Infectious Prions

Prion diseases are marked by the appearance of a pathologic form of PrP, typically designated PrP^Sc (Table 181-1). This pathologic form differs from PrP^C in a number of biochemical properties. First, PrP^Sc is resistant to digestion proteases.^18,33 Thus, the serine endoprotease proteinase K rapidly hydrolyzes PrP^C, whereas the carboxyl-terminal region of PrP^Sc resists digestion in most forms of prion disease. Generation of protease-resistant carboxyl-terminal fragments of characteristic size continues to be the most widely used assay for the pathogenic form of the prion protein. Second, PrP^C is readily soluble in mild non-ionic detergents, whereas PrP^Sc is not. Finally, studies using techniques such as circular dichroism and infrared spectroscopy indicate that approximately 40% of the PrP^Sc polypeptide backbone is in a β-sheet conformation, in contrast to PrP^C, which contains only a very short stretch of β-sheet structure.³⁴

Taken together, these data indicate that PrP^Sc is composed of tightly bound aggregates of PrP. The aggregates sterically exclude proteases from attacking the carboxyl terminus of PrP in the aggregates, thus conferring protease resistance. The aggregates are large and dense, and thus insoluble. The presence of extensive β-sheet structure suggests that the peptides in the aggregates are bound together by intermolecular β-sheets. In contrast, PrP^C exists as monomers or perhaps low-order multimers. High-resolution structures for PrP^C have been obtained by nuclear magnetic resonance (NMR) spectroscopy and x-ray crystallography. These show PrP^C to be a globular protein composed of three α-helical segments and two short β-strands that form a small antiparallel β-sheet. A curious feature of the protein is the absence of any regular structure of the purified protein at the amino terminus (amino acids 23 to 121) (Fig. 181-1).^35–37 Presumably, this region assumes some more regular structure in vivo through association with other macromolecules or small molecule ligands. The structure of PrP^Sc has proved more difficult to determine, in part because available methods for high-resolution determination of protein structure require that the protein be soluble. Because the conformation of PrP^Sc appears to be central to the process of prion propagation, efforts to decipher this structure using advanced techniques are under way. As yet, these methods have led to no definite determination of the structure of PrP^Sc aggregates.³⁸

Some molecule other than PrP might form a minor but important part of the infectious prion.^39,40 There is evidence that linear polyanionic molecules, such as RNA, may facilitate the conversion of PrP^C to PrP^Sc.³⁹ Although RNA may be a component of natural prions, it is important to emphasize that such RNA carries no specific information; it appears that the linear polyanionic structure, rather than the specific base sequence, is important in conversion.

Other proteins, although not part of the infectious particle, may play a role in the conversion of PrP^C to PrP^Sc. In the yeast prion state [PSI+] (see later for a further description of yeast prions), which is mediated by aggregates of the protein Sup35, the protein chaperone HSP104, as well as chaperones of the HSP70 and HSP40 families, can catalyze or inhibit the formation of prions.^41,42 A perhaps a similar effect occurs in mice that overexpress HSP70 and manifest prolonged mouse-adapted scrapie incubation times relative to wild-type mice.⁴³ The propagation of human prions in mice expressing human PrP is inhibited by the coexpression of mouse PrP. This has been taken as evidence that a factor, termed “protein X,” facilitates the conversion of PrP^C to PrP^Sc in mice and that this factor binds mouse PrP^C with greater avidity than human PrP^C.^44,45 Despite these lines of indirect evidence, no protein other than PrP has been proved to participate in mammalian prion propagation. Genome-wide surveys of human populations have suggested that genes other than PRNP may contribute to a risk for prion disease, but conclusive evidence is lacking.^46–48

Prion diseases are endemic in several species of ruminants to which humans are exposed through food consumption and other routes. The transmission of prion diseases across species is generally less efficient than transmission within the species, a phenomenon known as the “species barrier.” One crucial determinant of the species barrier is differences between species in the amino-acid sequence of PrP. Studies in transgenic mice demonstrate that the species barrier can be abrogated by the introduction of a gene directing expression of PrP of the prion donor species into the host.^49,50 Thus, mice, which are usually not susceptible to human sporadic CJD, are readily infected if the mouse Prnp gene has been replaced by a transgene coding for the human PrP sequence. This phenomenon has been exploited to generate transgenic mice that can be used as models and bioassay of bovine, ovine, human, or cervid forms of prion disease.⁴⁹ A second major determinant of the efficiency of cross-species transmission of prions is the prion strain involved, as discussed later.

