Prion-Related Diseases 

Updated: Dec 18, 2017
Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM 

Overview

Background

The prion diseases are a large group of related neurodegenerative conditions, which affect both animals and humans.[1] Included are Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker (GSS) in humans, bovine spongiform encephalopathy (BSE, or "mad cow disease") in cattle, chronic wasting disease (CWD) in mule deer and elk, and scrapie in sheep. These diseases all have long incubation periods but are typically rapidly progressive once clinical symptoms begin. All prion diseases are fatal, with no effective form of treatment currently; however, increased understanding of their pathogenesis has recently led to the promise of effective therapeutic interventions in the near future.

Prion diseases are unique in that they can be inherited, they can occur sporadically, or they can be infectious. The infectious agent in the prion disease is composed mainly or entirely of an abnormal conformation of a host-encoded glycoprotein called the prion protein. The replication of prions involves the recruitment of the normally expressed prion protein, which has mainly an alpha-helical structure, into a disease-specific conformation that is rich in beta-sheet.[2]

The first of these diseases to be described was scrapie, a disease of sheep recognized for over 250 years. This illness, manifested by hyperexcitability, itching, and ataxia, leads to paralysis and death. It is called scrapie because of the tendency of affected animals to rub against the fences of their pens in order to stay upright, reflecting their cerebellar dysfunction. The transmission of this disease was demonstrated first in 1943 when a population of Scottish sheep was accidentally inoculated against a common virus using a formalin extract of lymphoid tissue from an animal with scrapie.[3] Accidental transmission of prions is a recurrent event in the history of these agents and is related to their unusual biophysical properties.

For related information, see Medscape Reference article Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy.

Pathophysiology

A unifying feature of all the prionoses is their neuropathology. These illnesses tend to affect the gray matter of the central nervous system (CNS), producing neuronal loss, gliosis, and characteristic spongiform change. The latter is a vacuolation of the neuropil, and to a variable degree, of the neurons, shown below.

Prion-related diseases. Spongiform change in prion Prion-related diseases. Spongiform change in prion disease. This section shows mild parenchymal vacuolation and prominent reactive astrocytosis.

In addition, plaques with the typical staining properties of amyloid (eg, apple-green birefringence after Congo Red staining when viewed under polarized light) are observed in many of these conditions. In approximately 10% of patients with CJD, amyloid is present in the cerebellum or in the cerebral hemispheres. All cases of GSS are associated with multicentric cerebellar plaques. These amyloid plaques are immunoreactive with antibodies to the prion protein and do not immunoreact with antibodies to other amyloidogenic proteins, such as the amyloid-beta (which is deposited in Alzheimer disease).

Etiology of PrP-related diseases

Highly divergent hypotheses have been put forward regarding the makeup of the prions, including that they consist of nucleic acid only or protein only, are lacking both protein and nucleic acid, or are a polysaccharide. The most widely accepted hypothesis, first described by Griffith[4] and more explicitly detailed by Stanley Prusiner, MD, is the protein only hypothesis.[5] Prusiner introduced the term prion to indicate that scrapie is related to a proteinaceous infectious particle (PrP).[6]

This hypothesis was initially greeted with great skepticism in the scientific community; now it represents the current dogma, and Prusiner won the 1998 Noble Prize for Science. This hypothesis suggests that prions contain no nucleic acid and are referred to as PrPSc. The latter represents a conformationally modified form of a normal cellular PrPC, which is a normal host protein found on the surface of many cells, in particular neurons. PrPSc, when introduced into normal healthy cells, causes the conversion of PrPC into PrPSc, initiating a self-perpetuating vicious cycle.[5]

Other hypotheses for prion have included the virino hypothesis.[7] This hypothesis suggests that the infectious agent consists of a nucleic acid with host-derived PrPSc serving as a coat. The latter would explain the lack of an immunological and inflammatory response, while the presence of a nucleic acid provides an explanation for the numerous strains of scrapie, each with distinctive features. Other investigators have also suggested that the scrapie agent is a conventional virus with highly atypical properties. However, despite extensive searches, no nucleic acid associated with prion infection has been detected so far.

The protein-only hypothesis of prion propagation proposes the existence of an infectious agent composed solely of protein.[6] Recent reports claim that apart from the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.[8, 9, 10]

Cell biology of prions - Normal cellular function of PrP

The human PrP gene (PRNP) is found on chromosome 20 and encodes a protein of 253 amino acids. PrPC is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein; some have speculated that it may have a role in cell adhesion or signaling processes, but its exact cellular function remains unknown. The N-terminal region of PrP contains a segment of 5 repeats of an 8–amino acid sequence (ie, octapeptide repeat region) that contains a high-affinity binding site for copper ions; hence, PrP may have a role in copper transport or metabolism. Recent evidence suggests that copper imbalance is an early change during prion infections.[11] The function(s) of PrPC is likely to be of some importance because PrP is highly conserved among mammals and is found in all vertebrates.[12, 13] Also, prionlike proteins called PSI and URE3 are expressed in yeast.[14]

PrP is found in most tissues of the body but is expressed at highest levels in the CNS, in particular in neurons. PrP is also expressed widely on cells of the immune system. PrP knockout mice, which are engineered not to express the PrP gene, show no obvious pathological phenotype.[15] However, these mice have been shown to have abnormalities in synaptic physiology[16] and in circadian rhythms and sleep.[17]

The secondary structure of PrPC was first elucidated by nuclear magnetic resonance (NMR) imaging using recombinant mouse PrP protein.[18] More recently, this has been achieved using recombinant hamster and human PrP.[19, 20, 21] These studies have shown that PrPC is about 40% alpha-helix and about 3% beta-sheet. No high-resolution structural studies, such as NMR imaging, have been performed on PrPSc because it is highly insoluble and aggregated, which are properties that prevent use of these techniques. However, less exact structural methods such as circular dichroism and Fourier transform infrared spectroscopy have shown PrPSc to contain about 45% beta-sheet and 30% alpha-helix.[22, 23] This high beta-sheet content correlates with PrPSc resistance to enzymatic digestion and infectivity.

