Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: prospective case-control study

BMJ 1998;316:577-582 ( 21 February )

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Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: prospective case-control study

See editorial by Pocchiari and p 593

Markus Otto, group leader, laboratory diagnosis of CJD, ^a Jens Wiltfang, senior research fellow, ^b Ekkehard Schütz, research fellow, ^c Inga Zerr, research fellow, ^a Anke Otto, research fellow, ^a Annette Pfahlberg, statistician, ^d Olaf Gefeller, associate professor of medical statistics, ^d Manfred Uhr, research fellow, ^e Armin Giese, research fellow, ^f Thomas Weber, head, department of neurology, ^g Hans A Kretzschmar, head, department of neuropathology, ^f Sigrid Poser, head, epidemiology and early diagnosis of CJD. ^a

^a Neurologische Klinik und Poliklinik, Georg-August-Universität Göttingen, Robert-Koch Strasse 40, D-37075 Göttingen, Germany, ^b Psychiatrische Klinik und Poliklinik, Georg-August-Universität Göttingen, ^c Abteilung Klinische Chemie, Georg-August-Universität Göttingen, ^d Abteilung Medizinische Statistik, Georg-August-Universität Göttingen, ^e Max-Planck Institut für Psychiatrie, Kraepelinstrasse 10, D-80804 Munich, Germany, ^f Institut für Neuropathologie, Georg-August-Universität Göttingen, ^g Neurologische Abteilung Marienkrankenhaus Hamburg, Alfredstrasse 9, D-22087 Hamburg, Germany

Correspondence to: Dr Otto 100634.133{at}compuserve.com

Abstract
Objective: To analyse serum concentrations of brain specific S100 protein in patients with Creutzfeldt-Jakob diseaseand in controls.
Design: Prospective case-control study.
Setting: National Creutzfeldt-Jakob disease surveillance unit.
Subjects: 224 patients referred to the surveillance unit with suspected Creutzfeldt-Jakob disease and 35 control patientswithout dementia.
Main outcome measure: Serum concentration of S100 protein in patients with Creutzfeldt-Jakob disease, in patients withother diseases causing dementia, and in the control group.
Results: Of the 224 patients with suspected Creutzfeldt-Jakob disease, 65 were classed as definitely having the diseaseafter neuropathological verification, an additional 6 were classedas definitely having the disease as a result of a genetic mutation,43 as probably having the disease, 36 as possibly having the disease,and 74 patients were classed as having other disease. In the 108patients classed as definitely or probably having Creutzfeldt-Jakobdisease the median serum concentration of S100 was 395 pg/ml (SD387 pg/ml). This was significantly higher than concentrationsfound in the 74 patients classed as having other diseases (median109 pg/ml; SD 177 pg/ml; P=0.0001). At a cut off point of 213 pg/mlsensitivity for the diagnosis of the disease was 77.8% (95% confidenceinterval 68.8% to 85.2%) and specificity was 81.1% (70.3% to 89.3%).There was a significant difference in survival at different concentrationsof S100 in Kaplan-Meier curves (P=0.023).
Conclusion: Measurement of serum concentrations of S100 is a valuable tool which can be used more easily than testson cerebrospinal fluid in the differential diagnosis of Creutzfeldt-Jakobdisease. More studies are needed to determine whether serial testingof serum S100 improves diagnostic accuracy.

Key messages

Creutzfeldt-Jakob disease is a rare, fatal neurodegenerative disease. Diagnosis is made clinically and neuropathologically
There is no serum test which allows the diagnosis to be made while the patient is alive
In this study raised serum concentrations of S100 protein were found in patients with Creutzfeldt-Jakob disease
Serum concentrations of S100 could be used with a sensitivity of 77.8% and a specificity of 81.1% to confirm Creutzfeldt-Jakob disease in the differential diagnosis of diseases that cause dementia
Serial measurement of S100 concentrations will enhance diagnostic accuracy

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