How common is prion disease?: research

What does a long national series look like?

France has 25 years of prospective active surveillance. Denouel and colleagues included all suspected cases notified from January 1992 to December 2016 and all deaths with a definite or probable diagnosis by EuroCJD criteria. In total 25,676 suspected cases were notified and 2,907 diagnosed as prion disease: 2,510 sporadic CJD, 86 percent; 240 genetic, 8 percent; and 157 acquired, 6 percent.

Both suspected and sporadic cases increased over the period. Patients aged 50 or under with sporadic disease had phenotypes reflecting a different molecular subtype distribution from older patients. France recorded more growth hormone iatrogenic cases than other European countries and the second highest number of variant CJD cases after the United Kingdom, with both declining over time. The authors read the fall in acquired forms as evidence that measures limiting human exposure worked, and state that active surveillance remains needed given uncertainty about future variant CJD, the possible zoonotic potential of chronic wasting disease and the rising sporadic trend seen in France and elsewhere.

The ratio of suspected to diagnosed cases, roughly nine to one, is itself a finding: a surveillance system that detects most cases also investigates many patients who do not have the disease.

Is sporadic CJD becoming more common, or better counted?

Both explanations are standard, and the second analysis separates them as far as the data allow. Denouel and colleagues estimated sporadic CJD mortality rates in France from 1992 to 2016 in 2,475 cases aged 45 to 89 and fitted age-period-cohort Poisson models.

Mortality rates rose with age, peaked between 75 and 79 and fell thereafter. Rates were higher in women than men at younger ages and lower at older ages. The best fitting model included age, period and cohort effects with a sex by age interaction, and mortality rates increased progressively with successive birth cohorts. The authors state that the identification of cohort effects suggests environmental exposures may play a role in the cause of sporadic disease.

A cohort effect is a statistical pattern, not an exposure. The stated limits of the analysis are that patients under 45 were excluded, that non-M1 strains were too few to model separately, that the M1 subgroup had less power, and that the model is descriptive. The authors ask for replication in other countries, for studies of specific exposures, and for watching whether the measures taken after the BSE crisis change future sporadic CJD mortality.

Does occupation matter?

Hermann and colleagues examined occupational information in German surveillance records: 1,250 patients from 1993 to 2005, of whom 4, or 0.32 percent, were physicians, and 1,491 patients from 2006 to 2016, of whom 13, or 0.87 percent, were physicians. None of the physicians was a neurologist, neurosurgeon, psychiatrist or pathologist. A cumulative sum test showed an increase in reported physicians over time, and data for 2017 to 2018 gave 5 physicians among 239 notified cases, 2.1 percent, using the German population as the comparison group.

The authors state that their data suggest the possibility of an increased risk among physicians, that they can only speculate about reasons, and that larger multinational studies are needed. The weaknesses are visible in the design: occupation is recorded in surveillance data of varying completeness, the comparison group is the general population rather than an occupationally matched one, and the absence of cases in the specialties with the most tissue exposure argues against an occupational transmission route.

How do other national counts compare?

Canada recorded 662 definite and probable CJD deaths in residents from 1998 to 2013: 613 sporadic, 43 genetic, 4 iatrogenic and 2 variant, supported by 635 genetic analyses and 861 neuropathological examinations. The authors judged the rising sporadic rate to reflect better case finding rather than more disease, which is the opposite emphasis to the French cohort analysis and rests on different data.

Denmark reported an average of seven sporadic cases a year between 1997 and 2011, range 4 to 12, with 54 percent autopsy confirmed, and no hereditary, iatrogenic or variant cases notified in that period. Suspected cases are notified on form 1515 to the Statens Serum Institut, with neuropathology at Copenhagen University Hospital.

Comparing these numbers directly would be a mistake. Autopsy rate, the availability of RT-QuIC, referral practice and population age structure all move the count, and the subtype-dependent assay failures described at sporadic CJD subtypes mean some cases are missed systematically rather than at random.

Related: research hub, diseases and the field guide.