AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Bovine spongiform encephalopathy

Bovine spongiform encephalopathy (BSE), also known as mad cow disease, and variant Creutzfeldt-Jakob disease (CJD) are related disorders. 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.
 
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

On December 9, 2003, a "downer" (nonambulatory and disabled) dairy cow was 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). Samples taken from this animal as a part of targeted surveillance tested positive for BSE on December 23. This was confirmed by the BSE International Reference Laboratory in Weybridge, England on December 25.

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 (USDA News Release, Veneman Announces Additional Protection Measures to Guard Against BSE). Subsequently, the infected cow was discovered to have originated in Alberta, Canada and was imported into the United States in September of 2001.

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. A complete summary is available at USDA, Animal and Plant Health Inspection Service, BSE Update.

While this was the first case of BSE in the United States, worldwide, as of January 26, 2007, more than 190,000 confirmed clinical cases have been reported since 1986, and approximately 184, 000 cases were from the United Kingdom alone (see Media Files 1-2). 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.^{1, 2} Most of these infected animals were slaughtered for human consumption before any clinical signs of BSE were noted.

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. 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. See the Alabama BSE Investigation; Final Epidemiology Report, May 2006.
 
Further cases of BSE cases 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 (see Media File 2).

Approximately 5 million head of cattle have been slaughtered in the United Kingdom in an effort to halt the epidemic. The epidemic has slowed significantly, and, since 1992, the number of cases has decreased an average of 40% per year, although new cases continue to be reported. However, this preemptive slaughter has crippled the British livestock industry and has affected the tallow, gelatin, and pharmaceutical industries, all of which make bovine-derived products.³

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 towards 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

• Microscopic examination of brain tissue, which shows characteristic changes, including a predominantly vacuolar spongiform change distributed uniformly throughout the brain^{4, 5}
• Immunohistochemical labeling of the disease-associated (abnormal) prion protein (PrPSc)
• Detection of scrapie-associated fibrils (SAF) by electron microscopy

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.⁶ 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.^{7, 8, 9, 10}

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.¹¹ Similarly, the spread of spongiform encephalopathies in farmed mink and captive and zoo animals may have resulted from prion-contaminated feed.^{12, 13}

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. See BSE Inquiry Report for the full report.

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 Media File 3).

Furthermore, specified risk material, which comprises brain, spinal cord, eyes, tonsils, thymus, spleen, and intestine, is removed from all foodstuffs at slaughter.¹⁴ 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.¹⁵

Variant CJD

Within weeks of identification of the first case of BSE, concern was expressed about human risk.^{16, 17, 18} 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.^{19, 20}

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, had behavioral symptoms at onset, and had symptoms that progressed somewhat more slowly than those of 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.²¹ So far, 201 cases of variant CJD have been described, most from the United Kingdom (see International frequency).

The risk factors for the development of variant CJD include age, residence in the United Kingdom, and methionine homozygosity at codon 129 of the prion protein gene (PRNP).²² 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.²³ 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.²⁴ Past surgery, previous blood transfusion, or occupation have so far 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.

Recent 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.²⁵

Pathophysiology

Convincing evidence now indicates that variant CJD is indeed a new disease. 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 BSE to human variant CJD.^{26, 27, 28} Interestingly, while the BSE epizootic has apparently led to other newly host-switched TSEs in domestic and large cats, sheep fed the BSE agent experimentally acquire a scrapielike disease.²⁹ 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.²⁶

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 can be demonstrated in skeletal muscles remains controversial.^{30, 31, 32, 33} 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 CJD³⁴, Despite this evidence, the infection probably resulted from beef products contaminated by nervous tissue because neural tissues have a much higher concentration of PrPSc compared with any other peripheral tissue.

The amount of infectious agent ingested, together with host susceptibility as determined by the human genotype at PRNP codon 129, appear to play an important role 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.³⁵

A functional immune system is required for prion replication and transport outside the CNS.³⁶ 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.^{37, 38} The other possible route is via blood; this was suggested by experiments showing BSE transmission from sheep to sheep by blood transfusion.³⁹ Which of these mechanisms is the more important route of prion invasion is not known at this time.

Frequency

United States

Cases of variant CJD acquired in the United States have not been documented.

