Clinical guidance together with increasing use of disposable surgical instruments, control of inadvertent migration of potentially tainted instruments between surgical sets, and improvement of the processing and decontamination cycle, are considered to be the most important preventive measures to minimize potential CJD transmission by invasive medical procedures. This study shows that patients with sCJD in the clinical stage, TW-5, undergo a considerably high frequency of main SPs, for the most part neurosurgical and gastrointestinal, and minor SPs in particular, mostly in the form of lumbar punctures. It also suggests that, prior to clinical onset, TW-4, subsidiary procedures such as lumbar punctures and endoscopies, particularly of the digestive tract, as well as gastrointestinal surgery and a miscellaneous group of main SPs, occur at a higher than expected frequency for individuals who will develop sCJD. Identification of such potentially higher-risk events, particularly prior to CJD diagnosis, might well constitute a priority in clinical settings. Evidence-based guidance development will require consideration of multiple aspects of the potential transmission process and impact of preventive measures.
While the present study is unique in its use of registry-based assessment of surgical histories, randomly chosen controls and accurate life-time measurement, its limitations include a lack of access to hospital surgical records -offset in part by the high validity of registered SPs-  and exclusion of out-patient surgery and invasive diagnostic procedures. Lack of data on surgical judgement and neurological diagnostic processes hampers assessment of surgical indication and hospital preventive measures taken. However, case-selection and case–control differential SP registration are unlikely . However, the younger age of controls might perhaps bias comparisons of surgery of fertile age when using UMCs.
Lumbar punctures, frequently performed in out patient care, out and gastrostomy form part of the routine diagnosis and care of demented patients in both countries. Their presence in TW-4 casts serious doubts on the accuracy of the operational time point of clinical onset of sCJD, indicating that both the onset of clinical manifestations and the neurological or medical examinations, frequently conducted at different hospitals, predated the operational date of clinical onset adopted after examining only one or two selected hospital records. As a consequence, our results may have overestimated differences between cases and controls in TW-4 and underestimated those in TW-5, particularly as regards endoscopies, lumbar punctures and digestive system surgery, which constitute a shared pattern. In practice, this would mean that surgery undergone prior to clinical onset would be reduced to almost expected levels vis-à-vis rates in controls, and that the excess medical procedures and identification of high-risk predictors would be ascribed to the early clinical period. Laske et al. reported statistically non-significant ORs of 6.97 and 3.39 for surgery up to 0.5 and 1 years prior to clinical onset .
Only one patient in TW-4 and none in TW-5 underwent ophthalmological surgery, thereby differing from the higher frequencies suggested by British and Japanese studies [17, 18]. It is difficult to establish whether this negative finding is due to our study’s comparatively lower statistical power or to high clinical standards in Denmark and Sweden aimed at avoiding unnecessary interventions in cases where both cataract and cortical visual symptoms are possibly present at clinical onset of CJD. The excess of gastrointestinal surgery in TW-5 can be presumed to be mainly related to care, which, in TW-4, might in part be attributable to sCJD-related complaints that may either have unveiled other ailments or, alternatively, misled clinicians facing a patient who might not have been cognitively intact before sCJD diagnosis. Interestingly, Laske et al. deemed surgery and other stressful events to be a trigger of sCJD clinical onset within six months .
The statistically non-significant higher frequency of coronary surgery in TW-4 is a particularly interesting finding, since the only statistical significant association for specific body systems observed during the nine years preceding onset/ID-2 with OR 2.03 and 2.58 as compared to MCs and UMCs, respectively; and at >1 year before onset/ID-2, was surgery of heart and major vessels, i.e., coronary surgery . The recalculated figures for TWs 3 and 4, i.e., the 10-year period, using a binary variable for exposure, were OR 2.27 (1.03–5.02) and 3.30 (1.42–7.00), when compared to MCs and UMCs, respectively. Our results suggest that coronary surgery is more frequently conducted within a several-year period predating sCJD onset, adding further fuel to the debate on reuse of angioplasty catheters [28, 29].
In Denmark and Sweden, digestive tract and peripheral vessel surgery and interventions pertaining to peritoneum, skeletal muscle and “other tissues” constituted risk factors for sCJD, when conducted at considerable lags . Furthermore, the results show that most are also associated with sCJD after clinical onset. Gastrointestinal and orthopedic SPs undertaken at end of life in persons with sCJD might generate infective remnants of skeletal muscle, “other tissues” and abdominal structures adhering to instruments, consistent both with the “lower” infectivity level assigned to such tissue by the WHO tissue infectivity tables  and with results of the abovementioned experimental observations [20–23]. Accordingly, warnings proposed for neurosurgical procedures in general, and for ophthalmological SPs in Japan and the UK in particular [17, 18], may also apply to procedures overrepresented late in life among individuals with sCJD. To recapitulate, experimental, clinical and epidemiological observations would support the notion that algorithms designed to assess risk when planning surgical interventions in some EU Member States should include neurosurgical, ophthalmological and gastrointestinal procedures among those with higher infective potential.
The results of this and two earlier studies [9, 10] cover all in-patient registered surgery undergone by persons with sCJD in Denmark and Sweden, and enable an overall picture to be formed of the relationship between surgery and sCJD since the early 1970s, which could well be valid for populations across the industrial world. Surgery is, in general, only directly associated with the disorder, and displays the following three, principal, etiologically different patterns: 1) surgery potentially causing sCJD, mainly conducted 20 or more years before disease onset; 2) surgery potentially or definitely caused by sCJD, mainly conducted at some point, early or otherwise, during the clinical course of the disease; and, 3) coronary surgery conducted in the 10 years preceding onset, which we contend represents a confounding effect of vascular risk factors acting concurrently as a cause of both coronary artheriosclerosis and sCJD. Subject to confirmation being obtained from independent studies, all three types of associations raise points relevant for designing specific guidelines for the prevention of sCJD transmission in medical settings.
In surgical practice, national and local traditions vary. Our results may not necessarily mimic the findings of prior studies nor be replicated in studies pertaining to other countries or time intervals. Clinical guidance for prevention of CJD transmission in medical settings calls for the study of recent surgical practice in countries where application of the relevant recommendations is envisaged, as well as analysis of temporarily overlooked yet relevant patient-SP specific events, denoted as incidents a posteriori. Despite a non-neurosurgical incident implicating consecutive use of same instrument by two persons diagnosed with sCJD has never been reported, incident assessment and management constitutes a distinct, mixed (clinical and public health) element of guidance for CJD prevention as current guidelines frequently show .