Predictive Factors for Sustained Pain after (sub)acute Osteoporotic Vertebral Fractures. Combined Results from the VERTOS II and VERTOS IV Trial.

PURPOSE: Osteoporotic vertebral compression fractures are treated conservatively or in selected cases with percutaneous vertebroplasty (PV). The purpose of this retrospective analysis is to determine predictive factors for a high visual analogue scale (VAS) pain score after conservative, sham or PV and is based on previously published randomized trials. METHODS: The VERTOS II compared conservative versus PV, and VERTOS IV compared sham versus PV treatment. The conservative group received pain medication. The sham and PV group received subcutaneous lidocaine/bupivacaine. In addition, the PV group received cementation, which was simulated in the sham group. Nineteen different predictors of high (≥ 5) versus low (< 5) VAS pain score at 12 months were investigated. RESULTS: 20.7% of patients in the PV group demonstrated a VAS ≥ 5 at the 12-month, compared to 40.1% in the conservative or sham group, with a significant difference (χ2(1) = 15.26, p < 0.0001, OR = 2.57, 95% CI = 1.59 to 4.15). In the subgroup analysis, we detected five predictors for the risk of high pain scores (VAS ≥ 5 after 12 months follow-up), namely: female, baseline VAS > 8, long-term baseline pain, mild/severe Genant and new fractures. CONCLUSIONS: Statistically significant more patients had a high pain score at 12 months in the sham and conservative group when compared with the PV group. Five predictors were identified for sustained high local back pain, regardless of the received treatment. Patients with moderate fracture deformity were less likely to have high pain scores at 12 months if they received PV than if they had sham or conservative therapy.

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations.

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.

The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.

BACKGROUND: Friedreich ataxia (FRDA) is the most common familial ataxia syndrome in Central and Southern Europe but rare in Scandinavia. Biallelic mutations in SH3 domain and tetratricopeptide repeats 2 (SH3TC2) cause Charcot-Marie-Tooth disease type 4C (CMT4C), one of the most common autosomal recessive polyneuropathies associated with early onset, slow disease progression and scoliosis. Beyond nystagmus reported in some patients, neither ataxia nor cerebellar atrophy has been documented as part of the CMT4C phenotype. METHODS: Here we describe a single centre CMT4C cohort. All patients underwent a comprehensive characterization that included physical examination, neurophysiological studies, neuroimaging and genetic testing. In a patient with cerebellar features, an evaluation of the vestibular system was performed. RESULTS: All five patients in this cohort harbored the R954X mutation in SH3TC2 suggesting a founder effect. Two patients had been diagnosed as FRDA. One of them, an 80-year-old woman had onset of unsteadiness during childhood leading to gradual loss of mobility. She also had scoliosis and hearing loss. On examination she had generalized muscle atrophy, leg flaccidity, pes cavus, facial myokymia, limb dysmetria, dysarthria and gaze-evoked nystagmus. She exhibited bilateral vestibular areflexia. Neuroimaging demonstrated atrophy in the frontoparietal regions and cerebellar hemispheres. CONCLUSIONS: CMTC4A may present with a cerebellar phenotype and mimic a flaccid-ataxic form of FRDA. Absence of cardiomyopathy or endocrine abnormalities and lack of pathological dentate iron accumulation in CMT4C distinguish it from FRDA.

Percutaneous Vertebroplasty is no Risk Factor for New Vertebral Fractures and Protects Against Further Height Loss (VERTOS IV).