International

As of November 3, 2006, 201 definite and probable cases of variant CJD have been reported worldwide (164 in the United Kingdom; 21 in France; 4 in Ireland; 3 in the United States; 2 in the Netherlands; and 1 each in Canada, Hong Kong, Italy, Japan, Portugal, Saudi Arabia, and Spain). See The National Creutzfeldt-Jakob Disease Surveillance Unit for more information. Of these, 2 of the 4 cases from Ireland, 3 of the 3 cases from the United States, 1 of the 21 cases from France, and single cases from Canada and Japan were probably exposed to the BSE agent while a resident in the United Kingdom.
 
So far, 199 of the 201 cases of variant CJD have included documented exposure to food products in countries where BSE occurs and 2 cases have occurred secondarily as a result of exposure to blood transfusion from individuals who then developed variant CJD.^{45, 46} One patient who died of an unrelated cause was found to have a subclinical infection, very likely secondary to a blood transfusion from a variant CJD–positive donor who subsequently went on to develop the disease.⁴⁷

Whether the cases from the United Kingdom represent the beginning of an epidemic or whether the numbers will remain low or even decline is unclear. Estimates of the possible size of the epidemic have ranged from 70-136,000 cases.^{48, 49} Recent models provide more conservative estimates of 403-1000 at 95% confidence intervals.^{50, 51}

The number of cases peaked in 2000 at 28 and then steadied at 20 cases in 2001, 17 in 2002, and 18 in 2003 (see Media File 1). Nine new cases were reported in 2004 and another 5 in 2005. This raises the possibility that the epidemic may have peaked.⁵² 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, all over the world. Other forms of prion diseases are even rarer.

Mortality/Morbidity

• Like other prion-related diseases, variant CJD is relentlessly progressive and inevitably leads to death.
• The mean duration for variant CJD is 16 months, which is somewhat longer than sporadic CJD at 8 months.
• The mean duration for variant CJD is shorter compared with familial CJD, which is 26 months, and Gerstmann-Sträussler-Scheinker disease, which is 60 months.

Race

Variant CJD has been mainly reported from Europe, with most cases in the United Kingdom; therefore, no particular racial predilection can be discerned.

Sex

No sex preponderance has been noted for variant CJD. Among other prionoses, only kuru is more prevalent in women, which is likely because women ate the brains as a part of ritual cannibalism and the neural tissue has the highest concentration of PrPSc.

Age

The mean age of onset of variant CJD is 29 years, with a range of 14-74 years.⁵³ Various models suggest that variant CJD infection seems to preferentially affect young people and that the older subjects are probably more resistant.^{51, 54}

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The incubation period of variant CJD is not known. However, based on the assumptions that most cases of variant CJD were exposed to 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 in kuru⁵⁵ and 12-17 years in iatrogenic CJD following intramuscular injection of human growth hormone.⁵⁶ However, cases of kuru and iatrogenic CJD have been seen 40 and 38 years after exposure, respectively. Prolonged incubation periods for these conditions have been associated with heterozygosity at codon 129 of PRNP. As mentioned above, all clinical cases of variant CJD to date have been homozygous for methionine at codon 129 of PRNP.

The incubation period for secondary transmission for variant CJD by blood transfusion is probably shorter, as suggested by the development of the disease in 2 cases 6 and 8 years following blood transfusion, respectively.^{45, 46} In the third patient with blood transfusion–related, secondarily transmitted variant CJD infection, the disease was subclinical at the time of death from an unrelated cause 5 years following the 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.^{47, 57, 58}

The clinical course of variant CJD is characterized by distinct features, with psychiatric abnormalities dominating the initial course of the disease. In a large study of 100 cases⁵⁹, 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 beginning. 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; of course, 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.^{60, 61, 62, 63, 64, 59}

• Table 1 and Table 2 in Physical list the psychiatric and neurologic features of variant CJD as they evolve. 
• A typical case history of variant CJD is as follows: 
• • A 33-year-old male farmer and resident of the United Kingdom 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 7s. He had poor 3-object registration and recall and scored 12 out of possible 30 on 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.
  • His 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 (CSF) 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.

