One in a million: Diagnosis of Sporadic Creutzfeldt-Jakob Disease in the Context of Negative Neuroimaging.

Case Report: Introduction



     Prion diseases are a diverse group of rare neurodegenerative conditions caused by the conversion of a normal prion protein (prion-related protein or PrPc) into an abnormal form (prion-related protein scrapie or PrPsc) that causes neurologic damage. [1] It is a rare disease, with an annual incidence estimated to be 1 to 1.5 per 1.000.000 worldwide. In the US the incidence is about 1.2 per 1.000.000.  Multiple types have been characterized including Creutzfeldt – Jakob disease (CJD), which can be sporadic (sCJD), genetic (gCJD) or acquired including iatrogenic (iCJD). They are characterized by long incubation periods and multifocal neuropathologic presentations that are all due to neurodegeneration. Given its features, the CDC has well defined diagnostic criteria for CJD, which usually include rapidly progressive dementia and additional characteristic findings on MRI, EEG and CSF, with brain tissue examination being necessary for definitive diagnosis. We present a case of prion disease, most likely sCJD, with premortem diagnosis in the absence of typical MRI or EEG findings. 

 

Case presentation



     A 79-year-old Hispanic female, significantly independent at baseline, presented to the hospital after 3 weeks of disorientation and mood swings, paranoia, visual and tactile hallucinations as well as generalized paralysis. She was not able to recognize her family. Per her husband her symptoms had begun after she returned from a 4 month stay in rural Mexico, when she began experiencing dizziness and gait imbalance, reason why she visited her primary care provider (PCP) who prescribed meclizine. Physical exam on admission was only pertinent for altered mental status, she was alert and oriented only to person, with visual and tactile hallucinations, overall rigidity, muscle strength 4/5 throughout and positive Babinski sign bilaterally, along with resting tremor, bradykinesia, slurred speech and echolalia. Initial labs reported: AST 60 (normal 10 - 40 U/L), UA with positive nitrates and urine WBC 400 (normal 0-3 HPF) . Rest of labs within normal limits. A CT Head done on admission only reported signs of cerebral atrophy, however no acute findings.
     Initially the patient was admitted for treatment of delirium, which was thought to be secondary to UTI or secondary to Meclizine, yet despite withdrawal of all delirium causing agents and Ceftriaxone she continued to decline. By day 5 of admission she became non-verbal, and began presenting dysphagia, bladder and bowel incontinence, as well as decorticate posture. Further workup including Vit D, Vit B12, CRP, ESR, RPR were all negative. Given rapid neurologic decline, MRI, EEG and CSF were obtained.
    MRI Brain with IV contrast with DWI and FLAIR images on day 5 showed chronic microvascular ischemic changes but no abnormal enhancement. Two more MRIs were repeated with the same technique on days 7 and 13, which demonstrated the same findings. EEGs on day 5 and 11 recorded diffuse severe slowing with triphasic appearance at 3-7 hertz. CSF showed >1,200 RBC (normal 0 U/L) with little decrease from first to fourth tubes, 2 WBCs (normal 0-8 U/L), raising concern for HSV encephalitis, prompting empiric treatment with Acyclovir. CSF sample was also sent for AFB +culture, HSV 1 and 2 PCR and antibodies, encephalitis panel, GAD antibodies, cryptococcal antigen, all which were negative. RT QuIC, Tau protein and 14-3-3 protein were also sent to the National Prion Disease Pathology Surveillance Center (NPDPSC), and on hospital day 18 the results showed a positive RT QuIC (normal is a negative result) and elevated Tau protein >4000 (normal range 0 - 1499 pg/ml), reported as >98% likelihood of prion disease. The patient met criteria for Probable Prion Disease.
     After having a conversation with the family explaining the poor prognosis, the consensus was to transfer the patient to inpatient hospice, after which the patient expired, approximately 3 months after her presentation. An autopsy was offered to the family, however they refused.