Prion strains and the species barrier

Many lines of evidence support the protein only hypothesis of prion propagation; however, a difficulty is the existence of several distinct isolates or strains of prions that can be stably passaged among inbred mice of the same genotype.[24] The existence of strains suggests that PrPSc could adopt multiple distinct pathological conformations. Strains are defined by the production of distinct patterns of incubation time, distributions of CNS involvement, and the pattern of proteolytic cleavage of PrPSc following proteinase K (PK) digestion.[5, 25] For example, at least 14 significantly different scrapie strains have been isolated from natural sheep scrapie by passage into mice.[24, 26]

The best studied are the two strains of transmissible mink encephalopathy (TME) called hyper (HY) and drowsy (DY).[27, 28] The truncated DY PrPSc fragments (PrP27-30) migrate 1-2 kd faster than similar preparations of HY because sites of PK cleavage differ and the two strains differ in terms of beta-sheet content.[28, 27]

Parchi et al defined 2 distinct types of sporadic CJD based on the analysis of PrP codon 129, which encodes either a valine or a methionine, and by the pattern of sodium dodecyl sulfate-polyacrylamide (SDS-PAGE) migration of the PrP27-30. Type 1 sporadic CJD has a molecular weight of the deglycosylated PrP27-30 of about 21 kd, while type 2 has a mobility of about 19 kd.[29] Collinge et al reported 2 further types related to infectious CJD.[30] These distinct types of sporadic CJD appear to have slightly different beta-sheet content that correlates with the degree of resistance to proteinase K digestion of each strain.[22]

Each strain of prion has characteristic range of infectivity. For example the 263K strain is pathogenic for hamsters but does not infect mice.[31] This effect is called a species barrier and is related to PrPSc being an effective template for homologous PrPC and a poor template for heterologous PrPC; hence, mouse PrPSc can effectively convert mouse PrPC, but it is a very poor template for human or hamster PrPC. This species barrier is not absolute, as is illustrated by the emergence of new variant CJD (vCJD).

The structure and folding properties of the cellular prion protein are well characterized, and, although its precise function remains enigmatic, constitutive knockout of protein expression in mice produces apparently healthy animals that are fully resistant to prion infection. In addition, data show that neuronal knockout of the gene encoding for prion protein during established brain infection leads to reversal of pathology and behavioral deficits.[32]

How prions reach the CNS

Prion diseases are transmitted naturally by peripheral routes, either orally or transcutaneously; hence, how prions are able to reach the CNS is an important issue. Although the prion diseases are neurological conditions, critical events in their pathogenesis take place in restricted sites out of the nervous system, especially in peripheral lymphoid organs.[33]

Lymphoid organs have long been known to be involved in the early stages of prion diseases.[34, 35, 36] In particular, the spleen and lymph nodes have been demonstrated to be the first sites of PrPSc replication after infection by peripheral routes, and they are also affected significantly following intracerebral challenge. Their importance for neuroinvasion after peripheral inoculation was suggested by studies showing that splenectomy and other methods that reduce peripheral lymphoid structures delay clinical manifestations.[35]

The hematogenic spread of prions to the CNS is suggested by experiments that show BSE to be transmissible from sheep to sheep by blood transfusion.[37] Three cases of vCJD infection associated with blood transfusion have also been observed (Health Protection Agency, Variant CJD and blood products). All received nonleucodepleted red blood cells.

The first case developed vCJD in 2003, 6.5 years following transfusion from a donor who developed vCJD 3.5 years following donation. The second patient died of causes unrelated to vCJD in 2004, 5 years following the transfusion. At autopsy, this individual had abnormal prion protein in the spleen and cervical lymph node but not in the brain, and other pathological features of vCJD were not observed. The donor developed symptoms of vCJD 18 months after his donation. The third patient developed vCJD in 2006, about 8 years following transfusion from a donor who was diagnosed with vCJD about 20 months after donation.

Hematogenic neuroinvasion has been shown to be dependent on the presence of B lymphocytes.[38] However, because expression of the cellular prion protein by B cells is not required for neuroinvasion, some have suggested that their main function is to allow maintenance of follicular dendritic cells.[39] However, more recent studies suggest that neuroinvasion is possible in the absence of both B cells and follicular dendritic cells.[40] Other studies have implicated the distinct CD11c+ dendritic cell population in prion neuroinvasion.[22, 41]

In addition to hematogenous spread, prions can reach the brain via the parasympathetic vagus nerve.[42] Hence, following intraperitoneal delivery of prions, disease can be delayed by sympathectomy or can be accelerated by sympathetic hyperinnervation of lymphoreticular organs.[43]

Which of these two routes for neuroinvasion is most important remains unclear; it may be scrapie strain–dependent. However, a more complete understanding of these stages and the cells involved in prion spread from the periphery may allow for development of a pharmacological gatekeeper that can be used to stop the movement of infectivity.

Epidemiology

Frequency

United States

The most common prion disease is CJD, with a uniform incidence of approximately 1 case per million population both in the United States and internationally. Familial forms of prion diseases, such as GSS and fatal familial insomnia (FFI), are much more rare. About 10% of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PRNP gene.

International

As of February 2006, 159 cases of definite or probable vCJD have been reported in the United Kingdom of which 153 persons have died (see The National Creutzfeldt-Jakob Disease Surveillance Unit). Whether these patients represent the beginning of a growing epidemic (such as that which occurred with BSE) or whether the number of cases will remain relatively low remains unclear. The first confirmed 3 cases were reported in 1995, with numbers of subsequent cases remaining relatively stable between 1996 and 2004 (9-28 cases per year). Only 5 cases were confirmed in 2005.

Two populations are disproportionally affected by CJD: Libyan-born Israelis and some populations in restricted areas of Slovakia where the incidence of CJD is 60-100 times greater than expected. These clusters were postulated to be related to dietary exposure of the scrapie agent; however, this was not supported by case-controlled studies. These local high rates of CJD are linked to a high prevalence of codon 200 mutations in the PRNP gene.

Mortality/Morbidity

Prion-related diseases are relentlessly progressive and invariably lead to death.

  • The mean duration of sporadic CJD is 8 months.

  • vCJD has a slightly longer course, with a mean duration of 14 months.

