Development of novel clinical examination scales for the measurement of disease severity in Creutzfeldt-Jakob disease

ObjectiveTo use a robust statistical methodology to develop and validate clinical rating scales quantifying longitudinal motor and cognitive dysfunction in sporadic Creutzfeldt-Jakob disease (sCJD) at the bedside.MethodsRasch analysis was used to iteratively construct interval scales measuring composite cognitive and motor dysfunction from pooled bedside neurocognitive examinations collected as part of the prospective National Prion Monitoring Cohort study, October 2008–December 2016.A longitudinal clinical examination dataset constructed from 528 patients with sCJD, comprising 1030 Motor Scale and 757 Cognitive Scale scores over 130 patient-years of study, was used to demonstrate scale utility.ResultsThe Rasch-derived Motor Scale consists of 8 items, including assessments reliant on pyramidal, extrapyramidal and cerebellar systems. The Cognitive Scale comprises 6 items, and includes measures of executive function, language, visual perception and memory. Both scales are unidimensional, perform independently of age or gender and have excellent inter-rater reliability. They can be completed in minutes at the bedside, as part of a normal neurocognitive examination. A composite Examination Scale can be derived by averaging both scores. Several scale uses, in measuring longitudinal change, prognosis and phenotypic heterogeneity are illustrated.ConclusionsThese two novel sCJD Motor and Cognitive Scales and the composite Examination Scale should prove useful to objectively measure phenotypic and clinical change in future clinical trials and for patient stratification. This statistical approach can help to overcome obstacles to assessing clinical change in rapidly progressive, multisystem conditions with limited longitudinal follow-up.

Validation and Application of Skin RT-QuIC to Patients in China with Probable CJD

The definite diagnosis of human sporadic Creutzfeldt–Jakob disease (sCJD) largely depends on postmortem neuropathology and PrPSc detection in the brain. The development of real-time quaking-induced conversion (RT-QuIC) of cerebrospinal fluid (CSF) samples makes it possible for premortem diagnosis for sCJD. To test the diagnostic potential of RT-QuIC of skin specimens for probable sCJD, we collected the paired skin and CSF samples from 51 recruited living patients referred to the Chinese CJD surveillance center, including 34 probable sCJD, 14 non-CJD, and 3 genetic prion disease (gPrD). The samples were subjected to RT-QuIC assays using recombinant hamster PrP protein rHaPrP90-231 as the substrate. Using skin RT-QuIC assay, 91.2% (31/34) probable sCJD patients, and 1 T188K genetic CJD (gCJD) cases showed positive prion-seeding activity, while 85.7% (12/14) non-CJD patients were negative. CSF RT-QuIC positive seeding activity was only observed in 14 probable sCJD patients. Analysis of the reactivity of 38 positive skin RT-QuIC tests revealed that the positive rates in the preparations of 10−2, 10−3 and 10−4 diluted skin samples were 88.6% (39/44), 63.6% (28/44), and 25.0% (11/44), respectively. Eleven probable sCJD patients donated two skin specimens collected at different sites simultaneously. Although 95.5% (21/22) skin RT-QuIC elicited positive reaction, the reactivity varied. Our preliminary data indicate high sensitivity and specificity of skin RT-QuIC in prion detection for Chinese probable sCJD and highlight that skin prion-seeding activity is a reliable biomarker for premortem diagnosis of human prion disease.

Close patient observation and electroencephalography play an important role in the diagnosis of rare diseases. Presentation of a case of Creutzfeldt-Jakob disease

Creutzfeldt–Jakob disease is a rare, progressive spongiform encephalopathy caused by infectious proteins called prions. It is characterised by rapidly progressive dementia accompanied by cerebellar, visual, extrapyramidal, and pyramidal symptoms, as well as myoclonus and mutism in later stage of the disease. The most common type is sporadic Creutzfeldt– Jakob disease, accounting for 85% of all cases. Treatment of the disease is symptomatic. An important role in making the diagnosis is attributed to the observation of the patient and electroencephalography, showing characteristic cyclical discharges. We present the case of a patient whose first symptoms were psychiatric in nature, and who was diagnosed with Creutzfeldt–Jakob disease based on careful observation, presence of myoclonus, and repeated electroencephalography examinations in which typical 1–2 seconds of sharp and slow wave discharges appeared. By presenting this case of severe progressive encephalopathy, we would like to highlight the fact that even in the age of modern diagnostic methods, electroencephalography, which has been in use for many years, may be crucial in the diagnostic process. We would also like to point out that the initial symptoms of Creutzfeldt–Jakob disease may suggest a psychiatric disorder.