Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

Piracetam for acute ischaemic stroke.

BACKGROUND: Piracetam has neuroprotective and antithrombotic effects which may help to reduce death and disability in people with acute stroke. OBJECTIVES: The objective of this review was to assess the effects of piracetam in acute presumed ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched 20 June 2005). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to April 2005), EMBASE (1980 to April 2005), and ISI Science Citation Index (1981 to April 2005). We also contacted the manufacturer of piracetam to identify further published and unpublished studies. SELECTION CRITERIA: Randomised trials comparing piracetam with control, with at least mortality reported and entry to the trial within approximately 48 hours of stroke onset. DATA COLLECTION AND ANALYSIS: Two authors extracted data and assessed trial quality and this was checked by the other two authors. Study authors were contacted for missing information. MAIN RESULTS: Three trials involving 1002 people were included, with one trial contributing 93% of the data. Participants' ages ranged from 40 to 85, and both sexes were equally represented. Piracetam was associated with a statistically non-significant increase in death at one month (approximately 31% increase, 95% confidence interval 81% increase to 5% reduction). This trend was no longer apparent in the large trial after correction for imbalance in stroke severity. Limited data showed no difference between the treatment and control groups for functional outcome, dependency or proportion of patients dead or dependent. Adverse effects were not reported. AUTHORS' CONCLUSIONS: There is some suggestion (but no statistically significant result) of an unfavourable effect of piracetam on early death, but this may have been caused by baseline differences in stroke severity in the trials. There is not enough evidence to assess the effect of piracetam on dependency.

Double-blind evaluation of short-term analgesic efficacy of orally administered diclofenac, diclofenac plus codeine, and diclofenac plus imipramine in chronic cancer pain.

A prospective double-blind randomized trial was conducted on 184 cancer patients with moderate to severe chronic pain to evaluate the analgesic efficacy and tolerability of diclofenac alone (50 mg q.i.d.) or in combination with a weak opioid (codeine 40 mg q.i.d.), or with an anti-depressant (imipramine, 10 or 25 mg t.i.d.). All demographic and clinical characteristics including cancer type, presence of bone metastases, baseline pain severity, neuropathic and nociceptive pain, and depressive state, were well balanced between the three treatment groups. The main analysis of the study was on the VAS scores at visit 2 (day 4). The mean VAS values for both associations imipramine plus diclofenac and codeine plus diclofenac were similar to the association placebo plus diclofenac. Patients on imipramine plus diclofenac and on placebo plus diclofenac were withdrawn mainly for inadequate efficacy, while patients on codeine plus diclofenac discontinued equally for inadequate efficacy or adverse events. In conclusion, in a short-term evaluation the addition of a tricyclic anti-depressant or a weak opioid to diclofenac did not provide further analgesia with respect to diclofenac administration alone.

Piracetam in acute stroke: a systematic review.

We studied whether the administration of piracetam in acute, presumed ischemic stroke affects case fatality and functional outcome. The Cochrane Stroke Group strategy was used to evaluate all randomized controlled trials of patients with presumed ischemic stroke examined within 48 h; death and (when available) functional outcome were used as end points. Three studies were included; the most recent one contributed more than 97% of the data. There were 501 patients treated with piracetam and 501 controls. Piracetam was associated with a nonsignificant 31% increase in the odds of death (95% CI -5% to 81%). This result was due almost completely to the effect of the larger trial, which, however, reported that the difference in case fatality rate between piracetam and control disappeared after correcting for the imbalance in stroke severity between the two groups. Data on functional outcome were available only for the largest study, and no difference was reported. Data obtained from the manufacturer suggested a nonsignificant trend (-10%) towards reduction in dependency with piracetam (CI -33% to 20%); the proportions of patients dead or dependent in the two groups were the same. Relevant adverse effects were not reported. The evidence from this review does not support routine administration of piracetam in patients with acute ischemic stroke; however, since a possible beneficial effect cannot completely be ruled out, further controlled trials are warranted.

A community-based study of incidence, risk factors and outcome of transient ischaemic attacks in Umbria, Italy: the SEPIVAC study.