  • Familial CJD has a mean duration of 26 months, while GSS has the longest course, about 60 months.

Race

Sporadic CJD occurs throughout the world in people of all races and typically has similar features.

  • Some familial forms of prion disease, such as familial CJD, can have distinct features in an ethnic group. For example, familial CJD in the Libyan Jewish population associated with a codon 200 mutation has features of a peripheral neuropathy in addition to the more typical manifestations of CJD.[44, 45]

  • vCJD has been limited to Europe, with almost all cases occurring in the United Kingdom.

Sex

No sex preponderance is known in prion diseases, with some rare exceptions. For example, women had a greater tendency than men to develop kuru because it was part of the ritual cannibalism for women to eat the brains (and neural tissue has the highest dose of PrPSc).

Age

The mean age of onset of sporadic CJD is 62 years. The incidence of sporadic CJD is about 1 case per million population; however, among individuals aged 60-74 years, the incidence is 5 cases per million population.[46] The age range can be broad; cases have been reported in people as young as 17 years and as old as 83 years.[47, 48]

vCJD occurs in younger patients, with a mean age of onset of 28 years.

Familial CJD, GSS, and FFI have mean ages of onset ranging from 45-49 years.

 

Presentation

History

Several different forms of prion disease exist (see Table 1 below). The first human prionosis to be described is called kuru.[49, 50, 51] This is an illness of the Fore people living in the highlands of New Guinea that is thought to be linked to ritualistic cannibalism. Presumably, this illness originated with the consumption of an initial patient with sporadic CJD. Kuru was once the major cause of death among Fore women; however, the disease has virtually disappeared with the end of cannibalistic rituals. Similar to scrapie, patients clinically present with difficulty walking and they develop progressive signs of cerebellar dysfunction. Death occurs approximately 1 year following onset of symptoms.

The neuropathology of kuru, in common with all prionoses to a variable extent, includes widespread spongiform change and astrocytosis, as well as neuronal loss affecting the cerebral hemispheres and cerebellum. More intraneuronal vacuolation is observed in kuru compared to CJD (see below). In about 70% of cases, amyloid plaques are found, with amyloid deposition being a common, but not invariable, accompaniment of the prionoses. Gajdusek's detailed description of this illness led Hadlow to suggest that kuru might be the human representation of scrapie.[4] This in turn inspired Gajdusek and his team to test whether kuru was also transmissible. In 1966, they first showed kuru was transmissible to chimpanzees, after a long incubation.[52] Gajdusek was awarded the Noble Prize in 1976 for this work.

Table 1. Prion-Related Diseases, Hosts, and Mechanism of Transmission (Open Table in a new window)

Disease

Host

Mechanism

Kuru

Human

Cannibalism

Sporadic CJD

Human

Spontaneous PrPC to PrPSc conversion or somatic mutation

Iatrogenic CJD

Human

Infection from prion-containing material, eg, dura mater, electrode

Familial CJD

Human

Mutations in the PrP gene

vCJD

Human

Infection from BSE

GSS

Human

Mutations in the PrP gene

FFI

Human

D178N mutation in the PrP gene, with M129 polymorphism

Sporadic fatal insomnia

Human

Spontaneous PrPC to PrPSc conversion or somatic mutation

Scrapie

Sheep

Infection in susceptible sheep

BSE

Cattle

Infection from contaminated food

TME

Mink

Infection from sheep or cattle in food

CWD

Mule, deer, elk

Unclear

Feline spongiform encephalopathy

Cats

Infection from contaminated food

Exotic ungulate encephalopathy

Nyala, oryx, kudu

Infection from contaminated food

By far the most common human prion disease is CJD, accounting for about 85% of all human prion disease. CJD was initially described by Jacob in 1921[53] ; ironically, the case reported by Creutzfeldt a year earlier is probably unrelated to the disease that carries his name. Clinically, CJD is characterized by a rapidly progressive dementia associated with myoclonic jerks, as well as a variable constellation of pyramidal, extrapyramidal, and cerebellar signs. The EEG findings typically show distinctive changes of high-voltage slow (1-2 Hz) and sharp wave complexes on an increasingly slow and low-voltage background. CJD is found throughout the world, with an incidence of about 1 case per million population. In addition to extensive cortical spongiosis, gliosis, and neuronal loss, 10% of CJD cases have amyloid plaques.[5] Ten percent of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PrP gene.[54]

Creutzfeldt-Jakob disease

Sporadic CJD is characterized by a rapidly progressive multifocal neurological dysfunction, myoclonic jerks, a terminal state of global severe cognitive impairment, and death in about 8 months.

About 40% of patients with sporadic CJD present with rapidly progressive cognitive impairment, 40% with cerebellar dysfunction, and the remaining 20% with a combination of both.

The clinical picture rapidly expands to include behavioral abnormalities, higher cortical dysfunction, cortical visual abnormalities, cerebellar dysfunction, and both pyramidal and extrapyramidal signs.

Almost all patients with sporadic CJD develop myoclonic jerks that involve either the entire body or a limb. These myoclonic jerks can occur spontaneously or can be precipitated by auditory or tactile stimulation.

During the course of sporadic CJD, most patients develop a characteristic picture on EEG with periodic or pseudoperiodic paroxysms of sharp waves or spikes on a slow background. These periodic complexes have a sensitivity and specificity of 67% and 87% respectively on a single EEG. However, if repeated recordings are obtained, more then 90% of patients show periodic EEG abnormalities.[55]

When evaluating a patient for possible sporadic CJD, the clinician should be guided by published case definitions; they are as follows:

  • Definite CJD

    • Characteristic neuropathology

    • Protease-resistant PrP by Western blot

  • Probable CJD

    • Progressive dementia

    • Typical findings on EEG

    • At least 2 of the following - Myoclonus, visual impairment, cerebellar signs, pyramidal or extrapyramidal signs, or akinetic mutism

  • Possible CJD

    • Progressive dementia

    • Atypical findings on EEG or EEG not available

    • At least 2 of the following - Myoclonus, visual impairment, cerebellar signs, pyramidal or extrapyramidal signs, or akinetic mutism

    • Duration less than 2 years

Gerstmann-Sträussler-Scheinker disease

Gerstmann-Sträussler-Scheinker disease was described in a large kindred in 1936.[56]

Patients with this illness present with a slowly progressive limb and truncal ataxia, as well as dementia. Death occurs 3–8 years following presentation.

