Creutzfeldt-Jakob disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.

Creutzfeldt-Jakob disease is a very rare, invariably fatal degenerative neurological disorder of the brain. It is caused by the presence of a prion protein, an abnormal isoform of a cellular glycoprotein.^[1] Creutzfeldt-Jakob disease may be classified into either sporadic, familial and iatrogenic forms. The sporadic form may be further categorized into either classic or variant Creutzfeldt-Jakob disease. The majority of cases of Creutzfeldt-Jakob disease are thought to occur sporadically from prions by an unknown route of transmission. Reports on transmission by human growth hormone products, grafting, surgical electrode implantation, and consumption of infected products have been described. Once transmitted, the CJD prion promotes refolding of the native proteins into the diseased state. The number of misfolded protein molecules increases exponentially, and the process leads to a large quantity of insoluble prions in the affected cells, resulting in cell death. Risk factors for Creutzfeldt-Jakob disease include advanced age, positive family history, personal history of psychosis, history of surgical procedures, grafts or implants, and history of ingestion of human growth hormones or contaminated meat. Once symptoms develop, Creutzfeldt-Jakob disease is rapidly progressive and almost always fatal. Early symptoms are often non-specific. Patients’ relatives usually report rapidly progressive dementia, personality changes, uncontrolled sporadic laughter, and sleep disorders. The majority of patients (85% of patients) die within 1 year of symptom-onset. Common complications of Creutzfeldt-Jakob disease include overwhelming infections, congestive heart failure, or respiratory failure. The diagnosis of Creutzfeldt Jakob disease depends on a combination of positive findings from physical examination and laboratory testing. Based on the findings, the diagnosis of Creutzfeldt Jakob disease may be either probable or possible. There are no definitive criteria for the diagnosis of Creutzfeldt Jakob disease. Typical EEG findings in Creutzfeldt-Jakob disease include periodic biphasic or triphasic sharp wave complexes (PSWCs). Periodic synchronous discharges (PSDs) occur either before or in synchronicity with myoclonus. Biopsy of the brain tissue is the definitive diagnostic test for Creutzfeldt-Jakob disease, but is not usually performed. Management of Creutzfeldt-Jakob disease is directed towards palliative care. There is no effective treatment or vaccine for Creutzfeldt Jakob disease.

Creutzfeldt Jakob disease was first described in 1920-1921 by two German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob.

Creutzfeldt-Jakob disease may be classified into either sporadic, familial and iatrogenic forms. The sporadic form may be further categorized into either classic or variant Creutzfeldt-Jakob disease.

The majority of cases of Creutzfeldt-Jakob disease are thought to occur sporadically from prions by an unknown route of transmission. Reports on transmission by human growth hormone products, grafting, surgical electrode implantation, and consumption of infected products have been described. Once transmitted, the CJD prion promotes refolding of the native proteins into the diseased state. The number of misfolded protein molecules increases exponentially, and the process leads to a large quantity of insoluble prions in the affected cells, resulting in cell death. On gross histopathological analysis, the brain tissue appears “spongy” with areas of perforation within the brain tissue. On microscopic histopathological analysis, spongiform changes, neuronal loss, astrocyte proliferation, and deposition of prion proteins in the brain are characteristic findings.

Creutzfeldt-Jakob disease (CJD) is caused by the presence of a prion protein, an abnormal isoform of a cellular glycoprotein.^[1]

Creutzfeldt-Jakob disease must be differentiated from other causes of rapidly progressive dementia, such as other neurodegenerative diseases, infections, Alzheimer’s disease, vascular dementia, and dementia due to metabolic or toxic etiology.^[2]

Creutzfeldt-Jakob disease is a rare disorder with an incidence of approximately 0.1 to 0.3 cases per 100,000 individuals. In the USA, less than 300 cases of Creutzfeldt-Jakob disease have been reported. Individuals > 50 years of age are at higher risk of developing Creutzfeldt-Jakob disease than younger individuals. The most common age at diagnosis is approximately 60-65 years (range 45-90). On the other hand, variant (non-classic) Creutzfeldt-Jakob disease is more common among younger individuals. There is no gender or racial predilection for the development of Creutzfeldt-Jakob disease. Creutzfeldt-Jakob disease is more commonly described in Africa, but this is thought to be attributed to cannibalism practices in certain African tribes in the 1950s and ingestion of infected human brains, rather than true racial variation.

