eMedicine Specialties > Neurology > Neurological Infections

Prion-Related Diseases

Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
Coauthor(s): Arun Ramachandran, State University of New York Upstate Medical University
Contributor Information and Disclosures

Updated: Sep 21, 2009

Introduction

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-Strãussler-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.

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.2 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 eMedicine 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 (see Media file 1).

Prion-related diseases. Spongiform change in prio...

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

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Prion-related diseases. Spongiform change in prio...

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 Griffith3 and more explicitly detailed by Stanley Prusiner, MD, is the protein only hypothesis.4 Prusiner introduced the term prion to indicate that scrapie is related to a proteinaceous infectious particle (PrP).5

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.4

Other hypotheses for prion have included the virino hypothesis.6 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.5 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.7,8,9

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.10 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.11,12 Also, prionlike proteins called PSI and URE3 are expressed in yeast.13

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.14 However, these mice have been shown to have abnormalities in synaptic physiology15 and in circadian rhythms and sleep.16

The secondary structure of PrPC was first elucidated by nuclear magnetic resonance (NMR) imaging using recombinant mouse PrP protein.17 More recently, this has been achieved using recombinant hamster and human PrP.18,19,20 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.21,22 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.23 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.4,24 For example, at least 14 significantly different scrapie strains have been isolated from natural sheep scrapie by passage into mice.23,25

The best studied are the two strains of transmissible mink encephalopathy (TME) called hyper (HY) and drowsy (DY).26,27 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.27,26

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.28 Collinge et al reported 2 further types related to infectious CJD.29 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.21

Each strain of prion has characteristic range of infectivity. For example the 263K strain is pathogenic for hamsters but does not infect mice.30 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.31

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.32

Lymphoid organs have long been known to be involved in the early stages of prion diseases.33,34,35 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.34

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.36 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.37 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.38 However, more recent studies suggest that neuroinvasion is possible in the absence of both B cells and follicular dendritic cells.39 Other studies have implicated the distinct CD11c+ dendritic cell population in prion neuroinvasion.21

In addition to hematogenous spread, prions can reach the brain via the parasympathetic vagus nerve.40 Hence, following intraperitoneal delivery of prions, disease can be delayed by sympathectomy or can be accelerated by sympathetic hyperinnervation of lymphoreticular organs.41

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.

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.42,43
  • 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.44 The age range can be broad; cases have been reported in people as young as 17 years and as old as 83 years.45,46
  • 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.

Clinical

History

Several different forms of prion disease exist (see Table 1 below). The first human prionosis to be described is called kuru.47,48 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.3 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.49 Gajdusek was awarded the Noble Prize in 1976 for this work.

 Table 1. Prion-Related Diseases, Hosts, and Mechanism of Transmission

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Table
DiseaseHostMechanism
KuruHumanCannibalism
Sporadic CJDHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
Iatrogenic CJDHumanInfection from prion-containing material, eg, dura mater, electrode
Familial CJDHumanMutations in the PrP gene
vCJDHumanInfection from BSE
GSSHumanMutations in the PrP gene
FFIHumanD178N mutation in the PrP gene, with M129 polymorphism
Sporadic fatal insomniaHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
ScrapieSheepInfection in susceptible sheep
BSECattleInfection from contaminated food
TMEMinkInfection from sheep or cattle in food
CWDMule, deer, elkUnclear
Feline spongiform encephalopathyCatsInfection from contaminated food
Exotic ungulate encephalopathyNyala, oryx, kuduInfection from contaminated food
DiseaseHostMechanism
KuruHumanCannibalism
Sporadic CJDHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
Iatrogenic CJDHumanInfection from prion-containing material, eg, dura mater, electrode
Familial CJDHumanMutations in the PrP gene
vCJDHumanInfection from BSE
GSSHumanMutations in the PrP gene
FFIHumanD178N mutation in the PrP gene, with M129 polymorphism
Sporadic fatal insomniaHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
ScrapieSheepInfection in susceptible sheep
BSECattleInfection from contaminated food
TMEMinkInfection from sheep or cattle in food
CWDMule, deer, elkUnclear
Feline spongiform encephalopathyCatsInfection from contaminated food
Exotic ungulate encephalopathyNyala, oryx, kuduInfection 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 192150 ; 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.4 Ten percent of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PrP gene.

  • 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.51
    • 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-Strãussler-Scheinker disease, as described in a large kindred in 1936.52
    • 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.53 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.54 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.55 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 129.56 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.57
    • 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.58
  • 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.59 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).60 The first cases of vCJD were reported in 1995, when CJD was found in 2 British teenagers.61,62
    • 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.63,64 Significantly, such florid amyloid plaques are also a feature of chronic wasting disease.65
    • 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.66

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.
    • Recently, 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.67
    • 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.65 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.68 These observations have led to the speculation that limited transmission of CWD to humans has occurred recently in the United States.

