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.

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.

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.

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.

Radiation-induced myelopathy in long-term surviving metastatic spinal cord compression patients after hypofractionated radiotherapy: a clinical and magnetic resonance imaging analysis.

BACKGROUND AND PURPOSE: Hypofractionated radiotherapy is often administered in metastatic spinal cord compression (MSCC), but no studies have been published on the incidence of radiation-induced myelopathy (RIM) in long-term surviving patients. Our report addresses this topic. PATIENTS AND METHODS: Of 465 consecutive MSCC patients submitted to radiotherapy between 1988 and 1997, 13 live patients (seven females, six males, median age 69 years, median follow-up 69 months) surviving for 2 years or more were retrospectively reviewed to evaluate RIM. All patients underwent radiotherapy. Eight patients underwent a short-course regimen of 8 Gy, with 7 days rest, and then another 8 Gy. Five patients underwent a split-course regimen of 5 Gy x 3, 4 days rest, and then 3 Gy x 5. Only one patient also underwent laminectomy. Full neurological examination and magnetic resonance imaging (MRI) were performed. RESULTS: Of 12 patients submitted to radiotherapy alone, 11 were ambulant (eight without support and three with support) with good bladder function. In nine of these 11 patients, MRI was negative; in one case MRI evidenced an in-field relapse 30 months after the end of radiotherapy, and in the other, two new MSCC foci outside the irradiated spine. In the remaining patient RIM was suspected at 18 months after radiotherapy when the patient became paraplegic and cystoplegic, and magnetic resonance images evidenced an ischemic injury in the irradiated area. The only patient treated with surgery plus postoperative radiotherapy worsened and remained paraparetic. Magnetic resonance images showed cord atrophy at the surgical level, explained as an ischemic necrosis due to surgery injury. CONCLUSIONS: On the grounds of our data regarding RIM in long-term surviving MSCC patients, we believe that a hypofractionated radiotherapy regimen can be used for the majority of patients. For a minority of patients, more protracted radiation regimens could be considered.

Charcot-Marie-Tooth disease type I and related demyelinating neuropathies: Mutation analysis in a large cohort of Italian families.

Charcot-Marie-Tooth neuropathy type 1 (CMT1), the most common hereditary neurological disorder in humans, is characterized by clinical and genetic heterogeneity. It is caused mainly by a 1.5 Mb duplication in 17p11.2, but also by mutations in the myelin genes PMP22 (peripheral myelin protein 22), MPZ (myelin protein zero), Cx32 (connexin 32; also called GJB1), and EGR2 (early growth response 2). In this study, we have screened 172 index cases of Italian families in which there was at least one subject with a CMT1 diagnosis for the duplication on 17p11.2 and mutations in these genes. Among 170 informative unrelated patients, the overall duplication frequency was 57.6%. A difference could be observed between the duplication frequency in familial cases (71.6%) and that observed in non-familial cases (36.8%). Among the non-duplicated patients, 12 were mutated in Cx32, four in MPZ, two in PMP22, and none in the EGR2. In the non-duplicated cases, the overall point mutation frequency for these genes was 25.0%. We describe the mutations identified, and consider possible genotype-phenotype correlation.

Human immunodeficiency virus type 1 modulates telomerase activity in peripheral blood lymphocytes.

The effect of human immunodeficiency virus type 1 (HIV-1) on telomerase activity in peripheral blood lymphocytes (PBL) was examined. Telomerase is an enzyme that is involved in mechanisms that control cell life span and replicative potential. HIV-1 reduced telomerase activity in in vitro-infected PBL and impaired enzyme activation upon cell stimulation. Telomerase activity was significantly lower in PBL from 23 HIV-1-infected patients than in PBL from healthy donors and significantly increased during highly active antiretroviral therapy (HAART) in 10 patients who had both a virological and an immunological response and in 5 and 8 patients with a virological or an immunological response, respectively. Further analyses of fractionated cells revealed that telomerase activity increased mainly in CD4(+) lymphocytes. Overall, these findings demonstrate that HIV-1 infection down-modulates telomerase activity and suggest that both the HIV-1 decline and immunorestoration in response to HAART contribute to increased telomerase activity in CD4(+) lymphocytes.

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.

Hereditary spastic paraplegia associated with peripheral neuropathy: a distinct clinical and genetic entity.

Hereditary motor and sensory neuropathy type V is a very rare disease in which hereditary spastic paraplegia is associated with peripheral motor and sensory neuropathy. The symptomatic onset of the disorder is usually in the second decade of life or later and the course is progressive over many years. Hereditary motor and sensory neuropathy type V is inherited as an autosomal dominant trait usually showing incomplete penetrance. So far, no molecular data are available in the literature about this disease. In our study we present clinical and molecular data from a large Italian family displaying hereditary motor and sensory neuropathy type V. Taking into account the clinical features in this family, we have performed a linkage analysis for markers strictly associated with all the known loci for autosomal dominant and autosomal recessive forms of hereditary spastic paraplegia and hereditary motor and sensory neuropathy type II, and have found no linkage to these loci. Our study suggests that hereditary motor and sensory neuropathy type V is not only a distinct clinical entity but also a distinct genetic entity.

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.

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.

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.

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.

[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.

[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.

Clinical methods for diagnostic confirmation of stroke subtypes.

Clinicians faced with a patient having a sudden-onset, focal neurological deficit must answer three fundamental questions: is it a stroke?, is it ischemia or hemorrhage? and what kind of ischemic stroke is it? Clinical information (that is, history and examination) is immediately available to every physician, and its role in answering these questions is extremely important, even though a 100% certainty can only be obtained with instrumental diagnostic tools. In fact, when diagnosis is based on properly designed clinical criteria, the percentage of diagnostic mistakes is quite low. Clinical methods are still the best way of orientating topographic and etiologic diagnosis, as well as prognosis. In addition, time might be saved if randomization in clinical trials could be done using clinical methods before complex investigations are applied.