BACKGROUND: Percutaneous vertebroplasty (PV) is an alternative option to treat pain after an osteoporotic vertebral compression fracture (OVCF). Controversy exists as to whether PV increases the risk of new OVCFs or prevents further vertebral height loss in treated levels. We assessed both during 1-year follow-up in patients with acute OVCF randomised to PV or a sham procedure. METHODS: VERTOS IV is a prospective, multicentre, randomised controlled trial comparing PV with sham therapy in 180 patients. New OVCFs and further vertebral height loss were assessed at 3, 6, and 12 months. RESULTS: After a median follow-up of 12 months (interquartile range (IQR) = 12-12) 31 new fractures were reported in 15 patients from the PV group and 28 new fractures in 19 patients from the sham group. The occurrence of new vertebral fractures did not significantly differ between the groups (χ2(1) = 0.83, p = 0.36, OR = .71, 95%CI = 0.33-1.50). There was no higher fracture risk of adjacent versus distant vertebrae. After sham procedure, further height loss of treated vertebrae occurred more frequently (7 patients (8%) in the PV group and 39 (45%) in the sham group (χ2(1) = 28.85, p < 0.001, OR = 9.84, 95%CI = 4.08-23.73)) and was more severe (p < .001) than after PV. CONCLUSIONS: The risk of further vertebral height loss is significantly lower after PV compared to a sham intervention, i.e. PV protects against progressive vertebral height loss. In addition, PV does not increase the risk of new adjacent and distant OVCFs. LEVEL OF EVIDENCE: Level 1a, therapeutic study. ClinicalTrials.gov number, NCT01200277.

Vertebroplasty versus sham procedure for painful acute osteoporotic vertebral compression fractures (VERTOS IV): randomised sham controlled clinical trial.

OBJECTIVE: To assess whether percutaneous vertebroplasty results in more pain relief than a sham procedure in patients with acute osteoporotic compression fractures of the vertebral body. DESIGN: Randomised, double blind, sham controlled clinical trial. SETTING: Four community hospitals in the Netherlands, 2011-15. PARTICIPANTS: 180 participants requiring treatment for acute osteoporotic vertebral compression fractures were randomised to either vertebroplasty (n=91) or a sham procedure (n=89). INTERVENTIONS: Participants received local subcutaneous lidocaine (lignocaine) and bupivacaine at each pedicle. The vertebroplasty group also received cementation, which was simulated in the sham procedure group. MAIN OUTCOME MEASURES: Main outcome measure was mean reduction in visual analogue scale (VAS) scores at one day, one week, and one, three, six, and 12 months. Clinically significant pain relief was defined as a decrease of 1.5 points in VAS scores from baseline. Secondary outcome measures were the differences between groups for changes in the quality of life for osteoporosis and Roland-Morris disability questionnaire scores during 12 months' follow-up. RESULTS: The mean reduction in VAS score was statistically significant in the vertebroplasty and sham procedure groups at all follow-up points after the procedure compared with baseline. The mean difference in VAS scores between groups was 0.20 (95% confidence interval -0.53 to 0.94) at baseline, -0.43 (-1.17 to 0.31) at one day, -0.11 (-0.85 to 0.63) at one week, 0.41 (-0.33 to 1.15) at one month, 0.21 (-0.54 to 0.96) at three months, 0.39 (-0.37 to 1.15) at six months, and 0.45 (-0.37 to 1.24) at 12 months. These changes in VAS scores did not, however, differ statistically significantly between the groups during 12 months' follow-up. The results for secondary outcomes were not statistically significant. Use of analgesics (non-opioids, weak opioids, strong opioids) decreased statistically significantly in both groups at all time points, with no statistically significant differences between groups. Two adverse events occurred in the vertebroplasty group: one respiratory insufficiency and one vasovagal reaction. CONCLUSIONS: Percutaneous vertebroplasty did not result in statistically significantly greater pain relief than a sham procedure during 12 months' follow-up among patients with acute osteoporotic vertebral compression fractures. TRIAL REGISTRATION: ClinicalTrials.gov NCT01200277.

A randomised sham controlled trial of vertebroplasty for painful acute osteoporotic vertebral fractures (VERTOS IV).

