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NI FEATURE: THE EDITORIAL DEBATE-- PROS AND CONS
Year : 2016  |  Volume : 64  |  Issue : 3  |  Page : 380-381

Sporadic Creutzfeldt Jakob disease


Department of Neurology, M. G. M. Medical College, Indore, Madhya Pradesh, India

Date of Web Publication3-May-2016

Correspondence Address:
Apoorva Pauranik
Department of Neurology, M. G. M. Medical College, Indore, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.181563

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How to cite this article:
Pauranik A. Sporadic Creutzfeldt Jakob disease. Neurol India 2016;64:380-1

How to cite this URL:
Pauranik A. Sporadic Creutzfeldt Jakob disease. Neurol India [serial online] 2016 [cited 2019 Dec 15];64:380-1. Available from: http://www.neurologyindia.com/text.asp?2016/64/3/380/181563


Sporadic Creutzfeldt Jakob Disease (sCJD) is an uncommon but well known and characteristic type of rapidly progressive dementia. According to the WHO diagnostic criteria (1998), definite CJD can only be diagnosed by documenting the neuropathology or by confirmation of protease resistant prion protein (PRNP) on Western blot or immunocytochemistry, or by the presence of scrapie associated neurofibrils. Short of the above, the diagnosis requires progressive dementia of less than two year duration, with at least two of the following features: myoclonous, visual impairment, cerebellar signs, extrapyramidal/pyramidal signs and akinetic mutism, and typical EEG or CSF-14-3-3 positive analysis for probable sCJD. Possible sCJD may still be suspected in the absence of EEG or 14-3-3 protein. The WHO criteria were proposed when understanding about the observations on the magnetic resonance imaging (MRI) of the brain was still evolving. During the subsequent two decades, clinical and imaging features have been further refined.

The University of California San Francisco (UCSF 2007) and European (2009) criteria have included high signal abnormalities on DWI and FLAIR sequences of MRI as one of the criteria. Pure MRI based criteria have also been defined at the UCSF (2011).

An international collaborative study has been undertaken comprising of 2451 pathologically confirmed (definite) patients as a part of a multinational CJD surveillance programme (EURO CJD) since 1993.[1] The authors evaluated the effect of the patient's clinical features such as age at onset, duration of the illness, and PRNP codon 129 polymorphism on the diagnostic sensitivity of electroencephalography (EEG), cerebrospinal fluid (CSF) 14-3-3 immunoassay and cerebral MRI. They found that the overall sensitivity for typical changes on MRI scan was lower than that reported in much smaller studies. Since the publication of this study (2006), many more authors have described MRI findings. Only four out these 15 studies had more than 40 subjects. Over the last one decade, there have been many improvements in the diagnostic sensitivity of pulse sequences used for this illness.

In this context, Divya et al., have made an important contribution.[2] Their's is one of the largest case series (n = 41) of probable and possible CJD reported from a single center in India.[2] The applicability of the findings of this study in the absence of CSF – 14-3-3 protein and molecular or genetic confirmation reflects its utility at centers with resource constraints. The authors are aware of the limitations of their study like the lack of autopsy, with lack of immunohistochemistry and genetic data. It was a retrospective chart review. Apparent Diffusion Coefficient (ADC) maps were obtained for some of the subjects and DWI-FLAIR mismatch was studied, but the data for both of them are not provided and not discussed. The authors do allude to 'nonprion rapidly progressive dementias' in their results and discussion, again without data. It appears that there was no proper 'control' group. It was intriguing to note that the MRI findings in the 3 groups (definite CJD, probable CJD, and patients not satisfying criteria for CJD) had no significant correlation with EEG and clinical features. The overall sensitivity of MRI in the diagnosis of sCJD was 73%, which is comparable with most other studies. It is sobering to note that EEG served as a rescue criteria for MRI-negative patients, thus somewhat obviating the need for CSF 14-3-3 protein assay, which is still not available easily and economically in India.

Unfortunately, the overall variability in radiological patterns on MRI limits the chances of defining a 'typical' or 'classical' pattern of the disease. Yet the “common pattern” is helpful in the differential diagnosis amongst various causes of rapidly progressive dementias. For example, isolated limbic involvement is never present in patients with sCJD.

