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Infectious Disease and Microbiology – Creutzfeldt–Jakob Disease
Creutzfeldt–Jakob disease (CJD) is a transmissible spongiform encephalopathy, a group of chronic, progressive, and invariably fatal neurodegenerative disorders affecting humans and animals. Animal forms include scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle. Human prion diseases include CJD, kuru, Gerstmann–Sträussler–Scheinker syndrome, and fatal familial insomnia. CJD is the most common human prion disease and is characterized by rapidly progressive dementia, myoclonus, and motor dysfunction. It occurs in sporadic, familial, iatrogenic, and variant forms, with sporadic CJD (sCJD) accounting for approximately 85% of cases.
The incidence of sporadic CJD is about 1 case per million people per year, typically affecting individuals between 50 and 60 years of age. Familial cases follow an autosomal dominant inheritance pattern and are linked to mutations in the PRNP gene. Higher frequencies of familial CJD have been reported in certain regions, including North Africa, the Middle East, Italy, and Slovakia. Iatrogenic transmission has occurred through corneal transplantation, dural grafts, contaminated neurosurgical instruments, stereotactic electrodes, and cadaveric human growth hormone or gonadotropin therapy. Variant CJD (vCJD), first identified in 1996 during the BSE outbreak in the United Kingdom, represents animal-to-human transmission. A small number of cases have been documented in the United States.
The pathophysiology involves accumulation of abnormal misfolded prion protein (PrPSc), derived from the normal cellular prion protein encoded by PRNP. These abnormal proteins aggregate in neuronal tissue, leading to neuronal loss, gliosis, and the characteristic spongiform changes—small vacuoles within the neuropil. Inflammation is notably absent. Pathologic changes are most prominent in the cerebral cortex but may also involve basal ganglia, cerebellum, and thalamus. Prion plaques and rods on electron microscopy are pathognomonic.
Clinically, CJD presents with rapidly progressive dementia, myoclonus (present in more than 90% of patients), pyramidal and extrapyramidal signs, and cerebellar dysfunction. Early features include cognitive slowing, impaired concentration, memory loss, mood changes, emotional lability, and hallucinations. As the disease progresses, patients may develop tremor, choreoathetosis, rigidity, hypokinesia, hyperreflexia, spasticity, and extensor plantar responses. Autonomic and endocrine disturbances may occur in certain prion syndromes such as fatal familial insomnia.
Variant CJD typically affects younger patients (19–41 years) and presents initially with behavioral and psychiatric symptoms, followed by ataxia, myoclonus, and dementia. Disease progression leads to death within 7–23 months. Kuru, historically described in Papua New Guinea, is characterized by tremors, ataxia, and later dementia, with incubation periods that may extend up to 50 years.
Definitive diagnosis requires histopathologic examination of brain tissue. Cerebrospinal fluid (CSF) is typically unremarkable, though mild protein elevation may occur. Detection of 14-3-3 protein in CSF may support the diagnosis, but sensitivity and specificity range from 60–90%, and elevations can occur in other neurologic disorders. Genetic testing can identify PRNP mutations in familial cases. Serum S100 protein levels may be elevated. EEG in sporadic CJD often shows periodic sharp-wave complexes, with sensitivity around 64% and specificity 91%, though this pattern is not typical in variant or familial forms. MRI may reveal hyperintense signals in the striatum or other deep brain structures, often disproportionate to visible cortical atrophy. In variant CJD, periodic EEG findings are usually absent.
The differential diagnosis of rapidly progressive dementia with myoclonus includes Alzheimer disease, frontotemporal dementia, Lewy body dementia, HIV-associated dementia, neurosyphilis, tuberculous meningitis, Whipple disease, progressive multifocal leukoencephalopathy, lymphoma, metabolic disorders, autoimmune encephalitis, and paraneoplastic syndromes.
There is currently no effective treatment. CJD is uniformly fatal. Various agents, including amantadine, flupirtine, chlorpromazine, and other experimental therapies targeting prion protein aggregation, have been studied without demonstrated survival benefit. Management is supportive.
Preventive measures in the United States include strict regulations to prevent BSE introduction, control of high-risk bovine materials in the food supply, and adherence to infection control guidelines in medical procedures. The overall risk of transmission is considered minimal under current public health measures.
Prognosis is poor, with progressive neurologic decline leading to death, often within one year of symptom onset in sporadic cases. Serial imaging may demonstrate rapid brain atrophy and ventricular enlargement as the disease advances.
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