      Recent findings indicate that transgenic mice that express the deer/elk prion protein can be infected with intracerebral injection of muscle tissue from symptomatic cervids,69 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.70
  • 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. Media file 2 is a representation of the human PrP gene, PRNP.

      Prion-related diseases. A representation of the h...

      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).

      [ CLOSE WINDOW ]
      Prion-related diseases. A representation of the h...

      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.71
  • 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.

More on Prion-Related Diseases

Overview: Prion-Related Diseases
Differential Diagnoses & Workup: Prion-Related Diseases
Treatment & Medication: Prion-Related Diseases
Follow-up: Prion-Related Diseases
Multimedia: Prion-Related Diseases
References
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References

  1. Sadowski M, Verma A, Wisniewski T. Prion Diseases. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinial Practice. Philadelphia: Elsevier Inc; 2004:1613-1630.

  2. Gordon WS. Advances in veterinary research. Vet Rec. 1946;58:518-525.

  3. Griffith JS, Hadlow WJ. Scrapie and kuru. Lancet. 1959;11:289-290.

  4. Prusiner SB, Scott MR, DeArmond SJ, Cohen FE. Prion protein biology. Cell. May 1 1998;93(3):337-48. [Medline].

  5. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. Apr 9 1982;216(4542):136-44. [Medline].

  6. Weissmann C. The Ninth Datta Lecture. Molecular biology of transmissible spongiform encephalopathies. FEBS Lett. Jun 24 1996;389(1):3-11. [Medline].

  7. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. Jul 2009;11(7):909-13. [Medline].

  8. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. May 8 2009;284(19):12845-52. [Medline].

  9. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. Feb 2009;11(2):219-25. [Medline].

  10. Thackray AM, Knight R, Haswell SJ, Bujdoso R, Brown DR. Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem J. Feb 15 2002;362:253-8. [Medline].

  11. Harris DA, Lele P, Snider WD. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc Natl Acad Sci U S A. May 1 1993;90(9):4309-13. [Medline].

  12. Windl O, Dempster M, Estibeiro P, Lathe R. A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene. Jul 4 1995;159(2):181-6. [Medline].

  13. Masison DC, Edskes HK, Maddelein ML, Taylor KL, Wickner RB. [URE3] and [PSI] are prions of yeast and evidence for new fungal prions. Curr Issues Mol Biol. Apr 2000;2(2):51-9. [Medline].

  14. Büeler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell. Jul 2 1993;73(7):1339-47. [Medline].

  15. Collinge J, Whittington MA, Sidle KC, et al. Prion protein is necessary for normal synaptic function. Nature. Jul 28 1994;370(6487):295-7. [Medline].

  16. Tobler I, Gaus SE, Deboer T, et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature. Apr 18 1996;380(6575):639-42. [Medline].

  17. Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K. NMR structure of the mouse prion protein domain PrP(121-321). Nature. Jul 11 1996;382(6587):180-2. [Medline].

  18. Hosszu LL, Baxter NJ, Jackson GS, et al. Structural mobility of the human prion protein probed by backbone hydrogen exchange. Nat Struct Biol. Aug 1999;6(8):740-3. [Medline].

  19. James TL, Liu H, Ulyanov NB, et al. Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. Proc Natl Acad Sci U S A. Sep 16 1997;94(19):10086-91. [Medline].

  20. Knaus KJ, Morillas M, Swietnicki W, Malone M, Surewicz WK, Yee VC. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nat Struct Biol. Sep 2001;8(9):770-4. [Medline].

  21. Aucouturier P, Geissmann F, Damotte D, et al. Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest. Sep 2001;108(5):703-8. [Medline].

  22. Pan KM, Baldwin M, Nguyen J, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. Dec 1 1993;90(23):10962-6. [Medline].

  23. Baron T. Identification of inter-species transmission of prion strains. J Neuropathol Exp Neurol. May 2002;61(5):377-83. [Medline].

  24. Kascsak RJ, Rubenstein R, Merz PA, et al. Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains. J Virol. Sep 1986;59(3):676-83. [Medline].

  25. Carp RI, Rubenstein R. Diversity and significance of scrapie strains. Semin Virol. 1991;2:203-13.

  26. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol. Dec 1994;68(12):7859-68. [Medline].

  27. Caughey B, Raymond GJ, Bessen RA. Strain-dependent differences in beta-sheet conformations of abnormal prion protein. J Biol Chem. Nov 27 1998;273(48):32230-5. [Medline].

  28. Parchi P, Castellani R, Capellari S, et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol. Jun 1996;39(6):767-78. [Medline].

  29. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature. Oct 24 1996;383(6602):685-90. [Medline].