One of the most enigmatic features of prion diseases is the existence of what are termed prion “strains.”⁵¹ These are infectious isolates distinguishable by clinical, pathologic, and biochemical features, even in genetically identical hosts (Table 181-2). It appears that differences in the clinical manifestation of certain human prion diseases (e.g., sporadic CJD, fatal insomnia, variant CJD, and so-called “variable protease-sensitive prionopathy”) may relate to differences in the strain of the prion involved. Because the prion consists only of host-derived PrP and perhaps other host-derived components, the means by which the properties of individual strains are maintained is puzzling.

Prion strains can be distinguished by clinical features such as incubation time or clinical signs at disease onset in genetically defined hosts.⁵² Strains can differ pathologically by the region of the brain in which PrP^Sc accumulates, by the microscopic pattern of PrP^Sc aggregates, by the degree of brain vacuolization, and by the morphology and distribution of PrP amyloid accumulation. Of particular importance from the point of view of human health in the presence of prion zoonoses, the barrier to transmission of prion disease between species seen with one strain of prions may be readily overcome by a different strain.⁵¹

The biochemical basis of prion strain variety is understood incompletely, but it appears to reflect conformational differences between the PrP^Sc associated with the various strains (Fig. 181-2). The size of the protease-resistant carboxyl-terminal fragment can differ slightly between strains, as can the stability of the PrP aggregate to denaturation with chaotropic salts. Taken together, these and other observations indicate that subtle conformational differences between PrP^Sc associated with the various strains somehow dictate the clinical and pathologic differences.

Only a small proportion of cases of human prion disease are infectiously transmitted, but intraspecies transmission through the oral route is the major cause of prion disease in animals. The reticuloendothelial system plays a major role in the initial propagation of prions outside the central nervous system (CNS) and in carrying infection to the CNS. After oral challenge with prions, titers rise first in gut-associated lymphoid tissue. Mice deficient in the number of functional Peyer’s patches show increased resistance to oral prion challenge.⁵³ Similarly, a number of studies document that follicular dendritic cells are necessary for mice inoculated intraperitoneally with mouse-adapted scrapie to propagate prions in the brain.⁵⁴ Prion infection is carried to the brain from lymphoid tissue by axoplasmic transport in neurons of the sympathetic nervous system.^55–60 In some models of scrapie infection, the vagus nerve is also important to spread infection to the CNS. The “drowsy” strain of hamster scrapie spreads to the brain without infecting lymphoreticular tissue after inoculation in the tongue, apparently by spreading through the motor neurons of the hypoglossal nerve and the gustatory sensory neurons of the nucleus of the solitary tract.⁶¹

The precise mechanism of prion propagation is not completely understood. A popular model views prion propagation as similar to the “seeded polymerization” mechanism of amyloid formation. The term amyloid is defined histopathologically as an accumulation of protein that binds the dye Congo red and alters its staining properties so that it exhibits an apple-green color under certain angles of polarized light. This occurs because amyloid is formed of fibrils composed of protein monomers, bound together in β-sheets, oriented perpendicularly to the long axis of the fibril. The kinetics of amyloid fibril formation in vitro suggests a mechanism for prion propagation: Typically, a pure solution of monomers of an amyloidogenic peptide will exhibit a lag phase, often days in duration, before the rapid conversion of monomers into amyloid fibrils. If a small “seed” fibril is introduced into a solution of monomeric peptides, the lag phase is eliminated, and the monomers rapidly polymerize. PrP amyloid of the histopathologically defined type (amyloid plaques) is seen in some forms of human and animal prion disease. Uncertainty persists over whether amyloid fibrils or a protofibrillary state may be the actual infectious moiety of prion diseases.^62–64 Models of prion propagation other than seeded polymerization exist.^62,65