The SEPIVAC study is a community-based epidemiological survey of incidence and outcome of transient ischaemic attacks (TIAs) and strokes in the territory of the 6th Local Health Unit, Umbria, Italy, where 49,218 people live, from 1 September 1986 to 31 August 1989. All cases were registered with the study either by notification from general practitioners (GPs) or by a check of hospital admission within the study area and in the two hospitals of Perugia. There were 94 incident cases of TIAs (45 males, 49 females), thus giving a crude rate of 0.64 per 1000 per year [95% conficence intervals (CI) 0.52/0.78]. The rate adjusted to the European population is 0.42 (CI 0.33/0.54). Mean age was 69.4 years, and females were significantly older than males. The weighted relative risk for males was 1.19 (CI 0.79/1.79). Thirty-one patients were treated at home by their GPs. Females had hypertension more frequently than males, whereas males smoked more frequently; we did not find any other statistically significant difference in the distribution of risk factors. Twelve patients out of 58 who had CT had an infarct, and 29 out of 54 submitted to Doppler ultrasonography had carotid stenosis. At 1 month, 4 patients had suffered an ischaemic stroke, 1 of whom died. At 6 months, 3 further strokes and 2 further deaths (1 due to myocardial infarction) had occurred.

Was it infarction or haemorrhage? A clinical diagnosis by means of the Allen score.

Since the clinical distinction between haemorrhagic and ischaemic stroke cannot be achieved with a simple clinical evaluation, and it is virtually impossible to submit all stroke patients to CT, a weighted clinical score may offer some advantages to physicians who are involved in stroke management. The Allen score (also referred to as the Guy's Hospital score), a validated clinical score, has been tested in two different clinical settings, comprising 289 patients. When only the values under 4 and those over 24 are taken into account (i.e. greater than 90% probability of ischaemia and haemorrhage), the global accuracy of the score is 97%, and the diagnostic gain (given a pretest probability for haemorrhage of 11% and a likelihood ratio of 194) is 85%. Therefore, we conclude that this simple clinical method can be used for epidemiological studies of stroke incidence and outcome, as well as for a first bedside screening to decide which patients should have priority for CT.

Fatty acid dietary intake and the risk of ischaemic stroke: a multicentre case-control study. UFA Study Group.

A low dietary intake of unsaturated fatty acids has been found in male patients with stroke as compared with controls in Italy, and a high consumption of meat has been associated with an increased risk of stroke in Australia. We present a case-control study, comparing the unsaturated and saturated fatty acids content of red cell membranes (which reflects the dietary intake of saturated and unsaturated fats) in 89 patients with ischaemic stroke and 89 controls matched for age and sex. In univariate analysis, besides hypertension, atrial fibrillation, ischaemic changes in ECG and hypercholesterolaemia, stroke patients showed a lower level of oleic acid (P = 0.000), but a higher level of eicosatrienoic acid (P = 0.009). Conditional logistic regression (dependent variable; being a case) showed that the best model included atrial fibrillation, hypertension, oleic acid and eicosatrienoic acids. These results confirm a possible protective role of unsaturated fatty acids against vascular diseases; however, we did not find any difference in the content of omega3 acids, which have been considered in the past to protect against coronary heart disease. We conclude that the preceding diet of patients with ischaemic stroke may be poor in unsaturated fatty acids (namely, oleic acid), and this defect is independent of other vascular risk factors. Only further studies will show whether changes in diet and/or supplement of unsaturated fatty acids might reduce the incidence of ischaemic stroke.

Piracetam for acute ischaemic stroke.

