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Neuropsychological rehabilitation efficacy in multiple sclerosis (MS) is a currently investigated issue. We reported, in a single blind controlled study, that an intensive short duration cognitive training of attention and executive functions significantly improves the treated functions and reduces depression in MS. The persistence of these effects over time are unknown.

To evaluate the incidence and dose-dependency of mitoxantrone (MTX)-associated acute myelocytic leukemia (AML) in the network of Italian multiple sclerosis (MS) clinics.

To describe the effect of natalizumab in the treatment of subjects with active multiple sclerosis (MS) treated before the age of 18 years.

The Geant4-DNA project proposes to develop an open-source simulation software based and fully included in the general-purpose Geant4 Monte-Carlo simulation toolkit. The main objective of this software is to simulate biological damages induced by ionizing radiations at the cellular and sub-cellular scale. This project was originally initiated by the European Space Agency for the prediction of the deleterious effects of radiations that may affect astronauts during future long duration space exploration missions. In this paper, the Geant4-DNA collaboration presents an overview of the whole on-going project, including its most recent developments that are available in the Geant4 toolkit since December 2009 (release 9.3), as well as an illustration example simulating the direct irradiation of a biological chromatin fiber. Expected extensions involving several research domains, such as particle physics, chemistry and cellular and molecular biology, within a fully interdisciplinary activity of the Geant4 collaboration are also discussed.

Interferon-beta (IFN-β) therapy has a central place in the management of multiple sclerosis (MS). The three recombinant IFN-β preparations currently available have shown benefit on activity measures (relapses and active lesions apparent on magnetic resonance imaging), while therapy advantages on progression measures (disability and total lesion burden) are less consistent. Moreover, IFN-β is effective only in a percentage of patients, since in many of them neutralizing anti-IFN-β antibodies develop after 6-18 months of treatment, leading to loss of drug bioactivity. Comparative data across studies made with different IFN-β preparations suggest that the optimal choice of IFN-β subtype, preparation and dose regimen are important determinants of efficacy. Because IFN-β actions depend on the activation of IFN-inducible genes, in addition to the direct quantification of anti-IFN-β antibodies, several other methods for the measure of IFN-β biologic activity have been recently developed. Among these, the determination of the IFN-β-inducible gene product Myxovirus protein A (MxA) has proven to be the most reliable one. Another still open point is the role of the differential expression of IFN-β receptor (IFNAR) components, since IFNAR2 subunit can be synthesized in three isoforms: functional, truncated non-functional and soluble. While this and other important issues require further studies, this article reviews and discusses the importance, potential and limits of the methods currently available to monitor IFN-β therapy in MS patients.

Although in benign multiple sclerosis (BMS) locomotor disability is absent or only minimal, subclinical cognitive impairment seems to occur in many cases. Diffusion tensor (DT) MRI enables us to quantify the extent of “actual” tissue damage, which goes undetected when using conventional MRI. Against this background, we investigated the extent of structural brain damage underlying cognitive dysfunction in BMS, with the ultimate aim to move a first step toward a more reliable definition of this disease phenotype.

In patients with primary progressive (PP) multiple sclerosis, brain MRI lesion activity and burden are low, despite the presence of severe neurological impairment. On the contrary, the degree of cord atrophy and diffuse tissue damage in the brain and cervical cord have been found to be associated with clinical disability. Against this background, this study aimed at providing an in vivo indirect assessment of brain and cervical cord pathology in a large cohort of PP multiple sclerosis patients, using conventional MRI and magnetization transfer imaging (MTI). Ninety-one PP multiple sclerosis patients, 36 secondary progressive (SP) multiple sclerosis patients and 30 healthy controls underwent brain and cervical cord MRI scans, using dual echo (brain) or fast short-tau inversion recovery (cervical cord) MTI and T(1)-weighted sequences. For the brain, T(2) hyperintense and T(1) hypointense lesion volumes were calculated and the volume of the whole of the brain tissue measured. For the cervical cord, the number and burden of lesions and the cross-sectional area were assessed. MTI scans were post-processed and analysed to obtain magnetization transfer ratio (MTR) histograms from the whole of the brain and cervical cord tissue and from the normal-appearing brain tissue in isolation. In PP multiple sclerosis patients, brain, normal-appearing brain tissue and cervical cord MTR histogram-derived metrics revealed the presence of diffuse tissue damage whose characteristics did not significantly differ from those of SP multiple sclerosis patients, even though SP multiple sclerosis patients had higher MRI-visible lesion burdens. None of the correlations between MRI or MTI measures obtained from the brain and the cord were significant. PP multiple sclerosis patients' disability was significantly, albeit weakly associated with a composite MR model including measures of loss and intrinsic damage of cervical cord tissue. Our data indicate the presence of a diffuse tissue damage undetectable by conventional MRI in PP multiple sclerosis patients, whose extent seems to match that of SP multiple sclerosis patients with similar levels of disability. They also suggest that the severity of multiple sclerosis pathology in the cervical cord is one of the factors contributing to neurological impairment in PP multiple sclerosis.