  30. Kimberlin RH, Walker CA. Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol. Jun 1978;39(3):487-96. [Medline].

  31. Nicoll AJ, Collinge J. Preventing prion pathogenicity by targeting the cellular prion protein. Infect Disord Drug Targets. Feb 2009;9(1):48-57. [Medline].

  32. Aucouturier P, Carp RI, Carnaud C, Wisniewski T. Prion diseases and the immune system. Clin Immunol. Aug 2000;96(2):79-85. [Medline].

  33. Eklund CM, Kennedy RC, Hadlow WJ. Pathogenesis of scrapie virus infection in the mouse. J Infect Dis. Feb 1967;117(1):15-22. [Medline].

  34. Fraser H, Dickinson AG. Studies of the lymphoreticular system in the pathogenesis of scrapie: the role of spleen and thymus. J Comp Pathol. Oct 1978;88(4):563-73. [Medline].

  35. Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: dynamics of agent replication in spleen, spinal cord and brain after infection by different routes. J Comp Pathol. Oct 1979;89(4):551-62. [Medline].

  36. Houston F, Foster JD, Chong A, Hunter N, Bostock CJ. Transmission of BSE by blood transfusion in sheep. Lancet. Sep 16 2000;356(9234):999-1000. [Medline].

  37. Klein MA, Frigg R, Flechsig E, et al. A crucial role for B cells in neuroinvasive scrapie. Nature. Dec 18-25 1997;390(6661):687-90. [Medline].

  38. Montrasio F, Frigg R, Glatzel M, et al. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science. May 19 2000;288(5469):1257-9. [Medline].

  39. Shlomchik MJ, Radebold K, Duclos N, Manuelidis L. Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dendritic cells. Proc Natl Acad Sci U S A. Jul 31 2001;98(16):9289-94. [Medline].

  40. Beekes M, McBride PA, Baldauf E. Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol. Mar 1998;79 ( Pt 3):601-7. [Medline].

  41. Glatzel M, Heppner FL, Albers KM, Aguzzi A. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron. Jul 19 2001;31(1):25-34. [Medline].

  42. Meiner Z, Halimi M, Polakiewicz RD, Prusiner SB, Gabizon R. Presence of prion protein in peripheral tissues of Libyan Jews with Creutzfeldt-Jakob disease. Neurology. Jul 1992;42(7):1355-60. [Medline].

  43. Neufeld MY, Josiphov J, Korczyn AD. Demyelinating peripheral neuropathy in Creutzfeldt-Jakob disease. Muscle Nerve. Nov 1992;15(11):1234-9. [Medline].

  44. Holman RC, Khan AS, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States, 1979-1994: using national mortality data to assess the possible occurrence of variant cases. Emerg Infect Dis. Oct-Dec 1996;2(4):333-7. [Medline].

  45. Masters CL, Harris JO, Gajdusek DC, Gibbs CJ Jr, Bernoulli C, Asher DM. Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol. Feb 1979;5(2):177-88. [Medline].

  46. Cathala F, Baron H. Clinical Aspects of Creutzfeldt-Jakob Disease. In: Prusiner SB, McKinley MP, eds. Prions: novel infectious pathogens causing scrapie and Creutzfeldt-Jakob disease. New York, NY: Academic Press; 1987:467-509.

  47. Gajdusek DC, Zigas V. Degenerative disease of the central nervous system in New Guinea: the epidemic occurrence of "kuru" in the native population. N Engl J Med. 1957;257:974-978.

  48. Gajdusek DC, Zigas V. Clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the eastern highlands of New Guinea. Am J Med. 1959;26:442-469.

  49. Gajdusek DC, Gibbs CJ, Alpers M. Experimental transmission of a Kuru-like syndrome to chimpanzees. Nature. Feb 19 1966;209(5025):794-6. [Medline].

  50. Jacob A. Uber eigenaritge erkrankungen des zentral-nervensystems mit bemerkenswertem anatomischen befunde (spastische pseudosklerose-encephalomyelopathie mit disseminierten degenerationsherden). Z Gesamte Neurol Psychiatre. 1921;64:147-228.

  51. Chiofalo N, Fuentes A, Galvez S. Serial EEG findings in 27 cases of Creutzfeldt-Jakob disease. Arch Neurol. Mar 1980;37(3):143-5. [Medline].

  52. Gerstmann J, Straussler E, Scheinker I. Über eine eigenartige hereditar-familiare Erkrankung des Zentralnervensystems zugleich ein Beitrag zür frage des vorzeitigen kokalen Alterns. Z Neurol. 1936;154:736-762.

  53. Ghetti B, Tagliavini F, Giaccone G, et al. Familial Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles. Mol Neurobiol. Feb 1994;8(1):41-8. [Medline].

  54. Ghetti B, Piccardo P, Spillantini MG, et al. Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. Proc Natl Acad Sci U S A. Jan 23 1996;93(2):744-8. [Medline].

  55. Medori R, Tritschler HJ, LeBlanc A, et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med. Feb 13 1992;326(7):444-9. [Medline].

