MM2 is where the standard diagnostic criteria fail most often. Both of its forms arise with methionine homozygosity and PrPSc type 2, and they were separated in the original classification as a thalamic form of CJD and a phenotype of prominent dementia with cortical pathology. See the subtypes hub for the scheme.
How often is MM2 missed?
Hamaguchi and colleagues reviewed the Japanese CJD Surveillance Study from April 1999 to September 2019, covering 254 patients with pathologically confirmed prion disease, including 9 MM2-cortical and 10 MM2-thalamic cases, and 607 patients with non-prion diseases.
Under the conventional criteria, 4 of the 9 cortical cases and 7 of the 10 thalamic cases could not be diagnosed as probable sporadic CJD before death. Compared with other subtypes, MM2-cortical cases showed slower progression and a cortical distribution of hyperintensity on diffusion-weighted MRI. MM2-thalamic cases also progressed relatively slowly and were negative on most established investigations. The criteria the authors propose for the cortical form distinguished probable MM2-cortical cases from other subtypes, genetic and acquired prion disease, and non-prion controls with 77.8 percent sensitivity and 98.5 percent specificity. For the thalamic form they state that clinical and laboratory features are not yet characterised well enough to define criteria.
Chen and colleagues reached a similar conclusion in a Chinese cohort of 209 sporadic CJD patients admitted between February 2012 and August 2022. Fifty-one patients, 24.4 percent, were clinically diagnosed with MM2-type disease, 44 cortical and 7 thalamic. Without RT-QuIC, 27 of the 44 cortical patients, 61.3 percent, did not meet the US CDC criteria for possible sporadic CJD on admission, despite a mean interval from onset to admission of 6.0 months. All of them had cortical hyperintensity on diffusion-weighted imaging. The thalamic group had a higher proportion of men, earlier onset, longer duration and more frequent bilateral thalamic hypometabolism or hypoperfusion. Their recommendation is that cortical hyperintensity on DWI, in the absence of multiple typical features within six months, should raise concern for MM2-cortical disease once other causes are excluded.
These are clinically diagnosed proportions in referral cohorts, not population frequencies, and the Chinese series classified cases by clinical criteria rather than by autopsy typing, so the 24.4 percent figure should not be read as the share of MM2 among sporadic CJD.
What does the EEG show?
Periodic sharp wave complexes, the classic finding, appear in fewer than half of MM2-cortical patients and only late. Matsubayashi and colleagues compared EEGs from 6 MM2-cortical and 8 MM1 or classic sporadic CJD patients. Median onset ages were 75.0 years, range 60 to 83, in the MM2-cortical group and 72.5 years, range 51 to 74, in the comparison group, with average intervals from onset to first EEG of 9.17 months and 1.88 months respectively.
In the MM2-cortical patients, early EEGs showed focal sharp waves or focal spike-and-wave complexes in brain regions corresponding to the cortical hyperintensities on MRI. In the MM1 and classic patients, early EEGs showed lateralised or generalised diffuse sharp waves and spike-and-wave complexes that were not confined to regions of MRI change. The authors present the focal, MRI-matched pattern as an early marker of the cortical form.
Six cases against eight is a small comparison, and the intervals from onset to first EEG differed by about seven months between the groups, which is itself a consequence of the slower presentation.
Why do the assays underperform here?
Franceschini and colleagues, testing CSF from 239 prion disease patients and 100 controls, report that second generation IQ-CSF RT-QuIC had high sensitivity for human prions overall with sub-optimal sensitivity specifically for the MM2C and MM2T subtypes. The UK surveillance analysis cited on the subtypes hub found MM2 overrepresented among RT-QuIC negative definite cases, at 21 percent against 3 percent of positive cases.
The combination is what makes this subtype hard: slow progression that does not trigger suspicion, an EEG that lacks the classic pattern early, and the CSF assay that would otherwise settle the question performing worst in exactly these patients. Imaging carries most of the diagnostic weight, and in both series above it was cortical DWI hyperintensity that was present when other findings were absent. Interpretation of an individual scan or assay belongs with the treating team; see how it is diagnosed.
Related: MM1, MV2, VV1 and fatal familial insomnia, which shares thalamic pathology with the MM2-thalamic form.
Sources for this page
- Hamaguchi T and others (2020) MM2-type sporadic Creutzfeldt-Jakob disease: new diagnostic criteria for MM2-cortical type, J Neurol Neurosurg Psychiatry 91(11):1158-1165
- Chen Z and others (2023) Toward an early clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, Ann Clin Transl Neurol 10(8):1209-1218
- Matsubayashi T and others (2020) Focal sharp waves are a specific early-stage marker of the MM2-cortical form of sporadic Creutzfeldt-Jakob disease, Prion 14(1):207-213
- Franceschini A and others (2017) High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions, Sci Rep 7:10655
- Parchi P and others (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects, Ann Neurol 46(2):224-233