Creutzfeldt-Jakob Disease
This 53 year old, previously healthy gentleman presented with a 1 1/2 year history of progressive memory loss, word finding difficulties and difficulties with visuospatial orientation. His clinical examination and neuropsychological testing suggested a dementing illness with mixed cortical and subcortical features. MRI of the brain revealed striking abnormalities confined to the cortical gray matter on T2-weighted, FLAIR and diffusion-weighted sequences. EEG showed left temporal focal slow activity superimposed on a diffusely slow background, but did not suggest a specific diagnosis. Laboratory studies did not reveal a systemic cause for his dementia. There was no family history of similar problems. A CSF study for the 14-3-3 protein was nondiagnostic. In view of the sporadic and early onset, together with rapid progression of deficits by history, the patient underwent brain biopsy.
Pathologic findings suggested a spongiform encephalopathy, and Western analysis of brain tissue demonstrated protease-resistant prion protein, consistent with a diagnosis of Creutzfeldt-Jakob Disease (CJD). CJD, one of the transmissible spongiform encephalopathies (TSEs) including Gerstmann-Straussler-Scheinker Syndrome, kuru and fatal familial insomnia, is a dementing illness with an invariably fatal outcome.
There are approximately 0.5-2.0 cases of CJD reported per million persons annually. As the mean life span from symptom onset is less than one year (3-9 months), incidence and prevalence for practical purposes are the same. Patients typically present in the 6th to 8th decades of life, with most reports showing no gender predilection. The majority of cases (90%) are sporadic, with most of the remaining 10% attributed to familial forms. There are a small number of iatrogenic cases, usually the result of infected corneal or dural grafts, neurosurgical instruments/invasive EEG electrodes, or recipients of cadaveric human growth hormone. New variant CJD (nvCJD) is believed to arise from the consumption of cattle infected with bovine spongiform encephalopathy (BSE, or "mad cow disease").
There may be a prodrome of vegetative symptoms preceding the onset of dementia by several months. Initial symptoms include asthenia, change in sleep patterns and appetite, weight loss, and decreased libido. The hallmark feature of advancing disease is dementia. One third of patients will also have other mental function changes such as personality changes, apathy, paranoia, self-neglect, depression, disorientation, hallucinations and emotional lability. Another one-third of patients, in addition to dementia, manifest pyramidal or extrapyramidal, cerebellar, or visual system features. These may include gait ataxia, clumsiness, myoclonic movements (i.e., startle myoclonus) or choreatheform movements, dysarthria, diplopia, nystagmus, supranuclear palsies, visual agnosia, altered color perception, visual field defects (and late in the disease, cortical blindness). A final one-third of patients will have symptoms common to both of the previous groups. Headache, vertigo and sensory symptoms, lower motor neuron signs and seizures are less common, but may occur. There is progressive impairment such that patients are usually mute, akinetic, globally demented and bed-bound at death. Patients with new variant CJD tend to be younger (average age 28 years) and more commonly have psychiatric or sensory symptoms at presentation. The life span of patients with nvCJD is also slightly longer than that of the sporadic disease, around 14 months.
The differential diagnosis of CJD, especially early in the course of disease, is extensive. Characteristic EEG findings and CSF assays for 14-3-3 protein, together with a suggestive clinical presentation and a rapidly progressing clinical course, are often sufficient to establish the diagnosis. However, brain biopsy is occasionally necessary to establish the diagnosis and rule out other causes of rapidly progressing dementia.
The causative agent of CJD appears to be an abnormal form of prion protein. Prions, "small proteinaceous, infectious particle(s) which resist most procedures that modify nucleic acids" (they are inactivated by treatments that disrupt proteins) were hypothesized by S. Prusiner to represent the causative agent of CJD. Although initially the prion hypothesis encountered considerable opposition, in that the abnormal protein conformation is believed to be transmitted from protein to protein, rather than via a nucleic acid intermediary, increasing evidence from in vivo transfer experiments and from biophysical studies of protein conformation suggests that the prion concept of disease pathogenesis is valid. Sporadic cases of CJD are believed to result from either a rare spontaneous conformational conversion (a post-translational change) of normal host prion protein to an abnormal form, or by somatic mutations of the human prion protein gene, resulting in abnormally conformed protein product. This conformational change results in conversion of the predominantly alpha-helical structure of normal prion protein into a predominantly beta pleated-sheet structure of the abnormal form. According to the prion hypothesis, abnormally conformed prion protein then enhances the conversion of additional normally conformed prion protein into the abnormal form. As the abnormal form of prion protein is relatively resistant to degradation by intracellular proteases, it accumulates in neural cells, disrupting function and leading to cell vacuolization and death.
The familial forms of CJD are linked to various mutations in the human prion protein (PRNP) gene, most commonly a point mutation at codon 200. Transmission is autosomal dominant, usually with complete penetrance.