BACKGROUND: Piracetam has neuroprotective and antithrombotic effects which may help to reduce death and disability in people with acute stroke. OBJECTIVES: The objective of this review was to assess the effects of piracetam in acute presumed ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Review Group Trials Register (last searched April 2001). In addition we searched the Cochrane Controlled Trials Register (Cochrane Library 2001, issue 2), MEDLINE (1966-April 2001), EMBASE (1980-April 2001), and ISI Science Citation Index (1981- April 2001). We also handsearched 15 journals and contacted the manufacturer to identify further published and unpublished studies. SELECTION CRITERIA: Randomised trials comparing piracetam with control, with at least mortality reported and entry to the trial within approximately 48 hours of stroke onset. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed trial quality and this was checked by the other two reviewers. Study authors were contacted for missing information. MAIN RESULTS: Three trials involving 1002 people were included, with one trial contributing 93% of the data. Participants' ages ranged from 40 to 85, and both sexes were equally represented. Piracetam was associated with a statistically non significant increase in death at one month (approximately 31% increase, 95% confidence interval 81% increase to 5% reduction). This trend was no longer apparent in the large trial after correction for imbalance in stroke severity. Limited data showed no difference between the treatment and control groups for functional outcome, dependency or proportion of patients dead or dependent. Adverse effects were not reported. REVIEWER'S CONCLUSIONS: There is some suggestion (but no statistically significant result) of an unfavourable effect of piracetam on early death, but this may have been caused by baseline differences in stroke severity in the trials. There is not enough evidence to assess the effect of piracetam on dependency.

Piracetam for acute ischaemic stroke.

BACKGROUND: Piracetam has neuroprotective and antithrombotic effects which may help to reduce death and disability in people with acute stroke. OBJECTIVES: The objective of this review was to assess the effects of piracetam in acute presumed ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Review Group trials register, Medline (from 1965), Embase (from 1980), BIDIS ISI (from 1981). We also contacted manufacturers and handsearched 15 journals. SELECTION CRITERIA: Randomised trials comparing piracetam with control, with at least mortality reported and entry to the trial within approximately 48 hours of stroke onset. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed trial quality and this was checked by the other two reviewers. Study authors were contacted for missing information. MAIN RESULTS: Three trials involving 1002 people were included, with one trial contributing 97% of the data. Participants' ages ranged from 40 to 85, and both sexes were equally represented. Piracetam was associated with a statistically non significant increase in death (31% increase, 95% confidence interval 81% increase to 5% reduction). This trend was no longer apparent in the large trial after correction for imbalance in stroke severity. Limited data showed no difference between the treatment and control groups for functional outcome, dependency or proportion of patients dead or dependent. Adverse effects were not reported. REVIEWER'S CONCLUSIONS: There is some suggestion of an unfavourable effect of piracetam on early death, but this may have been caused by baseline differences in stroke severity in the trials. Piracetam does not appear to reduce dependency for stroke patients.

Glycerol for acute stroke.

BACKGROUND: Brain oedema is a major cause of early death after stroke. A 10% solution of glycerol is a hyperosmolar agent that is claimed to reduce brain oedema. OBJECTIVES: To determine whether intravenous (I.V.) glycerol treatment in acute stroke, either ischaemic or haemorrhagic, influences death rates and functional outcome in the short or long term, and whether the treatment is safe. SEARCH STRATEGY: The Cochrane Stroke Group trials register was searched (January 2003), and some trialists were personally contacted. SELECTION CRITERIA: All completed, randomised and quasi-randomised, controlled, published and unpublished comparisons, evaluating clinical outcome in which I.V. glycerol treatment was initiated within the first days after stroke onset. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, assessed the trial quality and extracted data and this was checked with all co-reviewers. Death from all causes, functional outcome, and adverse effects were analysed. MAIN RESULTS: Eleven completed, randomised trials comparing I.V. glycerol and control were considered. Analysis of death during the scheduled treatment period for acute ischaemic and/or haemorrhagic stroke was possible in 10 trials where 482 glycerol treated patients were compared with 463 control patients. Glycerol was associated with a non-significant reduction in the odds of death within the scheduled treatment period (Odds Ratio (OR) 0.78, 95% Confidence Intervals (CI) 0.58 to 1.06). Among patients with definite or probable ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (OR 0.65, 95% CI 0.44 to 0.97). However, at the end of the scheduled follow up period, there was no significant difference in the odds of death (OR 0.98, 95% CI 0.73 to 1.31). Functional outcome was reported in only two studies but there were non-significantly more patients who had a good outcome at the end of scheduled follow up (OR 0.73, 95% CI 0.37 to 1.42). Haemolysis seems to be the only relevant adverse effect of glycerol treatment. REVIEWERS' CONCLUSIONS: This systematic review suggests a favourable effect of glycerol treatment on short term survival in patients with probable or definite ischaemic stroke but the confidence intervals were wide and the magnitude of the treatment effect may be only minimal. Due to the relatively small number of patients, and that the trials were performed in the pre-CT era, the results must be interpreted cautiously. The lack of evidence of benefit in long term survival does not support the routine or selective use of glycerol treatment in patients with acute stroke.