  56. Goldfarb LG, Brown P, Haltia M, et al. Creutzfeldt-Jakob disease cosegregates with the codon 178Asn PRNP mutation in families of European origin. Ann Neurol. Mar 1992;31(3):274-81. [Medline].

  57. Solvason HB, Harris B, Zeifert P, Flores BH, Hayward C. Psychological versus biological clinical interpretation: a patient with prion disease. Am J Psychiatry. Apr 2002;159(4):528-37. [Medline].

  58. Oliveros RG, Saracibar N, Gutierrez M, , Munon T, Gonzalez-Pinto A. Catatonia due to a prion familial disease. Schizophr Res. Mar 2009;108(1-3):309-10. [Medline].

  59. Collinge J. Human prion diseases and bovine spongiform encephalopathy (BSE). Hum Mol Genet. 1997;6(10):1699-705. [Medline].

  60. Collinge J, Rossor M. A new variant of prion disease. Lancet. Apr 6 1996;347(9006):916-7. [Medline].

  61. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet. Oct 28 1995;346(8983):1155-6. [Medline].

  62. Britton TC, al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK. Lancet. Oct 28 1995;346(8983):1155. [Medline].

  63. Collee JG, Bradley R. BSE: a decade on--Part I. Lancet. Mar 1 1997;349(9052):636-41. [Medline].

  64. Will RG. Surveillance of prion disease in humans. In: HF Baker, Ridley RM, eds. Methods in Molecular Medicine: Prion Diseases. Totowa, NJ: Humana Press Inc; 1996:119-137.

  65. Liberski PP, Guiroy DC, Williams ES, Walis A, Budka H. Deposition patterns of disease-associated prion protein in captive mule deer brains with chronic wasting disease. Acta Neuropathol. Nov 2001;102(5):496-500. [Medline].

  66. Khan RM, Gunaratne LA, Kinmont JC. Rapid fracture healing in a patient with inherited prion disease. Ann R Coll Surg Engl. Apr 2009;91(3):261-2. [Medline].

  67. Belay ED, Gambetti P, Schonberger LB, et al. Creutzfeldt-Jakob disease in unusually young patients who consumed venison. Arch Neurol. Oct 2001;58(10):1673-8. [Medline].

  68. Raymond GJ, Bossers A, Raymond LD, et al. Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease. EMBO J. Sep 1 2000;19(17):4425-30. [Medline].

  69. Angers RC, Browning SR, Seward TS, et al. Prions in skeletal muscles of deer with chronic wasting disease. Science. Feb 24 2006;311(5764):1117. [Medline].

  70. Marsh RF, Kincaid AE, Bessen RA, Bartz JC. Interspecies transmission of chronic wasting disease prions to squirrel monkeys (Saimiri sciureus). J Virol. Nov 2005;79(21):13794-6. [Medline].

  71. Hamaguchi T, Noguchi-Shinohara M, Nozaki I, Nakamura Y, Sato T, Kitamoto T. Medical procedures and risk for sporadic Creutzfeldt-Jakob disease, Japan, 1999-2008. Emerg Infect Dis. Feb 2009;15(2):265-71. [Medline].

  72. Seipelt M, Zerr I, Nau R, et al. Hashimoto's encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry. Feb 1999;66(2):172-6. [Medline].

  73. Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. Feb 2006;63(2):197-202. [Medline].

  74. Cossu G, Melis M, Molari A, et al. Creutzfeldt-Jakob disease associated with high titer of antithyroid autoantibodies: case report and literature review. Neurol Sci. Oct 2003;24(3):138-40. [Medline].

  75. Young GS, Geschwind MD, Fischbein NJ, et al. Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: high sensitivity and specificity for diagnosis. AJNR Am J Neuroradiol. Jun-Jul 2005;26(6):1551-62. [Medline].

  76. Rees HC, Maddison BC, Owen JP, Whitelam GC, Gough KC. Concentration of disease-associated prion protein with silicon dioxide. Mol Biotechnol. Mar 2009;41(3):254-62. [Medline].

  77. Laude H. Beringue V. Newly discovered forms of prion diseases in ruminants. [Review]. Pathologie Biologie. 2009;57(2):117-26.

  78. Sim VL. Caughey B. Recent advances in prion chemotherapeutics. [Review]. Infectious Disorders - Drug Targets. 2009;9(1):81-91.

  79. Relano-Gines A. Gabelle A. Lehmann S. Milhavet O. Crozet C. Gene and cell therapy for prion diseases. [Review]. Infectious Disorders - Drug Targets. 2009;9(1):58-68.

  80. Caspi S, Halimi M, Yanai A, Sasson SB, Taraboulos A, Gabizon R. The anti-prion activity of Congo red. Putative mechanism. J Biol Chem. Feb 6 1998;273(6):3484-9. [Medline].