Objective Magnetisation transfer imaging (MTI) provides information about brain damage with increased pathological specificity over conventional MRI and detects subtle abnormalities in the normal appearing brain tissue, which go undetected with conventional scanning. Brain MRI and MTI findings were compared in patients with multiple sclerosis (MS) and systemic immune mediated diseases (SIDs) affecting the CNS to investigate their roles in understanding the nature of brain damage in these diseases. Methods Brain dual echo, T1 weighted and MTI scans were obtained in patients affected by systemic lupus erithematosus (SLE) with (NSLE, n=9) and without clinical CNS involvement (n=15), Behçet's disease (BD) (n=5), Wegener's granulomatosis (WG) (n=9), and antiphospholipid antibody syndrome (APLAS) (n=6). Ten patients with clinically definite MS and 15 healthy controls also underwent the same scanning protocol. Brain MRI and MT ratio (MTR) images of the same subject were coregistered and postprocessed to obtain MTR histograms of the whole brain and of the NABT. Results Brain hyperintense lesions were found in all patients with MS and with NSLE and in 5/15 patients with SLE, 5/9 with WG, 1/5 with BD, and 3/6 with APLAS. The lesion burden in the brain was significantly higher in patients with MS compared with all the other disease groups. All MTR histogram parameters were significantly different among patient subgroups. Patients with MS had significantly lower average MTR than all except patients with NSLE and significantly lower peak height and location than patients with SLE. patients with NSLE had significantly lower average MTR than patients with SLE. Conclusions Microscopic brain tissue damage is relevant in patients with MS, but, apart from patients with NSLE, it seems to be absent in systemic immune mediated diseases, even in the presence of macroscopic MRI lesions or clinical evidence of CNS involvement.

To assess MRI and magnetization transfer (MT) imaging changes in the brain and cervical cord from patients with Devic's neuromyelitis optica (DNO), and to compare them with those from patients with MS.

In this study we assessed the safety, efficacy and cost-effectiveness of the use of triple dose gadolinium-DTPA (Gd) in serial monthly brain MRI of patients with multiple sclerosis, such as could be selected for clinical trials. The number of enhancing lesions, the number of new enhancing lesions and the number of active scans were used to evaluate the sensitivity of the contrast-enhanced MRI to disease activity. The dose of Gd, and the effect of introducing a delay between the contrast injection and the scan were both appraised. Every 4 weeks for 3 months, and in two separate sessions, scans were obtained from 40 patients with relapsing-remitting or secondary progressive multiple sclerosis, 5 min (early) and 20 min (delayed) after a standard dose (0.1 mmol/kg) or triple dose (0.3 mmol/kg) Gd injection. There were 435 enhancing lesions (242 of which were new) on the early standard dose scans, 479 (263 new) on the delayed standard dose, 772 (365 new) on the early triple dose and 827 (404 new) on the delayed triple dose. There were 109 scans revealing active disease on the early standard dose scans, 112 on the delayed standard dose, 119 on the early triple dose and 120 on the delayed triple dose. Statistical simulations indicated that the sample sizes needed for both cross-over and parallel-group trials with similar powers are lower if serial monthly triple dose MRI is used. No side-effects were reported and no significant changes in blood test parameters were found throughout the study. This study shows that the serial use of triple dose Gd is safe, and that it increases the sensitivity of serial monthly enhanced MRI in detecting multiple sclerosis activity significantly. Its use should enable preliminary trials of experimental therapies for multiple sclerosis to be conducted in small patients populations over a short period of time.Key words: multiple sclerosis; MRI, gadolinium-DTPA; triple dose; disease activity

