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CASE REPORT
Year : 2020  |  Volume : 68  |  Issue : 4  |  Page : 927-929

A Complete and State of the Art Pre-mortem Diagnostic Approach to Creutzfeldt-Jakob Disease: A Case Report


1 Centro Especializado en Neurocirugía y Neurociencias México (CENNM), Mexico City, Mexico
2 Departamento de Anatomía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico

Date of Web Publication26-Aug-2020

Correspondence Address:
Dr. Parmenides Guadarrama-Ortiz
Centro Especializado en Neurocirugia y Neurociencias Mexico, Manzanillo and Tlaxcala 94, Roma Sur 06760, Mexico City
Mexico
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.293483

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 » Abstract 


Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal and rapidly progressive form of dementia caused by the spread of a prion protein within the brain. Its real incidence is unknown since its definitive diagnosis requires histopathological analysis of brain specimens. However, novel tests that detect prion proteins in cerebrospinal fluid samples, such as the real-time quaking-induced conversion (RT-QuIC) technique, now allow the pre-mortem diagnosis of sCJD. Here, we report the first case of sCJD confirmed by RT-QuIC in Latin America, providing evidence of its diagnostic performance and clinical correlation.


Keywords: 14-3-3 protein, Creutzfeldt-Jakob disease, prion, rapidly progressive dementia, real-time quaking-induced conversion, T-tau protein
Key Message: We report one of the first cases of sCJD confirmed using the RT-QuIC test, a technique that detects prions in biological samples with high sensitivity.


How to cite this article:
Guadarrama-Ortiz P, Choreno-Parra JA, Carnalla-Cortes M, Rodriguez-Munoz PE, Angeles-Castellanos M. A Complete and State of the Art Pre-mortem Diagnostic Approach to Creutzfeldt-Jakob Disease: A Case Report. Neurol India 2020;68:927-9

How to cite this URL:
Guadarrama-Ortiz P, Choreno-Parra JA, Carnalla-Cortes M, Rodriguez-Munoz PE, Angeles-Castellanos M. A Complete and State of the Art Pre-mortem Diagnostic Approach to Creutzfeldt-Jakob Disease: A Case Report. Neurol India [serial online] 2020 [cited 2020 Sep 18];68:927-9. Available from: http://www.neurologyindia.com/text.asp?2020/68/4/927/293483




Creutzfeldt-Jakob disease (CJD) is a rapidly progressive form of dementia caused by global loss of cerebral parenchyma resulting from the spread of a prion protein (PrPSc) within the brain.[1] Sporadic CJD (sCJD) accounts for 90% of all CJD cases and has a global incidence of one case per million persons/year.[2] Currently, the definitive confirmation of CJD is by histopathological analysis of brain tissue.[3] However, novel cerebrospinal-fluid (CSF) molecular biomarkers along with better magnetic resonance imaging (MRI) modalities have improved the pre-mortem diagnosis of CJD.[4] Furthermore, the new real-time quaking-induced conversion (RT-QuIC) test has shown the highest diagnostic performance to detect PrPSc in CSF samples, although such technique is not yet widely available, especially in Latin American countries.[5]

Here, we report the case of a Mexican patient with sCJD diagnosed by RT-QuIC, providing further evidence of the utility and high clinical correlation of this novel test.


 » Case History Top


A 51-year-old right-handed Mexican woman attended to our center with rapidly progressive dementia. One year earlier, she started with abnormal sleep circadian rhythm, hyperhidrosis, palpitations, dysphagia, and anxiety. Also, 3 months earlier, she was admitted to a psychiatric hospital due to acute memory impairment and anxiety, receiving atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) which caused mild improvement. Her past medical/family history was irrelevant. Her relatives denied any toxic exposure, drug abuse, travel, and animal contact history.