Risk factors for Creutzfeldt-Jakob disease include advanced age, positive family history, personal history of psychosis, history of surgical procedures, grafts or implants, and history of ingestion of human growth hormones or contaminated meat.

Once symptoms develop, Creutzfeldt-Jakob disease is rapidly progressive and almost always fatal. Early symptoms are often non-specific. Patients’ relatives usually report rapidly progressive dementia, personality changes, uncontrolled sporadic laughter, and sleep disorders. The majority of patients (85% of patients) die within 1 year of symptom-onset. Common complications of Creutzfeldt-Jakob disease include overwhelming infections, congestive heart failure, or respiratory failure.

The diagnosis of Creutzfeldt Jakob disease depends on a combination of positive findings from physical examination and laboratory testing. Based on the findings, the diagnosis of Creutzfeldt Jakob disease may be either probable or possible. There are no definitive criteria for the diagnosis of Creutzfeldt Jakob disease.

Common symptoms of Creutzfeldt-Jakob disease include progressive dementia, depression, personality changes, uncontrolled sporadic laughter, sleep disorders, and jerky movements (characteristic myoclonus).^[3]

Physical examination is required for the diagnosis of ‪Creutzfeldt-Jakob disease‬. Physical examination findings of ‪Creutzfeldt-Jakob disease‬findings include myoclonus, extrapyramidal signs, akinetic mutism, and visual or cerebellar signs^[4]

Routine laboratory tests are usually normal in Creutzfeldt Jakob disease. Analysis of CSF for 14-3-3 protein may be helpful in the diagnosis of Creutzfeldt-Jakob disease‬.^[5] Other elevated proteins in CSF may include S-100, neuron specific enolase, and Tau protein.

MRI findings in CJD include high signal abnormalities in caudate nucleus and/or putamen on diffusion-weighted imaging (DWI) or fluid attenuated inversion recovery (FLAIR).^[1] Additional findings on diffusion weighted imaging include cortical, subcortical, and thalamic involvement. An abnormal signal in the poster thalami on T2 (pulvinar sign) and diffusion weighted images and fluid-attenuated inversion recovery sequences on brain MRI, in the appropriate clinical context, is highly specific for variant Creutzfeldt-Jakob disease.

CT and PET scans are generally normal in Creutzfeldt-Jakob disease and may be helpful in ruling out other diseases. On CT scan, rapidly progressive ventricular enlargement and cortical atrophy may be present. On PET scan, abnormalities in thalamic regions may be present.

EEG findings are not diagnostic of CJD, but may help in the diagnosis of CJD. Typical EEG findings in Creutzfeldt-Jakob disease include periodic biphasic or triphasic sharp wave complexes (PSWCs). Periodic synchronous discharges (PSDs) occur either before or in synchronicity with myoclonus.^[6]

Biopsy of the brain tissue is the definitive diagnostic test for Creutzfeldt-Jakob disease, but is not usually performed. Deposits of prion protein (scrapie), PrP^Sc, can be found in the skeletal muscle and/or the spleen (approximately 30% of cases).

Management of Creutzfeldt-Jakob disease is directed towards palliative care. There is no effective treatment for Creutzfeldt Jakob disease.

