Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy 

Updated: Jan 11, 2016
Author: Erik Z Krause, DO; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM 

Overview

Background

Bovine spongiform encephalopathy (BSE), also known as mad cow disease, and variant Creutzfeldt-Jakob disease (CJD) are related disorders.[1] They belong to the family of diseases known as the transmissible spongiform encephalopathies (TSEs). TSEs are caused by a transmissible proteinaceous particle, which is yet to be fully characterized. Other TSEs include scrapie (a disease of sheep), feline spongiform encephalopathy, transmissible mink encephalopathy, and chronic wasting disease of deer and elk. Human forms include classic CJD, variant CJD, kuru, Gerstmann-Sträussler-Scheinker disease, familial fatal insomnia, and sporadic fatal insomnia.[2, 3, 4, 5, 6, 7, 8]

Human TSEs share the following characteristics:

  • A prolonged incubation period of several years

  • A progressive debilitating neurologic syndrome that is invariably fatal

  • Pathological changes that are confined to the CNS and consist of the following 3 classic features: spongiosis, gliosis, and neuronal loss

  • A transmissible agent that does not elicit any specific immunologic response in the host and is unusually resistant to conventional inactivation procedures

Bovine spongiform encephalopathy

On December 23, 2003, targeted surveillance identified a “downer” dairy cow (ie, nonambulatory and disabled) that tested positive for BSE. This was confirmed by the BSE International Reference Laboratory in Weybridge, England, on December 25. On December 9, 2003, the downer dairy cow had been slaughtered in the state of Washington. Because the animal's condition was attributed to complications from calving, the meat was considered safe for human consumption by the US Department of Agriculture (USDA). Tissues such as brain, spinal cord, and small intestine, which may have a higher likelihood of containing the pathogenic agent of BSE, were removed during slaughter and sent for rendering (often to be used as nonruminant animal feed).

Not surprisingly, international reaction was swift. Within a week, 53 countries had imposed a ban on imports of US beef and beef products. On December 30, the USDA announced new rules banning all downer cattle from the chain of human food production and other measures. Subsequently, the infected cow was discovered to have originated in Alberta, Canada, and was imported into the United States in September 2001.[9]

On January 26, 2004, the US Food and Drug Administration (FDA) announced new rules to further strengthen existing protection against BSE, including banning a wide range of bovine material from human food (United States Department of Health and Human Services, Expanded "Mad Cow" Safeguards Announced To Strengthen Existing Firewalls Against BSE Transmission). On February 9, 2004, the USDA completed its investigations.

Although this was the first case of BSE in the United States, more than 190,000 confirmed clinical cases have been reported worldwide since 1986, and approximately 184,000 cases were from the United Kingdom alone (see the images below). Additional information is available at OIE, Bovine Spongiform Encephalopathy (BSE). Based on mathematical modeling of the BSE epidemic, estimates suggest that 1-3 million cattle may have been infected with the BSE agent in the United Kingdom.[10, 11] Most of these infected animals were slaughtered for human consumption before any clinical signs of BSE were noted.

Incidence of bovine spongiform encephalopathy (BSE Incidence of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in Great Britain. The BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed. The associated human disease, variant CJD, was not defined until 1996, 7 years after a ban was introduced in Britain on the use of specified offal from cattle in human food.
Geographic distribution of bovine spongiform encep Geographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.

Other countries where BSE has been confirmed in native-born cattle include Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Japan, Luxembourg, Liechtenstein, the Netherlands, Poland, Portugal, Slovakia, Slovenia, Switzerland, and Spain. Additional cases of BSE have also been confirmed in North America: 9 in Canada (one cow was imported from the United Kingdom) and 3 in the United States (2 were imported from Canada). The third case of BSE reported from the United States was in a downer cow on a farm in Alabama, and the herd of origin could not be identified in spite of a thorough investigation.[12]

A fourth case in the United States (the first since 2006) was detected as part of a screening program in California and did not enter the food chain.[13]

Further cases of BSE were reported in imported cattle in the Falkland Islands (imported from the United Kingdom) and Oman (imported from the United Kingdom). No documented cases have been reported from Africa, Australia, New Zealand, or South America.

Approximately 5 million head of cattle were slaughtered in the United Kingdom to halt the epidemic. Since 1992, the number of cases has decreased an average of 40% per year, although new cases continue to be reported. However, the preemptive slaughter crippled the British livestock industry and affected the tallow, gelatin, and pharmaceutical industries.[14]

The incubation period for BSE ranges from 2-8 years. Most cases in the United Kingdom have occurred in dairy cows aged 3-6 years. The clinical features include the following:

  • Changes in temperament such as nervousness or apprehensiveness

  • Aggression toward other cattle or humans

  • Kicking when being milked

  • Reluctance to cross concrete, turn corners, and enter yards or doorways

  • Head shyness with head held low

  • Abnormal posture

  • High-stepping gait, particularly of hind legs

  • Incoordination

  • Difficulty in rising or walking

  • Skin tremors

  • Decreased milk production

  • Weight loss despite good appetite

No treatment is available for BSE; the disease is relentlessly progressive until the animal dies or is destroyed. This usually occurs in 2 weeks to 6 months.