The prominent involvement of the brainstem often leads to symptoms suggestive of olivopontocerebellar degeneration. The pattern of inheritance is autosomal dominant and is caused by mutations of the PrP gene. The neuropathology of GSS is remarkable in that extensive and invariable amyloid deposition occurs, in addition to the typical spongiform change, gliosis, and neuronal loss. Interestingly, in several kindreds of GSS, extensive neurofibrillary tangle (NFT) formation is found.[57] NFTs are an essential feature of Alzheimer disease, but are also observed in other neurodegenerative conditions.

Another variation of autosomal dominantly inherited human prionosis has been termed prion protein congophilic angiopathy (ie, prion protein cerebral amyloid angiopathy [PrP-CAA]), which is characterized by cerebral vessel amyloid deposition and the presence of NFT.[58] Cerebral amyloid angiopathy (CAA) is also an essential feature of Alzheimer disease. Both these variants of prionoses further link the pathogenesis of Alzheimer disease and the prion-related diseases.

Fatal familial insomnia

Patients with FFI present with intractable insomnia, dysautonomia (ie, hyperthermia, hypertension, tachycardia, tachypnea, hyperhydrosis), dementia, and motor paralysis; however, the phenotypic expression is very variable even within the same family.[59] The age of onset is also variable, ranging from 18-60 years. Once symptoms begin, the course ranges from 6 months to 3 years. Because of the diversity of clinical presentations of this disorder, genotyping is very important for definitive diagnosis. Neuropathologically, marked atrophy of the anterior ventral and mediodorsal thalamic nuclei occurs because of neuronal loss and gliosis. Unlike other prionoses, spongiform change can be a minor feature or can be absent altogether.

All patients with FFI have a missense mutation at codon 178 of the PrP gene where Asn is replaced by Asp, coupled with a Met at the polymorphic codon 129.[60] The somewhat divergent clinical and neuropathological features of FFI, in comparison to other human prionoses, highlight the wide spectrum of disease associated with PrP dysfunction and suggest that other human illnesses have yet to be recognized as prionoses.

Fatal familial insomnia and Creutzfeldt-Jakob disease are associated with a D178N mutation of the PRNP gene located on chromosome 20. D178N mutation changes the aspartate to asparagine at codon 178. In this disease, the mutant chromosome encodes methionine in the polymorphism of codon 129. The cortex is spared but the thalamus is particularly susceptible to this type of prion disease; therefore, fatal insomnia is situated at the extreme end of a spectrum of prion diseases with frequent psychiatric presentations.[61]

There is an unusual incidence of this disease in Basque Country (Spain). Oliveros et al report a patient with postmortem diagnosis of fatal insomnia who had a phenotypic presentation of catatonia and they stress the importance of considering this disease in catatonia nonresponsive to ECT.[62]

Variant Creutzfeldt-Jakob disease

A recent epidemic of a new prionosis has occurred; BSE has led to more then 160,000 cattle deaths in the United Kingdom.[63] This new disease is thought to be caused by meat and bone meal dietary supplements to cattle that were contaminated with scrapie-infected sheep and other cattle with BSE. Extensive evidence suggests that BSE has also lead to a new type of CJD, called variant CJD (vCJD).[64] The first cases of vCJD were reported in 1995, when CJD was found in 2 British teenagers.[65, 66]

Only 4 cases of sporadic CJD have been reported previously among teenagers; the peak incidence of onset of sporadic CJD is in people aged 60-65 years. In addition to the early age, these cases had distinctive neuropathology that included so-called florid amyloid plaques, which are reminiscent of kuru-associated PrP amyloid plaques.[67, 68] Significantly, such florid amyloid plaques are also a feature of chronic wasting disease.[69]

As of February 2006, 159 cases of vCJD have been diagnosed in Great Britain (see The National Creutzfeldt-Jakob Disease Surveillance Unit). The latest numbers from other countries as of November 2005 are 15 in France, 3 from Ireland, 2 in the United States, and one each from Canada, Italy, Japan, Netherlands, Portugal, Saudi Arabia, and Spain (see Centers for Disease Control and Prevention, Variant Creutzfeldt-Jakob Disease). Both of the US cases, 1 of the 3 in Ireland, and the single cases from Canada and Japan were likely exposed while living in the UK. The emergence of vCJD has raised the specter of an epidemic of prion-related disease among the British population (and possibly a wider population) similar to that of BSE in cattle.

Physical

Physical signs and symptoms vary with the type of prion disease. vCJD differs from sporadic CJD in that psychiatric abnormalities and sensory symptoms are much more common at presentation of vCJD.

  • Mental status and/or neuropsychological examination

    • This shows a rapidly worsening global cognitive status. The most common initial symptoms are cognitive impairment and ataxia.

    • Many less common variations exist, such as presentations with initial cortical blindness (ie, Heidenhain variant).

    • In sporadic CJD, an important and almost universal physical feature is the presence of myoclonus.

    • Cerebellar findings are present in all patients with vCJD, while about 40% of those with sporadic CJD have cerebellar dysfunction.

In 2009, Kahn et al reported a patient with inherited prion disease who sustained fractures that were successfully managed conservatively with unusual results, such as accelerated healing, akin to that seen in traumatic head injuries. Local growth factors, inflammatory cytokines, and endogenous bone morphogenic proteins have all been implicated in head injuries and the authors propose that similar factors may be responsible in prion disease, common to both conditions.[70]

Causes

Prion-related diseases are unique in that they can be related to infectious, sporadic, or familial causes (see Pathophysiology).

Infectious causes

Kuru, a form of prion disease, occurred among the Fore people of the Eastern Highlands of New Guinea and was related to ritualistic cannibalism. The disease is believed to have started with the ingestion of body parts of a patient with sporadic CJD, followed by a serial passage of the disease.