There is no vaccine against Creutzfeldt-Jakob disease. Preventive measures to reduce Creutzfeldt-Jakob disease have not been studied and may or may not be helpful. Preventive measures may include sterilizing medical equipment before use, avoiding the use of infected patients as cornea donors, managing infected animals (e.g. cows), and not accepting transfusions from individuals with certain travel histories (e.g. travel to UK for > 6 months between 1980-1996).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

Creutzfeldt Jakob disease was first described in 1920-1921 by two German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob. Creutzfeldt Jakob disease was first described in 1920-1921 by two German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob. The term Creutzfeldt Jakob was first coined by Spielmeyer in 1922 in honor of Creutzfeldt and Jakob’s report. In 1997, Stanley B. Prusiner was awarded the Nobel Prize in physiology or medicine for his discovery of prions. In 2007, Laura Manuelidis, an American neuropathologist, and her colleagues described a virus-like particle without nucleic acid in less than 10% of the cells a scrapie-infected cell line and in a mouse cell line infected by a human Creutzfeldt Jakob disease agent.

• Creutzfeldt Jakob disease was first described in 1920-1921 by two German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob.
• The term Creutzfeldt Jakob was first coined by Spielmeyer in 1922 in honor of Creutzfeldt and Jakob’s report.^[1]
• In 1997, Stanley B. Prusiner was awarded the Nobel Prize in physiology or medicine for his discovery of prions.
• In 2007, Laura Manuelidis, an American neuropathologist, and her colleagues described a virus-like particle without nucleic acid in less than 10% of the cells a scrapie-infected cell line and in a mouse cell line infected by a human Creutzfeldt Jakob disease agent.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: , Mohamadmostafa Jahansouz M.D.[2]

Creutzfeldt-Jakob disease may be classified into four groups: Sporadic CJD, familial CJD and iatrogenic CJ. Sporadic CJD is the most common type and is idiopathic. Familial CJD is caused by inheritance of abnormal prions and is exceptionally rare. Iatrogenic CJ is very rare and the principal sources of outbreaks are: contaminated growth hormone derived from human cadavers with undiagnosed CJD infections, contaminated dura mater grafts, neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone and transfusion of blood products.

Creutzfeldt-Jakob disease may be classified into four groups:^[1]

• Sporadic CJD^[2]
  • Most common, idiopathic
  • Average age of onset is approximately 65 years

• Familial CJD^[3]
  • Inheritance of abnormal prion
  • Exceptionally rare

• Iatrogenic CJ^[4]
  • Very rare: only occasional cases with exceptionally long incubation periods are still appearing.
  • The principal sources of these outbreaks are:^[4][5]
    • Contaminated growth hormone derived from human cadavers with undiagnosed CJD infections
    • Contaminated dura mater grafts
    • Neurosurgical instrument contamination
    • Corneal grafts
    • Gonadotrophic hormone
    • Transfusion of blood products

Sporadic CJD (sCJD) may be classified based on molecular and phenotypic features into the following subtypes:^[6]

Abbreviations: PrP=Prion protein
MM, VV and MV are genotypes of PrP
MM1: MM genotype type 1 (M:Methionine;V:Valine), MV1:MV genotype type 1, VV2:VV genotype type 2, MV2:MV genotype type 2
Type 1 and type 2 are based on the molecular mass of PrP, type 1: 19 kd, type 2: 21kd

The following table demonstrates distinguishing features for classic and variant Creutzfeldt-Jakob disease:

Adapted from Belay E. Schonberger L. Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Clin Lab Med. 2002;22:849-62.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: , Mohamadmostafa Jahansouz M.D.[2]

The majority of cases of Creutzfeldt-Jakob disease are thought to occur sporadically from prions by an unknown route of transmission. Reports on transmission by human growth hormone products, grafting, surgical electrode implantation, and consumption of infected products have been described. Once transmitted, the CJD prion promotes refolding of the native proteins into the diseased state. The number of misfolded protein molecules increases exponentially, and the process leads to a large quantity of insoluble prions in the affected cells, resulting in cell death. On gross histopathological analysis, the brain tissue appears “spongy” with areas of perforation within the brain tissue. On microscopic histopathological analysis, spongiform changes, neuronal loss, astrocyte proliferation, and deposition of prion proteins in the brain are characteristic findings.