Arriving at good measures of sensitivity and specificity for neuro-imaging and other biomarkers remains alluding because of the heterogeneous nature of the studies and the possible subtypes existing within the sCJD populations. The folly of “lumping the entities” which are different, masks true differences. sCJD does have many subtypes on clinical, radiological, genotypic and metabolic criteria. It is crucial to know where to draw the lines while parsing the subgroups and finding meaningful associations. The contrarian trap of being a “splitter” also haunts the researchers. For example, the typical EEG changes are mostly seen in MM 1 type and least commonly, in the MV1, MV2, VV2 types. Typical MRI changes are common in the VV2 type. Patients with isolated cortical involvement on DWI (about one third of all) usually show relatively prolonged disease duration.

The MM1 and MM2 subtypes have a typical presentation and constitute about 70% of all cases. Uncommon variants (VV1, VV2, VV2) have a slower course, The familial form of CJD (fCJD) does not differ significantly from the sporadic form. However, DWI seems to be more specific for fCJD. Although it was less sensitive in detecting lesions in the basal ganglia, it was far more accurate in detecting cortical lesions. The pulvinar sign may be common in variant CJD, but is not specific. Thalamic ADC values may help in differentiation, with an antero-posterior gradient.

There appears to be a sort of a single hump curve depicting the relationships between the severity of biomarkers (imaging, electrophysiological and possibly biochemical) and the duration plus severity of illness. MRI hyperintensities (DWI, Flair) are subtle and minimal in the earlier stages, followed by successive involvement of many more regions with increasing signal intensity as the clinical features worsen; and finally decline in signal changes occurs, when the pathology changes from vacuolization to neuronal loss and gliosis. Similarly, apparent diffusion coefficient (ADC) values are reduced in the affected regions of the brain with spongiform changes, followed by their increase when neuronal loss and gliosis set in. On MR spectroscopy, N-acetyl aspartate (NAA) initially declines, being a marker of neuronal stress and death, and later returns to normal.

The search for biomarkers is important for carriers in families with CJD or when the presentation is subtle, mild and atypical as seen in the early sporadic form of CJD.

ADC values may start declining before hyperintense signals appear. The findings on fluorodeoxyglucose positron emission tomography (PET) along with computed tomographic (CT) scan have been reported to be superior than MRI in detecting basal ganglia and thalamic involvement in the early stage of the disease.

Many facets of neuropathology and patho-physiology of CJD are being studied by old and new methods, like cerebral blood flow and perfusion by single photon emission computed tomography (SPECT); arterial spin labeling on MRI; astrocytosis by N-[11 C-methyl]-L-deuterodeprenyl (DED) and 15 O water for brain perfusion by 15 O water on PET; grey and white matter atrophy and density on T1 volumetry; diffusivity of water molecules (thereby reflecting the size of the vacuoles) by diffusion tensor imaging; and, integrity of white matter by reduced fractional anisotropy on tractography. New acquisition parameters for diffusion weighted imaging (DWI) and other sequences are being developed based upon mathematical models to understand the correlations between micro- structural changes and MR signal alterations. Figini et al., acquired DWI data with a wide range of echo-times and diffusion weightings and provided noninvasive estimates of radius of the restricted compartment (the vacuole size).[3]

Finally, it will always remain important to understand the limitations of any test before accepting the diagnosis solely on its basis. Combination of tests and repetitions at intervals will always be needed, particularly for uncommon and atypical variants.

The neuroscience community is awaiting results from the prospective EURO-CJD collaborative project for assessing the true diagnostic sensitivity and clinical utility of MRI. Means to pick up the disease early and meticulously follow its evolution over time will help in better planning of therapeutic trials. This will hopefully be possible in the near future.

 
  References Top

1.
Collins SJ, Sanchez-Juan P, Masters CL, Klug GM, van Duijn C, Poleggi A, et al. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain 2006;129(Pt 9):2278-87.  Back to cited text no. 1
    
2.
Divya KP, Menon RN, Bejoy T, Nair M. A hospital based registry of Creutzfeldt-Jacob disease: Can neuroimaging serve as a surrogate biomarker? Neurol India 2016;64:411-8.  Back to cited text no. 2
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3.
Figini M, Alexander DC, Redaelli V, Fasano F, Grisoli M, Baselli G, et al. Mathematical models for the diffusion magnetic resonance signal abnormality in patients with prion diseases. Neuroimage Clin 2014;7:142-54.  Back to cited text no. 3
    




 

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