Many cases of iatrogenic CJD have been reported. In clinical practice, CJD has been transmitted by surgical instruments, EEG electrodes, corneal transplants, dura mater grafts, human pituitary-derived gonadotrophins, and human-derived growth hormone. Concerns that vCJD could be transmitted by blood transfusion have been borne out with 3 documented case.

vCJD in humans is presumed to have been caused by ingestion of beef products contaminated with BSE. BSE is presumed to have started because of the practice of supplementing the diets of calves and dairy cows with meat and bone products. These meat and bone products are thought to have been contaminated with scrapie material (from sheep) and/or with material from cattle with a sporadic form of bovine prion disease.

A number of cases of apparent sporadic CJD have occurred in the United States among young individuals (< 30 y). The incidence of sporadic CJD among such young individuals has historically been about 1 case per billion population. In the years 1979-1996, 4 cases of sporadic CJD were reported in the United States among individuals younger than 30 years. In the years 1997-2000, 5 cases have occurred in the United States among young patients. Two of these individuals came from adjacent counties in Michigan (ages at onset were 26 and 28 y), and 3 cases occurred among individuals who were known hunters of deer and/or elk.[71]

Over the same period, a major outbreak of CWD occurred among the deer and elk populations in many western states, which has now spread to at least 10 states (see Chronic Wasting Disease Alliance). CWD is a form of prion disease that occurs naturally in the deer and elk population; however, the pathology has many similarities to BSE, including the presence of florid plaques.[69] Significantly, transmission studies of CWD PrPSc in the laboratory have shown that it can cross the species barrier from deer to human PrP at about the same efficiency as the BSE prion agent.[72] These observations have led to the speculation that limited transmission of CWD to humans has occurred recently in the United States.

Findings indicated that transgenic mice that express the deer/elk prion protein can be infected with intracerebral injection of muscle tissue from symptomatic cervids,[73] which raises concerns about infectivity of meat products from these animals. Also, a nonhuman primate developed prion disease after intracerebral injection with brain material from symptomatic deer.[74]

Familial causes

The cause of familial forms of prion disease is related to mutations in the PrP gene. A number of mutations in the PrP gene are linked to autosomal dominant forms of prion disease. The image below is a representation of the human PrP gene, PRNP.

Prion-related diseases. A representation of the hu Prion-related diseases. A representation of the human proteinaceous infectious particle, or PrP, gene. Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations. The locations of the 4 putative helical regions, H1-H4, correspond to residues 109-122, 129-141, 178-191, and 202-218, respectively. This diagram does not illustrate all of the alpha-helical regions. A diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial Creutzfeldt-Jakob disease (CJD).

A signal peptide of 22 amino acids (dotted area) is cleaved at the amino terminus (N-terminus) synthesis, and a further sequence at the carboxyl terminus (dotted area) is removed during the addition of a glycosyl-phosphatidylinositol anchor (GPI).

Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations.

The locations of the 4 putative helical regions are indicated by the boxes labeled H1 through H4, corresponding to residues 144-154, 179-193, and 200-218, respectively.

The diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial CJD.

Mutations at codons 102, 105, and 117 have been associated with GSS, while mutations at codons 198 and 217 are found in pedigrees with GSS and NFTs.

PrP-CAA has been linked to a point mutation at codon 145 that results in a stop codon. Familial CJD has been associated with mutations at codons 178, 180, 200, 210, and 232.

Interestingly, kindreds with FFI have the same D178N mutation as 178 familial CJD kindreds; however, the FFI phenotype is associated with a Met at codon 129, whereas the mutated allele in 178 CJD patients has a Val at the polymorphic codon 129.

Sporadic causes

Sporadic CJD is the most common form of prion disease.

It probably arises as a spontaneous conformational change in PrPC to a PrPSc form. The PrPSc form is then self-propagating, inducing more PrPC to convert to the PrPSc form.

The risk of transmission depends on both the type of procedure and the type of tissue involved, with brain, spinal cord, and eye having the highest risk.

To study the association between medical procedures and sporadic Creutzfeldt-Jakob disease (sCJD), Hamaguchi et al analyzed medical procedures (any surgical procedure, neurosurgery, ophthalmic surgery, and blood transfusion) for patients registered by the CJD Surveillance Committee in Japan from 1999–2008. The study included 753 patients with sCJD and 210 controls and patients who underwent neurosurgical or ophthalmic surgical procedures at the same hospital. No evidence was found that prion disease was transmitted through the investigated medical procedures before the onset of sCJD. After the onset of sCJD, 4.5% of the patients with sCJD underwent operations, and no special precautions against transmission of prion diseases were taken. The authors have not identified patients with prion disease attributed to these operations and conclude that surgical procedures or blood transfusion has little effect on the incidence of sCJD.[75]

Transfusion transmission of the prion, the agent of variant Creutzfeldt-Jakob disease (vCJD), is now established. Subjects infected through food may transmit the disease through blood donations.

 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

  • Nonherpes viral encephalitis

  • Diffuse Lewy body disease

  • Chronic meningitis

  • Dementia as a paraneoplastic syndrome

  • Familial myoclonic dementia

  • Lithium poisoning

  • Dementia in motor neuron disease

  • Limbic encephalitis (and other paraneoplastic syndromes)

  • Hashimoto encephalopathy (or Steroid-responsive encephalopathy associated with autoimmune thyroiditis [SREAT])

Rule out all other causes of dementia, particularly causes of a rapidly progressive dementia that could be treatable, such as herpes encephalitis.[76] In herpes encephalitis, the CSF has pleocytosis and an elevated protein content, while in CJD the cell count and protein content are within the reference range. In addition, herpes encephalitis has characteristic MRI and EEG findings. Other entities that are in the differential diagnosis are neurodegenerative disease such as Alzheimer disease, Pick disease, corticobasal ganglionic degeneration, familial myoclonic dementia, and multisystem atrophy. However, the progression of the dementia and other neurological symptoms is slower in all these disorders compared to CJD.

