Prions

The reason we call it Creuztfeldt-Jakob Disease originates from some of the first original descriptions. And if there is anything to remember about in medicine, if you want to be remembered for something, you’ve got to be the first person to describe it. In the early 1920s, a German physician by the name of Alfons Maria Jakob described the first five cases of possible prion disease. And just a few years later, a similar case was described by Dr. Hans Gerhard Creuzfeldt. For many subsequent years, the disease was titled, Jakob disease, or Jakob-Creuzfeldt by some. However, one expert has argued that an investigator by the name of Clarence J. Gibbs popularized the term, Creuzfeldt-Jakob disease because it had a much greater semblance to that of Clarence’s initials (“CJ”). Dr. Michael Geschwind, of UCSF, and many others still continue to call it Jakob disease or Jakob-Creuzfeldt disease because—if anything—2 of the 5 cases described by Alfons Jakob had clinical manifestations of a prion disease whereas Hans Creuzfeldt’s case did not bear any resemblance to what we now recognize as prion disease. Out of respect for Alfons Jakob and researchers like Geschwind, I’ll be referring to the disorder as the Jakob-Creuzfeldt disease, or JCD, throughout the blog. For more information on the history of prion disease, the concept of “slow viruses,” and Stanley Prusiner’s seminal work that ultimately awarded him the Nobel Prize in 1997, I’d recommend the 2015 historical review by Zabel and Reid in Pathogens and Disease.

Epidemiology in brief. JCD occurs at a rate of 1 in a million per year, with 80-95% of cases being sporadic JCD, 10-15% being genetic, and <1% being acquired. It is horrifying that the most common form of JCD, the sporadic version, occurs when the normally folded PrPC spontaneously converts to

Conformational changes of prion protein SC (left) from C (right). Adapted from https://www.flickr.com/photos/ajc1/464066753/ under a Creative Commons license.

Conformational changes of prion protein SC (left) from C (right). Adapted from https://www.flickr.com/photos/ajc1/464066753/ under a Creative Commons license.

PrPSC with its inexorable downstream consequences. Genetic causes of PrPSC are thought only to make the normal prion protein more capable of misfolding, either by impaired ubiquitination or other protein monitoring mechanisms. Sporadic prion diseases, like sporadic JCD and a related disorder called the variably protease-sensitive proteinopathy, are most commonly observed in patients in their 60s and they carry a 6-8 month life expectancy, although rare patients have survived more than a year after symptom onset. The most common presenting symptoms and signs of sporadic JCD are a change in behavior, followed by visual disturbances, an ataxic gait, parkinsonism, and eventually myoclonus. Before patients even reach clinical attention, the patient or family may have observed more non-specific manifestations, things like fatigue, headache, dizziness, sleep disturbances or other constitutional symptoms like unintended weight loss–in addition to memory disturbance.

Diagnostic criteria. The diagnosis of sporadic Jakob-Creutzfeldt Disease is confirmed pathologically, requiring either brain biopsy or autopsy. When a brain biopsy is necessary for diagnosis, a neurosurgeon interested in doing this biopsy may be hard to come by. This is because of the special protocols required by facilities for the disposal of all operative instruments after the biopsy in cases suspected of prion diseases. Because these proteins cannot be inactivated by traditional denaturation methods, they will remain infectious despite routine sterilization techniques. Interestingly, many hospitals lack special protocols for disinfection of instruments used in other procedures for these patients. What scares me most is that prion proteins exist not only in the central nervous system, where their concentration is the greatest, but also in the liver, in skeletal muscle, in the lymph nodes, the lung, and the spleen. It is even present in the urine of patients with variant JCD! That being said, the only iatrogenic cases of JCD have been acquired from the inoculation with CNS samples—things like growth hormone supplementation (226 cases), dura mater grafts (228 cases), corneal transplants (3 cases), and repeated use of medical instrumentation (2 cases). What’s probably most terrifying here is the latency from dura mater graft to symptom development was a median of 12 years, so there may still be more cases of iatrogenic JCD to come. In one experiment, depth electrodes from a patient with JCD were sterilized using benzene and 70% alcohol and formaldehyde vapor, then 2 years later they were implanted into a chimpanzee, who later developed the disease. To date, there have been no known cases of transmission using blood products or other transplanted organs, and definitely no cases from physical contact, airborne, or droplet transmission between patients and providers. So standard hospital precautions are typically sufficient unless the central nervous system is being accessed.