No test can detect the disease in a live animal, although in an epidemic setting, clinical features are sufficiently distinctive to provide a clinical diagnosis. Currently, 3 laboratory methods are used to confirm the diagnosis of BSE, including the following:

  • Microscopic examination of brain tissue, which shows characteristic changes, including a predominantly vacuolar spongiform change distributed uniformly throughout the brain[15, 16]

  • Immunohistochemical labeling of the disease-associated (abnormal) prion protein (PrPSc)

  • Detection of scrapie-associated fibrils (SAF) by electron microscopy

Hypotheses of origin

Different hypotheses are proposed regarding the origins of BSE. The most compelling hypothesis is that BSE originated from scrapie, an endemic spongiform encephalopathy of sheep and goats that has been endemic in Europe since the mid-18th century.[17] Scrapie has since spread to most sheep-breeding countries and is widespread in the United Kingdom, where, until 1988, the rendered carcasses of livestock (including sheep) were fed to ruminants and other animals as a protein-rich nutritional supplement. The epidemiologic data appear to implicate feed containing TSE-contaminated meat and bone meal, which was used as a protein source. The causative agent is suspected to be from either scrapie-affected sheep or cattle with previously unidentified TSE.[18, 19, 20, 21]

Changes in the rendering process that took place in the early 1980s, particularly the removal of a solvent extraction process that included a steam heat treatment, probably allowed the etiologic agent to survive, contaminate the protein supplement, and infect cattle. Recycling of infected bovine carcasses within the cattle population (turning the herbivorous cows into "animal cannibals") amplified the levels of the pathogen, which had become adapted to cattle, in the feeds and eventually caused a full-scale epizootic.[22] Similarly, the spread of spongiform encephalopathies in farmed mink and captive and zoo animals may have resulted from prion-contaminated feed.[23, 24]

An alternative hypothesis was proposed in the controversial final BSE inquiry report in the United Kingdom that was released October 24, 2000, suggesting that a pathogenic mutation occurred in cattle in the 1970s, with BSE occurring as a consequence of recycling of infected cattle. The report asserts that BSE cases identified from 1986-1988 were not index cases, nor were they the result of the transmission of scrapie.

Recognition of the source of infection led to several countermeasures to break the cycle of cattle reinfection, restrict the geographic spread, and eliminate the potential source of new infection. The most important step was banning ruminant feed in 1988, extending it to include the feeding of specified bovine offal. By 1992, this ban started to bring the epidemic under control. See the image below.

Time course of epidemic bovine spongiform encephal Time course of epidemic bovine spongiform encephalopathy (BSE) in the United Kingdom, 1986-2000, with dates of major precautionary interventions. SBO stands for specified bovine offal (ie, brain, spinal cord, thymus, spleen, and intestines from cattle aged >6 mo). MBM stands for meat and bone meal (protein residue produced by rendering). From Brown P, Will RG, Bradley R, et al. "Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution and current concerns". Emerging Infectious Diseases, 2001;7: 6-16.

Furthermore, specified risk material, which comprises brain, spinal cord, eyes, tonsils, thymus, spleen, and intestine, is removed from all foodstuffs at slaughter.[25] In addition, cattle aged 30 months or older must not be used for consumption unless they test negative for BSE, which is known as the “over-thirty-month” rule.[26]

Variant CJD

Within weeks of identification of the first case of BSE, concern was expressed about human risk.[27, 28, 29] A national TSE surveillance was instituted in Britain in 1990 despite lack of evidence of human acquisition of scrapie based on the then-speculative grounds that exposure of millions of Britons to an apparently new bovine TSE might unmask low-frequency transmission in humans. Unfortunately, this fear proved to be well founded. The first cases of variant CJD (initially called new variant CJD) were reported in 1995.[30, 31]

By 1996, 10 patients, who had distinctive clinical and neuropathologic characteristics, had been reported to the National CJD Surveillance Unit with atypical CJD-like features. Clinically, they were younger than 40 years, with an average age of younger than 30 years; had behavioral symptoms, ataxia, and sensory changes early on; and progressed more slowly than in classic CJD. None had periodic complexes on EEG. Neuropathologic findings resembled those of kuru, with extensive florid plaques in which an amyloid core is surrounded by petals of spongiform change. The report concluded that this hitherto unrecognized variant of CJD was probably due to exposure to BSE.[32] So far, 217 cases of variant CJD have been described, most from the United Kingdom.[6]

The risk factors for the development of variant CJD include younger age (as compared with classic CJD), residence in the United Kingdom, and methionine homozygosity at codon 129 of the prion protein gene (PRNP).[33, 34] The encoding alternatives, methionine (Met) and valine (Val), are distributed in white populations in the approximate proportions of 50% Met/Val, 40% Met/Met, and 10% Val/Val. All patients with variant CJD who have been tested have been homozygous for methionine.[35] A reduced frequency of HLA class II type DQ7 has been described in patients with variant CJD but not in those with classic CJD; this may have important implications for understanding host susceptibility to infection by BSE prions.[36] Past surgery, previous blood transfusion, and occupation have not been shown to be associated with increased risk, although 2 cases have been reported in patients who received blood transfusions from donors who then went on to develop variant CJD.

Experiments in transgenic mice have shown that a significant species barrier exists that restricts the transmission of BSE to humans; however, the barrier is significantly reduced for human-to-human transmission, with increasing transmission efficiency from Met/Met to Met/Val to Val/Val genotypes.[37]

Pathophysiology and Etiology

Convincing evidence indicates that variant Creutzfeldt-Jakob disease (CJD) is a new disease. Despite its name, variant CJD appears to be a human variant of BSE derived from a cow-to-human species switch, rather than an actual variant of human sporadic CJD.[38] Epidemiologic, biological, and biochemical data favor the hypothesis that variant CJD is a BSE zoonosis, probably arising from a double-species switch from sheep scrapie to BSE and then from bovine spongiform encephalopathy (BSE) to human variant CJD.[38, 39, 40]

Although the BSE epizootic has apparently led to other newly host-switched transmissible spongiform encephalopathies (TSEs) in domestic and large cats, sheep who have been fed the BSE agent experimentally have acquired a scrapie-like disease.[41] Such occurrences widen the scope of possible TSE species switches and back-switches and suggest that the BSE agent may be an uncharacteristically promiscuous prion.[38]

BSE and variant CJD are similar on the basis of patterns of infectable mouse strains, incubation time, survival time, lesion distribution in the mouse brain, PrPSc gel banding patterns, and neuropathology, which are readily distinguishable from other TSEs, such as scrapie and sporadic CJD.[42, 43, 44, 45, 46]  Pathological investigation shows characteristic spongiform change and gliosis in the brain. These changes are most predominant in basal ganglia and cerebellum.