Also consider Hashimoto encephalitis (also referred to as steroid-responsive encephalopathy associated with autoimmune thyroiditis [STEAT]) in the differential diagnosis.[77, 78, 79] The clinical symptomatology of Hashimoto encephalitis can be very similar to possible CJD, with the presence of a rapidly progressive dementia, myoclonus, ataxia, and psychosis; however, this autoimmune disorder responds well to treatment with immunosuppression. The diagnosis of Hashimoto encephalopathy can be made by finding high serum levels of thyroperoxidase autoantibodies (TPO). Patients with Hashimoto encephalitis do not show the 14-3-3 protein in the CSF nor do they have the typical periodic sharp wave complexes on EEG.

Differential Diagnoses

 

Workup

Laboratory Studies

Initial workup includes laboratory tests as for dementia. To rule out a toxic and/or metabolic encephalopathy, evaluate CBC count, serum chemistry panel, liver function test results, ammonium levels, and erythrocyte sedimentation rate. Perform blood cultures if any type of bacterial infection is suspected.

In addition, evaluate thyroid function, B-12 levels, and folate levels and perform tests for neurosyphilis. The rapid plasma reagent (RPR) test or Venereal Disease Research Laboratory (VDRL) test results may be negative in neurosyphilis; hence, if this diagnosis is suspected, perform a fluorescent treponemal antibody test. Perform HIV testing if any risk factors are present.

To rule out Hashimoto encephalopathy, serum levels of anti-thyroperoxidase antibodies (formally known as antimicrosomal antibody) should be determined.[78]

If a paraneoplastic syndrome is possible (ie, when a history of malignancy or imaging studies finding an occult neoplasm), then the presence of autoantibodies should be investigated. These are reviewed in Dropcho 2005. A partial list of possible paraneoplastic syndromes and their associated tumors and autoantibodies is shown in Table 2.

Table 2. Paraneoplastic Syndromes, Associated Tumors, and Autoantibodies (Open Table in a new window)

Clinical Syndrome

Neoplasm

Autoantibodies

Limbic encephalitis

Small cell lung carcinoma

Testicular/breast, thymoma

Anti-Hu, antiCV2,PCA-2, ANNA-3

Anti-Ma2 Anti-VGKC, anti-CV2

Cerebellar degeneration

Breast, ovary, lung, others

Anti-Yo, anti-Ma, anti-Ri

Anti-Hu, anti-CV2

Opsoclonus myoclonus

Breast, ovarian, small cell carcinoma of lung

Neuroblastoma

Anti-Ri, anti-Yo, Anti-Hu,

Anti-amphiphysin Anti-Hu

 

Imaging Studies

MRI is an important imaging test. MRI may show hyperintense signals in the cortical ribbon, basal ganglia, and the thalamus on diffusion-weighted images (DWI) and fluid-attenuated inversion recovery (FLAIR) images. See the image below. In a recent review, DWI and FLAIR imaging was found to be 91% sensitive, 95% specific, and 94% accurate for the diagnosis of sporadic CJD.[80]

Shows characteristic signal changes of an MRI take Shows characteristic signal changes of an MRI taken from a patient with sporadic CJD, using diffusion-weighted imaging (DWI). An abnormal signal is shown in both the basal ganglia (red arrows) and the cortical ribbon (yellow arrow).

Two characteristic radiological signs have been described. The "hockey stick" sign, which refers to increased signal in the putamen and head of the caudate nucleus resembling a hockey stick, and the "pulvinar" sign, which corresponds to a usually bilaterally increased signal in the pulvinar thalamic nuclei. The latter sign has been found especially in patients with vCJD.

In a few patients, positron emission tomography (PET) scan has been performed in which regional hypometabolism of glucose was noted that correlated with the neuropathologic lesions found at autopsy.

CJD presents with multifaceted clinical signs including ataxia, visual, pyramidal, myoclonus, limb apraxia, limb dystonia, sensory, parkinsonism, and corticobasal syndrome (CBS). In their effort to study the relationship between clinical pattern and cerebral glucose metabolism on [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in CJD, Renard et al. report hypometabolism in brain areas related to some specific signs (i.e., ataxia, visual signs, and CBS), in addition to lateralized frontal and parietal hypometabolism previously reported in CJD.[81]  

In addition to MRI and PET imaging to finding changes characteristic of prion disease, it is often prudent to obtain imaging (contrast CT scans) of the chest, abdomen, and pelvis in patients to rule out the possibility of a malignancy that could be producing a paraneoplastic syndrome.

Other Tests

EEG

During the course of sporadic CJD, most patients develop a characteristic finding on EEG with periodic or pseudoperiodic paroxysms of sharp waves or spikes on a slow background.

These periodic complexes have a sensitivity and specificity of 67% and 87%, respectively, on a single EEG. However, if repeated recordings are obtained, more then 90% of patients show periodic EEG abnormalities.

In vCJD, EEG does not show the typical changes observed in sporadic CJD, and findings often are normal.

Procedures

Perform lumbar puncture (LP) in all suspected cases.

  • Check the opening pressure.

  • Evaluate the cerebrospinal fluid (CSF) for cell count, protein, glucose, bacterial cultures, viral cultures, VDRL, cryptococcal antigen, and acid-fast bacilli (AFB).

  • CSF is typically normal in sporadic CJD, although the CSF protein may be elevated slightly (but never >100 mg/dL).

  • Test CSF for the 14-3-3 protein. The sensitivity and specificity of this test exceed 90%. Information on obtaining this test is found at National Prion Disease Pathology Surveillance Center. This test is performed free of charge at the National Prion Disease Pathology Surveillance Center.

  • Perform a brain biopsy if the diagnosis is in doubt and a potentially treatable cause must be ruled out.

Disease-associated prion proteins include both PrPC and PrPSc. To detect low levels of this disease marker in biological material with high sensitivity, reagents that can precipitate the disease-associated prion protein are vital. Rees et al report that among the range of minerals available for this purpose, silicon dioxide is unaffected by the PrPSc strain or host species and the method can be used to precipitate bovine BSE.[82] This method can also reliably concentrate protease-resistant ovine PrPSc (PrPres) and has increased detection sensitivity by more than 1,500-fold.