Eversion versus conventional carotid endarterectomy for preventing stroke.

BACKGROUND: Carotid endarterectomy is conventionally undertaken by a longitudinal arteriotomy. Eversion carotid endarterectomy (CEA), which employs a transverse arteriotomy and reimplantation of the carotid artery, is reported to be associated with low perioperative stroke and restenosis rates but an increased risk of complications associated with a distal intimal flap. OBJECTIVES: The objective of this review was to determine whether eversion CEA was safe and more effective than conventional CEA. The null-hypothesis was that there was no difference between the eversion and the conventional CEA techniques (performed either with primary closure or patch angioplasty). SEARCH STRATEGY: The reviewers searched MEDLINE and the Cochrane Stroke Group Trials Register (last searched: December 1999), and hand searched eight surgical journals and conference proceedings. Researchers were contacted to identify additional published and unpublished studies. SELECTION CRITERIA: All randomised trials comparing eversion to conventional techniques in patients undergoing carotid endarterectomy were examined in this review. Outcomes were stroke and death, carotid restenosis/occlusion and local complications. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers to assess eligibility and describe trial characteristics, and by one reviewer for the meta-analyses. Discrepancies were resolved by discussion. When possible, unpublished data were obtained from investigators. MAIN RESULTS: Five trials were included for a total of 2465 patients and 2590 arteries. Three trials included bilateral carotid endarterectomies. In one trial, arteries rather than patients were randomised so that it was not clear how many patients had been randomised in each group, therefore, information on the risk of stroke and death from this study were considered in a separate analysis. There were no significant differences in the rate of perioperative stroke and/or death (1.7% vs 2.6%, odds ratio [OR] 0.44, 95% confidence interval [CI] 0.10-1.82) and stroke during follow-up (1.4% vs 1.7%, OR: 0.84, 95% CI: 0.43-1.64) between eversion and conventional CEA techniques. Eversion CEA was associated with a significantly lower rate of restenosis >50% during follow-up (2.5% vs 5.2%, OR: 0.48, 95% CI: 0.32 -0.72). However, there was no evidence that the eversion technique for CEA was associated with a lower rate of neurological events when compared to conventional CEA. There were no statistically significant differences in local complications between the eversion and conventional group. No data were available to define the cost-benefit of eversion CEA technique. REVIEWER'S CONCLUSIONS: Eversion CEA may be associated with low risk of arterial occlusion and restenosis. However, numbers are too small to definitively assess benefits or harms. Reduced restenosis rates did not appear to be associated with clinical benefit in terms of reduced stroke risk, either perioperatively or later. Until further evidence is available, the choice of the CEA technique should depend on the experience and familiarity of the individual surgeon.

Glycerol for acute stroke.

