Fig. 10.1
Molecular strain types of Creutzfeldt-Jakob disease (CJD). Schematic representation of distinct PrPSc conformers associated with CJD. PrPSc types are identified, based on the different fragment sizes seen on western blots, after treatment with proteinase K, and on the different glycosylation pattern (i.e., the proportion of di-, mono-, and unglycosylated fragments of the PrP). PrP polymorphism at residue 129 [methionine (M) or valine (V)] contributes to genetic susceptibility to both sporadic and acquired forms. Box sizes represent the relative difference in intensity of the three PrP glycoforms
10.3 Demographics
TSEs are rare in human beings. The overall incidence is approximately 1.5 per million people per year.
sCJD – It accounts for 80–85 % of human TSEs. The incidence is equal in men and women [6].
VPSPr – It accounts for about 2–3 % of sporadic prion diseases, but many cases of VPSPr are not clinically recognized [7].
Inherited prion diseases – Approximately 10–15 % of human prion diseases are associated with autosomal dominant PRNP mutations [3].
Kuru – It affects the Fore people of the Eastern highlands of Papua New Guinea, due to the diffusion of cannibalism in postmortem rituals. Today only a few cases of kuru are seen.
vCJD – It is the human form of bovine spongiform encephalopathy (BSE). vCJD affects younger individuals than sCJD (typically age 14–50 years). Primary infection in vCJD occurs by oral route, via meat products contaminated with the BSE agent [8].
iCJD – Prions have been transmitted by human growth hormone and gonadotropin prepared from cadaveric pituitary glands, by corneal and dural grafting, and by brain electrodes; such cases are rare [8].
10.4 Clinical Features
sCJD
Classical sCJD presents as rapidly progressive dementia usually with myoclonus. Additional neurological features include pyramidal and extrapyramidal signs, cerebellar ataxia, and cortical blindness. The onset is usually in the 45–75 years age group with median age at death of 68 years [3]. The clinical evolution is typically over weeks, progressing to akinetic mutism with a median disease duration of 5 months.
Atypical forms of sCJD are well recognized. Ten percent of CJD cases have a much more prolonged clinical course with a disease duration of over 2 years, and may present with cerebellar ataxia rather than cognitive impairment (ataxic CJD), extensive degeneration of the cerebral white matter in addition to spongiform vacuolation of the gray matter (panencephalopathic CJD), or prominent early muscle wasting (amyotrophic CJD) [3].
The molecular determinants of this heterogeneity are the M/V polymorphism at codon 129 of PRNP and the type of PrPSc that accumulates in brain tissue. Indeed, more than 90 % of patients with sCJD who are 129-MM have type 1 PrPSc, whereas more than 80 % of patients who are 129-VV and 129-MV have PrPSc type 2A (Fig. 10.1). Grouping of all cases of sporadic prion diseases according to the pairing of the 129 genotype with the PrPSc type results in the recognition of six disease subgroups, five presenting with a sCJD phenotype (sCJDMM1/sCJDMV1 , sCJDMV2, sCJDVV1, sCJDVV2, sCJDMM2 “cortical”) and one occurring with the features of sporadic fatal insomnia (sCJDMM2 “thalamic”). These subgroups actually match most clinical subtypes previously described [7].
VPSPr
The most common clinical presentation involves a triad consisting of psychiatric signs (psychosis or behavior and mood changes), speech deficit, and cognitive decline often with prominent involvement of frontal lobe functions. Progressive motor impairment, especially parkinsonism and ataxia, are succeeding features along the course of the illness [7].
Inherited prion diseases (fCJD, GSS, fFI)
The clinical and neuropathological phenotype of fCJD widely overlaps that of sCJD. GSS is an autosomal dominant neurodegenerative disease caused by missense (P102L, P105L, A117V, F198S, D202N, Q212P, Q217R) or insertional PRNP mutations [9] and classically presents as a chronic cerebellar ataxia with pyramidal features, while dementia usually occurs later in a clinical course that is typically longer than in classical CJD.