Different isolates from the same host species with transmissible spongiform encephalopathies (TSEs) may show different eletrophoretic profiles, reflecting the existence of different prion strains. Experimental transmission of these atypical cases to various transgenic mouse lines has led to the recognition of a novel scrapie strain in sheep and goats, called Nor98, and of 2 variant strains of spongiform encephalopathy in cattle.[83]

In this study, streptomycin demonstrated its efficiency to detect PrPres both in the central nervous system and in the lymphoid tissue without practical difficulty and with rapid preparation. Because of its ability to act as a good agent for PrPSc examination in different tissues, recovery of PrPSc in biological fluids using streptomycin should open further perspectives of applications in CJD diagnostics. Streptomycin effects in vivo might thus also be questioned.

Histologic Findings

See Pathophysiology.

Staging

Clinical diagnosis is sometimes difficult (particularly in atypical sCJD cases such as MM2, MV2, VV1, or VV2 types) according to 6 phenotypes of sCJD divided by codon 129 polymorphisms of PrP (methionine/valine) and type of infectious PrP by Western blotting.

 

Treatment

Medical Care

Discontinue any medication that could impair memory or cause confusion.

A number of potential therapeutic interventions are under current development, as discussed in Medication.

The transmissible spongiform encephalopathies are rapidly progressive neurodegenerative diseases, and outcome is inexorably fatal. No treatments have proven efficacious. Chemotherapeutic approaches have focused on blocking the conversion of the normal form of prion protein (PrPC) to its abnormal counterpart (PrPres) either by directly binding PrPC or PrPres, or by redistributing, sequestering, or downregulating PrPC, thus preventing its conversion. Others aim to enhance the clearance of PrPres. Other targets include accessory molecules such as the laminin receptor precursor, which influences conversion (or cell-signaling molecules) that may be required for pathogenesis.[84]

Other promising therapeutic approaches aimed to block the production of PrPSc are based on PrP RNA interference, passive or active immunization, dominant negative inhibition of PrPSc formation, as well as inhibition of interactions between PrPSc and other cofactors. An alternative strategy consists of combining gene therapy with cell therapy.[85]

Evidence is accumulating that PrPC may act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer's disease.

A general consensus on the role of PrPC and its physiological function within the brain is yet to be established. Lowering PrPC levels in the brain is predicted to be a powerful therapeutic strategy for the treatment of prion disease and the precise reason for PrPC's existence continues to remain enigmatic. 

Miguelez-Rodriguez et al. report that the existence of copathology significantly prolongs survival in patients with rapidly progressive dementia due to CJD. To further understand the molecular mechanisms behind prion diseases they suggest the study of major neurodegenerative-associated proteins in brains with CJD.[86]  

Consultations

You may wish to consult with a neurologist and/or an infectious disease specialist.

 

Medication

Medication Summary

All prion diseases are fatal; no effective treatment is available. Patients are currently provided symptomatic treatment. Hence, some patients with CJD who develop seizures should be administered antiepileptic drugs, while those with extrapyramidal symptoms should be administered anti-Parkinson drugs.

A number of medications have been shown in experimental systems to be effective at preventing prion propagation. These have included Congo red and its analogs,[87, 88, 89, 90] anthracyclines[91] , amphotericin B and its analogs,[92, 93, 94, 95, 96] sulfated polyanions,[97, 98, 99] and tetrapyrroles.[100, 101] Some of these have been shown to delay the incubation times of animals infected with scrapie, but these agents have limitations in terms of toxic effects and/or unfavorable pharmacokinetic properties. Of these compounds, amphotericin B failed to ameliorate CJD in a single patient.[102]

In addition, tissue culture studies have shown that acridine and phenothiazine derivatives (eg, quinacrine, chlorpromazine) can inhibit the conversion of PrPC to PrPSc.[103] These types of drugs have been used in humans for many years as antimalarial and antipsychotic drugs; however, recent reports of anecdotal use of these agents in limited numbers of patients with sporadic CJD or vCJD have so far not supported their use,[104] and animal studies have also been negative.[105, 89, 106] An extensive clinical trial (PRION-1) on this approach was initiated in the UK in 2004 (see National Prion Clinic).

Another compound that is being tested in patients is pentosan polysulphate, which seemed promising based on an animal study.[89] This compound does not cross the blood-brain barrier and has been delivered by intraventricular administration to symptomatic patients. In the only reported vCDJ case study using this approach, no obvious side effects were observed, and the clinical symptoms appeared to be slightly attenuated, although brain atrophy progressed based on CT scans.[107]

The author and their colleagues have recently designed a number of compounds that interact with the PrPSc structure and act as beta-sheet breakers,[108, 109, 110] inhibiting the conformation of PrP associated with disease. These compounds were designed by first synthesizing a large number of different PrP homologous peptides. These were then screened for inhibitory activity on the conversion of PrPC to PrPSc using an in vitro system. That synthetic peptides corresponding to PrP residues 109-141 can reproduce some of the properties of PrPSc in vitro is well known.[111, 112, 113] The author's studies determined the ability of these various candidate beta-sheet breaker peptides to inhibit amyloidlike fibril formation of PrP109-141 using a fluorometric assay based on the fluorescence emission of thioflavine T.[114, 115] This assay showed that a 13-residue peptide (iPrP13) had the greatest beta-sheet–breaking capability. Using this peptide,the author and his colleagues were able to show that the proteinase K sensitivity of extracted mouse PrPSc and of human PrPSc extracted from patients with sporadic CJD or from patients with vCJD was increased in a concentration-dependent fashion by iPrP13.[108]

The in vivo effect of iPrP13 was tested by using mouse-adapted scrapie strain 139A. Incubation time assays were performed using 3 different 10-fold dilutions of extracted 139A PrPSc, in the presence or absence of an equimolar concentration of iPrP13. At each dilution, one group of mice was injected with untreated and nonincubated PrPSc, a second group was inoculated with PrPSc that was incubated for 48 hours alone, a third group was inoculated with PrPSc and nonincubated iPrP13, and a fourth group was inoculated with PrPSc and iPrP13 incubated for 48 hours. iPrP13 induced a substantial delay in the appearance of disease. These results suggest that beta-sheet breakers may have therapeutic potential in the prionoses.