Because no occupational exposure of patients with variant CJD to cattle on farms or in abattoirs has been identified, spread is likely to occur through consumption of BSE-contaminated meat products. Whether PrPSc (prion protein, scrapie isoform) can be demonstrated in skeletal muscles remains controversial.[47, 48, 49, 50] However, a high-sensitivity Western blotting technique identified muscle PrPSc in 8 of the 17 patients studied, although in much lower concentrations than in the cerebral cortex, suggesting a potential role for skeletal muscle in the transmission of variant CJD.[51] Despite this evidence, the infection probably resulted from beef products contaminated by nervous tissue, because neural tissues have a much higher concentration of PrPSc than other peripheral tissues.

The amount of infectious agent ingested and host susceptibility, as determined by the human genotype at PRNP codon 129, appear to play important roles in the development of variant CJD. However, how oral consumption of BSE-contaminated beef leads to infection of the CNS is unknown. In the early preclinical stages of the disease, PrPSc can be detected in lymphoid tissues, suggesting a possible route of transmission from the gut. Prions probably cross the mucosa via transmembranous tunneling of the membranous epithelial cells (M-cells) and come in contact with the mucosa-associated lymphoid system, including Peyer patches, where accumulation is found first.[52]

A functional immune system is required for prion replication and transport outside of the CNS.[53] Mechanisms of further prion transport to other compartments of the lymphoreticular system (LRS) are unclear. Prions accumulate in cells of the LRS, most prominently in the follicular dendritic cells and in sympathetic nerve endings in the LRS. Then, prions reach the CNS via splanchnic nerves at the level of the thoracic spinal cord and via parasympathetic fibers connecting with the brain.[54, 55] The other possible route is blood, which was suggested by experiments showing BSE transmission from sheep to sheep by blood transfusion.[56]

Variant CJD is known to affect the brain, lymphoreticular system, pituitary and adrenal glands, and gastrointestinal tract. One case report identified protease-resistant prion protein in the dura mater, liver, pancreas, kidney, ovary, uterus, and skin of a patient with variant CJD, indicating that organ involvement may actually be even more widespread.[57]

Variant CJD in the blood supply

Concern is widespread that the blood supply might be contaminated with the variant CJD agent. This possibility is supported by evidence that BSE in sheep can be transmitted by blood transfusion.[56] This concern progressed to fear with a report of a patient who died of variant CJD 6.5 years after receiving a transfusion of red blood cells donated by an individual who subsequently developed variant CJD.[58] The authors do not present direct evidence that the disease was transmitted by blood transfusion, but the chance that this case is not transfusion related is very small.

One more case of blood transfusion–related variant CJD has been reported.[59] This case is unique and very important in terms of its implications. This patient died from a non-neurologic disorder 5 years after receiving a blood transfusion from a donor who subsequently developed variant CJD, and he had no symptoms suggestive of variant CJD at the time of his death. Protease-resistant prion protein (PrPres) was detected in the spleen and a cervical lymph node but not in the brain. He was heterozygote at codon 129 of PRNP, suggesting that susceptibility to variant CJD infection is not confined to methionine homozygous PRNP genotype.

In the late 1990s, the United Kingdom implemented strategies for risk reduction. These included importation of plasma from the United States for preparation of plasma derivatives (i.e., clotting factors), disposal of certain surgical instruments, and universal leukoreduction in transfusions. There have been a total of four affected individuals from the United Kingdom who received non-leucoreduced red cell concentrates from UK donors. 

This possibility, combined with the probable existence of subclinical carriers, raises the specter of an iatrogenic human-to-human wave of variant CJD transmission.[60] This again highlights the need for reliable detection methods for prion-tainted blood products.[61] In addition, a finding of preclinical infection in a patient heterozygous at codon 129 of PRNP has significant implications regarding the future estimates and surveillance of variant CJD.

Epidemiology

A study of 32,441 appendices obtained from 41 hospitals in the United Kingdom, which had been archived over some 6 decades, detected 16 instances of abnormal PrP protein, indicating a prevalence of approximately 1 case in 2,000. There was no bias based on sex, date of collection, or geographical region. Given that the CNS is less hospitable to PrP than lymphoid tissue, this finding does not translate into an assumption of a clinical prevalence of 1 case in 2,000.[62]

According to the World Health Organization fact sheet on variant CJD (revised February 2012), 224 total cases of variant CJD were reported worldwide through March 2011: 175 cases in the United Kingdom and 49 cases in other countries (25 in France, 5 in Spain, 4 in Ireland, 3 in the Netherlands, 3 in the United States, 2 in Canada, 2 in Italy, 2 in Portugal, 1 in Japan, 1 in Saudi Arabia, and 1 in Taiwan).[63, 64, 7] . According to the National CJD Research and Surveillance Unit in Edinburgh, UK (2015), there have been a total of 229 cases of variant CJD reported worldwide and no new-onset cases since 2012.

