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 [79] and 12-17 years for iatrogenic CJD following intramuscular injection of human growth hormone [80] ). However, cases of kuru and iatrogenic CJD have been seen 40 and 38 years [81] 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. [59, 67] 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. [60, 82, 83]
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, [84] 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. [85, 86, 87, 88, 89, 84]
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 [84] ) (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 [84] ) (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. [65, 90] 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 [65] (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. [91, 92, 93] 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. [94]
Standard precautions have been deemed sufficient for routine care of prion disease patients when no CNS tissue is being handled. [95]
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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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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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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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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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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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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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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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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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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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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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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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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.
Tables
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 |
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 |
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 |
