Table 1.

Diagnostic criteria for pure and mixed human TSE histotypes

Histotype	Typical features	Major criteria for exclusion
Pure phenotypes
MM/MV 1	Spongiform change characterized by small vacuoles with predominant corticostriatal-thalamic and cerebellar involvementa Relative sparing of hippocampus compared to occipital cortexb Absence of a definite/clear-cut laminar pattern (i.e. predominant involvement of deep layers) of spongiform change and PrP deposition in the cerebral cortexc Synaptic pattern of PrP deposition	Clusters of large, confluent vacuoles in the grey matter Coarse or perivacuolar PrP deposition in the grey matter PrP plaque-like deposition PrP-positive amyloid plaques
VV2	Spongiform change characterized by small and medium-sized vacuoles Significant spongiform change in subcortical grey matter which is often more severe in striatum than in cerebral neocortex More severe spongiform change in the hippocampal CA1 and subiculum than in the occipital cortex Definite laminar pattern (i.e. predominant involvement of deep layers) of spongiform change and PrP deposition in at least one specimen from the cerebral cortex Plaque-like PrP deposition (best seen in cerebellar granular layer and white matter), usually associated with a perineuronal pattern in deep cortical layers and CA4 Significant cerebellar atrophy (particularly involving the granule cell layer) in comparison to that of occipital cortex	Clusters of large, confluent vacuoles associated with perivacuolar/coarse PrP deposition in the grey matter Typical fully formed PrP-positive amyloid plaques of the kuru-type or florid plaques in the cerebellum or other areas Absence of plaque-like PrP deposition
MV 2K	Widespread cortical and subcortical pathology with plaque-like PrP deposition and amyloid plaques of kuru type mainly localized in the cerebellar granular layer	Clusters of large confluent vacuoles associated to perivacuolar PrP deposition in the grey matter Absence of PrP-positive amyloid plaques of the kuru type in the cerebellum Amyloid plaques of the florid type in the cerebral cortex
MM/MV 2C	Corticostriatal distribution of pathology with relative sparing of brainstem and cerebellum Spongiform change mainly comprising grape-like clusters of relatively large confluent vacuoles	PrP-positive amyloid plaques Synaptic-type PrP staining in the molecular layer of cerebellum
MM 2T (sFI)	Moderate to severe selective atrophy of thalamic nuclei (i.e. anterior, dorsomedial, and pulvinar) in the absence of definite spongiform change in the same regions and not associated with severe cortical atrophy Moderate to severe selective atrophy of inferior olivary nuclei Absence of definite spongiform change in the cerebellum Relative sparing of striatum compared to the thalamus	Definite PrP plaque-like or perivacuolar deposition PrP-positive amyloid plaques
VV1	Corticostriatal distribution of pathology with relative sparing of cerebellum compared to the cerebral cortex Spongiform change comprising medium-sized vacuoles Synaptic PrP deposition (usually faint) Presence of (often) ballooned neurons in the most severely affected areas of the cerebral cortex	Clusters of large vacuoles in the grey matter Definite coarse or perivacuolar PrP deposition in the grey matter Plaque-like PrP deposition in the grey matter PrP-positive amyloid plaques The cerebellum is more involved (i.e. shows more significant pathological changes) than the frontal cortex
vCJD (MM 2V)	Multiple florid plaques in the cerebral cortex (all lobes) and cerebellar cortex Spongiform encephalopathy most marked in the caudate nucleus and putamen Severe neuronal loss and gliosis in the pulvinar of the thalamus PrP-positive florid plaques, small cluster plaques and amorphous pericellular and pericapillary deposits	Absence of florid plaques in routinely stained sections Lack of PrP-positive florid plaques, small cluster plaques and amorphous pericellular and pericapillary deposits
Mixed phenotypes
MM/MV 1+2C	Fits most criteria for MM/MV 1, but: Also shows clusters of large vacuoles associated with perivacuolar and coarse PrP deposition in the grey matter (most commonly in cerebral cortex or thalamus) or Fits most criteria for MM 2C, but also shows synaptic-type PrP staining in the molecular layer of the cerebellum
MV 2K+C	Fits most criteria for MV 2K, but also shows clusters of large vacuoles associated with perivacuolar and coarse PrP deposition in the grey matter (most commonly in cerebral cortex or thalamus)
Atypical	Any case which does not fit the criteria for the pure or mixed phenotypes outlined above

^aThe vacuolation largely disappears and is replaced by status spongiosus in cases with long duration and severe atrophy and gliosis

^bIn cases with long duration and severe cortical atrophy and astrogliosis, this assessment should not be based on the degree of spongiform change but rather on the extent of neuronal loss and astrogliosis

^cAn apparent predominant PrP deposition in the deep cortical layers may be seen in cases with long duration and severe cortical atrophy and astrogliosis