  81. Demaimay R, Harper J, Gordon H, Weaver D, Chesebro B, Caughey B. Structural aspects of Congo red as an inhibitor of protease-resistant prion protein formation. J Neurochem. Dec 1998;71(6):2534-41. [Medline].

  82. Doh-ura K, Ishikawa K, Murakami-Kubo I, et al. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J Virol. May 2004;78(10):4999-5006. [Medline].

  83. Demaimay R, Chesebro B, Caughey B. Inhibition of formation of protease-resistant prion protein by Trypan Blue, Sirius Red and other Congo Red analogs. Arch Virol Suppl. 2000;277-83. [Medline].

  84. Tagliavini F, McArthur RA, Canciani B, et al. Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science. May 16 1997;276(5315):1119-22. [Medline].

  85. Adjou KT, Demaimay R, Lasmezas CI, Seman M, Deslys JP, Dormont D. Differential effects of a new amphotericin B derivative, MS-8209, on mouse BSE and scrapie: implications for the mechanism of action of polyene antibiotics. Res Virol. Jul-Aug 1996;147(4):213-8. [Medline].

  86. Adjou KT, Demaimay R, Deslys JP, et al. MS-8209, a water-soluble amphotericin B derivative, affects both scrapie agent replication and PrPres accumulation in Syrian hamster scrapie. J Gen Virol. Apr 1999;80 ( Pt 4):1079-85. [Medline].

  87. Adjou KT, Privat N, Demart S, et al. MS-8209, an amphotericin B analogue, delays the appearance of spongiosis, astrogliosis and PrPres accumulation in the brain of scrapie-infected hamsters. J Comp Pathol. Jan 2000;122(1):3-8. [Medline].

  88. Mange A, Milhavet O, McMahon HE, Casanova D, Lehmann S. Effect of amphotericin B on wild-type and mutated prion proteins in cultured cells: putative mechanism of action in transmissible spongiform encephalopathies. J Neurochem. Feb 2000;74(2):754-62. [Medline].

  89. Mange A, Nishida N, Milhavet O, McMahon HE, Casanova D, Lehmann S. Amphotericin B inhibits the generation of the scrapie isoform of the prion protein in infected cultures. J Virol. Apr 2000;74(7):3135-40. [Medline].

  90. Farquhar C, Dickinson A, Bruce M. Prophylactic potential of pentosan polysulphate in transmissible spongiform encephalopathies. Lancet. Jan 9 1999;353(9147):117. [Medline].

  91. Ladogana A, Casaccia P, Ingrosso L, et al. Sulphate polyanions prolong the incubation period of scrapie-infected hamsters. J Gen Virol. Mar 1992;73 ( Pt 3):661-5. [Medline].

  92. Farquhar CF, Dickinson AG. Prolongation of scrapie incubation period by an injection of dextran sulphate 500 within the month before or after infection. J Gen Virol. Mar 1986;67 ( Pt 3):463-73. [Medline].

  93. Priola SA, Raines A, Caughey WS. Porphyrin and phthalocyanine antiscrapie compounds. Science. Feb 25 2000;287(5457):1503-6. [Medline].

  94. Priola SA, Raines A, Caughey W. Prophylactic and therapeutic effects of phthalocyanine tetrasulfonate in scrapie-infected mice. J Infect Dis. Sep 1 2003;188(5):699-705. [Medline].

  95. Masullo C, Macchi G, Xi YG, Pocchiari M. Failure to ameliorate Creutzfeldt-Jakob disease with amphotericin B therapy. J Infect Dis. Apr 1992;165(4):784-5. [Medline].

  96. Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. Aug 14 2001;98(17):9836-41. [Medline].

  97. Nakajima M, Yamada T, Kusuhara T, et al. Results of quinacrine administration to patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord. 2004;17(3):158-63. [Medline].

  98. Barret A, Tagliavini F, Forloni G, et al. Evaluation of quinacrine treatment for prion diseases. J Virol. Aug 2003;77(15):8462-9. [Medline].

  99. Collins SJ, Lewis V, Brazier M, Hill AF, Fletcher A, Masters CL. Quinacrine does not prolong survival in a murine Creutzfeldt-Jakob disease model. Ann Neurol. Oct 2002;52(4):503-6. [Medline].

  100. Todd NV, Morrow J, Doh-ura K, et al. Cerebroventricular infusion of pentosan polysulphate in human variant Creutzfeldt-Jakob disease. J Infect. Jun 2005;50(5):394-6. [Medline].

  101. Soto C, Kascsak RJ, Saborio GP, et al. Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides. Lancet. Jan 15 2000;355(9199):192-7. [Medline].

  102. Wisniewski T, Aucouturier P, Soto C, Frangione B. The prionoses and other conformational disorders. Amyloid. Sep 1998;5(3):212-24. [Medline].