BACKGROUND: Brain oedema is a major cause of early death after stroke. A 10% solution of glycerol is a hyperosmolar agent that is claimed to reduce brain oedema. OBJECTIVES: To determine whether I.V. glycerol treatment in acute stroke, either ischaemic or haemorrhagic, influences death rates and functional outcome in the short or long term and whether the treatment is safe. SEARCH STRATEGY: The Cochrane Stroke Group Trials Register was searched, conference proceedings were screened and some trialists were personally contacted. SELECTION CRITERIA: All completed, randomised and quasi-randomized, controlled, published and unpublished comparisons, evaluating clinical outcome in which intravenous (I.V.) glycerol treatment was initiated within the first days after stroke onset. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, assessed the trial quality and extracted data and this was checked with all co-reviewers. Death from all causes, functional outcome and adverse effects were analysed. MAIN RESULTS: Eleven completed, randomised trials comparing I.V. glycerol and control were considered. Analysis of death during the scheduled treatment period for acute ischaemic and/or haemorrhagic stroke was possible in ten trials where 482 glycerol treated patients were compared with 463 control patients. Glycerol was associated with a non-significant reduction in the odds of death within the scheduled treatment period (OR 0.78, 95% Confidence Intervals 0.58 - 1.06). Among patients with definite or probable ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (odds ratio 0.65, 95% CI 0.44-0.97). However, at the end of the scheduled follow up period, there was no significant difference in the odds of death (odds ratio 0.98, 95% CI 0.73-1.31). Functional outcome was reported in only two studies but there were non-significantly more patients who had a good outcome at the end of scheduled follow up (odds ratio 0.73, 95% CI 0.37-1.42). Haemolysis seems to be the only relevant adverse effect of glycerol treatment. REVIEWER'S CONCLUSIONS: This systematic review suggests a favourable effect of glycerol treatment on short term survival in patients with probable or definite ischaemic stroke but the magnitude of the treatment effect may be minimal (as low as a 3% reduction in odds). Due to the relatively small number of patients and that the trials have been performed in the pre-CT era, the results must be interpreted cautiously. The lack of evidence of benefit in long term survival does not support the routine or selective use of glycerol treatment in patients with acute stroke.

[Diagnostic approach to the patient with stroke]. / Approccio diagnostico al paziente con ictus.

In the case of a patient with sudden-onset focal neurological deficit, clinicians must answer three fundamental questions: is it a stroke? is it ischemia or hemorrhage? and what kind of ischemic stroke is it? Clinical information (i.e., history and examination) is available in any situation, and its role in answering these questions is extremely important, even though certainty can only be achieved from instrumental diagnostic tools. In fact, when diagnosis is based on properly designed clinical criteria, the percentage of mistakes is quite low. Clinical methods are still the best way to orient topographic and etiologic diagnosis, as well as estimate prognosis. In addition, time might be saved if randomization in clinical trials were performed using clinical methods before initiating complex investigations.

Comparability and validity of two clinical scores in the early differential diagnosis of acute stroke.

OBJECTIVE: To compare two available clinical scores for the differential diagnosis of cerebral ischaemia and haemorrhage in acute stroke patients. DESIGN: Prospective, multicentre study of acute stroke patients evaluated with computed tomography and Allen and Siriraj scores; the scores were tested for comparability (kappa statistic) and validity (sensitivity, specificity, positive and negative predictive values, diagnostic gain). The effect of a policy of using Allen and Siriraj scores to determine pathological type of stroke before computed tomography was calculated. SETTING: Three hospitals in Italy, all participating in the international stroke trial, with different access facilities to computed tomography. SUBJECTS: 231 consecutive patients who were screened in the three hospitals for possible inclusion in the international stroke trial from 1 November 1991 to 31 May 1993. RESULTS: The prevalence of haemorrhage (diagnosed with computed tomography) was 14.7% (95% confidence interval 10.1% to 19.3%). Allen scores were "uncertain" in 44 cases and Siriraj scores in 38 cases; in the 164 cases with both the scores in the range of "certainty" kappa was 0.72. Sensitivity, specificity, positive and negative predictive values, and diagnostic gain for haemorrhage were 0.38, 0.98, 0.71, 0.91, and 0.58 for Allen scores and 0.61, 0.94, 0.63, 0.93, and 0.48 for Siriraj scores; positive predictive values for infarction were 91% for Allen scores and 93% for Siriraj scores. According to these data, of 1000 patients with acute stroke, 680 would be correctly and 70 wrongly diagnosed as "ischaemic" with the Allen score; the figures would be 671 and 48 with Siriraj score. CONCLUSION: When computed tomography is not immediately available and the clinician wishes to start antithrombotic treatment (or randomise patients in a clinical trial), the Siriraj score (and possibly the Allen score) can be useful to identify patients at low risk of intracerebral haemorrhage.