The mechanism by which propagation of PrP^Sc leads to neurodegeneration remains unknown. Although the phenotypic expression of yeast prions, discussed later, is in several instances due to the loss of the protein’s normal function, this does not appear to be the case with mammalian prions. Rather, the conversion of PrP^C to PrP^Sc causes a toxic “gain of function.”⁶⁶ The nature of this toxic function remains poorly understood. Toxicity requires expression of PrP,⁶⁶ and this PrP must be GPI anchored.⁶⁷ As with other neurodegenerative diseases associated with protein aggregates, dysfunction of the ubiquitin-proteasome system has been invoked as a cause of neurodegeneration in prion disease.⁶⁸

Yeast Prions

Wickner⁶⁹ first proposed that certain epigenetic traits of yeast could be manifestations of a process analogous to that which occurs in mammalian prion diseases. To date, at least 10 yeast prions and 1 prion of the filamentous fungus Podospora anserina ([Het-s]) have been identified.⁷⁰ These traits are transmitted through exchange of cytoplasm but are not linked to the mitochondrial genome.^71–73 Each particular prion trait is linked to a different protein, encoded by the nuclear genome, that is found to be in an aggregated state when the prion trait is expressed.⁷⁴ Unlike the mammalian PrP prion, the phenotype of at least some yeast prions is equivalent to an inactivating mutation in the cognate protein. The [Het-s] prion is particularly interesting in that it appears to convey a useful property, mating incompatibility, upon its host. Yeast prions are intensively studied as models of mammalian prions and the processes of protein folding and aggregation in general. Yeast prions do not play any role in the initiation or transmission of mammalian prion diseases.

Sporadic Creutzfeldt-Jakob Disease

Sporadic CJD (sCJD) comprises approximately 85% to 94% of all cases of human prion disease.^85,86 It shows no gender predilection. Mean age at onset is 57 to 66 years, although patients as young as 17 years and older than 80 years with sCJD have been reported.⁸⁶ Several studies found a peak incidence, approaching 6 per 1 million, in the eighth decade and then a distinct decline in incidence in those older than 80 years.^84–86

The most distinctive clinical feature of sCJD is the pace of its progression, typically described as “rapid” or “subacute.” In the context of neurodegenerative conditions, these terms refer to perceptible declines in cognitive and motor function that are obvious over a period of a few weeks. In contrast, in more common neurodegenerative conditions, such as Alzheimer’s or Parkinson’s disease, decline is typically only apparent over periods ranging from months to years. Some observers have noted that the pace of decline in CJD accelerates until the later stages of akinetic mutism, when neurologic dysfunction is so severe that it is difficult to appreciate further decline. A second distinctive feature of CJD is the prominent involvement of multiple brain systems in which motor signs, such as ataxia, bradykinesia, or spasticity, are combined with memory and other cognitive deficits. There is a great deal of variability in the clinical manifestations of CJD, and this has led to attempts to describe a variety of clinical subtypes, including those with predominance of visual,⁸⁷ cerebellar,⁸⁸ thalamic,⁸⁹ and striatal^90,91 features. The existence of these syndromes indicates that CJD may affect particular brain regions disproportionately. In some cases, the particular regional predominance of pathology may reflect the strain of prion involved.

In many patients with sCJD, there is a prodromal phase of psychiatric disturbance before the onset of neurologic signs. Of 126 mostly sporadic cases of CJD, 26% of patients had psychiatric signs in the prodromal or presenting phase.⁹² Most common were sleep disturbance, depression, and anxiety. In approximately one third of patients, prominent initial visual or cerebellar symptoms may overshadow dementia. Mental deterioration typically is rapidly progressive, and the average duration of illness from onset of symptoms to death is 7 to 9 months. In addition to profound and rapidly progressive mental deterioration, another very common feature is myoclonus. However, myoclonus in demented patients is not pathognomonic of CJD. It can occasionally occur in Alzheimer’s disease and is common in Lewy body dementia. Extrapyramidal and cerebellar signs, including bradykinesia, rigidity, ataxia, nystagmus, and tremor, ultimately develop in approximately two thirds of patients. Approximately 40% to 80% of patients have signs of corticospinal tract dysfunction, including hyperreflexia, spasticity, and extensor plantar responses. Prominent visual disturbances, which can include visual field cuts, cortical blindness, and visual agnosia, occur in 50% of CJD patients.

