction can be found in striatum in extrapontine myelinolysis22
and Wilson disease,23
and in the posteromesial thalamus in Wernicke encephalopathy24
and in Bartonella
Since our study was completed, we have identified 2 patients with npRPD (hyperglycemia with seizures and extrapontine myelinolysis) with some MRI findings overlapping those of CJD, DWI hyperintensity, and ADC hypointensity in the striatum (manuscript in preparation). A few npRPDs, such as anti-CV2 limbic encephalopathy and neurofilament inclusion body disease, have striatal T2/FLAIR hyperintensity similar to CJD; in these conditions, however, DWI/ADC abnormalities are absent. Cortical diffusion restriction can be seen in the acute phase of viral encephalitis26
and focal epileptic status.27
Importantly, status epilepticus occurs in npRPDs, such as limbic encephalopathy, and might mimic CJD clinically.28
“Strategic” stroke dementia can show cortical hyperintensity.29
Acute viral encephalitis, focal epileptic status, and stroke usually present cortical swelling, subcortical abnormalities, and often contrast enhancement.26,27
Although DWI and ADC are the most important sequences for diagnosing sCJD, FLAIR images and, in selected cases, T1 pre- and postcontrast must be carefully evaluated in all patients with rapidly progressive dementia. These conditions must be considered when evaluating a patient with suspected CJD.
Isolated limbic involvement might help distinguish sCJD from npRPD, for it was found only in our npRPD group, typically in autoimmune encephalopathy. To our knowledge, ADC decreases have never been reported in these encephalopathies, but this might occur with seizures, although this should disappear after seizures have been controlled. If isolated limbic hyperintensity is greater on FLAIR than DWI, we suggest that this be a criterion for “probably not CJD.” If isolated limbic hyperintensity is greater on DWI, particularly with accompanying ADC hypointensity, encephalitis and seizures should be considered.
Another distinguishing feature of sCJD was its pattern of gray matter involvement. Consistent with prior studies,3,4
we found that hyperintensities were more commonly cortical than subcortical (table e-3). We also identified the same most frequently involved cortical regions as another study,30
except we rarely found occipital cortical involvement. Although the highest frequencies of any specific area of gray matter involvement in that study were significantly higher than in our cohort (85%–95% compared to 50%–65%), 13 cases were studied without DWI images and no control group was included. As they knew all cases were CJD, they might have overestimated hyperintensities, possibly explaining the more frequent involvement of the precentral gyrus in their study (40%) compared to ours (5%), and why parahippocampal hyperintensities, involved in 50% of our sCJD cohort, were not reported. Susceptibility artifacts make evaluating the anterior parahippocampal gyrus difficult, but the posterior portion can be evaluated more reliably. Thus, to help determine if the abnormal intensities are real or artifact, we recommend performing (or at least reviewing) the DWI/ADC sequences in 2 planes, axial and coronal.
The areas with less frequent FLAIR/DWI hyperintensity in sCJD were the pallidus and precentral gyrus. This characteristic “precentral sparing” sign was especially notable in subjects with sCJD and subjects with fCJD with diffuse cortical involvement (). Although motor deficits are common in CJD, the sparing of the motor strip might reflect the absence of frank paralysis in most patients. Conversely, because precentral gyrus and the pallidus accumulate the most age-related iron, they have the most hypointense T2-weighted signal.31,32
Although the pallidus can be relatively spared on DWI in sCJD,33
pallidal T1 hyperintensity might be pathologically associated with high levels of prion deposits.34
We suspect that involvement of pallidus and precentral gyrus is underestimated on FLAIR and DWI sequences because the concurrent iron-related hypointensity masks the hyperintense signal from prion disease. This “T2 blackout” effect is significant in FLAIR, T2-weighted, and probably greater in echoplanar DWI images.35
One sCJD study demonstrated ADC decrease, despite normal DWI, in the precentral gyrus.36
Of note, our sCJD MM2-thalamic case had a normal MRI, consistent with most cases in the literature.37
The MRI pattern in our patients with fCJD generally resembled those of sCJD, but in most GSS cases this pattern was not found. As subcortical ADC maps were examined only in cases with DWI subcortical hyperintensity, after the study, we noted subcortical ADC hypointensity without DWI hyperintensity in some GSS cases; this may be due to the “T2 blackout” effect. Although the P102L case did not have typical sCJD MRI findings, and nor have subsequent cases seen at our center, at least one case has been reported to have a classic CJD MRI.38
As we found variability among readers, it seems clear that accurate interpretation of MRIs in subjects with CJD requires knowledge of the findings and experience with CJD. Our new criteria should improve diagnostic accuracy and reduce this variability. It is paramount that neurologists and radiologists familiarize themselves with these findings. Future studies should address issues of inter- and intrarater reliability and also might use postprocessing methods to accurately quantitate mean diffusivity values (ADC map).
The patterns of FLAIR and DWI abnormalities can differentiate sCJD from npRPD with high accuracy, whereas only some genetic prion cases have overlapping MRI features with sCJD. We propose modification of our prior sCJD MRI () criteria to improve the sensitivity and specificity of the MRI findings, based on the anatomic distribution of DWI-FLAIR hyperintensities, the relative DWI to FLAIR signal, and the ADC map in subcortical areas. MRI with DWI and ADC should be included in sCJD diagnostic criteria.