The vast majority of cases of variant CJD have included documented exposure to food products in countries where bovine spongiform encephalopathy (BSE) occurs, and 2 cases have occurred secondarily as a result of exposure to blood transfusion from individuals who then developed variant CJD.[58, 65] One patient who died of an unrelated cause was found to have a subclinical infection, which was very likely secondary to a blood transfusion from a variant CJD–positive donor who subsequently went on to develop the disease.[59]

The number of cases of variant CJD peaked in 2000 in the United Kingdom at 28 and then steadied at 20 cases in 2001, 17 in 2002, and 18 in 2003. Nine new cases were reported in 2004 and another 5 in 2005. The rate has since declined to about 2 cases per year, through 2008.[7] This raises the possibility that the epidemic may have peaked.[66] Despite the optimism, uncertainty remains about the likely size of the total variant CJD epidemic, because such calculations depend on assumptions, including the mean incubation period in humans or the infectious dose of BSE for humans. In contrast, sporadic CJD occurs with a uniform incidence of 1 case per million population per year worldwide.[67] Other forms of prion diseases are even rarer.

Whether the cases from the United Kingdom represent the beginning of an epidemic or whether the numbers will remain low or even continue to decline is unclear. Estimates of the possible size of the epidemic have ranged from 70-136,000 cases.[68, 69] Models provide more conservative estimates of 403-1000 at 95% confidence intervals.[70, 71] It is reassuring that among 63,007 surgically removed tonsils, none tested positive for PrP,[72] as a distinctive PrPSc subtype (4t) is consistently observed in antemortem and postmortem tonsil examinations in cases of variant CJD.[47]

In the United States and Europe, surveillance of patients with prion diseases is performed. Therefore, reporting any suspected prion disease, in particular suspected variant CJD, to surveillance agencies is necessary. Two of the surveillance agencies in the United States are the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio, and the California Creutzfeldt-Jakob Disease (CJD) Surveillance Project.[33, 73]

Autopsies are performed in only an estimated 22% of cases of CJD in California. The autopsy rates of suspected cases of CJD should be increased because only a pathologic review of tissue can distinguish between classic and variant forms of CJD.

Prognosis

Like other prion-related diseases, variant CJD is relentlessly progressive and inevitably leads to death.

In contrast to the traditional forms of Creutzfeldt-Jakob disease (CJD), variant CJD affects younger patients, with the median age at death being 28 years, as compared with 68 years for traditional forms of CJD.[7] The age range of patients with variant CJD is 14-74 years.[74] Various models suggest that variant CJD infection preferentially affects young people and that older individuals are probably more resistant.[71, 75]

Variant CJD also has a relatively longer duration of illness (median of 14 months for variant CJD, as compared with 4.5 months for traditional CJD).[7]

 

Presentation

History

Incubation period

The incubation period of variant Creutzfeldt-Jakob disease (CJD) is not known. However, based on the assumptions that most cases of variant CJD were exposed to bovine spongiform encephalopathy (BSE) in the 1980s and that the incidence peaked in 2000, an average incubation period of 11-12 years can be estimated. Similar conclusions can be derived from cases of variant CJD in patients from other countries, who were probably exposed to BSE during their residence in the United Kingdom. This is similar to the median incubation periods for other human CJD epidemics caused by human-to-human transmission (eg, 10-13 years for kuru[76] and 12-17 years for iatrogenic CJD following intramuscular injection of human growth hormone[77] ). However, cases of kuru and iatrogenic CJD have been seen 40 and 38 years[78] after exposure, respectively. Prolonged incubation periods for these conditions have been associated with heterozygosity at codon 129 of PRNP. All clinical cases of variant CJD to date havebeen homozygous for methionine at codon 129 of PRNP.

Because the incubation period of variant CJD is likely long, patients may be infectious during the clinically silent period. Therefore, determine if patients donated blood or other body tissues during that period. This concern is particularly relevant for variant CJD because systemic organs, especially lymphoid tissues, contain a fairly large amount of infectious material.

The incubation period for secondary transmission of variant CJD by blood transfusion is probably shorter, as suggested by the development of the disease in one case 6 years after and another case 8 years after blood transfusion.[58, 65] In a third patient, the disease was subclinical at the time of death from an unrelated cause 5 years after transfusion; this patient was heterozygous for Met/Val at codon 129, raising the possibility of a prolonged incubation period or the development of a permanent carrier state.[59, 79, 80]

Case history

A typical case history of variant CJD is that of a 33-year-old male farmer and resident of the United Kingdom who was referred to the neurology clinic with a 5-month history of slurred speech, clumsy upper limbs, impaired hand writing, and progressive gait problems. He also reported worsening memory for recent events, which he attributed to impaired concentration. A diagnosis of depression was made, and his mood improved somewhat on selective serotonin reuptake inhibitors. He denied any visual, swallowing, or sphincter difficulties. However, he reported uncomfortable sensations in both his lower extremities. His general health had been good, and he had no previous history of neurologic disease. He had no family history of similar neurologic disease. He did not smoke, he drank occasionally, and he did not use any recreational drugs.

The findings upon general examination were unremarkable, other than the patient’s flat affect. Higher-function testing revealed that he was unable to name the day or the month, had no knowledge of current events, could not name the current British prime minister or US president, and failed at serial 7 s. He had poor 3-object registration and recall and scored 12 out of possible 30 on the Mini-Mental State Examination. A formal neuropsychological evaluation showed impairment of attention span, verbal fluency, language, memory (both verbal and nonverbal), spatial skills, judgment, and insight, indicating a generalized cortical disease process.

