BREMSO: a simple score to predict early the natural course of multiple sclerosis.

BACKGROUND AND PURPOSE: Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. METHODS: An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. RESULTS: Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS≥ third quartile vs. ≤ first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. CONCLUSIONS: BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting.

Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude.

BACKGROUND: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) status-for the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power. METHODS: In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome. RESULTS: A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude (p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change (p < 0.001). CONCLUSIONS: The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.

Azathioprine for multiple sclerosis.

BACKGROUND: Azathioprine (AZA) is an immunosuppressive drug widely prescribed for the treatment of multiple sclerosis (MS) until the first half of the 1990s. It could be an alternative to interferon beta because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, have been raised. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in MS. OBJECTIVES: To compare azathioprine with placebo. To assess the effect of azathioprine on major clinical outcomes (ie, disability progression and relapses) in patients with MS, and to evaluate the drug's safety. METHODS: The Cochrane MS Group search strategy was adopted to identify relevant articles. All randomised controlled trials comparing azathioprine treatment of a least 1 year duration with placebo for patients with MS were eligible for the review. Cohorts, case controls, case series and case reports were also considered to assess adverse effects. Regulatory agencies were additional sources of information for adverse effects. More details are available in the full review.

Prevalence and incidence of multiple sclerosis in Salerno (southern Italy) and its province.

Many multiple sclerosis (MS) prevalence studies in Italian northern and central areas, since 1980, have put Italy in a high risk zone; none concerns southern Italy. The MS registry of Salerno Center was reviewed, including the city and 16 towns at different distances (9-149 km) better connected to our Center. Population screened: 259 681 persons (Salerno = 136 678; province = 123 003). Prevalence day was December 31, 2005. Data on 186 patients were collected of which 55 were males, 131 females; crude total prevalence = 71.6263 (62.03-82.303, ranging from 50.1128 (Oliveto Citra) to 431.499 (Controne). Salerno prevalence rate is 70.9697 (57.41-86.583); standardized = 72.02. Incidence rate ranges from 2.38585 (1.6-3.39) (1991-95) to 4.31997 (3.24-5.6) (2001-05). Our data can be underestimated because some patients could have skipped the local center. This emphasizes that the results, except for Sardinia, are comparable to Italian literature data. They confirm that this territory is a high risk area for MS. There is also an indirect indication against a latitude gradient for MS.

Azathioprine for multiple sclerosis.

BACKGROUND: Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis (MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in multiple sclerosis. OBJECTIVES: To compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with multiple sclerosis. SEARCH STRATEGY: The Multiple Sclerosis Group's Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2006), Cochrane Database of Systematic Reviews (CDSR - Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE - searched 28.12.06) MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006). Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with multiple sclerosis. Cohorts, case controls, case series and case reports were also used to assess adverse effects. DATA COLLECTION AND ANALYSIS: Potentially relevant references were evaluated and all data extracted by two independent authors. MAIN RESULTS: The five trials that met our criteria included 698 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients at one year's, from 488 (70%) at two years' and from 415 (59.5%) at three years' follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years' (RRR =23%; 95% CI = 12% to 33%) and three years' (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies. Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years' follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials. Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%). Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g. AUTHORS' CONCLUSIONS: Azathioprine is an appropriate maintenance treatment for patients with multiple sclerosis who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating multiple sclerosis. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in multiple sclerosis has not been made.

Endovascular procedures in critical leg ischemia of elderly patients.