CSF examination may be normal or show only slightly elevated protein (usually less than 100 mg/dL). In some reports, up to 20% of patients may have oligoclonal bands on CSF electrophoresis. Testing for CSF 14-3-3 proteins in the setting of high clinical suspicion has proven to be helpful (with sensitivity of 96-97% and specificity of 87-99% in sporadic CJD, about 50% for familial CJD, not as useful for nvCJD). It should be emphasized that CSF increases in 14-3-3 proteins, which play key roles in signal transduction and subcellular protein localization, may be seen in disorders other than CJD, and results from these studies must be interpreted in the context of clinical suspicion. Abnormal prion protein may be found in the tonsils of individuals affected with nvCJD.
EEG findings in CJD may be normal or reveal only slowing of background activity, especially early in the course of disease. The virtually pathognomonic EEG findings of sporadic CJD are variable, usually triphasic sharp waves recurring every 0.5-2.0 seconds on an abnormal, diffusely slow background. There may be a temporal correlation between the complexes and the myoclonic jerking exhibited by some patients. These findings may only be observed in some patients after a number of EEG studies have been performed. Therefore, lack of a characteristic pattern does not rule out a diagnosis of CJD.
CT scanning usually shows no abnormality, but cortical atrophy is sometimes seen. MR imaging may also show T2-weighted signal alterations, usually located in the caudate, putamen and thalami. FLAIR sequences are preferred, as they may show hyperintense areas of gray matter, particularly in the cerebral cortex, not otherwise appreciated on conventional T2-weighted images. As noted in this case, diffusion-weighted MRI scans may suggest that abnormal cortical signal results from intracellular edema or cytotoxicity.
Definitive diagnosis of CJD requires brain biopsy or autopsy confirmation. Spongiform degeneration, atrophy, loss of nerve cells and astrocytic gliosis are the typical microscopic features. The spongiform changes (vacuoles in the neuropil) are usually most prominent in the cerebral cortex, striatum, and molecular layers of the cerebellum. In 5-10% of sporadic CJD patients, amyloid plaques may be seen as well. Western blotting of brain tissue demonstrates the presence of protease-resistant prion protein. In nvCJD, the most prominent pathologic feature has been widespread amyloid plaques surrounded by spongiosis (daisy plaques), along with astrocytosis and neuronal loss.
A number of studies have suggested that brain biopsy can be avoided in patients with a typical clinical presentation and confirmatory screening tests. In general, the combination of dementia, myoclonus, and cerebellar signs, together with an elevated CSF 14-3-3 protein level and typical EEG findings suggestive of CJD, establishes a diagnosis with high precision. Unfortunately, in this patient, myoclonus and cerebellar signs were absent, the EEG was not confirmatory of the diagnosis, and the CSF 14-3-3 protein screen was nondiagnostic. The MRI findings and clinical progression, however, did suggest a highly destructive cortical process, and therefore we proceeded to brain biopsy.
As this patient was an elk hunter, a question of interspecies transmission of prion disease was considered. Captive and-free roaming deer and elk in parts of the United States and Canada have been found to carry a form of prion disease known as Chronic Wasting Disease (as the name implies, the animals become anorexic and asthenic for a protracted period before dying). No cases of transmission of CWD from deer or elk to humans have been documented to date. However, the pathologic features of CWD overlap with those of the human spongiform encephalopathies (Williams & Young, 1993). In Rocky Mountain elk, sequence analysis of the PrP gene shows an over-representation of one polymorphism (resulting in a single amino acid change from Met to Leu at codon 132) in CWD-affected animals compared with unaffected control elk (O'Rourke et al., 1999). In humans, homozygosity for methionine at the corresponding site (Met to Val at codon 129) has been documented in all cases to date of nvCJD, the only human prion disease believed at this time to result from interspecies transmission. Preliminary data not available at the time of initial posting of this case do not suggest such a susceptibility in this patient. However, the broader question of whether transmission of CWD to humans is possible, at least in predisposed invididuals, remains a subject for further investigation.
CJD is invariably fatal. Clinically, course is usually relentlessly progressive until death at about seven months (slightly longer for nvCJD) after onset of symptoms. Death is usually the result of infection.
There are no means to prevent either sporadic or familial cases. However, the incidence of iatrogenic cases has been reduced. Cadaveric growth hormone has not been used since 1985, although previous recipients may still be incubating the agent. The infected dural grafts were traced back to a single German manufacturer. Neurosurgical instruments and brain electrodes should be sterilized via autoclaving at 132 degrees Celsius and 15-lb./square inch pressure for one hour. Alternatively, instruments may be soaked in 5% sodium hypochlorite solution for one hour. There has been no report of spread among casual skin contacts. There are no known cases of transmission via sexual contact at this time. Precautions should be taken when handling all body fluids of an infected individual, especially spinal fluid. Gloves should be worn during procedures (e.g. lumbar puncture) and accidental skin contamination should be rinsed with a 1:10 dilution of sodium hypochlorite (household bleach). Specimens from known or suspected infected patients should be marked as such, so that laboratories may handle and dispose of them appropriately. The current risk of transmission of BSE to humans (and therefore presumably nvCJD) in the United States is felt to be very low, with appropriate safeguards maintained.
Special thanks to Drs. Clay Goodman and David Carrier for their help with the pathology and imaging slides.
-- Dennis R. Mosier, M.D., Ph.D.
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