FFI is characterized by progressive untreatable insomnia, dysautonomia, motor abnormalities, and dementia. Disruption of the circadian oscillations of endocrine functions are observed early in the disease. FFI is linked to the D178N mutation in PRNP associated with methionine at codon 129 and is neuropathologically characterized by rather selective thalamic degeneration.
Acquired prion diseases – iCJD
The clinical phenotype of iCJD is influenced by the route of exposure. In cases with inoculation into the central nervous system – for example, via neurosurgical instruments – the clinical features are indistinguishable from sCJD. Peripheral route of infection, such as human pituitary hormone treatment, is initially marked by a progressive cerebellar syndrome, while other focal signs such as myoclonus usually develop later [10].
vCJD
vCJD presents as a progressive neuropsychiatric disorder (chronic depression, social withdrawal, psychotic features) with peripheral pain or dysesthesia followed by cognitive decline and ataxia. A number of patients also develop chorea or dystonia and less commonly myoclonus. Progression is less rapid than in sCJD [7].
Kuru
The clinical course of the disease is characterized by a progressive cerebellar ataxia associated with tremors. Dementia is late and may be absent [3].
10.5 Diagnostic Markers
MRI.
CJD: Brain atrophy is a common but late finding. Signal hyperintensity at diffusion weighted imaging (DWI) is detected in the neocortex and striatum in more than 65 % of sCJD patients, in the neocortex alone in less than 20 %, and in the striatum alone in 10 %. Other regions, such as the thalamus, can also be involved. The sensitivity and specificity of DWI are over 90 % [7, 11].
The most pronounced signal enhancements in vCJD are observed in the posterior thalamus (“pulvinar sign”). This signal pattern is present in 78 % of the vCJD cases [12].
GSS – Neuro-imaging may be normal or show nonspecific atrophy affecting the cerebral hemispheres and/or cerebellum.
FI – Aspecific changes.
PET: Thalamic hypometabolism, with variable participation of cerebral cortical regions in FI [7].
CSF
sCJD and fCJD patients bearing the E200K and V210I mutations: detection of 14-3-3 in the CSF is valuable for the diagnosis, although high variable values of specificity and sensitivity have been reported [13].
fFI – 14-3-3 is absent.
GSS – detection of 14-3-3 is uncommon.
iCJD – sensitivity of the test is lower (60 %).
vCJD – only half of the patients have elevated 14-3-3 levels.
VPSPr – 14-3-3 test is negative in most cases [7].
It is noteworthy that 14-3-3 is expected to be increased also in other acute illnesses with extensive neuronal damage [12].
Tau protein is usually elevated in CSF of CJD patients, with specificity ranging from 40 to 67 % and sensitivity 87 % [13].
The real-time quaking-induced conversion (RT-QuIC) is a CSF test with sensitivity greater than 83–87 % and 100 % specificity. It is based on rapid detection of minute amounts of PrPSc by in vitro conversion of recombinant PrPC [14].
Genetics – 10–15 % of human prion diseases are associated with autosomal dominant mutations in PRNP. Over 30 pathogenic mutations have been described [2].
EEG – From nonspecific changes in early stages to periodic sharp wave complexes (PSWCs) in middle and late stages of sCJD and fCJD. The EEG is not informative in iCJD and vCJD. PSWCs are not constant features in VPSPr and are usually absent in FI and GSS [12].
Visual evoked potentials (VEPs) and electroretinogram (ERGs) – Definite, though nonspecific abnormalities in CJD patients [15]:
VEPs – From deteriorated to enlarged cortical responses;
ERGs – B-wave attenuation/prolonged latencies, flicker deterioration, and attenuation of oscillatory potentials.
Polysomnogram – Reduction of sleep-related EEG activities, even in the early phase of the disease in FI.
Tonsil biopsy
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