• The majority of cases of Creutzfeldt-Jakob disease are thought to occur sporadically from prions by an unknown route of transmission.
• The defective protein associated with Creutzfeldt-Jakob disease can be inherited (familial form) or transmitted (iatrogenic form) through the following:
  • Human growth hormone (hGH) products
  • Corneal grafting
  • Dural grafts or electrode implants^[1][2][3]
  • Use of HGH drawn from the pituitary glands of cadavers^[4]
  • Consumption of infected animals
  • Cannibalism
• The incubation period of prions is unknonw, but it is speculated that the disease may develop many years (up to 30-50 years) after initial exposure. However, these reports remain controversial.^[5]

• The CJD prion promotes refolding of the native proteins into the diseased state.
• The number of misfolded protein molecules increases exponentially, and the process leads to a large quantity of insoluble prions in the affected cells.
• This mass of misfolded proteins disrupts cell function and causes cell death.
• Once the prion is transmitted, the defective proteins invade the brain and are produced in a self-sustaining feedback loop, causing exponential spread of the prion.

• Mutations in the gene responsible for the production of prion protein can cause misfolding of the alpha helical regions into beta pleated sheets.
• This change in the conformation disables the ability of the protein to undergo digestion.
• Individuals may also acquire CJD genetically through the mutation occurring PRNP gene.

• On gross histopathological analysis, the brain tissue appears “spongy” with areas of perforation within the brain tissue.

• CJD is associated with the build-up of abnormal prion proteins.

• The following microscopic findings may be present in CJD:
  • Presence of florid plaques, defined as round, packed deposits of abnormal prion protein (in variant CJD)
  • Spongiform changes
  • Neuronal loss
  • Astrocyte proliferation
  • Deposition of prion protein throughout the brain^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: , Mohamadmostafa Jahansouz M.D.[2]

Creutzfeldt-Jakob disease is caused by the presence of a prion protein, an abnormal isoform of a cellular glycoprotein. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high beta-sheet content.

• Creutzfeldt-Jakob disease is caused by the presence of a prion protein, an abnormal isoform of a cellular glycoprotein.^[1]
• Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high beta-sheet content.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2] Twinkle Singh, M.B.B.S. [3]

Creutzfeldt-Jakob disease must be differentiated from other causes of rapidly progressive dementia, such as variant Creutzfeldt-Jakob disease, Mad Cow disease, Alzheimer disease, Dementia with Lewy bodies, Frontotemporal dementia, Corticobasal degeneration, Normal pressure hydrocephalus, parkinsonian disorder, Paraneoplastic syndrome, Vasculitis, Neurosarcoidosis,Encephalitis, Whipple disease, Rabies, Herpes simplex virus, postinfectious syndrome, Vitamin B12 deficiency, Hypothyroidism, Wernicke-Korsakoff syndrome and urinary tract infections.

• CJD should be differentiated from other diseases presenting with dementia, ataxia, pyramidal/extrapyramidal signs, myoclonus, rigidity and visual hallucinations. The major differentials of CJD include the following:

• Differential diagnosis of Creutzfeldt-Jakob disease includes the following:^[1][2][3][4]

• Alzheimer disease
• Dementia with Lewy bodies
• Frontotemporal dementia
• Corticobasal degeneration
• Normal pressure hydrocephalus
• Parkinsonian disorder

• Paraneoplastic syndrome
• Vasculitis
• Neurosarcoidosis

• Encephalitis
• Whipple disease
• Rabies
• Herpes simplex virus
• Postinfectious syndrome

• Vitamin B12 deficiency
• Hypothyroidism
• Adverse drug reaction
• Wernicke-Korsakoff syndrome
• Urinary tract infection^[1]

Clinical and pathologic characteristics of classic CJD and variant CJD:^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