Some patients have vague sensory complaints, including pruritus and aching limbs. It is unclear if these sensations are of peripheral or central origin.⁹³ Signs of a motor or sensory peripheral neuropathy are occasionally found in sCJD, although these signs are almost always overshadowed by the dramatic signs of CNS dysfunction. One study found clinical evidence of peripheral neuropathy in approximately 20% of cases examined and electrophysiologic abnormalities in 14 of 16 surveyed cases of sCJD.⁹⁴ On occasion, signs of sensory or motor neuropathy may dominate the early disease course. Rarely, fasciculations and muscle wasting will be so prominent as to suggest amyotrophic lateral sclerosis.^95,96 Some cases of CJD also have been reported in which the clinical features indicated prominent autonomic nervous system involvement. These features included hypohidrosis, bowel dysfunction, abnormal pupillary responses to autonomic drugs, abnormal diurnal blood pressure variation, and electrocardiogram abnormalities. Such findings are a cardinal feature of FFI.

Certain neurologic disturbances occur only rarely as prominent features in CJD, and their presence should prompt clinicians to consider other diagnostic possibilities. Although seizures occur in 10% to 20% of cases, they are rarely a dominant feature and typically are amenable to therapy. Cranial nerve involvement is never prominent, although isolated cases have been reported with involvement of the pupils; extraocular movements; and trigeminal, auditory, and vestibular systems.⁹⁷

At least two distinctive sporadic forms of CJD bear the hallmarks of discrete prion strains. First, very rare sporadic cases of a clinical and pathologic syndrome indistinguishable from FFI (see “Genetic Creutzfeldt-Jakob Diseases”) will be encountered in patients without PRNP mutations.^98,99 This form of sporadic prion disease maintains a biochemical signature identical to that of FFI upon serial transmission in transgenic mice expressing human PrP. It thus behaves as a distinct human prion strain.

Second, a recently described condition, “variable protease-sensitive prionopathy” is a form of sporadic CJD with fewer and less prominent motor and sensory signs and a pattern of cognitive impairment said to resemble frontotemporal dementia (although a few published clinical descriptions suggest the pattern of dementia may sometimes be similar to Alzheimer’s disease).^100,101 Progression is slower than typical sCJD, with a mean duration of 30 months. PrP^Sc from these patients is more sensitive to protease digestion than in typical sCJD. The predominant protease-resistant fragment is 8-kDa and cleaved at both the amino and carboxyl termini, whereas in sCJD, the predominant fragment is cleaved only at the amino terminus and is 19- or 21-kDa in size. The disease is quite rare; 13 cases were identified by the main U.S. prion disease pathology center over an 8-year period, and 5 cases were identified in Britain in a retrospective review of 20 years.^101,102 Ignoring ascertainment problems, which may be significant, these translate into an annual incidence of ≈0.5 per 100 million in either population. The disease has been successfully transmitted (to an unusual assay animal, the bank vole), although the serial transmissions needed to confirm it as a distinct strain are still in progress.^101,103

Genetic Creutzfeldt-Jakob Diseases

Approximately 10% of cases of human prion disease are caused by some nonconservative (i.e., amino-acid sequence–changing) mutation in PRNP, although the precise proportion varies among countries.⁸⁵ PRNP mutations are found in all cases from families with a history of inherited prion disease, as well as approximately 5% of apparently sporadic cases. Familial prion diseases are transmitted in an autosomal-dominant pattern, usually with high, but not always complete, penetrance.

