Case Study: Creutzfeldt-Jakob Disease Confirmed With RT QuIC

Figure 1. Routine EEG with moderate, generalized slowing

Figure 2. Routine EEG with generalized, periodic, sharp/slow waves at 1 cycle/second

Figure 3. MRI Brain Axial Diffusion Weighted Image (DWI) with “cortical ribboning”

CASE REPORT

A 66-year-old previously healthy woman was admitted with 2 weeks of altered mental status. She had become increasingly confused, forgetful, and had visual hallucinations. Her sister said the patient reported seeing deceased relatives and elephants.

On examination, she was oriented to person and place, but had poor attention. Motor and sensory exams were normal. Reflexes were symmetric, but included a positive grasp reflex. When she walked, she listed to the right and tended to fall backwards.

Over the next 2 weeks, her neurologic status declined rapidly. She became anxious, fearful, and almost mute. She startled easily to voice and touch, had limb rigidity, often appeared to be shivering, and remained bedbound. She could only eat if food was placed in her mouth.

While awaiting laboratory studies, the patient received a 7-day course of high-dose steroids for possible paraneoplastic encephalitis. There was no improvement.

Laboratories

Routine CBC, chemistry panel, liver tests, B12 and TSH were normal. Urine drug screen and HIV were negative. Lumbar puncture had < 1000 red cells, no white cells, glucose 85, and protein 15. CSF VDRL was negative.

An initial EEG revealed moderate generalized background slowing consistent with encephalopathy (Figure 1). A follow up EEG 2 weeks later demonstrated periodic sharp/slow complexes occurring at 1 Hz (cycle/second) (Figure 2).

Although the MRI was blurred by motion artifact, cortical ribboning of the cerebral cortex can be appreciated, particularly on the right hemisphere (Figure 3).

CSF 14-3-3 protein was positive, as was T-tau protein, >4,000 pg/mL (Normal: 0-1,149 pg/ml). A positive real-time quaking-induced conversion (RT-QuIC) assay confirmed the clinical impression of sporadic Creutzfeldt-Jacob disease (CJD)

After a family conference, the patient was discharged to hospice. She died one week later.

Diagnosis: Creutzfeldt-Jakob Disease Confirmed With RT QuIC

Discussion

Sporadic Creutzfeldt-Jacob disease is a rare, fatal disease caused by prions, which are proteinaceous, infectious particles without genetic material.¹ Clinical diagnosis can be difficult as the presentation is variable, but rapidly progressive dementia and characteristic features such as myoclonus and ataxia are highly suggestive. Psychiatric symptoms such as agitation, anxiety, depression and hallucinations occur in 90% of patients.² Human prion disease is usually sporadic, but may also be genetic or iatrogenic. Neuropathology reveals spongiform vacuolation, neuronal loss, astrogliosis and abnormal prion protein in the brain.¹

Diagnostic criteria

The Centers for Disease Control and Prevention (CDC) has published diagnostic criteria for “definite,” “probable,” and “possible” Creutzfeldt-Jacob disease. A “definite” diagnosis requires neuropathological demonstration of protease-resistant prion protein (PrP) and/or scrapie-associated fibrils.

“Probable” Creutzfeldt-Jacob disease requires the presence of a rapidly progressive dementia associated with at least 2 of the following 4 symptoms (akinetic mutism, myoclonus, pyramidal/extrapyramidal signs, or cerebellar signs) as well as at least one of the following: EEG with periodic sharp waves, 14-3-3 CSF protein, or MRI with typical caudate and/or putamen abnormalities. A “possible” diagnosis has similar clinical presentation without laboratory confirmation.

MRI

MRI abnormalities in Creutzfeldt-Jacob disease occur in the caudate and putamen, cortex, and thalamus.³ The combination of distinctive diffusion-weighted (DWI) and fluid-attenuated inversion recovery (FLAIR) images has greater than 90% sensitivity and specificity.^3,4

CSF

CSF 14-3-3 is sensitive but not specific for Creutzfeldt-Jacob disease, with a low positive predictive value.5A variety of other central nervous system disorders such as Alzheimer disease, anoxic encephalopathy, carcinomatous meningitis, dementia with Lewy bodies, frontotemporal dementia, paraneoplastic syndrome, and vascular dementia may result in positive 14-3-3 tests.⁵

A new CSF diagnostic test, real-time quaking-induced conversion (RT-QuIC) assay, promises to facilitate the diagnosis of Creutzfeldt-Jacob disease.⁶ RT-QuIC detects amyloid fibrils formed from misfolded recombinant prion proteins.¹ RT-QuIC can be performed on CSF or olfactory mucosa.

A recent case-control study of 61 cases of Creutzfeldt-Jacob disease and 71 controls demonstrated that combined RT-QuIC CSF and olfactory mucosa testing had 100% sensitivity and 100% specificity for sporadic Creutzfeldt-Jacob disease.⁷ RT-QuIC is not yet included in the CDC diagnostic criteria, but is likely to become the new laboratory standard for sporadic Creutzfeldt-Jacob disease diagnosis.⁶

Key Points

1. Creutzfeldt-Jacob disease should be considered in the setting of a rapidly progressive dementia with psychiatric symptoms, ataxia, mutism, myoclonus, and pyramidal or extrapyramidal signs.
2. Typical EEG findings of Creutzfeldt-Jacob disease may require serial EEGs.
3. MRI with DWI and FLAIR sequences may reveal characteristic features of Creutzfeldt-Jacob disease.
4. CSF 14-3-3 may be positive in other neurologic disorders.
5. RT-QuIC, a new test for Creutzfeldt-Jacob disease, has high sensitivity and specificity.

Conclusions

Creutzfeldt-Jacob disease is a rare, fatal disease caused by prions. Our patient’s clinical presentation of hallucinations, rapidly progressive dementia, akinetic mutism, rigidity, startle myoclonus, cortical ribboning on MRI, periodic sharp waves on EEG, and 14-3-3 CSF protein fulfilled the CDC criteria of probable Creutzfeldt-Jacob disease. The positive RT-QuIC test affirmed the diagnosis. Although there is no specific treatment for Creutzfeldt-Jacob disease, the diagnosis helped the family accept hospice care.

Disclosures:

Dr. Wilner's latest book, Bullets and Brains, is a collection of over 100 essays that focus on the intersection of neurology and society. You can follow him on Twitter: @drwilner.

REFERENCES
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3. Young GS, Geschwind MD, Fischbein NJ, et al. Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: High sensitivity and specificity for diagnosis. AM J Neuroradiol. 2005;26:1551-1562.
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6. Brown P. A new standard for the laboratory diagnosis of sporadic Creutzfeldt-Jakob disease. JAMA. 2017;74:144-145.
7. Bongianni M, Orru C, Groveman BR et al. Diagnosis of human prion disease using real-time quaking-induced conversion testing of olfactory mucosa and cerebrospinal fluid samples. JAMA. 2017;74:155-162.