Cerebrovascular events after myocardial infarction: analysis of the GISSI trial. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI).

OBJECTIVES: To describe the epidemiology of cerebrovascular events in patients given or not given fibrinolytic treatment and to assess the prognostic implications and risk factors. DESIGN: Case series derived from the GISSI randomised trial. SETTING: 176 coronary care units in Italy giving various levels of care. PATIENTS: 5860 patients with acute myocardial infarction treated with 1.5 million units of intravenous streptokinase and 5852 patients not given fibrinolytic treatment. MAIN OUTCOME MEASURES: Cerebrovascular event, sex, age, blood pressure, history of previous infarct, site of infarction, and Killip class. RESULTS: 99 of 11,712 patients (0.84%) had a cerebrovascular event. Older age, worse Killip class, and anterior location of infarction seemed to be risk factors for cerebrovascular events (40/3201 aged 65-75 v 42/7295 aged less than 65, odds ratio 2.18; 9/437 class 3 v 55/8277 class 1, 1.81; and 57/4878 anterior v 24/4013 posterior, 1.96). No significant difference was found in the rate of cerebrovascular events between patients treated with streptokinase and controls (45/5852 (0.92%) streptokinase v 54/5860 (0.77) control). More patients in the streptokinase group than in the control group had cerebrovascular events (especially haemorrhagic strokes) on day 0-1 after randomisation (27 streptokinase v 7, control), although this was balanced by late events in control patients (54 streptokinase v 45 control at one year). The mortality of patients who had a cerebrovascular event was higher than that of those who did not (47% (47/99) v 11.6% (1350/11,613]. CONCLUSIONS: Although the incidence of cerebrovascular events complicating myocardial infarction was low, they increased morbidity and mortality. Treatment with streptokinase did not significantly alter the incidence, but age and poor haemodynamic state were associated with an increased risk.

[Efficacy in neurology]. / L'efficacia in neurologia.

The great technological progress in the Neurosciences area, which has appeared in the last few years, can cause, beside obvious scientific and practical advantages, an important risk: in fact, efficiency might be preferred at the expense of efficacy. In this paper we try and outline a sort of "efficacy route in Neurology", based on well known general principles of Clinical Epidemiology, both for diagnosis and treatment. We stress the fact that clinical evaluation is still an essential instrument in the diagnostic process, and that the result of any therapeutic procedure must be evaluated by means of hard end points, strictly related to the real problems of the neurological patient.

Development of clinical guidelines: methodological and practical issues.

The key elements for developing a clinical guideline are (a) guidelines are developed by multidisciplinary groups, (b) they are based on a systematic review of the scientific evidence, and (c) recommendations are explicitly linked to the supporting evidence and graded according to the strength of that evidence. Besides reporting the statistical strength of the randomised controlled trial results, it is necessary to consider the strength of the evidence, the methodological quality of the studies and the external validity by applying a "considered judgement" to the whole amount of the data. The Scottish Intercollegiate Guidelines Network (SIGN) process for developing guidelines is based on 4 steps: (a) methodological evaluation, (b) synthesis of evidence, (c) considered judgement and (d) grading system. The judgement on grading of recommendations is made on the basis of an (objective) assessment of the study design and quality, and a (perhaps more subjective) judgement of the consistency, clinical relevance and external validity of the evidence. The SPREAD group decided to adopt this methodology starting from the 3rd edition (2003); however, it was agreed to integrate the principles of the SIGN [4] with the statistical considerations on alpha and beta error size suggested by the Centre for Evidence-Based Medicine methodology [6], to give a more comprehensive evaluation of the available evidence. By being the product of a multidisciplinary approach, being explicit and providing information on the way agreement has been reached or on the reasons of disagreement, the SPREAD guidelines seem to fulfil the needs for shared guidelines, and to avoid the concerns related to pitfalls in the transparency of the process and in the reaching of a consensus.