At least 30 distinct mutations in the PRNP gene are known to be associated with the inherited prion diseases (see Fig. 181-1).^104,105 Not all patients with genetic forms of prion disease present with a family history of dementia.¹⁰⁶ In a large European survey of prion disease, a family history of a CJD-like dementia was elicited in only half of genetic cases.¹⁰⁷

Specific mutations in the PRNP gene tend to be associated with particular clinical and pathologic disease phenotypes.¹⁰⁷ However, significant variability is seen both within and between kindreds harboring identical mutations. The disease associated with many mutations is essentially indistinguishable from sporadic CJD. Among these is the most common mutation worldwide, a lysine-for-glutamic acid substitution in codon 200 (E200K).¹⁰⁵ This mutation has been found in geographic clusters of familial CJD in Slovakia and Chile and among Sephardic Jews in Greece, Libya, Tunisia, and Israel. Before the mutation was discovered to be prevalent in Libyan Jews, the high rate of CJD in this group was misattributed to the consumption of sheep brains or eyeballs.¹⁰⁸ The median age of onset is 58 years. The mutation is highly but incompletely penetrant so that approximately 80% of carriers will develop CJD by the eighth decade of life.¹⁰⁹ Because the mutation is found in inbred populations, rare carriers are homozygous for the mutation. Surprisingly, these people seem to develop illness only slightly earlier than heterozygotes (50 vs. 59 years).¹¹⁰

Some PRNP mutations are associated with syndromes markedly different from sCJD.

Infectiously Transmitted Human Prion Disease

In most countries, less than 1% of human prion disease is infectiously acquired. Yet, study of an epidemic of infectious prion disease in New Guinea led to the recognition of prions as a cause of neurodegenerative illness in humans and transmission of prion disease from animals or humans to humans continues to be an issue of great concern.

Kuru

Kuru is a neurodegenerative disease that was endemic within the Fore linguistic tribal group of the Eastern Highlands of Papua New Guinea.^6,139 It is thought to have arisen in the early 20th century and have been transmitted through the practice of ritual endocannibalism at funeral feasts.¹⁴⁰ No one born since the cessation of this practice has developed kuru.¹⁴⁰ The mean incubation period was 10 to 13 years, with 90% of cases occurring within 21 to 27 years of exposure. The incubation period was likely related to exposure dose and was shorter in women than in men and shorter in older women than in younger women, reflecting the likelihood of participation in cannibalistic practices.¹⁴¹ Rare cases of kuru continue to occur, likely as a result of exposure before ritual cannibalism ceased in 1960. Thus, in some cases, the incubation period for kuru can exceed 50 years.¹⁴⁰

Kuru remains important conceptually, even as it disappears as a clinical entity, as the largest outbreak of human-to-human transmission of a prion disease and as an example of human prion disease transmitted via the oral route. In its clinical and pathologic manifestations, it is distinct from most human prion disease. Kuru typically begins insidiously with a prodrome of headaches and aching limbs that may last for several months.¹⁴² This prodrome is followed by the development of an inexorably progressive neurologic disease resulting in death within 3 to 24 months of onset, usually from intercurrent pneumonia and malnutrition. Typical disease duration is 12 months.¹⁴² The cardinal clinical features include cerebellar ataxia, action tremor, and involuntary movements (choreoathetosis, myoclonic jerks, and coarse fasciculations). Dementia is usually not noted until late in the illness, 8 or more months after the onset of ataxia.

Neuropathologic examination of kuru brains shows neuronal loss, astrogliosis, and the accumulation of PrP^Sc, all findings typical of prion disease.^143–146 The pathologic hallmark of kuru is the presence of PrP amyloid plaques, predominantly in cerebellar tissue. These plaques are usually unicentric, located in the granular layer of the cerebellum, and often associated with microglial cells. Kuru cases show a higher-than-expected incidence of MM homozygosity at polymorphic codon 129 of the PRNP gene, as is seen in sCJD. In contrast, older women who potentially were exposed to infected brain material during the era of cannibalism and survived without developing kuru show a higher-than-expected frequency of heterozygosity at codon 129. Thus, this heterozygosity may have played a protective role against the transmission of prion diseases among the Fore. More strikingly, a PRNP G127V mutation is found only among survivors of the kuru epidemic and their descendants, and in no other population in the world.¹⁴⁷ This mutation appears to have conferred resistance to kuru and to have been strongly selected for during the epidemic.