  103. Wisniewski T, Sigurdsson EM, Aucouturier P, et al. Conformation as a therapeutic target in the prionoses and other neurodegenerative conditions. In: Molecular and Cellular Pathology in Prion Disease. 2001.

  104. De Gioia L, Selvaggini C, Ghibaudi E, et al. Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein. J Biol Chem. Mar 18 1994;269(11):7859-62. [Medline].

  105. Nguyen J, Baldwin MA, Cohen FE, Prusiner SB. Prion protein peptides induce alpha-helix to beta-sheet conformational transitions. Biochemistry. Apr 4 1995;34(13):4186-92. [Medline].

  106. Zhang H, Kaneko K, Nguyen JT, et al. Conformational transitions in peptides containing two putative alpha-helices of the prion protein. J Mol Biol. Jul 21 1995;250(4):514-26. [Medline].

  107. Naiki H, Higuchi K, Nakakuki K, Takeda T. Kinetic analysis of amyloid fibril polymerization in vitro. Lab Invest. Jul 1991;65(1):104-10. [Medline].

  108. Wisniewski T, Castano EM, Golabek A, Vogel T, Frangione B. Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. Am J Pathol. Nov 1994;145(5):1030-5. [Medline].

  109. Sigurdsson EM, Permanne B, Soto C, Wisniewski T, Frangione B. In vivo reversal of amyloid-beta lesions in rat brain. J Neuropathol Exp Neurol. Jan 2000;59(1):11-7. [Medline].

  110. Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castano EM, Frangione B. Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy. Nat Med. Jul 1998;4(7):822-6. [Medline].

  111. Vidal R, Ghiso J, Wisniewski T, Frangione B. Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. Identification of a novel splice variant. FEBS Lett. Sep 9 1996;393(1):19-23. [Medline].

  112. Sigurdsson EM, Brown DR, Alim MA, Scholtzova H, Carp R, Meeker HC, et al. Copper chelation delays the onset of prion disease. J Biol Chem. Nov 21 2003;278(47):46199-202. [Medline].

  113. Sigurdsson EM. Immunotherapy for conformational diseases. Curr Pharm Des. 2006;12(20):2569-85. [Medline].

  114. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. Jul 8 1999;400(6740):173-7. [Medline].

  115. Weiner HL, Lemere CA, Maron R, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol. Oct 2000;48(4):567-79. [Medline].

  116. Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. Dec 21-28 2000;408(6815):979-82. [Medline].

  117. Morgan D, Diamond DM, Gottschall PE, et al. Arendash GW Ab peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2001;408:982-985.

  118. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. Aug 2000;6(8):916-9. [Medline].

  119. Sigurdsson EM, Brown DR, Daniels M, et al. Immunization delays the onset of prion disease in mice. Am J Pathol. Jul 2002;161(1):13-7. [Medline].

  120. Goni F, Knudsen E, Schreiber F, et al. Mucosal vaccination delays or prevents prion infection via an oral route. Neuroscience. 2005;133(2):413-21. [Medline].

  121. Pankiewicz J, Sadowski M, Kascsak R, et al. Therapeutic mechanisms of anti-prion antibodies in a tissue culture model of prion infection. Soc Neurosci Abst. 2005.

  122. Sigurdsson EM, Sy MS, Li R, Scholtzova H, Kascsak RJ, Kascsak R, et al. Anti-prion antibodies for prophylaxis following prion exposure in mice. Neurosci Lett. Jan 23 2003;336(3):185-7. [Medline].

  123. Manuelidis L. Vaccination with an attenuated Creutzfeldt-Jakob disease strain prevents expression of a virulent agent. Proc Natl Acad Sci U S A. Mar 3 1998;95(5):2520-5. [Medline].

  124. White AR, Enever P, Tayebi M, et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature. Mar 6 2003;422(6927):80-3. [Medline].

  125. Enari M, Flechsig E, Weissmann C. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci U S A. Jul 31 2001;98(16):9295-9. [Medline].

  126. Peretz D, Williamson RA, Kaneko K, et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. Aug 16 2001;412(6848):739-43. [Medline].

  127. Souan L, Tal Y, Felling Y, Cohen IR, Taraboulos A, Mor F. Modulation of proteinase-K resistant prion protein by prion peptide immunization. Eur J Immunol. Aug 2001;31(8):2338-46. [Medline].

  128. Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol. Aug 2001;159(2):439-47. [Medline].

  129. Sigurdsson EM, Knudsen E, Asuni A, Fitzer-Attas C, Sage D, Quartermain D, et al. An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives. J Neurosci. Jul 14 2004;24(28):6277-82. [Medline].

  130. Coste J. Prowse C. Eglin R. Fang C. Subgroup on TSE. A report on transmissible spongiform encephalopathies and transfusion safety. [Review]. Vox Sanguinis. 2009;96(4):284-291.