Creutzfeldt-Jakob disease is a rare disorder with an incidence of approximately 0.1 to 0.3 cases per 100,000 individuals. In the USA, less than 300 cases of Creutzfeldt-Jakob disease have been reported. Individuals > 50 years of age are at higher risk of developing Creutzfeldt-Jakob disease than younger individuals. The most common age at diagnosis is approximately 60-65 years (range 45-90). On the other hand, variant (non-classic) Creutzfeldt-Jakob disease is more common among younger individuals. There is no gender or racial predilection for the development of Creutzfeldt-Jakob disease. Creutzfeldt-Jakob disease is more commonly described in Africa, but this is thought to be attributed to cannibalism practices in certain African tribes in the 1950s and ingestion of infected human brains, rather than true racial variation.

• Creutzfeldt Jakob disease is a very rare disorder
• The incidence of Creutzfeldt Jakob disease is approximately 0.1 to 0.3 cases per 100,000 individuals.
• In the USA, less than 300 cases of Creutzfeldt Jakob disease have been reported.

• Individuals > 50 years of age are at higher risk of developing Creutzfeldt Jakob disease than younger individuals.
• The most common age at diagnosis is approximately 60-65 years (range 45-90).
• On the other hand, variant (non-classic) Creutzfeldt-Jakob disease is more common among younger individuals.

• There is no gender predilection for the development of Creutzfeldt Jakob disease.

• There is no racial predilection for the development of Creutzfeldt Jakob disease.
• Creutzfeldt Jakob disease is more commonly described in Africa, but this is thought to be attributed to cannibalism practices in certain African tribes in the 1950s and ingestion of infected human brains, rather than true racial variation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Risk factors for Creutzfeldt-Jakob disease include advanced age, positive family history, personal history of psychosis, history of surgical procedures, grafts or implants, and history of ingestion of human growth hormones or contaminated meat.

Risk factors for Creutzfeldt Jakob disease include the following:

• Advanced age
• Family history of Creutzfeldt-Jakob disease^[1]
• Personal history of psychosis^[1]
• Multiple surgical or graft procedures, such as electrode implantation, corneal grafting, or dura mater grafting^[2]
• Living on a farm for more than 10 yrs^[2]
• People receiving human growth hormone (HGH)
• Consumption of contaminated beef (associated with increased risk of variant Creutzfeldt-Jakob disease)^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

There is insufficient evidence to recommend routine screening for Creutzfeldt-Jakob disease.

There is insufficient evidence to recommend routine screening for Creutzfeldt-Jakob disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Once symptoms develop, Creutzfeldt-Jakob disease is rapidly progressive and almost always fatal. Early symptoms are often non-specific. Patients’ relatives usually report rapidly progressive dementia, personality changes, uncontrolled sporadic laughter, and sleep disorders. The majority of patients (85% of patients) die within 1 year of symptom-onset. Common complications of Creutzfeldt-Jakob disease include overwhelming infections, congestive heart failure, or respiratory failure.

• Once symptoms develop, Creutzfeldt-Jakob disease is rapidly progressive and almost always fatal.
• Early symptoms are often non-specific. Patients’ relatives usually report rapidly progressive dementia, personality changes, uncontrolled sporadic laughter, and sleep disorders.
• The majority of patients (85% of patients) die within 1 year of symptom-onset, often due to complications succh as overwhelming infections, congestive heart failure, or respiratory failure.^[1]

The following table demonstrates distinguishing features for classic and variant Creutzfeldt-Jakob disease:

Adapted from Belay E. Schonberger L. Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Clin Lab Med. 2002;22:849-62.^[2]

Complications of Creutzfeldt-Jakob disease include the following:

• Infection
• Heart failure
• Respiratory failure
• Death

• The prognosis of Creutzfeldt-Jakob disease is very poor.
• Patients usually die within 6 to 12 months of symptom-onset.
• A few reports described individuals surviving beyond than 1 or 2 years after diagnosis.

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