BACKGROUND: The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), a minimally invasive technique, is a new treatment option. Recent randomized controlled trials (RCT) provide conflicting results: two sham-controlled studies showed no benefit of PV while an unmasked but controlled RCT (VERTOS II) found effective pain relief at acceptable costs. The objective of this study is to compare pain relief after PV with a sham intervention in selected patients with an acute osteoporotic VCF using the same strict inclusion criteria as in VERTOS II. Secondary outcome measures are back pain related disability and quality of life. METHODS: The VERTOS IV study is a prospective, multicenter RCT with pain relief as primary endpoint. Patients with a painful osteoporotic VCF with bone edema on MR imaging, local back pain for 6 weeks or less, osteopenia and aged 50 years or older, after obtaining informed consent, are included and randomized for PV or a sham intervention. In total 180 patients will be enrolled. Follow-up is at regular intervals during a 1-year period with a standard Visual Analogue Scale (VAS) score for pain and pain medication. Necessary additional therapies and complications are recorded. DISCUSSION: The VERTOS IV study is a methodologically sound RCT designed to assess pain relief after PV compared to a sham intervention in patients with an acute osteoporotic VCF selected on strict inclusion criteria. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov., NCT01200277.

Peripheral vascular disease as a predictor of survival after coronary artery bypass grafting: comparison with a matched general population.

BACKGROUND: The European system for cardiac operative risk evaluation, the most popular European scoring system in cardiac surgery, uses the extracardiac arteriopathy as a risk factor for early mortality. We studied the effect of peripheral vascular disease (PVD) on early and late mortality in a large group of patients undergoing isolated coronary artery bypass surgery (CABG) surgery. METHODS: During a ten-year period (January 1998 through December 2007) 10,626 patients underwent isolated CABG in our hospital. The primary endpoints of this study were early and late all-cause mortality. For each year of the study period, general population cohorts were matched with the patient groups for age and gender (expected survival). RESULTS: Out of 10,504 patients included in the analysis, 1,222 (11.63%) patients had PVD. The PVD was identified as an independent risk factor for late mortality (death at any time after hospital discharge) (hazard ratio of 1.67 [1.43 to 1.95], p < 0.0001), but not for early mortality (death within 30 days or before discharge) (hazard ratio of 1.06 [0.70 to 1.60], p = 0.776). Patients without PVD had a better survival than patients with PVD (log-rank p < 0.0001) and even a better survival compared to the normal Dutch population survival (p value < 0.002). The PVD patients had a worse than expected survival (log-rank p < 0.0001). CONCLUSIONS: Peripheral vascular disease is an independent risk factor only for late mortality but not for early mortality. Compared with age-matched and sex-matched cohorts from the general Dutch population, the ten-year survival of patients with peripheral vascular disease was worse; whereas the survival of patients with no peripheral vascular disease was better.

Postoperative blood loss in patients undergoing coronary artery bypass surgery after preoperative treatment with clopidogrel. A prospective randomised controlled study.

OBJECTIVE: The optimal timing for discontinuation of clopidogrel before surgery remains under debate. The purpose of this study is to determine the effect of preoperative clopidogrel administration on postoperative blood loss and the total requirements of homologous blood products after coronary artery bypass grafting (CABG). We also evaluated the perioperative complications. METHODS: Consecutive patients (n=130) undergoing elective CABG were recruited and randomised between 2006 and 2007. In 38 patients (group 1), treatment with clopidogrel was discontinued 5 days prior to surgery, in 40 patients (group 2) 3 days before surgery and in 40 other patients (group 3) clopidogrel was stopped on the day of surgery. RESULTS: Significantly more postoperative blood loss was observed in group 3 compared to group 1 (929+/-472 ml vs 664+/-312 ml; p=0.009). Other group comparisons were not significant. Blood loss after 12 h and at drain removal was also significantly higher in group 3. Patients in group 3 also had higher total requirements of homologous blood products (p=0.046) and a significantly higher need for fresh frozen plasma (FFP) transfusion (p=0.034). Univariable regression analyses revealed that continuing clopidogrel till the day of surgery (group 3) was predictive for postoperative blood loss (beta=0.289; p=0.007) and the total requirements of homologous blood products after surgery (beta=0.280; p=0.008). These effects remained the same in multivariable analyses. CONCLUSIONS: Continuation of clopidogrel until the day of surgery induces significantly more postoperative blood loss and increases significantly the total requirements of homologous blood products and FFP transfusion after surgery. The blood loss and the use of blood products in the group that stopped at 3 days preoperatively were similar to that of the group that stopped at 5 days preoperatively.