This type of therapeutic approach, in which the disease-associated abnormal protein conformation is the target, currently is under extensive investigation for the prionoses as well as for other conformational disorders, such as Alzheimer disease.[116, 117]

Other more recent approaches include chelation therapy. Copper has been implicated in prion propagation,[118] and the authors have demonstrated that a chelator, D-penicillamine, which selectively chelates copper, delays the onset of prion disease in infected mice.[119] In vitro, copper enhanced the proteinase K resistance of the prion protein, which was counteracted by co-incubation with D-penicillamine. Overall, these findings indicate that copper levels can influence the conformational state of PrP, thereby enhancing its infectivity, and this effect can be attenuated by chelator-based therapy.

An additional therapeutic approach that may be of benefit for the prion diseases is immunological.[120] A number of recent reports have shown that immunization with alpha-helix peptides is highly successful at reducing cerebral amyloid accumulation, a key neuropathologic feature in Alzheimer disease, in transgenic mouse models of that disease.[121, 122, 123, 124]

Alpha-helix peptides are normal constituents of biological fluids such as blood and CSF at low concentrations, and they are the major component of the amyloid deposits that characterize Alzheimer disease. Passive immunization studies in the Alzheimer disease model mice suggest that an antibody-mediated clearance of alpha-helix peptides is critical for a therapeutic response.[125] The authors have extended this immunological approach to prion disease and suggest that this approach can be applied to all members of the extended category of neurodegenerative conformational diseases.[126, 127, 128, 129]

Interestingly, prior work has shown that vaccination with an attenuated CJD strain can prevent expression of a more virulent strain.[130] The authors have reported that vaccination with recombinant mouse prion protein (recPrP) delays the onset of prion disease in mice.[126] Vaccination was performed both prior to peripheral prion exposure and after exposure. A delay in disease onset was observed in both groups but was more effective in animals immunized prior to exposure. The increase in the incubation period closely correlated with the anti-PrP antibody titer. The mechanism of the delay with vaccination is not clear, but the correlation of the increased incubation time with antibody titer. The authors subsequently showed that passive immunization in mice using anti-PrP antibodies prolonged the incubation times, which suggests that humoral immunity is critical for a therapeutic response.[129]

Subsequent mouse studies using much higher doses of antibodies completely prevented symptoms of prion disease.[131] Antibody administration is unlikely to be used prophylactically in large populations because of high cost but can potentially be used in humans following accidental exposure.

The authors were recently able to prevent symptoms in about 30% of infected mice by administering a Salmonella -based prion vaccine,[127] which because of low cost has the potential to be used prophylactically in livestock and perhaps also in high-risk human populations. Antibody binding to PrPC and/or PrPSc may possibly interfere with PrPSc -mediated conversion of PrPC to PrPSc and thereby delay the onset of clinical symptoms. Recent in vitro studies support this view,[132, 133] and immunization with prion peptides of 20 amino acids has been shown to reduce the levels of PrPSc in scrapie-infected mouse tumors[134] without affecting PrPC levels. Hence, epitope mapping of the anti-PrP antibodies produced by immunization may provide insights on which portions of the prion molecule are important for prion replication.

The ultimate goal of such immunological approaches is for human testing; the recent problems with the phase II clinical trial of A-beta1-42 vaccination for Alzheimer disease highlight the difficulties of translating successful therapeutic approaches from mouse models to humans (in this trial of A-beta1-42, a significant number of patients developed encephalitis as a complication). A number of potential toxic side effects of vaccine-based approaches exist in humans; further animal and in vitro experimentation is required. One source of potential toxicity is from the immunogen that is used. In the authors' Alzheimer disease vaccine development studies, the A-beta sequence was altered, making it nonfibrillogenic and nontoxic while maintaining or increasing its immunogenicity, to overcome this source of toxicity.[135, 136]

Similar types of alterations are underway to limit any potential toxicity from using the native PrP sequence as an immunogen. The authors' in vivo findings serve as a starting point for the development of vaccine-based approaches for the prion diseases and suggest that prion-based immunization is promising as a potential therapy.

 

Follow-up

Further Outpatient Care

The rate of progression of prion diseases is rapid. Frequent follow-up care is necessary to assess the need for symptomatic treatments. If the patient develops seizures, parkinsonian features, or behavioral problems, appropriate pharmacological treatments can be administered.

Further Inpatient Care

The initial steps of the dementia workup (eg, LP) can be performed most speedily if the patient is admitted to the hospital.

If the diagnosis is not clear, inpatient care speeds up referral for a brain biopsy.

Deterrence/Prevention

Prion diseases may spread by iatrogenic means. Hence, take care not to reuse EEG and/or electromyography (EMG) needles, surgical instruments, and other tools that have been exposed to a patient with prion disease. The prion agent is remarkably resistant to inactivation; hence, routine sterilization procedures, such as autoclaving, are ineffective.

As the incidence of BSE in Europe continues to decline, iatrogenic transmission from person to person is considered a serious threat to public health.

Preventive measures include donor deferral policies, technologies for prion removal from labile blood components and prion detection in plasma, and establishing a sensitive and rapid reference assay able to confirm the positive results from any putative blood screening assay.[137]

Interestingly, passive immunization with antibodies against prion protein (PrP), a major component of the prion infectious agents, was shown to protect mice from infection, indicating the possibility of prion vaccines. However, PrP is a host protein; therefore, immune tolerance to PrP has hampered development of them.

In the absence of a large-scale screening test, it is impossible to establish the prevalence of infection in the blood donor population and transfused patients. This lack of a test also prevents specific screening of blood donations. Since leukoreduction is probably insufficient to totally eliminate the transfusion risk, recently developed prion-specific filters could be a solution.[138]

Complications

Any part of the CNS may be involved during the progression of prionoses; therefore, all types of CNS complications may be observed.

Prognosis

The prionoses are rapidly progressive. The median survival duration from the time of diagnosis to death varies from 8 months (as in sporadic CJD) to 60 months (as in GSS).

Patients with familial prion-related disease tend to have a longer course than those with sporadic disease.

Patient Education

For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education article Mad Cow Disease and Variant Creutzfeldt-Jakob Disease.