PURPOSE: Purpose of this study was to evaluate angiographic and clinical results of popliteal, infrapopliteal, and multi-level disease percutaneous transluminal angioplasty (PTA) in over-80 years old patients with chronical clitical leg ischemia. In fact such patients with extensive peripheral vascular disease and critical limb ischemia (CLI) are generally poor surgical candidates. METHODS: Between 1998 and 2003, 37 elderly patients aged 80-89 years old (mean age 83.3) with critical leg ischemia were treated with PTA. All patients were at high surgical risk. 31/37 (81.5%) patients had chronic non-healing wounds, and 14/37 (37%) had multi-level disease of superficial femoral, popliteal and crural arteries. One hundred and two lesions were treated by angioplasty. Immediate angiographic and 1 year clinical results were retrospectively analyzed. RESULTS: The overall procedural success rate was 32/37 (84.2%). There were three major complications (7.9%), but no deaths, and three technical failures, all were of infrapopliteal lesions. After 1 year, 27 patients could be followed, five patients died during the first year of unrelated causes. Twenty-three patients (85.2%), were clinically re-occluded within 1 year, but complete and partial wound healing was achieved in 80% (16/20) and rest pain improvement in 57% (4/7), so that overall limb salvage was 74% (20/27). CONCLUSIONS: Elderly patients with multi-level CCLI have a short patency term following angioplasty of 14.8% after 1 year. Nevertheless, this temporary vascular patency enables wound healing or improvement in 74% of these patients, thus such endovascular interventions are recommended in this age group.

Carotid endarterectomy under local anesthesia in elderly: is it worthwhile?

Carotid endarterectomy (CEA) has a positive effect on stroke free survival in patients with either symptomatic or asymptomatic severe carotid bifurcation stenosis. However, most trials have excluded elder patients. In addition, concerns have arisen regarding the benefits of CEA in the elderly population, especially in women. In this study, we performed an outcome analysis in patients undergoing CEA comparing those eighty and older to their younger counterparts. A total of 262 carotid operations were performed under local anaesthesia between 1998 and 2004; 76 (34%) were carotid reconstructions in 70 patients over 75 yr of age. Twenty patients (26%) presented with asymptomatic critical stenosis. Transient ischemic symptoms were the reason for presentation in 35 patients (46%). Progressive stroke was documented in two patients (3%) and a stroke with persisting neurological deficit was demonstrated in 19 cases (25%). Coronary artery disease was present in 47 patients (38%) and arterial hypertension in 55 (72%). Fifty-nine patients (84%) were classified as ASA group 3. Seventy-one thromboendarterectomies of the carotid bifurcation with direct closure were performed. Five patients had other types of reconstruction. Postoperative complications occurred in three patients. One had a transient neurological deficit and another a lethal stroke; the third patient died from myocardial infarction. The in-hospital mortality was 2.9%, which was not significantly higher than the results of the reconstructions in younger patients (1.5%). Surgery for carotid artery occlusive disease under local anaesthesia can be safely performed in selected patients of more than 75 yr of age.

Effect of topical ketanserin administration on intraocular pressure.

The effect of topical ketanserin on intraocular pressure (IOP) in normotensive and hypertensive eyes was evaluated. The study was performed on 10 healthy volunteers and 10 glaucomatous patients. Systolic arterial blood pressure (SBP), diastolic arterial blood pressure (DBP), heart rate (HR), IOP, tonographic outflow facility, pupil diameter, corneal thickness, and tear secretion were recorded at baseline and at 1 hour intervals for 12 hours after topical administration of 0.5% ketanserin or placebo, given in a randomised, double masked, crossover fashion. The alternative treatment was given 1 week later. In all subjects ketanserin significantly lowered IOP, while no variations in SBP, DBP, HR, pupil diameter, corneal thickness, and tear secretion were found. When subjects received placebo no significant variations of IOP occurred. Total outflow facility, measured by conventional tonography, increased significantly after drug administration in all subjects. Ketanserin is effective up to 6 hours in control subjects and 9 hours in glaucomatous patients. The placebo did not induce any change in this component of the aqueous humour dynamic in normal or in glaucomatous eyes. The findings indicate that topical ketanserin might be added to the list of antiglaucomatous agents.

[Post-phlebothrombotic venous insufficiency of the lower limbs. Echo-guided targetted surgery]. / Insufficienza venosa post-flebotrombotica degli arti inferiori. La chirurgia mirata eco-guidata.