Discussion



     The diagnosis of prion diseases is challenging. A high clinical suspicion must exist given the rarity of this cluster of diseases. [3] According to the CDC, diagnosis can be classified into Definite, Probable or Possible depending on the clinical presentation, which is characterized by rapidly progressive dementia in addition to myoclonus, cerebellar signs or akinetic mutism, associated with typical periodic sharp wave complexes on EEG, MRI with high signal on DWI in at least two cortical regions, a positive 14-3-3 assay on CSF or a positive RT-QuIC assay in CSF. For definite diagnosis an autopsy is required. [2]
    MRI has proven most useful as it has a 91% sensitivity and 95% specificity in diagnosis of prion disease. [4] Typical patterns include a) cerebral involvement or “cortical ribboning” which can be focal or diffuse, b) basal ganglia involvement and c) cerebellar atrophy, all seen on MRI with FLAIR and DWI/ADC.
    There are also some distinctive EEG findings characterized by typical periodic sharp wave complexes (PSWC), which are usually observed with or shortly after patients develop myoclonus and akinetic mutism. Some studies suggest the presence of frontal intermittent rhythmical delta activity (FIRDA) as early EEG signs of prion disease before PSWC develop. [6].
     Lastly, in the absence of a brain autopsy, diagnosis can be achieved by positive RT-QuIC assay on CSF which has been shown to have 91% sensitivity and 98% specificity. [7] It is only done by the National Prion Disease Pathologist Surveillance Center (NPDPSC). A positive diagnosis is equivalent to Probable Prion Disease. [2]
    Our patient had the typical clinical presentation, characterized by rapidly progressive dementia within 3 weeks of onset, associated with akinetic mutism and myoclonus, in addition to dysphagia. This warranted a high clinical suspicion. However multiple MRIs failed to show typical findings for prion disease, and two EEGs failed to show PSWC, reporting only severe diffuse slowing with triphasic morphology. Finally, a RT-QuIC assay from CSF sent thanks to having a high clinical suspicion came back positive, being consistent with the diagnosis.

 

Conclusion

 

     CJD is a rare but aggressive disease with fast progression and multiple comorbidities that are mostly due to deconditioning, with associated high mortality. In order to diagnose CJD and other prion diseases clinical suspicion must be high. Amongst our diagnostic tools we have MRI, EEG and CSF analysis. However, even in the abscence of typical findings on MRI and EEG, it is important to use our clinical criteria and to proceed with CSF analysis with molecular studies (RT-QuIC) when we have a high suspicion, given they have better NPV and PPV. In our case, the patient was diagnosed thanks to multiple attempts to obtain LP despite patient having resting tremor which difficulted obtaining sample, and a high clinical suspicion of the disease.

 References
 1.-Geschwind, M. D. (2016, May 25). Prion Diseases. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879966/pdf/nihms785480.pdf
2.-  CDC. (2019, January 25). Diagnostic criteria for Creutzfeldt-Jakob Disease. Centers for Disease Control and Prevention. https://www.cdc.gov/prions/cjd/diagnostic-criteria.html
3.- Kwon, G. T., & Kwon, M. S. (2019). Diagnostic challenge of rapidly progressing sporadic Creutzfeldt-Jakob disease. BMJ Case Reports, 12(9), e230535. https://doi.org/10.1136/bcr-2019-230535
4.- Young, G. S., & Geschwind, M. D. (2005). Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: high sensitivity and specificity for diagnosis. American Journal of Neuroradiology, 26, 1551 - 1562.
5.- Fragoso, D. C., & Gonçalves Filho, A. L. (2017). Imaging of Creutzfeldt-Jakob disease: Imaging patterns and their differential diagnosis. RadioGraphics, 37(1), 234-257. https://doi.org/10.1148/rg.2017160075
6.- Wieser, H. G., Schwarz, U., & Blättler, T. (2004). Serial EEG findings in sporadic and iatrogenic creutzfeldt–jakob disease. Clinical Neurophysiology, 115(11), 2467-2478. https://doi.org/10.1016/j.clinph.2004.05.032
7.- McGuire, L. I., Peden, A. H., & Orrú, C. D. (2012). Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Annals of Neurology, 72(2), 278-285. https://doi.org/10.1002/ana.23589