Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy Clinical Presentation

  • Author: Florian P Thomas, MD, MA, PhD, Drmed; Chief Editor: Karen L Roos, MD   more...
 
Updated: Jun 21, 2010
 

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 kuru[60] and 12-17 years in iatrogenic CJD following intramuscular injection of human growth hormone.[61] 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.[48, 49] 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.[50, 62, 63]

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 cases[64] , 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.[65, 66, 67, 68, 69, 64]

  • 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 7 s. 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.
Next

Physical

Table 1. Psychiatric Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 2002[64] ) (Open Table in a new window)

Psychiatric FeaturesEarly 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 (adapted from Spencer et al, 2002[64] ) (Open Table in a new window)

Neurologic FeaturesEarly Onset



< 4 mo



Later Onset



4 to < 6 mo



Late Onset



≥ 6 mo



Common



n ≥ 50



NoneGait disturbance



Slurring of speech



Hyperreflexia



Impaired coordination



Myoclonus



Incontinence



Eye features



Less common



n = 25 to < 50)



PainParesthesia



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



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Causes

See Pathophysiology.

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Contributor Information and Disclosures
Author

Florian P Thomas, MD, MA, PhD, Drmed  Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Amy A Pruitt, MD  Associate Professor of Neurology, University of Pennsylvania School of Medicine; Attending Neurologist, Hospital of the University of Pennsylvania

Amy A Pruitt, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Neil A Busis, MD  Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Karen L Roos, MD  John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Karen L Roos, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Chitharanjan V Rao, MD, MRCP, DM to the development and writing of this article.

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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.
Geographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.
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.
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.
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.
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 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.
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.
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 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 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 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.
Table 1. Psychiatric Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 2002[64] )
Psychiatric FeaturesEarly 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 (adapted from Spencer et al, 2002[64] )
Neurologic FeaturesEarly Onset



< 4 mo



Later Onset



4 to < 6 mo



Late Onset



≥ 6 mo



Common



n ≥ 50



NoneGait disturbance



Slurring of speech



Hyperreflexia



Impaired coordination



Myoclonus



Incontinence



Eye features



Less common



n = 25 to < 50)



PainParesthesia



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



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