The post-phlebothrombotic syndrome surgery has always had a limited space within the limits of the venous lower limbs surgery. This, either for the distrust of surgeon to operate a limb with deep thrombotic phenomenon, or because the range of possible operations is rather limited and constituted by very cruent and devasting operations. The introduction of very accurate method in the preoperative diagnostic, as the echo-color-Doppler, enables an accurate mapping of the new venous post-phlebothrombotic situation and a careful haemodynamic study of the deep or superficial venous circle. Hence, the surgeon has a new and significant chance to perform a minimal surgery generally directed to the ligation of the perforans veins that has become incontinent after the phlebothrombotic insult. In this way, the wide and devasting dissection can be avoided as previous Linton-type interventions.

[The "pedrada" ("coup-de-fouet") syndrome. A possibility to be considered in acute leg pain]. / Sindrome della "pedrada". Un'eventualità da considerare nel dolore acuto della gamba.

The authors describe a clinical case of pedrada syndrome in a patient formerly suffering from acute CID. It is a pathology enough rare and easily mistakable with phlebotrombosis of leg but from which is well to be able to do differential diagnosis because of therapy for an affection is clearly contraindicated for the other.

Biliary leaks after laparoscopic cholecystectomy. Results of the endoscopic treatment.

BACKGROUND: Significant postoperative bile leaks occur in approximately 0.8 to 1.1% of patients. The goal of endoscopic therapy is to eliminate the transpapillary pressure gradient, thereby permitting preferential transpapillary bile flow rather than extravasation at the site of leak. METHODS. Sixty-four patients were retrospectively evaluated. Endoscopic treatment comprised endoscopic sphincterotomy followed by insertion of a naso-biliary drainage or a stent. Retained stones were extracted by standard procedures. RESULTS: The cystic duct remnant was the site of bile extravasation in 50 cases, ducts of Luschka were the source in 4 cases, common bile duct in 6 cases and common hepatic duct in 4 cases. Retained bile duct stones were detected in 21 cases and papillary stenosis in 4 cases. Endoscopic therapy involved sphincterotomy in 25 cases with stones extraction in 21 cases followed by nasobiliary drain insertion, and placement of stent in the remainder. Bile leaks resolved in 96.9% of patients, on average 3 days in cases of associated stones or papillary stenosis, and 6.5 days in the remainder. Two cases of mild pancreatitis were evidenced from endoscopic treatment. CONCLUSIONS: Endoscopic management is the treatment of choice for postcholecystectomy bile leaks.

[Use of mechanical staplers in surgery of aneurysms of the abdominal aorta]. / L'impiego delle cucitrici meccaniche nella chirurgia degli aneurismi dell'aorta addominale.

This research aims to illustrate the advantages of using staplers in abdominal aorta surgery. The authors describe their experience in a personal case, of a patient suffering from aneurysmatic expansion of the abdominal aorta extending to both the common iliac arteries. The use of staplers for the closing of the distal stumps in particularly advantageous because it makes less problematic the dissection of the iliac and by hypogastric artery from their underlying veins. That involves a risk diminution of the iliac vein accidental lesions, better by hypogastric artery revascularization, shortening of any times and the perfect haemostatic holding of the mechanical suture, allowing a reduction in mortality and morbidity.

[Surgical treatment of thyroid diseases in geriatric patients]. / Il trattamento delle tireopatie chirurgiche nel paziente in età geriatrica.

Thyroid diseases have a characteristic evolution in geriatric age, whether for the symptomatology frequently mingled with typical manifestations of again, or for glandular involution. Moreover, in the aged patient, the particular aspect of the epidemiology, physiopathology, clinic and therapy are to know and interpret. In most cases, the presence of a uni- or multi-nodular goiter does not cause compression problems or cancerization risk. In the presence of these problems and in multi-nodular goiter, we prefer total thyroidectomy because, at the present time, it is possible to put at zero the risks of this operation, neither we fear hypothyroidism which all the same also appears in less extensive operations. Between thyroid diseases, cancer has a typical biological behaviour and prognosis in geriatric patients. While most tumors have a better curability in geriatric age, these have a worse prognosis. So therapeutic indications very as a function of age. About this the authors present preliminary data of a prospective trial started in 1992.

Prevalence and incidence of Multiple Sclerosis in Campobasso (Molise region chieftown, southern Italy).