Cerebellar dysarthria and brisk jaw jerk with exaggerated facial reflexes were noted. Eye movements were full in all directions. He had pyramidal tract signs but no focal weakness. He had a limb and gait ataxia but no Romberg sign. His cooperation with the sensory examination was unsatisfactory; however, pinprick was perceived equally all over.

The patient’s condition progressed slowly over the next few months, and approximately 9 months after presentation, he had become mute with marked spasticity of the lower limbs. He developed incontinence for bladder and bowel. Because of worsening pseudobulbar palsy, a feeding gastrostomy was placed. Fifteen months after the initial presentation, he was completely bed bound, with spontaneous eye opening and visual tracking without any verbal response. By this stage, he had developed diffuse myoclonic jerks, which could be brought on by startle stimuli. He finally succumbed to the disease after total disease duration of 24 months.

A detailed workup for causes of cerebellar syndromes with dementia and pyramidal signs yielded negative results. Serial EEGs showed progressive diffuse slowing. MRI of the brain in retrospect showed high–signal intensity signals in bilateral pulvinars on T2-weighted imaging. The cerebrospinal fluid was positive for 14-3-3 protein. Genetic studies showed the patient to be homozygous for methionine at codon 129 of the PRNP gene. He also had a tonsil biopsy, which showed marked immunoreactivity to prion protein antibodies. Autopsy confirmed the diagnosis of variant CJD

Psychiatric and Neurologic Features

The clinical course of variant CJD is characterized by distinct features, with psychiatric abnormalities dominating the initial course of the disease. In a study of 100 cases,[81] psychiatric symptoms preceded neurologic features in 63 cases and neurologic features preceded psychiatric features in 15. In the remaining 22 patients, both neurologic and psychiatric features were present from the outset. Common early psychiatric features include dysphoria, withdrawal, anxiety, irritability, insomnia, and loss of interest. In a small number of cases, pain, numbness, or ataxia may be present in the early stages. These neurologic symptoms, together with new-onset psychiatric symptoms in an appropriate clinical setting, may raise the possibility of variant CJD; cognitive impairment soon follows.

The first signs of cognitive decline are observed at a median of 5 months after the disease onset. The first neurologic deficits are usually observed 6-7 months after onset. Akinetic mutism usually develops after a median disease duration of 12 months.[82, 83, 84, 85, 86, 81]

Tables 1 and 2, below, list the psychiatric and neurologic features of variant CJD as they evolve.

Table 1. Psychiatric Features According to Frequency and Median Time of Onset [81] ) (Open Table in a new window)

Psychiatric Features

Early Onset

< 4 mo

Later Onset

4 to < 6 mo

Late Onset

=6 mo

Common

(n =50)

Dysphoria

Withdrawal

Anxiety

Irritability

Insomnia

Loss of interest

Poor memory

Impaired concentration

Disorientation

Agitation

Less common

(n = 25 to < 50)

Behavioral changes

Anergia

Poor performance

Tearfulness

Weight loss

Appetite change

Hypersomnia

Confusion

Hallucinations

Impaired self-care

Paranoid delusions

Inappropriate affect

Rare

(n < 25)

Obsessive features

Losing things

Suicidal ideation

Panic attacks

Psychomotor retardation

Diurnal mood variation

Loss of confidence

Bizarre behavior

Paranoid ideation

Recognition impairment

Confabulation

Lack of emotion

Perseveration

Impaired comprehension

Change in eating preferences

Impaired use of devices

Acalculia

Table 2. Neurologic Features According to Frequency and Median Time of Onset [81] ) (Open Table in a new window)

Neurologic Features

Early Onset

< 4 mo

Later Onset

4 to < 6 mo

Late Onset

=6 mo

Common

(n =50)

None

Gait disturbance

Slurring of speech

Hyperreflexia

Impaired coordination

Myoclonus

Incontinence

Eye features

Less common

(n = 25 to < 50)

Pain

Paresthesia

Numbness

Chorea

Extensor plantars

Dysphagia

Clonus

Hypertonia

Primitive reflexes

Rare

(n < 25)

Headaches

Dropping things

Sweatiness

Loss of consciousness

Tremors

Handwriting impairment

Coldness

Odd sensation

Dizziness

Cranial motor weakness

Dysdiadochokinesis

Taste disturbance

Startle response

Hypersensitivity

Peripheral motor weakness

Primitive reflexes

Staging

On May 17, 2001, the World Health Organization (WHO) convened a Consultation on the Revision of the Surveillance Case Definition for variant Creutzfeldt-Jakob Disease (variant CJD), which was held in Edinburgh, United Kingdom.[63, 87] The WHO revised case definition of variant CJD is provided in Table 3, below.

Table 3. WHO Revised Case Definition for variant Creutzfeldt-Jakob Disease [63] (Open Table in a new window)

Class I

A - Progressive neuropsychiatric disorder

B - Duration of illness longer than 6 months

C - Routine investigations not suggestive of alternative diagnosis

D - No history of iatrogenic exposure

E - No history of familial form of transmissible spongiform encephalopathy (TSE)

Class II

A - Early psychiatric symptoms (ie, depression, anxiety, apathy, withdrawal, delusions)

B - Persistent painful sensory symptoms (eg, frank pain and/or dysesthesia)

C - Ataxia

D - Myoclonus or chorea or dystonia

E - Dementia

Class III

A - EEG without typical appearance of sporadic CJD (ie, generalized triphasic periodic complexes at approximately one per second) or no EEG

B - Brain MRI showing bilateral symmetrical pulvinar high-signal intensity (relative to the signal intensity of the other deep gray matter nuclei and cortical gray matter)

Class IVA

Positive findings on tonsil biopsy (biopsy not routinely recommended and not recommended in cases with EEG appearance typical of sporadic CJD but may be helpful in suspected cases in which the clinical features are compatible with variant CJD without MRI findings of bilateral pulvinar high-signal intensity)

Diagnoses

Definite - Class IA and neuropathological confirmation of variant CJD (spongiform change and extensive prion protein deposition with florid plaques throughout the cerebrum and cerebellum)

Probable - Class I, 4 of 5 of class II, class IIIA, and class IIIB; or class I and class IVA

Possible - Class I and 4 of 5 of class II and IIIA

Complications

Any part of the central nervous system can be affected. Therefore, a range of CNS complications can be expected, such as gait difficulties due to spasticity and cerebellar ataxia, choreoathetosis, startle responses, myoclonus, dysphagia due to pseudobulbar palsy, incontinence, and akinetic mute state.

