A previously undiagnosed case of Gerstmann-Sträussler-Scheinker disease revealed by PRNP gene analysis in patients with adult-onset ataxia.

Ataxia is a frequently reported symptom in prion diseases (PD) and it is characteristic of Gerstmann-Sträussler-Scheinker syndrome (GSS), a genetic PD mainly related to the P102L mutation in the PRNP gene. Our aim was to screen for the P102L and other six known PRNP gene mutations (P105L, A117V, Y145X, E200K, D202N, and V210I) a group of 206 consecutive patients diagnosed with adult-onset cerebellar ataxia of unknown origin. The patients, negative for the most common acquired and genetic forms, were analyzed using a combination of restriction endonuclease digestion and pyrosequencing; eight, affected by ataxia and cognitive dysfunction, were also sequenced for the PRNP gene. One patient resulted to be heterozygous for the P102L mutation. Retrospectively, the clinical picture was consistent with a "classical" GSS phenotype. In conclusion, the screening for the P102L mutation, or even the sequencing of the PRNP gene should be taken in consideration in patients with late-onset ataxia (>50 years).

Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. METHODS: We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. FINDINGS: From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. INTERPRETATION: Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. FUNDING: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.

Chronic cerebrospinal venous insufficiency in multiple sclerosis: a sonographer-blinded case-control study.

OBJECTIVES: To evaluate the presence of chronic cerebrospinal venous insufficiency (CCSVI) and cerebral venous anomalies in a consecutive series of patients with multiple sclerosis (MS), other neurologic diseases (NEU) and healthy controls (HC). METHODS: A consecutive series of 80 MS patients, 41 HC and 26 NEU cases underwent a transcranial and extracranial echo-color Doppler (ECD) evaluation of cerebrospinal venous return in a sonographer-blinded fashion. According to the original Dr. Zamboni's protocol, CCSVI was diagnosed in presence of ≥2 ECD venous criteria. RESULTS: We did not observe any association between CCSVI and MS. CCSVI was detected in 17.5% of MS cases, 7.3% of HC and 11.5% of NEU patients (p=0.333). The prevalence of internal jugular vein stenosis (IJV) and the proportion of patients with any positive ECD criterion differed significantly among groups, being higher in MS cases versus HC (67.5% and 76.2% versus 48.8% and 41.5%, respectively; p=0.005 and p=0.006). No relationship between CCSVI and MS type and severity was evidenced. CONCLUSIONS: The present study argues against a positive link between CCSVI and MS risk or severity. Interestingly, a weak association between venous ECD anomalies (in particular IJV stenosis) and MS was observed in our population. This finding should be interpreted with caution due to the possible confounders and needs to be confirmed in large controlled studies.