The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial.

BACKGROUND: Fahr's disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr's disease or syndrome. METHODS: The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr's disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life. RESULTS: Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. CONCLUSIONS: Fahr's disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr's disease or syndrome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .

A screening programme on chronic solvent-induced encephalopathy among Dutch painters.

BACKGROUND: Long-term exposure to organic solvents may lead to chronic solvent induced encephalopathy (CSE) in painters. In combination with reduction of exposure, a workers' health surveillance programme was developed, resulting in a three-stage CSE screening procedure for early neurobehavioural changes possibly predicting chronic health effects. The screening consists of a questionnaire (Neurosymptom Screening Checklist 60, NSC-60), computerised neurobehavioural functioning testing (Neurobehavioural Evaluation System; NES2) and multidisciplinary differential diagnostic evaluation by experts (called 'Solvent Team'). Results from the screening were compared with the results of the 'care as usual' (CAU), in which symptomatic patients were referred directly to the Solvent Team by occupational physicians, general practitioners or medical specialists. Parallel to the screening programme, a legal ban on indoor use of solvent-based paints resulted in lower exposure to solvents. OBJECTIVE: To investigate the usefulness of the NSC-60 questionnaire as a screening tool for CSE among painters and to investigate the course of the number of CSE cases over the years as a potential consequence of improved prevention and control. RESULTS: From 1998 to 2004, more than 40,000 painters were invited to participate in a health surveillance programme including a periodical occupational health examination (PHE) and 50% did participate. Four percent (N=794) of these had a positive score on the NSC-60. The Solvent Team assessed 101 of these for CSE, which resulted in 27 CSE cases diagnosed. CAU during the same period of the surveillance (1998-2004) yielded 619 painters and 75 of these had the diagnosis CSE. After 2002 the number of CSE diagnosed cases dropped considerably and in 2004 only one case of CSE could be diagnosed. The substantially lower prevalence of CSE diagnosed cases in painters after 2002 might partly be explained as a result of a successful participation in the screening procedure of most prevalent CSE cases during the years 1998-2002. A second reason for the reduction of new diagnosed cases of CSE can be the effectiveness of the ban on indoor use of solvent-based paints resulting in lower exposure levels at work. CONCLUSION: The screening procedure is useful to screen for CSE among people taking part in the PHE programme. Control of CSE can be achieved by an integrated preventive approach with reduction of exposure and screening on early health effects.

Decision rules for assessment of chronic solvent-induced encephalopathy: Results in 2370 patients.

For the diagnosis of patients suspected of chronic solvent-induced encephalopathy (CSE), it would be helpful if the applied cognitive tests show a characteristic profile of impairment in this disease. We investigated the existence of such a profile. In 1997-2006 two expert teams in The Netherlands systematically examined 2370 patients referred for evaluation of suspected CSE. The procedure included two selection steps: (1) intake interview, using criteria of exposure, development of symptoms and absence of non-solvent causes, and (2) seven tests of the computerized Neurobehavioural Evaluation System (NES). Patients showing negligible impairments were considered free from CSE and were not further examined. The third step comprised a neuropsychological, neurological and exposure evaluation. Explicit decision rules for the diagnosis of CSE were developed, including a minimum score for cognitive impairment summarizing 25 cognitive tests. These rules were retroactively applied to 563 patients, comprising 513 patients who had regularly completed all diagnostic steps and a sample of 50 out of the approximately 450 patients with negligible impairments on the NES, who were fully examined. The data from this sample were extrapolated to the original number of 450. In the combined population of 963 patients, a calculated 301 patients were given the diagnosis 'Solely CSE', 242 'CSE and other disease', 158 'Other Disease' and 262 'No (known) disease'. In the Solely CSE patients, the most impaired tests regarded Verbal Fluency & -Similarities, Motor Speed and Simple Attention. A profile of test results that might support the identification of patients with CSE amongst the other referred patients, was not found. The diverging results of related cognitive tests indicate that the use of a core test battery is needed to improve comparability. We consider the decision rules as a step towards a more objective assessment of CSE.