Most patients succumb to bronchopneumonia, brought about by their bedridden state.

Special Concerns for Handling Prions

Because prions are highly resistant to inactivation, material from patients with variant CJD must be handled with special care. CNS tissue has the highest concentration of prion agent and needs to be handled with greatest caution. In variant CJD, unlike in other prion diseases, significant concentrations of prion agent are contained in body tissues, especially lymphoid material, which therefore merits particular care.

Special disinfection protocols have been developed by the WHO, and they should be meticulously followed (see WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies).

Individuals exposed to bovine spongiform encephalopathy (BSE) may be asymptomatic carriers of the infection.[88, 89, 90] Because of this potential problem, awareness of the need to use adequate sterilization procedures for surgical instruments is increasing. However, the recommended use of high-temperature autoclaving plus sodium hydroxide is difficult to achieve for some types of instruments.[91]

 

DDx

Diagnostic Considerations

Because psychiatric symptoms and limb pain are common presenting symptoms in variant Creutzfeldt-Jakob Disease (CJD), a workup for the disease in the early stage may be quite challenging. Therefore, the differential diagnosis includes peripheral neuropathy and a variety of psychiatric disorders.

Earlier age of onset necessitates inclusion of disorders such as Wilson disease in the differential diagnosis. Occurrence of the disease in older patients warrants a search for other conventional causes of dementia. However, sporadic CJD is still the most likely of the differential diagnoses for variant CJD.

Differential Diagnoses

 

Workup

Approach Considerations

The initial workup for variant Creutzfeldt-Jakob Disease (CJD) should include tests for dementia and encephalopathy. In addition, tests should include a serum chemistry profile, liver function tests, vitamin B-12 measurement, methylmalonic acid measurement, folate value, thyroid studies, ammonia value, erythrocyte sedimentation rate, C-reactive protein value, and neurosyphilis and HIV tests when appropriate.

While no current blood test exists for the detection of variant CJD, Jackson et al. explored the possiblity of developing a prototype test that can detect disease-associated prion protein from whole blood using stainless steel powder. The group concluded that the assay's high sensitivity (71.4%) and specificity (95%) supports the need to pursue further research in this particular screening assay.[92]

Findings from routine CSF studies are unremarkable; however, studies on brain-specific proteins, such as protein 14-3-3, neuron-specific enolase (NSE), S-100b, and total tau protein (t-tau) are helpful. The detection of CSF 14-3-3 is nonspecific. (The 14-3-3 protein test is performed as a service by the Laboratory of CNS Studies, National Institute of Neurologic Disorders and Stroke [NINDS], National Institutes of Health, Bethesda, Maryland [Telephone: 301-496-4821].) These proteins are not prion specific and are considered to be general markers for neuronal injury.

CSF tau protein has the best sensitivity (80%) and specificity (94%) of any of the proteins investigated in variant CJD. CSF tau protein is an axonal microtubular phosphoprotein, and it is unclear why it has a higher sensitivity than the neuronal markers 14-3-3 and NSE. The combination of a positive CSF 14-3-3 and an increased CSF tau protein has an increased sensitivity (86%) for the detection of variant CJD, with only a slight reduction in specificity (90%).[93]

Ubiquitin has the potential of serving as a CSF marker in CJD.[94] A specific reduction in the CSF uric acid levels has been shown in variant CJD but not in sporadic CJD, which may potentially help in the differential diagnosis of variant CJD.[95, 96]

A newer test called real-time quaking-induced conversion (RT-QuIC) has been shown to have modest potential for prion detection in CSF, but is still lacking substantial data.[97] . However, RT-QuIC has been negative in all vCJD assays to date.

Histologic Findings

Tonsil biopsy

In patients with variant Creutzfeldt-Jakob Disease (CJD), the abnormal prion protein (PrPSc) is detectable in follicular dendritic cells within germinal centers in lymphoid tissues, including the tonsils, lymph nodes, spleen, thymus, and gut-associated lymphoid tissues in the appendix and small intestine (see the image below).[47, 98] The lymphoreticular accumulation of PrPSc, as assessed by immunocytochemistry, has been shown to be a highly specific feature of variant CJD.[99]

Prion protein (PrP) accumulation in the tonsil in Prion protein (PrP) accumulation in the tonsil in variant Creutzfeldt-Jakob disease within follicular dendritic cells and macrophages in a germinal center as demonstrated by PrP immunocytochemistry. From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.

A distinctive PrPSc subtype (4t) is consistently observed in antemortem and postmortem tonsil examinations in cases of variant CJD.[47] In variant CJD, the proportion of the prion protein glycoforms in type 4t PrPSc in the tonsils differs from that in type 4 PrPSc in brain tissue, which implies the superimposition of tissue- and strain-specific effects of prion protein glycosylation.