The properties of kuru prions on transmission to transgenic mice expressing human PrP suggest that it is the same strain as that most commonly found in sporadic CJD.¹⁴⁸ This finding is consistent with the hypothesis that the kuru epidemic arose out of a naturally occurring case of sCJD that was then spread by cannibalism. It is puzzling that the clinical and pathologic features of kuru are quite distinct from those of typical sCJD. It is possible that the oral route of exposure alters the clinical and pathologic presentation, or that current methods of typing strains are insensitive to differences between kuru and sCJD.

Variant Creutzfeldt-Jakob Disease

Beginning in 1995, cases of a new variant of CJD were reported from the United Kingdom.^149,150,151 As of April 2013, a total of 176 cases have been reported to the U.K. Creutzfeldt-Jakob Disease Surveillance Unit (see www.cjd.ed.ac.uk/ for latest case totals). This includes 3 symptomatic “secondary” cases transmitted through nonleukocyte-depleted red blood cell transfusion and 2 asymptomatic cases—1 from red blood cell transfusion and the other probably transmitted through pooled plasma-derived factor VIII.^152–154 An additional 51 cases have occurred outside the United Kingdom, with 27 of these in France and the remainder in the Republic of Ireland, Italy, the Netherlands, Portugal, Spain, Japan, Saudi Arabia, the United States, and Canada.¹⁵⁵ Of the 5 North American cases, 4 appear to be due to exposure of the victims to infected beef products in the United Kingdom or Saudi Arabia.^155,156 Retrospective review of available autopsy material suggests that vCJD did emerge as a new disease entity in 1995; no current evidence suggests that cases occurred earlier.^157,158 It is likely that millions of people were exposed to BSE-infected food.¹⁵⁹ However, fears of a large epidemic of vCJD have not been realized. The largest number of annual cases, 28, was reported in 2000.¹⁵⁵ The incidence of vCJD is declining; there were no deaths from vCJD in Great Britain in 2012 and only 2 other cases in the world, both in France.¹⁵⁵

The epidemiologic, clinical, and pathologic features of the vCJD cases set them apart from typical sCJD.^150,160,161 Patients with vCJD have been considerably younger than patients with sCJD, with a mean age at onset of 26 years (range, 12 to 74 years) compared with 65 years for sCJD. Ninety percent of vCJD patients are younger than 40 years at the onset of their disease. The reason for this striking age dependence is not clear, but it appears to be due to greater susceptibility in the young rather than greater exposure to BSE-contaminated foodstuffs.¹⁶² The duration of illness in vCJD is longer (average, 14 months) than in sCJD (average, 4.5 months). This longer duration may be a reflection of the younger age of the patients because younger patients with sporadic CJD have a similar duration of illness.^163,164

Patients with vCJD frequently present with sensory disturbances and psychiatric manifestations. Such symptoms are not unusual in young-onset sCJD, but in vCJD, they are more prominent, perhaps because dementia and more obvious neurologic signs supervene later than in sCJD.¹⁶³ Among the sensory symptoms are vague pain, cold sensation, or paresthesias involving the face and limbs or in a hemisensory distribution. Most studied patients have had normal electromyography or mild abnormalities that do not point to a peripheral origin for the sensory disturbance.⁹³ It is speculated that they may be of thalamic origin.¹⁶⁵ Psychiatric manifestations frequently include dysphoria, withdrawal, anxiety, irritability, insomnia, and loss of interest in usual activities.^166,167 These symptoms often prompt an initial diagnosis of psychiatric illness. Neurologic signs and symptoms are uncommon within 4 months of onset. As disease progresses, the most frequent neurologic signs include dysarthria and gait disturbance. In the later stages of disease (>6 months after onset), prominent neurologic signs include hyperreflexia, myoclonus, incoordination, or other cerebellar signs.¹⁶⁶