Physical

Table 1. Psychiatric Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 2002⁵⁹)

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

The differential diagnosis includes the following:

Sporadic CJD
Psychiatric disease
Peripheral neuropathy
Wilson disease
Hashimoto encephalopathy
CNS vasculitis
Possible encephalitis lethargica
Inflammatory diseases of the CNS
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes)⁶⁵

Because psychiatric symptoms and limb pain are common presenting symptoms in variant CJD, a workup for the disease in the early stage may be quite challenging. Therefore, the differential diagnoses include 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 differential diagnosis of variant CJD.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The initial workup should include tests for dementia and encephalopathy. Include a serum chemistry profile, liver function tests, vitamin B-12 level, methylmalonic acid level, folate value, thyroid studies, ammonia value, erythrocyte sedimentation rate, C-reactive protein value, and neurosyphilis and HIV tests, in appropriate cases.
• No blood or serum studies have been found useful in diagnosing variant CJD.
• CSF workup includes the following:
• • 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 tau protein are helpful.
  • In sporadic CJD, detection of protein 14-3-3 is a reliable and sensitive marker for sporadic CJD, with sensitivity and specificity approaching 96%. In variant CJD, on the other hand, the sensitivity is 50% and the specificity is 91%.
  • 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 why it has a higher sensitivity than the other neuronal markers 14-3-3 and NSE is unclear. The combination of a positive CSF 14-3-3 and/or an increased CSF tau protein has an increased sensitivity (86%) for the detection of variant CJD, with only a slight reduction in specificity (90%).⁶⁶
  • Recently, a specific reduction in the CSF uric acid levels has been shown in variant CJD but not in sporadic CJD, thus potentially helping in the differential diagnosis of variant CJD.⁶⁷
  • 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).

Imaging Studies

• Magnetic resonance imaging
• • MRI demonstrates certain unique features in variant CJD, such as the pulvinar sign and the hockey stick sign.^{68, 69} 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. See the World Health Organization Case Definition for Variant CJD in Staging.
  • In a large 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 Media File 5).⁷⁰ Common additional MRI findings include hyperintensity of dorsomedial thalamic nuclei (93%), periaqueductal gray matter (83%), and caudate head (see Media File 6). Dorsomedial thalamic hyperintensity produces a characteristic hockey stick distribution of hyperintensity, as illustrated in Media File 7.^{68, 69, 70}
  • In contrast, MRI changes in sporadic CJD are usually more pronounced in the caudate and putamen and the changes can be asymmetric.^{71, 72} Rarely, hyperintensity in the pulvinar relative to other thalamic nuclei has been described in young patients with sporadic CJD, making the pulvinar more conspicuous. While this could be mistaken for variant CJD, the signal intensity of the pulvinar always remains less than that of the anterior putamen.{Ref72}
• Single-photon emission computed tomography (SPECT) scanning: SPECT scans were studied in 2 patients and showed nonspecific hypoperfusion abnormalities.⁷³

Other Tests

• Electroencephalography
• • Periodic sharp and slow wave complexes (PSWCs) are considered characteristic of 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. 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.
  • So far, only one patient with variant CJD has been reported to show PSWCs. This was seen in the Japanese patient whose initial EEG showed diffuse slowing and a follow-up EEG performed 2 years later showed periodic complexes typical for sporadic CJD.⁷⁴

Procedures

• Lumbar puncture (see Lab Studies)
• Tonsil and brain biopsy (see Histologic Findings)

Histologic Findings

Tonsil biopsy

Unlike sporadic CJD, in patients with variant CJD, 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 Media File 8).^{75, 76, 30} The lymphoreticular accumulation of PrPSc, as assessed by immunocytochemistry, has been shown to be a highly specific feature of variant CJD.⁷⁷

A distinctive PrPSc subtype (ie, 4t) is consistently observed in antemortem and postmortem tonsil examinations in cases of variant CJD.^{76, 30} Type 4t PrPSc in the tonsils differs from type 4 PrPSc observed in brain tissue in variant CJD in the proportion of the prion protein glycoforms, implying the superimposition of tissue- and strain-specific effects of prion protein glycosylation.⁷⁶

Tonsil biopsy has shown 100% sensitivity and specificity for the diagnosis of variant CJD. It allows diagnosis of variant CJD at an early clinical stage.^{78, 76, 30} 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 of a high-level preclinical variant CJD infection^{76, 79, 80}, 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.⁸¹ This study was limited by the fact that the median age of tonsillectomy specimens is less than 10 years and most of these patients would not have had a significant exposure to BSE. The 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.⁷⁷

Neuropathology

The pathology of variant CJD shows relatively uniform morphologic and immunocytochemical characteristics, which are distinct from other forms of CJD (see Media Files 9-12). The diagnostic pathological features are listed as follows (adapted from Ironside et al, 2002⁸²).