Tonsil biopsy has shown 100% sensitivity and specificity for the diagnosis of variant CJD and allows diagnosis of variant CJD at an early clinical stage.[98, 100] Therefore, a tonsil biopsy is an important diagnostic test for suspected variant CJD, particularly if characteristic MRI findings are absent.

Furthermore, large-scale anonymous screening of routine surgical tonsillectomy tissues may provide an early warning sign of a high-level preclinical variant CJD infection[101, 102] , although a relatively small sample of 2000 consecutive tonsillectomy specimens obtained in the United Kingdom did not detect any positive cases on analysis by both high-sensitivity immunoblotting and immunohistochemistry.[103] This study was limited by the fact that the median age of tonsillectomy specimens was less than 10 years and most of these patients would not have had a significant exposure to BSE.

A second study examined more than 16,000 tonsillectomy and appendectomy specimens from persons aged 10-30 years (the population at highest risk for variant CJD) and found 3 positive results, yielding a prevalence of 237 cases per million population.[99]

Studies have indicated that nearly 1 in 2000 people living in the United Kingdom are harboring latent variant CJD in their lymphoreticular system. It remains unknown whether there is disease progression or possibility of transmission.[104, 105, 106, 107]  These startling numbers are why citizens of bovine spongiform encephalopathy-infected countries are not allowed to donate blood in the United States. The United Kingdom mostly uses US-derived blood products.  

Neuropathology

The pathology of variant CJD shows relatively uniform morphologic and immunocytochemical characteristics, which are distinct from other forms of CJD (see the images below).

The florid plaque in the cerebral cortex in varian The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
The florid plaque in the cerebral cortex in varian The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at high magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (higher magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.

The diagnostic pathological features of variant CJD are as follows[108] ):

  • Multiple florid plaques in hematoxylin and eosin sections; numerous small cluster plaques in prion protein–stained sections; and amorphous pericellular and perivascular prion protein accumulation in the cerebral and cerebellar cortex

  • Severe spongiform change; perineuronal and axonal prion protein accumulation in the caudate and putamen; and marked astrocytosis and neuronal loss in the posterior thalamic nuclei and midbrain

  • Marked astrocytosis and neuronal loss in the posterior thalamic nuclei and midbrain, and reticular and perineuronal prion protein accumulation in the gray matter of the brainstem and spinal cord

  • Reticular and perineuronal prion protein accumulation in the gray matter of the brainstem and spinal cord

  • PrPSc accumulation in lymphoid tissues throughout the body

  • Predominance of diglycosylated PrPSc in CNS and lymphoid tissues

Relative uniformity of the pathological and biochemical features in the brain is a striking feature of variant CJD and is in keeping with the relatively consistent clinical phenotype for this disease.

By contrast, for sporadic CJD, at least 6 neuropathological and biochemical subtypes have been identified.[109] Although the biochemical profile of PrPSc in variant CJD resembles that in bovine spongiform encephalopathy (BSE) and BSE-related disorders in other species, the neuropathology of variant CJD is distinct from BSE.

Florid plaques are a neuropathological, but not uniform, hallmark of variant CJD. However, smaller cluster plaques are observed in all cases and have not been reported in any other type of human prion disease. Rarely, florid plaques have occurred in iatrogenic CJD in dura matter graft recipients in Japan, but these cases do not show any other distinctive neuropathological features of variant CJD.[110]

Kuru-type amyloid plaques observed in patients with sporadic CJD who are heterozygotes at codon 129 in their PRNP gene can be distinguished from florid plaques by their restricted distribution in the cerebral cortex and cerebellum, smaller size, compact plaque morphology, and absence of the rim of spongiform change in the neuropil.[109]

The pattern of thalamic neuronal loss and gliosis is distinct. In variant CJD, pulvinar and dorsomedial nuclei are affected.

Magnetic Resonance Imaging

There is large variability in MRI patterns that make "typical" patterns in variant CJD difficult to define. The majority of cases have cortical (frontal and parietal) and basal ganglia involement. MRI demonstrates certain unique features in variant CJD such as the "pulvinar sign" and the "hockey-stick sign.".[111, 112]  These findings are specific to variant CJD and, therefore, have been included in the World Health Organization (WHO) criteria for the diagnosis of variant CJD.[63] (See Staging, under Presentation.) DWI sequence is thought to be superior because of the detection of microvacuolation of neuritic processes causing spongiform degeneration. However, ADC sequence also seems to be important in differentiating between sporadic and variant forms. [107]

In a study of 86 patients, 71% of T2-weighted images and 100% of fluid-attenuated inversion recovery (FLAIR) images showed positive pulvinar signs, as defined by symmetric hyperintensity of the bilateral pulvinars relative to the anterior putamen (see the image below).[113] . 

Pulvinar sign of variant Creutzfeldt-Jakob disease Pulvinar sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows marked symmetrical hyperintensity of the pulvinar (posterior) thalamic nuclei, and this sign is present in 100% of cases imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.

Common additional MRI findings include hyperintensity of dorsomedial thalamic nuclei (93%), periaqueductal gray matter (83%), and caudate head. Dorsomedial and posterior thalamic hyperintensity bilaterally produces a characteristic hockey-stick distribution (see the images below).[111, 112, 113, 114]  However, this distribution of hyperintensity can also be seen in other forms of prion disease.

Axial fluid-attenuated inversion recovery (FLAIR) Axial fluid-attenuated inversion recovery (FLAIR) showing periaqueductal gray matter hyperintensity (arrow). Although not a specific sign, periaqueductal hyperintensity is observed in 83% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Hockey stick sign of variant Creutzfeldt-Jakob dis Hockey stick sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows symmetrical pulvinar and dorsomedial thalamic nuclear hyperintensity. This combination produces a characteristic hockey stick appearance and is present in 93% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.