Blood products have very likely transmitted vCJD on at least five occasions. Among a group of 66 individuals identified as having received blood components from donors who later developed vCJD, only 33 of the transfusion recipients survived more than 5 years after transfusion, with the rest dying of conditions other than CJD or dementia.^{153,168–170} Three of the remaining 33 recipients developed vCJD 6 to 8 years after transfusion. The donors had donated 16 months to 3.5 years before the onset of vCJD. One donor was linked to vCJD cases in 2 recipients. All cases received nonleukocyte-depleted red blood cells. The rate of vCJD in transfusion recipients from donors, who later developed vCJD, 4 per 66 or 6%, is four orders of magnitude greater than the rate of vCJD in the British population, conclusively implicating the transfusion as the cause of disease. Remarkably, in an autopsied case, PrP^Sc was found in the tonsils, suggesting that the accumulation of PrP^Sc within tonsils that is found in most vCJD cases is not due to the alimentary route of exposure but, rather, is a tropism inherent in the vCJD prion strain.¹⁵² Another of these 33 recipients died of causes unrelated to vCJD but was found at autopsy to have PrP^Sc in the spleen.¹⁷¹ Finally, a survey of tissue obtained at autopsy from 11 persons with hemophilia, known to have received U.K.-sourced, pooled, plasma-derived clotting factor concentrates, found PrP^Sc in a single spleen.¹⁷² Both cases of asymptomatic infection occurred in blood product recipients who were heterozygous (M/V) at PRNP codon 129, whereas that codon was homozygous M/M in the 3 symptomatic cases.

The neuropathologic features of vCJD are strikingly different than those of sCJD.¹⁵⁰ The most characteristic differences between the neuropathology of vCJD and sCJD seem to be the prominent involvement of the cerebellum in almost all cases of vCJD, compared with only a subset of cases with sCJD (Brownell-Oppenheimer variant and GSS cases). vCJD cases also show typical spongiform change, neuronal loss, and astrogliosis in the cortex, basal ganglia, and thalamus, but these do not distinguish vCJD from sCJD. vCJD cases have prominent amyloid plaques distributed throughout the cerebrum and cerebellum and, to a lesser extent, the basal ganglia and thalamus. These plaques have a dense eosinophilic center and pale periphery and are surrounded by vacuoles in the neuropil arranged around the plaque like petals on a flower (hence, the name “florid plaques”). The plaques stain strongly positive for PrP^Sc. This flower-like morphology is common in plaques from vCJD but is infrequently seen in other plaque-forming types of human prion disease, such as GSS, kuru, and some sporadic cases of CJD.¹⁷³ Patients with vCJD also have a consistent pattern of electrophoretic mobility of PrP^Sc protein (type 4 isoform) that is distinct from the mobility patterns encountered in sCJD and is similar to the pattern seen in BSE PrP^Sc.^174,175,176

Compelling evidence indicates that vCJD is the result of bovine-to-human transmission of BSE.^{175,177–180} From an epidemiologic standpoint, cases of vCJD followed a massive epidemic of BSE in the United Kingdom, with a lag period that is consistent with the known incubation period of prions. During the BSE epidemic, among the first cases, which were recognized retrospectively as early as April 1985, it was estimated that several hundred thousand BSE-infected cattle might have entered the human food chain.^181–183 The number of BSE-infected cattle peaked during 1992 and 1993 and subsequently declined steadily. This decline has been attributed to bans on using ruminant protein for ruminant feeds (July 1988) and on using bovine brain, spinal cord, and other specified offal as feed for nonruminant animals and poultry (September 1990). Another ban prohibited use of certain bovine tissues for human consumption (November 1989). It has been suggested that the BSE epidemic was triggered by changes in the rendering process, particularly the abandonment of the use of organic solvents.¹⁸⁴