• Multiple florid plaques in hematoxylin and eosin sections; numerous small cluster plaques in prion protein–stained sections; 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; marked astrocytosis and neuronal loss in the posterior thalamic nuclei and midbrain 
• Marked astrocytosis and neuronal loss in the posterior thalamic nuclei and midbrain; 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.⁸³ While the biochemical profile of PrPSc in variant CJD resembles that in 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.⁸⁴ 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.⁸³

The pattern of thalamic neuronal loss and gliosis is distinct. In both familial and sporadic fatal insomnia, anterior thalamic nuclei are predominantly involved, while in variant CJD, pulvinar and dorsomedial nuclei are affected.

Staging

WHO Case Definition for Variant CJD (adapted from the revision of the WHO surveillance case definition for variant CJD, 2001⁸⁵)

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 TSE

Class II

• A - Early psychiatric symptoms (ie, depression, anxiety, apathy, withdrawal, delusions)
• B - Persistent painful sensory symptoms (ie, including 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; modification of the case definition of the characteristic MRI features [IIIB] to brain MRI shows bilateral symmetrical pulvinar hyperintensity relative to the signal intensity of the anterior putamen is recommended to improve the accuracy of the pulvinar sign in variant CJD)

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)

Possible diagnoses

• Definite - Class IA and neuropathologic confirmation of variant CJD (ie, spongiform change and extensive prion protein deposition with florid plaques throughout the cerebrum and cerebellum)
• Probable - Class I and 4 of 5 of class II and classes IIIA and IIIB or class I and class IVA
• Possible - Class I and 4 of 5 of class II and class IIIA 

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

As is true for all prion diseases, no treatment is effective. However, some general principles apply, including the following:

• Discontinue any medication that could impair cognition or cause confusion.
• Many patients need psychiatric care, including antidepressants, which may provide a temporary relief.
• Others need treatment to ameliorate sensory symptoms in the limbs.
• All patients have increasing needs for supportive care, including palliative and terminal care.
• The family members also need significant support in coping with the emotional and care needs. They also need reassurance and information regarding the nature of disease transmission.

Consultations

• Neurologist
• Infectious disease specialist
• US Centers for Disease Control and Prevention
• CJD surveillance unit, Edinburgh, United Kingdom

Diet

No dietary restrictions are necessary.

Activity

No activity restrictions are indicated.

MEDICATION

Section 7 of 11  

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A number of experimental interventions are currently being studied.⁸⁶

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 (PrPSc) prion protein according to in vitro studies.⁸⁷ These drugs are currently being evaluated in treatment trials (PRION-1: Randomised trial of quinacrine in human prion disease).

Pentosan polysulphate (PPS) is another drug that 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, then an increase in the incubation period of disease may occur; in some instances, animals appear to be completely protected from the development of disease.⁸⁸ Based on these data, some individuals with prion diseases (the actual numbers and nature of prion disease are not known) have been treated with intraventricular PPS. Although the results are not known at this time, one patient with variant CJD reported has not shown any clear evidence of deterioration over a period of at least 23 months as of February 2005 (Potential Treatments for Creutzfeldt-Jakob Disease).

Another drug, flupirtine, has shown some beneficial effects on cognitive function in patients with CJD but without any evidence of increased survival with the treatment.⁸⁹

One strategy involves designer compounds that interact with PrPSc structure, inhibiting the conformation change of PrPc associated with the disease.⁹⁰

Another potential approach is immunologic, in which immunization with alpha s-helix peptides is used to reduce cerebral amyloid accumulation.⁹¹

FOLLOW-UP

Section 8 of 11  

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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

Patients may be admitted for an expedited workup, including lumbar puncture and biopsies. Some patients may need inpatient psychiatric care.

Further Outpatient Care

As discussed, patients may need treatment for psychiatric and sensory symptoms in addition to the increasing need for supportive care.