  131. Lefrere JJ, Hewitt P. From mad cows to sensible blood transfusion: the risk of prion transmission by labile blood components in the United Kingdom and in France. Transfusion. Apr 2009;49(4):797-812. [Medline].

  132. Brown P, Wolff A, Gajdusek DC. A simple and effective method for inactivating virus infectivity in formalin-fixed tissue samples from patients with Creutzfeldt-Jakob disease. Neurology. Jun 1990;40(6):887-90. [Medline].

  133. Ironside JW, Bell JE. The 'high-risk' neuropathological autopsy in AIDS and Creutzfeldt-Jakob disease: principles and practice. Neuropathol Appl Neurobiol. Oct 1996;22(5):388-93. [Medline].

  134. Budka H, Aguzzi A, Brown P, et al. Tissue handling in suspected Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol. Jul 1995;5(3):319-22. [Medline].

  135. Castilla J, Saa P, Soto C. Detection of prions in blood. Nat Med. Sep 2005;11(9):982-5. [Medline].

  136. Chang B, Cheng X, Pan T, et al. An ultra-sensitive assay for detecting prions in blood. Proc Natl Acad Sci (USA) in press. 2006.

  137. Aucouturier P, Kascsak RJ, Frangione B, Wisniewski T. Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt-Jakob disease. Neurosci Lett. Oct 15 1999;274(1):33-6. [Medline].

  138. Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ Jr, Gajdusek DC. New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600 degrees C suggests an inorganic template of replication. Proc Natl Acad Sci U S A. Mar 28 2000;97(7):3418-21. [Medline].

  139. Bueler H, Fischer M, Lang Y, et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature. Apr 16 1992;356(6370):577-82. [Medline].

  140. Citron M, Vigo-Pelfrey C, Teplow DB, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci U S A. Dec 6 1994;91(25):11993-7. [Medline].

  141. Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet. Jun 15 1991;337(8755):1441-2. [Medline].

  142. Collins SJ, Lawson VA, Masters CL. Transmissible spongiform encephalopathies. Lancet. Jan 3 2004;363(9402):51-61. [Medline].

  143. Dlouhy SR, Hsiao K, Farlow MR, et al. Linkage of the Indiana kindred of Gerstmann-Sträussler-Scheinker disease to the prion protein gene. Nat Genet. Apr 1992;1(1):64-7. [Medline].

  144. Dominguez DI, De Strooper B, Annaert W. Secretases as therapeutic targets for the treatment of Alzheimer's disease. Amyloid. Jun 2001;8(2):124-42. [Medline].

  145. Dropcho EJ. Update on paraneoplastic syndromes. Curr Opin Neurol. Jun 2005;18(3):331-6. [Medline].

  146. Finkenstaedt M, Szudra A, Zerr I, et al. MR imaging of Creutzfeldt-Jakob disease. Radiology. Jun 1996;199(3):793-8. [Medline].

  147. Foster PR. Prions and blood products. Ann Med. Oct 2000;32(7):501-13. [Medline].

  148. Gabizon R, Rosenmann H, Meiner Z, et al. Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD). Am J Hum Genet. Oct 1993;53(4):828-35. [Medline].

  149. Goldfarb LG, Brown P, Goldgaber D, et al. Creutzfeldt-Jakob disease and kuru patients lack a mutation consistently found in the Gerstmann-Sträussler-Scheinker syndrome. Exp Neurol. Jun 1990;108(3):247-50. [Medline].

  150. Goldfarb LG, Brown P, McCombie WR, et al. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc Natl Acad Sci U S A. Dec 1 1991;88(23):10926-30. [Medline].

  151. Goldfarb LG, Haltia M, Brown P, et al. New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish Creutzfeldt-Jakob kindred. Lancet. Feb 16 1991;337(8738):425. [Medline].

  152. Goldfarb LG, Mitrova E, Brown P, Toh BK, Gajdusek DC. Mutation in codon 200 of scrapie amyloid protein gene in two clusters of Creutzfeldt-Jakob disease in Slovakia. Lancet. Aug 25 1990;336(8713):514-5. [Medline].

  153. Goldfarb LG, Petersen RB, Tabaton M, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science. Oct 30 1992;258(5083):806-8. [Medline].

  154. Goldgaber D, Goldfarb LG, Brown P, et al. Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker's syndrome. Exp Neurol. Nov 1989;106(2):204-6. [Medline].

  155. Haass C, Hung AY, Schlossmacher MG, Teplow DB, Selkoe DJ. beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem. Feb 15 1993;268(5):3021-4. [Medline].

  156. Head MW, Bunn TJ, Bishop MT, et al. Prion protein heterogeneity in sporadic but not variant Creutzfeldt-Jakob disease: UK cases 1991-2002. Ann Neurol. Jun 2004;55(6):851-9. [Medline].

