As the isoforms of the prions that causes the sporadic disease have been characterized, clinical patterns have emerged as more or less typical of certain protein configurations and their underlying genotypes. The main classification system is based on: (a) the variant at codon 129 of the prion protein, which is characterized by methionine (M) or valine (V) and (b) which of two physicochemical properties (termed types 1 or 2) based on the fragment resulting from protease cleavage; see Parchi et al. The most common variants in most studies have been MM and the least common, VV, and type 1 is more frequent than type 2; MM1 and MV1 are the most common types overall, present in approximately two-thirds of sporadic cases. However, classification is complicated by the fact that some brain samples show more than one type of protein. Although several studies conflict on these points, a typical EEG pattern was most common in type 1 cases with at least one methionine, whereas MV2 cases were most likely to have MRI changes (see Laboratory Diagnosis). Some studies have suggested that the MV2 subtype, comprising a small proportion of cases, was likely to present with ataxia, psychiatric changes, a lack of positive sharp waves on EEG, and a prolonged duration of disease, but none of the distinctions has been absolute. There has also been controversy regarding the relationship of the genotype to the sensitivity of diagnostic tests discussed below. Details of these putative associations can be found in an extensive international study of 2,541 pathologically confirmed cases of CJD reported by Collins and colleagues.
Prion encephalopathy is in most cases a spontaneously occurring disease of late middle age, although it occurs in young adults. The sexes are affected equally. In the large series of pathologically verified cases reported by Brown and coworkers, prodromal symptoms—consisting of fatigue, depression, weight loss, and disorders of sleep and appetite lasting for several weeks—were observed in about one-third of the patients.
The early stages of the neurologic disease are characterized by a great variety of clinical manifestations, but the most frequent are changes in behavior, emotional response, and intellectual function, often followed by ataxia and abnormalities of vision, such as distortions of the shape and alignment of objects or impairment of visual acuity. Typically, the early phase of the disease is dominated by symptoms of confusion, with hallucinations, delusions, and agitation. In other instances, cerebellar ataxia (Brownell-Oppenheimer variant) or visual disturbances (Heidenhain variant) precede the mental changes and may be the most prominent features for several months. Headache, vertigo, and sensory symptoms are complaints in some patients but become quickly obscured by dementia and muteness.
As a rule, the disease progresses rapidly, so that obvious deterioration is seen from week to week and even day to day. Sooner or later, in almost all cases, myoclonic contractions of various muscle groups appear, perhaps unilaterally at first but later becoming generalized. Or, infrequently, the myoclonus may not appear for weeks or months after the initial mental changes. In a few patients, a startle response, that is elicitable for a brief period of time, is the only manifestation of myoclonus. In general, the myoclonic jerks are evocable by sudden sensory stimuli of all sorts, a startle response (to noise, bright light, touch) but they occur spontaneously as well. Twitches of individual fingers are typical but it should be emphasized that well-formed seizures are not a component of the illness. These changes gradually give way to a mute state, stupor, and coma, but the myoclonic contractions may continue to the end. Signs of degeneration of the pyramidal tracts or anterior horn cells, palsies of convergence and upgaze, and extrapyramidal signs occur in a small number of patients as the disease advances.