OBJECTIVE: Multiple Sclerosis in southern Italy was not epidemiologically studied until 2006 in Salerno (Campania region), with data based on the registry of district MS centers established since 1996 by Italian Ministry of Health. This paper reports data about Molise region by the same metodology as Campanian study. PATIENTS AND METHODS: The registry of MS center was searched for the city of Campobasso, chief town of Molise region. Population screened: 51,633 units. ISTAT 2005 data were used for comparison and age standardization. Prevalence day: September 30, 2009; incidence was calculated by cumulative rates 1996-2000 and 2001-2005. RESULTS: 47 patients were collected, 17 males, 30 females, age 44.10 (9-74, SD 14.38); female/male ratio=1.76/1; age onset 34.61 (4-61, SD 12.40); mean disease duration 9.48 years (0-24; SD 4.28). Males prevalence: 68.62/100,000; females: 111.68/100,000. Total prevalence: 91.02/100,000; standardized: 90.91/100,000. Incidence rates: 1996-2000: 10.84/100,000; 2001-2005: 4.26/100,000. CONCLUSIONS: Prevalence is coherent with previous Campanian data, and with last epidemiologic papers on middle Italy, confirming also the validity of MS district centers registries. A possible underestimation of data, for some patients could still migrate to northern centers, could contribute to the differences in incidence. Nevertheless, prevalence data confirm southern Italy as high risk area for MS, and stands against a latitude gradient in this country.

Ischemic cardiopathy and other heart disorders: differences in risk of cerebrovascular disease and in its association with carotid obstruction.

A series of 1003 patients examined by cervical Doppler is reviewed, stressing differences between ischemic cardiopathies and other heart diseases as to the risk of carotid cerebrovascular disease (CVD) and its pathogenesis. The authors find that in ischemic heart disease the risk of stroke is almost entirely linked to severe carotid obstruction; in other cardiac disorders (rheumatic valvulopathies, arrhythmias etc.) this risk is independent from arterial damage, and the risk subsequent to an associated carotid stenosis does not differ from that of the general population.

Ischemic cardiopathy and other heart diseases: differences in carotid atheromas examined by duplex scanner.

Differences of frequency and morphology of carotid plaques are studied in 39 patients with ischemic cardiopathy matched for sex and age with 39 patients with various cardiopathies and 78 controls without heart diseases. Ischemic patients have more plaques, and these are more extended along the vessels. The plaques of the other cardiopathies reach greater thickness and degree of stenosis.

Inhibition of rat lens aldose reductase by bendazac-L-lysine salt.

Authors describe the in vitro effect of bendazac-L-lysine salt on the activity of enzyme aldose reductase from rat lens. In the presence of bendazac the activity of the tested enzyme was inhibited. Lineweaver-Burk plot demonstrated that the inhibition was noncompetitive. The possible curative effects on diabetic cataract together with a better way of administration are pointed out.

Topical benzyl alcohol reduces cataract surgery need: two long-term double blind studies.

Substances derived from biotransformation of non-steroid antiinflammatory drugs (NSAID) produced by patients responsive to the biological liquid oxidant activity (BLOA) test, have been shown to have anticataract activity. They are all aromatic alcohols with physico-chemical properties similar to benzyl alcohols (BA); they were very efficacious in preventing in vitro (cyanate, heat) cataracts and in vivo (uveitis, radiation, selenite) cataracts but had no effect on sugar cataracts. The mechanism underlying this effect seems to be mainly antioxidant together with a stabilizing effect on lens membrane integrity and a stimulating effect on Na-K ATPase and membrane sodium pump. The well balanced lipo- and hydro-solubility of these compounds makes them very suitable for topical application to the eye as lipid solubility is the major factor governing transcorneal penetration of drugs. In the two long-term double blind studies on humans described here, comparing BA, placebo and Catalin in the topical treatment of progressive cataract rapid (2-3 weeks treatment) reversal of incipient cataract was obtained accompanied by a marked improvement of vision and by a significantly lower percentage of eyes requiring surgery after 22 months treatment with BA than with placebo and Catalin. In conclusion, further studies on the effect on the eye of BA and similar compounds such as phenyl-ethanol are advisable especially because they are already used as preservatives in eye-drop formulations.