In the absence of tissue, the diagnosis can be suggested by other non-invasive modalities. Occasionally, EEG changes are identified in the workup of altered mental status (below). But instead of seizures, you’ll see 1-2 Hz periodic sharp wave complexes, usually in the form of biphasic or triphasic waveforms in about 70% of cases. The EEG background is typically low and slow, meaning small amplitude waveforms of a low frequency. Notably, these sharp wave complexes may correspond with the myoclonus that is clinically observed in these patients, but these events are not considered to represent seizure activity.

Periodic sharp wave complexes in JCD.

Periodic sharp wave complexes in JCD.

Magnetic resonance imaging (MRI) offers a much greater sensitivity and specificity, higher than 90% for both when there is restricted diffusion in the cortex or deep grey nuclei. You can see a bright signal change on the FLAIR sequence as well, but it’s not as impressive as the DWI and ADC.

"Cortical ribboning" pattern of DWI signal abnormality in JCD.

“Cortical ribboning” pattern of DWI signal abnormality in JCD.

Besides the MRI, which offers probably the least invasive and highest sensitivity and specificity, CSF testing for 14-3-3 and tau antigens can be performed. The 14-3-3 antigen is about 80-90% sensitive and ranges from 40-100% in specificity. Head-to-head studies comparing the utility of 14-3-3 and tau have shown that CSF tau carries a higher sensitivity and specificity for sporadic JCD, but truthfully these and other markers like neuron specific enolase and S100 beta are simply indicators of neuronal damage and we have seen them elevated in stroke, encephalitis, and carcinomatous meningitis.

Sporadic JCD is not the only prion disease out there. As I mentioned before, about 10-15% of all cases of JCD are familial and due to mutations in the prion protein, PrP. And while we use the term “familial” to describe this JCD phenotype, 60% of cases are due to de novo germline mutations. Unlike sporadic JCD, the familial version presents between age 30 and 50 with significant ataxia and other motor manifestations. 1,000 times less common than JCD, Fatal Familial Insomnia and Gerstmann-Straussler-Scheinker syndrome are autosomal dominantly inherited prion diseases also attributed to a germline mutation in the PrP gene. Variant JCD is caused by the consumption of foods contaminated with prion proteins—take for instance the mad cow outbreak in the UK in 1993 where 120,000 cattle were diagnosed with bovine spongiform encephalopathy. Because of this, the USDA now tests nearly 40,000 cattle at random every year in attempt to monitor for outbreaks. (In the show, we actually referenced an older quoted number, 300,000, which was the number of cattle screened when bovine spongiform encephalopathy was in its heyday. The dramatic fall in cases of BSE since that time has permitted the FDA to loosen its reigns on BSE screening.) Since 2012, there have been no new cases of this type of prion disease, and only 229 cases have been identified worldwide.

Conclusion. All this being said, there’s a lot to think about when considering a prion disease, and not just these terrifying little proteins. The differential diagnosis is extremely broad, and it all depends on the history, exam, and imaging features. We go over all these elements in our episode this week, so be sure to check it out!

 

[Jim Siegler]


REFERENCES

Zabel MD and Reid C. A brief history of prions. Pathog Dis. 2015;73:ftv087.

Geschwind MD. Prion Diseases. Continuum (Minneap Minn). 2015;21:1612-38.

Rutala WA and Weber DJ. Creutzfeldt-Jakob disease: recommendations for disinfection and sterilization. Clin Infect Dis. 2001;32:1348-56.

Glatzel M, Abela E, Maissen M and Aguzzi A. Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease. The New England journal of medicine. 2003;349:1812-20.

Moda F, Gambetti P, Notari S, Concha-Marambio L, Catania M, Park KW, Maderna E, Suardi S, Haik S, Brandel JP, Ironside J, Knight R, Tagliavini F and Soto C. Prions in the urine of patients with variant Creutzfeldt-Jakob disease. The New England journal of medicine. 2014;371:530-9.

Wieser HG, Schindler K and Zumsteg D. EEG in Creutzfeldt-Jakob disease. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2006;117:935-51.

Lapergue B, Demeret S, Denys V, Laplanche JL, Galanaud D, Verny M, Sazdovitch V, Baulac M, Haik S, Hauw JJ, Bolgert F, Brandel JP and Navarro V. Sporadic Creutzfeldt-Jakob disease mimicking nonconvulsive status epilepticus. Neurology. 2010;74:1995-9.

Siegler JE, Jacobs DA, Amado D, Adams JL and Berger JR. Rapidly progressive dementia with hypoglycorrhachia. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2015;22:1685-7.

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