At her arrival to our center, she was in an akinetic mutism status, unable to follow simple commands nor name objects. Her language was non-fluent, perseverant and dysarthric with no facial expressions. Additionally, she presented alexia, apraxia, and agnosia. She was unable to perform the Mini-Mental State Examination and the Montreal Cognitive Assessment. Physical examination revealed spontaneous myoclonic movements in both upper and lower limbs without alterations of cranial nerve reflexes, muscle strength, deep tendon reflexes nor plantar reflexes. Her gait was ataxic and the finger-to-nose test was abnormal.

She was admitted for further analyses as we suspected of sCJD. Blood tests were normal, including thyroid, liver, and renal function, as well as serum levels of calcium, magnesium, sodium, potassium, and chloride. Hemoglobin A1c was 6.1% and the urine test revealed urinary tract infection. CSF analysis showed normal opening pressure, glucose of 77 mg/dL, proteins of 100 mg/dL, and no cells. The brain MRI showed global parenchymal loss. Diffusion weighted images (DWI) showed hyperintense signal in the cortical ribbon of the bilateral frontal, parietal, temporal, and occipital lobes, as well as in the insula and cingulate gyrus. Furthermore, we observed bilateral hyperintensities in the caudate and putamen nuclei, as well as in the thalamus [Figure 1]. The cerebellum was normal. The electroencephalogram (EEG) showed a global pseudo-periodic pattern consisting of sharp wave complexes with diffuse slow background activity [Figure 2]. CSF analysis showed an increase in 14-3-3 protein levels, T-tau protein >4000 pg/mL and a positive result in the RT-QuIC test. Finally, we informed her family that she had sCJD, but they refused the diagnosis. She was discharged with no further follow-up. The legal guardians of the patient provided writen informed consent to publish the case.
Figure 1: (a) MRI T2-weighted image showing global parenchymal loss. (b-f) DWI revealing multifocal hyperintensities in cortical gyri at bilateral frontal (b), parietal (c), temporal and occipital lobes (f), as well as at basal ganglia and thalamus (c-e)

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Figure 2: EEG of the patient that shows typical diffuse pseudoperiodic sharp-wave complexes

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 » Discussion Top


CJD remains a diagnostic challenge due to its rarity and unspecific manifestations, which can be confounded with other disorders featuring acute dementia, including some Alzheimer's disease variants.[6] The main neurological findings of sCJD are rapidly progressive dementia, myoclonus and periodic EEG activity. However, various forms of sCJD have been described according to the leading clinical sign at onset: myoclonic, Heidenhain (visual), classic (dyskinetic), thalamic, cerebellar (ataxic), amyotrophic and panencephalopathic.[6] The several forms of CJD are associated with genetic and molecular traits of the pathogenic PrPSc. Specifically in sCJD, a methionine (M) or valine (V) polymorphism at codon 129 of the PRNP gene, and the type of electrophoretic mobility pattern of PrPSc after protease digestion (type 1 and 2) group patients into three categories: cognitive subtypes (MM1, MV1, MM2 and VV1), ataxic subtypes (VV2, MV2) and other non-CJD subtypes.[7]

Definitive diagnosis of CJD is made by histological demonstration of astrogliosis, spongiform degeneration of the neuropil, vacuolization and amyloid deposits of PrPSc in brain biopsy/autopsy specimens.[3] Nonetheless, the pre-mortem confirmation of a case is important because it allows to differentiate CJD from other treatable causes of acute dementia. Therefore, the approach to a probable case of CJD should include an inquiry into the patient's medical history, physical examination, neuropsychological assessment, and laboratory testing, including blood count, renal, hepatic, and thyroid function tests, HIV and toxicological tests, vitamin B serum levels, autoantibodies, microbiological and molecular CSF tests. Other diagnostic tools include EEG, MRI, CSF 14-3-3 protein, T-tau protein, and neuron-specific enolase (NSE), which have variable diagnostic performance according to each CJD type and even sCJD subtype.[4] T-tau protein has a high sensitivity and specificity at a cut-off of 1150 pg/mL.[8] EEG, typically showing pseudo-periodic sharp-wave complexes with diffuse slow background activity, has a 64% sensitivity and 91% specificity.[9] MRI has the best diagnostic performance among all studies, especially when there are hyperintensities in at least 3 non-contiguous cortical gyrus and/or basal ganglia showed by DWI, which can be observed in ~60% of patients.[10] Recently, RT-QuIC has emerged as a novel alternative for the pre-mortem diagnosis of CJD with a higher performance compared with other CSF tests. This assay relies on thein vitro template conversion of recombinant PrPC into PrPSc which is detected by fluorescence, allowing to determine minute amounts of PrPSc in CSF with a 95.8% sensitivity and 100% specificity.[5]