Deterrence/Prevention

Variant CJD may spread by iatrogenic means; concern is even more necessary with variant CJD compared with other prion diseases because the titer of the causative agent appears to be high in systemic organs, although not as high as in the neural tissues.

Because the prion agent is highly resistant to inactivation, routine sterilization methods such as autoclaving are not effective. Hence, electromyography and EEG needles, surgical instruments, and other equipment that has been exposed to a patient with variant CJD should not be reused. When such equipment is used in patients with suspected prionoses, it can be quarantined while the definitive studies are pending. If variant CJD is proven, used equipment must be destroyed. If the diagnosis is disproved, equipment can be reused.

Complications

Any part of the CNS can be affected; therefore, a range of CNS complications can be expected. These include 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 bed-ridden state.

Patient Education

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center and Public Health Center. In addition, see eMedicine's patient education articles Mad Cow Disease and Variant Creutzfeldt-Jakob Disease and FDA Overview.

MISCELLANEOUS

Section 9 of 11  

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• Multimedia
• References

Medical/Legal Pitfalls

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.

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

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.

Because the incubation period of variant CJD is 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.

Special Concerns

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. Unlike other prion diseases, in variant CJD, other body tissues, especially lymphoid material, have significant concentrations of prion agent and, therefore, merit 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 BSE might be asymptomatic carriers of the infection.^{92, 93, 94} 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.⁹⁵

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.³⁹ This concern progressed to fear with a recent 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.⁴⁵ 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.⁴⁷ 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.

This possibility, combined with the probable existence of subclinical carriers, raises the specter of an iatrogenic human-to-human wave of variant CJD transmission.⁹⁶ This again highlights the need for reliable detection methods for prion-tainted blood products.⁹⁷ 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.

Although polymerase chain reaction–based assays have almost eliminated the risk of transmission of many blood-borne viruses, no tools of similar efficacy exist for prion detection.⁹⁸ However, a novel technique based on protein misfolding cyclic amplification of aggregated PrPSc may enable detection of very small quantities of PrPSc-priming template in the blood; as yet, this method is not suited to high-volume screening of blood donations.⁹⁹

UK Blood Transfusion Services have taken a number of measures to minimize the transmission of variant CJD by blood, plasma, and tissue products (UK Blood Transfusion & Tissue Transplantation Guidelines):

• Withdrawal and recall of any blood components, plasma derivatives, or tissue derivatives obtained from any individual who later develops variant CJD
• Importation of plasma from countries other than the United Kingdom for fractionation to manufacture plasma derivatives 
• Leukodepletion of all blood components 
• Deferral of whole blood donors who state that they have received a blood component transfusion, including those with UK-derived plasma; those who have received intravenous immunoglobulin in the United Kingdom since January 1, 1980; or those who have undergone plasma exchange 

Similarly, the US FDA has introduced progressively more stringent recommendations for deferral from blood donation from individuals who have traveled or resided in the United Kingdom and other parts of Europe (Guidance for Industry - Revised Preventative Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease [CJD] and Variant Creutzfeldt-Jakob Disease [vCJD] by Blood and Blood Products). According to these guidelines, blood donations from any individual who has traveled to or resided in the United Kingdom for longer than 3 months from 1980 through 1996, receipt of a blood transfusion in the United Kingdom since 1980, and travel or residence in a European country (including US military bases) for more than 5 years since 1980 are excluded. Implementation of these guidelines would probably result in deferral of 5-9% of donors.
 
Concerns about the prevalence of subclinical prion carriers and human-to-human transmission have caused considerable insecurity among public health authorities as to the potential size of the variant CJD epidemic. Therefore, despite the fact that cross-sectional studies to assess the prevalence of prion carriers pose organizational and ethical problems, no alternative is available for assessing the future of the variant CJD epidemic.¹⁰⁰

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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.
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Media file 2:  Geographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.
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Media file 3:  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.
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Media file 4:  Normal fluid-attenuated inversion recovery (FLAIR) image at the level of the basal ganglia shows that the thalamus is normally isointense or slightly hypointense relative to putamen. 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.
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Media file 5:  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.
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Media file 6:  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.
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Media file 7:  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.
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Media type:  MRI

Media file 8:  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.
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Media file 9:  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.
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Media file 10:  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.
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Media file 11:  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.
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Media file 12:  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.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up