  157. Hetz C, Soto C. Protein misfolding and disease: the case of prion disorders. Cell Mol Life Sci. Jan 2003;60(1):133-43. [Medline].

  158. Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet. Jan 11 1997;349(9045):99-100. [Medline].

  159. Hsiao K, Baker HF, Crow TJ, et al. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature. Mar 23 1989;338(6213):342-5. [Medline].

  160. Hsiao K, Dlouhy SR, Farlow MR, et al. Mutant prion proteins in Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles. Nat Genet. Apr 1992;1(1):68-71. [Medline].

  161. Hsiao K, Doh-ura K, KitamotoT. A prion protein amino acid substitution in ataxic Gerstmann-Straussler syndrome. Ann Neurol. 1989;26:137.

  162. Hsiao K, Meiner Z, Kahana E, et al. Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease. N Engl J Med. Apr 18 1991;324(16):1091-7. [Medline].

  163. Kitamoto T, Ohta M, Doh-ura K, Hitoshi S, Terao Y, Tateishi J. Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. Biochem Biophys Res Commun. Mar 15 1993;191(2):709-14. [Medline].

  164. Kovacs GG, Voigtlander T, Gelpi E, Budka H. Rationale for diagnosing human prion disease. World J Biol Psychiatry. Apr 2004;5(2):83-91. [Medline].

  165. Maness LM, Banks WA, Podlisny MB, Selkoe DJ, Kastin AJ. Passage of human amyloid beta-protein 1-40 across the murine blood-brain barrier. Life Sci. 1994;55(21):1643-50. [Medline].

  166. Miyazono M, Kitamoto T, Doh-ura K, Iwaki T, Tateishi J. Creutzfeldt-Jakob disease with codon 129 polymorphism (valine): a comparative study of patients with codon 102 point mutation or without mutations. Acta Neuropathol. 1992;84(4):349-54. [Medline].

  167. Nochlin D, Sumi SM, Bird TD, et al. Familial dementia with PrP-positive amyloid plaques: a variant of Gerstmann-Sträussler syndrome. Neurology. Jul 1989;39(7):910-8. [Medline].

  168. Owen F, Poulter M, Lofthouse R, et al. Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet. Jan 7 1989;1(8628):51-2. [Medline].

  169. Owen F, Poulter M, Shah T, et al. An in-frame insertion in the prion protein gene in familial Creutzfeldt-Jakob disease. Brain Res Mol Brain Res. Apr 1990;7(3):273-6. [Medline].

  170. Quadrio I, Ugnon-Cafe S, Dupin M, Esposito G, Streichenberger N, Krolak-Salmon P. Rapid diagnosis of human prion disease using streptomycin with tonsil and brain tissues. Lab Invest. Apr 2009;89(4):406-13. [Medline].

  171. Ripoll L, Laplanche JL, Salzmann M, et al. A new point mutation in the prion protein gene at codon 210 in Creutzfeldt-Jakob disease. Neurology. Oct 1993;43(10):1934-8. [Medline].

  172. Sakaguchi S. Prospects for preventative vaccines against prion diseases. Protein & Peptide Letters. 2009;16(3):260-70.

  173. Soto C, Saborio GP, Anderes L. Cyclic amplification of protein misfolding: application to prion-related disorders and beyond. Trends Neurosci. Aug 2002;25(8):390-4. [Medline].

  174. Weissmann C. Molecular genetics of transmissible spongiform encephalopathies. J Biol Chem. Jan 1 1999;274(1):3-6. [Medline].

  175. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. Apr 6 1996;347(9006):921-5. [Medline].

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Further Reading

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Keywords

transmissible spongiform encephalopathies, TSE, bovine spongiform encephalopathies, BSE, mad cow disease, mad-cow disease, Creutzfeldt-Jakob disease, CJD, new variant CJD, nvCJD, variant CJD, vCJD, prionosis, prionoses, prion diseases, PrP diseases, chronic wasting disease, CWD, scrapie, Gerstmann-Straussler-Scheinker, GSS, fatal familial insomnia, FFI, kuru

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Contributor Information and Disclosures

Author

Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners, American College of International Physicians, American College of Managed Care Medicine, American College of Physicians, American Heart Association, American Stroke Association, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, and Royal Society of Medicine
Disclosure: Abbott Labs  Honoraria Consulting; Teva Marion Honoraria Consulting; Boeringer-Ingelheim Honoraria Speaking and teaching

Coauthor(s)

Arun Ramachandran, State University of New York Upstate Medical University
Arun Ramachandran is a member of the following medical societies: American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Roberta J Seidman, MD, Associate Professor of Clinical Pathology, Stony Brook University; Director of Neuropathology, Department of Pathology, Stony Brook University Medical Center
Roberta J Seidman, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuropathologists, New York Association of Neuropathologists (The Neuroplex), and Suffolk County Society of Pathologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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