The case presented here has similar clinical characteristics as other cases reported previously. Hence, the relevance of this report resides in the sophisticated pre-mortem diagnostic approach to the disease. According to the Centers for Disease Control and Prevention (CDC) diagnostic criteria, the case is classified as probable sCJD. However, our grade of certainty about the disease was very high since our diagnostic approximation included CSF biomarkers and MRI. Furthermore, this is the first case of sCJD confirmed in a pre-mortem manner by using RT-QuIC in Mexico. Therefore, our communication provides evidence of the great correlation between neurological findings and the results of RT-QuIC, as well as other diagnostic tools when they are used in the appropriate clinical context.[11],[12]

Acknowledgements

To the medical, nursing and administrative staff of CENNM, for their technical and logistical support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Prusiner SB. The prion diseases. Brain Pathol 1998;8:499-513.  Back to cited text no. 1
    
2.
Delasnerei-Laupretre N, Alperovitch A. Epidemiology of Creutzfeldt-Jakob disease. Pathol Biol 1995;43:22-4.  Back to cited text no. 2
    
3.
Budka H. Neuropathology of prion diseases. Br Med Bull 2003;66:121-30.  Back to cited text no. 3
    
4.
Forner SA, Takada LT, Bettcher BM, Lobach IV, Tartaglia MC, Torres-Chae C, et al. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease. Neurol Clin Pract 2015;5:116-25.  Back to cited text no. 4
    
5.
Orrú CD, Groveman BR, Hughson AG, Zanusso G, Coulthart MB, Caughey B. Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. mBio 2015;6:e02451-14.  Back to cited text no. 5
    
6.
Mead S, Rudge P. CJD mimics and chameleons. Pract Neurol 2017;17:113-21.  Back to cited text no. 6
    
7.
Rossi M, Baiardi S, Parchi P. Understanding prions strains: Evidence from studies of the disease forms affecting humans. Viruses 2019;11:309.  Back to cited text no. 7
    
8.
Hamlin C, Puoti G, Berri S, Sting E, Harris C, Cohen M, et al. A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt-Jakob disease. Neurology 2012;79:547-52.  Back to cited text no. 8
    
9.
Wieser HG, Schindler K, Zumsteg D. EEG in Creutzfeldt-Jakob disease. Clin Neurophysiol 2006;117:935-51.  Back to cited text no. 9
    
10.
Fujita K, Harada M, Sasaki M, Yuasa T, Sakai K, Hamaguchi T, et al. Multicentre multiobserver study of diffusion-weighted and fluid-attenuated inversion recovery MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease: A reliability and agreement study. BMJ Open 2012;2:e000649.  Back to cited text no. 10
    
11.
Ahn SW, Park MS, Han SH, Yoon BN, Shin JY. Atypical sporadic Creutzfeldt-Jakob disease presenting as progressing schizophrenia. Neurol India 2018;66:529-31.  Back to cited text no. 11
[PUBMED]  [Full text]  
12.
Divya KP, Menon RN, Thomas B, Nair M. A hospital-based registry of Creutzfeldt-Jakob disease: Can neuroimaging serve as a surrogate biomarker? Neurol India 2016;64:411-8.  Back to cited text no. 12
[PUBMED]  [Full text]  


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