In contrast, MRI changes in sporadic CJD are usually more pronounced in the caudate and putamen, and the changes can be asymmetric.[115, 116] Rarely, hyperintensity in the pulvinar relative to other thalamic nuclei has been described in young patients with sporadic CJD, making the pulvinar more conspicuous. Although this could be mistaken for variant CJD, the signal intensity of the pulvinar always remains less than that of the anterior putamen. SPECT scans were studied in 2 patients and showed nonspecific hypoperfusion abnormalities.[117]

Electroencephalography

Nonspecific diffuse background slowing is the most common finding on EEG. Periodic sharp and slow-wave complexes (PSWCs) are considered characteristic of Creutzfeldt-Jakob Disease (CJD), however they are less apparent in variant CJD. They may appear as early as 3 weeks after the onset of the disease and occur in 60-70% of all patients with sporadic CJD during the course of the illness. It was previously thought that PSWCs were frontal and bilateral, however growing evidence points to a more temporal location in the prodromal stage of disease. Global bifrontal appearance appears later in the disease.[107, 97]  PSWCs also occur in some cases of familial CJD but are absent in iatrogenic human growth factor hormone–related CJD, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker syndrome.

Only one patient with variant CJD has been reported to show PSWCs. This was seen in a Japanese patient whose initial EEG showed diffuse slowing and a follow-up EEG performed 2 years later showed periodic complexes typical of sporadic CJD.[118]

Other Tests

PET/CT seems to be a promising diagnostic tool and has been suggested as able to detect lesions better than MRI in earlier stages of disease. PET imaging could be even more useful in the near future by developing an in vivo probe to label prion plaques.[119]

Some studies have indicated the possiblity of detecting PrP in urine of patients with variant CJD.[97] . Moda et al. used protein misfolding cyclic amplification (PMCA) to replicate PrPsc and analyze the urine of patients with various transmissible spongiform encephalopathies. PrPsc was detected in 13 of 14 urine samples of patients with variant CJD and none in the other samples consisting of healthy controls and other neurological conditions.[120]

Unfortunately, CSF biomarkers are less sensitive than for sporadic disease type.

 

Procedures

The gold standard for diagnosis is pathological confirmation via brain biopsy. However, the frequency of a positively diagnostic specimen is rather low. A CJD center in Germany evaluated 26 patients between 1993 and 2005 with suspected CJD and concluded 42% of the biopsies to be nondiagnostic.[121]  The reason for low diagnostic yield may be due to the methodology used where vacuolation is commonly missed in specimens. Safar et al. used a new technique called conformation-dependent immunoassay (CDI), which showed 100% accuracy and detection of PrPsc in any part of the brain.[122]  Biopsy has remained controversial due to both poor diagnostic yield and the fact that CJD remains untreatable. Manix et al. states that "brain biopsy should only be done after all noninvasive diagnostic avenues are exhausted, and do not point to a cause."[123]

 

Treatment

Approach Considerations

Although there is no cure for Creutzfeldt-Jakob disease (CJD), interleukins and other drugs may help slow the progression of disease. Medications to help treat the symptoms of CJD include antiepileptics to manage seizures (eg,diphenylhydantoin, carbamazepine, and gabapentin) and, occasionally, clonazepam to treat myoclonus. Antiepileptics are also used to treat violent outbursts.[124, 125, 126]

Dementia in patients with CJD can be treated with donepezil, galantamine, rivastigmine, and memantine. If a person develops disruptive behavior, antipsychotics can be used. Antidepressants may help patients come to terms with the prognosis.

Some general principles for the treatment of patients with variant CJD include the following:

  • Discontinue any medication that could impair cognition or cause confusion

  • Many patients need psychiatric care, including antidepressants, which may provide temporary relief

  • Some patients need treatment to ameliorate sensory symptoms in the limbs

  • All patients have increasing need for supportive care, including palliative and terminal care

  • Family members need significant support in coping with both emotional and care needs; they also need reassurance and information regarding the nature of disease transmission

Consultation with the following may be necessary:

  • Neurologist

  • Infectious disease specialist

  • US Centers for Disease Control and Prevention

  • CJD surveillance unit, Edinburgh, United Kingdom

Experimental Treatments

A number of experimental interventions are currently being studied.[127, 128] They include some of the conventional medications, such as the antimalarial quinacrine and the antipsychotic chlorpromazine, which prevent conversion of the normal prion protein (PrPc) to abnormal prion protein (PrPSc), according to in vitro studies.[129] These drugs are currently being evaluated in treatment trials.[130, 131, 132] Clinical trials currently ongoing include PRION-1: Quinacrine for Human Prion Disease[131] and the CJD (Creutzfeldt-Jakob Disease) Quinacrine Study.[132] (Quinacrine is not commercially available in the United States.)

Pentosan polysulphate (PPS) also has effects on prion protein production, replication, and associated cell toxicity. Some experimental results showed that if PPS is given to animals at a time relatively close to the point of experimental infection, an increase in the incubation period of disease may occur; in some instances, animals appear to be completely protected from the development of disease. On the basis of these data, some individuals with prion diseases have been treated with intraventricular PPS. One patient with variant CJD did not show any clear evidence of deterioration for a period of at least 23 months.

Flupirtine has shown some beneficial effects on cognitive function in patients with CJD but without any evidence of increased survival.[133] One strategy involves designer compounds that interact with PrPSc structure, inhibiting the conformation change of PrPc associated with the disease.[134]

Another potential approach is immunologic, in which immunization with alpha s-helix peptides is used to reduce cerebral amyloid accumulation.[135]