Additional evidence for a BSE-vCJD link comes from the close neuropathologic similarities between the two diseases. Transgenic mice expressing bovine PrP develop indistinguishable neurologic illness and neuropathologic changes after a similar incubation period when injected with brain material from either cattle with BSE or humans with vCJD, and this differs from the pattern and incubation time seen after inoculation with scrapie.¹⁸⁰ In addition, the PrP^Sc protein isoforms isolated from the brains of the BSE-inoculated or vCJD-inoculated mice show an identical fragment size and glycosylation pattern, which differs from that seen after scrapie inoculation.¹⁷⁹ Furthermore, macaques inoculated with BSE prions develop florid plaques histologically indistinguishable from those seen in vCJD, whereas those inoculated with sporadic CJD prions do not develop plaques.¹⁷⁸ Finally, the susceptibility of mice expressing murine PrP, or transgenic mice expressing PrP of humans, to vCJD more closely resembles the susceptibility of these same mice to BSE than to other forms of human prion disease.¹⁸⁵

With one possible exception, all vCJD patients tested to date are homozygous for methionine at polymorphic codon 129 (129M).^151,174 One young patient in Great Britain with the 129VV genotype developed CJD with clinical and pathologic features not typical of sporadic or variant CJD. Protease-resistant PrP^Sc from this patient showed a size and glycoform pattern identical to that found in vCJD.¹⁸⁶ Whether this was a sporadic case or, like vCJD, caused by exposure to BSE prions is undetermined. It is fortunate, though puzzling, that despite the widespread exposure of populations to BSE, comparatively few persons have developed vCJD. As mentioned earlier, genome-wide association studies have sought loci that might confer exceptional susceptibility to vCJD upon some people. No convincing evidence for genetic risk factors, except for homozygosity for methionine at PRNP codon 129 has been found.^46,47

The wide exposure of the British population to BSE-contaminated food products and the sometimes very long incubation period of prion diseases have raised concerns that human infection with BSE prions may be more prevalent than is apparent from the number of clinical cases. In this regard, in certain animal models of transmission of prions across species, animals can be efficiently infected, as indicated by demonstrable prion replication in the spleen and other organs of the reticuloendothelial system, but never show clinical signs of disease. Immunohistochemical surveys of large numbers of archived tonsils and appendices has been undertaken in Great Britain to look for subclinical prion infection.^187–190 A survey of approximately 11,000 appendices collected between 1995 and 1999 found 3 with immunohistochemically detected PrP^Sc.¹⁸⁷ The study was repeated on approximately 32,000 appendices collected between 2010 and 2012, and 16 were found to harbor PrP^Sc.¹⁹⁰ Together, these studies suggest that about 1 in 2000 Britons may be subclinically infected with prions. However, as yet, no study has been performed on a control group, for instance, a population not known to have exposure to BSE. Therefore, it is uncertain whether these findings are related to BSE exposure, represent some other aspect of prion biology, or are artifactual. If the PrP^Sc detected in appendices is the result of BSE prions propagating in human lymphoid tissue (i.e., subclinical vCJD), then it is possible that a large number of symptomatic cases could eventually occur and that donated blood products, organs, or tissues from subclinically infected Britons might transmit prion disease to recipients.

Diagnosis of vCJD should be considered when patients with a history of residence in a BSE endemic area, such as the United Kingdom, develop a progressive neurodegenerative disease. Table 181-3 lists the World Health Organization criteria for vCJD. These criteria identified vCJD cases with 77% sensitivity and 100% specificity.¹⁶¹

TABLE 181-3

Case Definitions for Sporadic and Variant Creutzfeldt-Jakob Disease

Sporadic CJD

Possible

Progressive dementia, and EEG atypical or not known, and Duration <2 years, and At least two of the following four clinical features: Myoclonus Visual or cerebellar disturbance Pyramidal/extrapyramidal dysfunction Akinetic mutism Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: Antiviral Agents Metronidazole Pharmacokinetics and Pharmacodynamics of Anti-infective Agents Infections in the Immunocompromised Host Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections Ticks, Including Tick Paralysis Stay updated, free articles. Join our Telegram channel Join Tags: Mandell Douglas and Bennetts Principles and Practice of Infect Jul 1, 2017 | Posted by admin in INFECTIOUS DISEASE | Comments Off on Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases) Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access