ObjectiveThe ability of recombinant human interferon β-1a (rh-IFN β-1a) to suppress multiple sclerosis activity, evaluated from MRI, was assessed across a range of lesions enhancing at different gadolinium-DTPA (Gd) doses and with different sizes. MethodsEvery 4 weeks, standard dose (Sd; 0.1 mmol/kg Gd) and triple dose (Td; 0.3 mmol/kgGd) MRI were obtained from 18 patients with relapsing-remitting multiple sclerosis for 3 months before and 4 months after starting treatment with 44 μg rh-IFN β-1a subcutaneously, once a week. ResultsThe total numbers of enhancing lesions were 145 and 126 on Sd scans and 278 and 192 on the Td scans obtained before and after treatment. The introduction of treatment decreased, on average, the rate of appearance of new enhancing lesions seen on Sd and Td scans by 37% (p<0.001). Treatment effects on new enhancing lesions seen on Td scans was, on average, 28% higher than on those seen on Sd scans. The distribution of lesion sizes on Td scans changed significantly during the treatment period (p=0.05), due to a marked decrease in the number of small lesions. Conclusions The effect of 44 μg rh-IFN β-1a in reducing multiple sclerosis disease activity, as monitored by Gd enhanced MRI, is not homogeneous, but graduated according to the pathological characteristics and size of the lesions.

This study assessed whether dysfunction of the blood-brain barrier is an obligatory early event in lesion formation in multiple sclerosis. Dual-echo and T1-weighted magnetic resonance imaging after the injection of a triple dose (0.3 mmol/kg) of gadolinium-DTPA were obtained from ten patients with relapsing-remitting multiple sclerosis every week for 2 months. Sixty-four newly active lesions were detected by the two techniques. All the 44 new lesions seen on dual-echo scans enhanced during the early phases of their formation: 33 at their first appearance, 10 1 week before their appearance on the dual-echo scans, and one the week thereafter. When the every fourth (monthly) scan was analyzed, a total of 55 newly active lesions were detected (i.e., 14% active lesions would have been missed compared to the number found on weekly scanning). Thirty-one of them were detected by both dual-echo and triple-dose scans, 15 only by enhanced scans, and nine only by dual-echo scans. This study confirms that with highly sensitive magnetic resonance imaging techniques dysfunction of the blood-brain barrier is an obligatory early event in new lesion formation in relapsing-remitting multiple sclerosis.

We report a case of acute autonomic neuropathy without any signs of peripheral neuropathy, which presented in a young woman with acute urinary retention. Exclusion of other possible etiologies, clinical indications and a precise diagnostic routine enabled us to recognise this uncommon but important pathology.

6 patients with severe chronic progressive multiple sclerosis were subjected to total lymphoid irradiation (TLI) to assess clinical efficacy and side effects. During a 4 year follow-up the disability progression was continuous. Side effects during TLI were well tolerated; side effects after TLI brought about a worsening of the quality of life. One patient died of pneumonia. In this preliminary study TLI did not reduce the worsening of disability in MS patients.

Nineteen moderately impaired patients with clinically definite multiple sclerosis and an initially relapsing-remitting course were included in a neuropsychological and magnetic resonance imaging (MRI) follow-up study. The average test/re-test interval was about 2 years. The neuropsychological findings were indicative of a very mild overall impairment; the patients, as a group, showed no evidence of cognitive deterioration in the follow-up period. A numerical estimation of the severity of cerebral demyelination shown by MRI did not indicate a significant change. No correlation between cognitive performance variations and MRI changes was found.

We performed this study to evaluate and compare the numbers of total and new enhancing lesions detected on serial monthly brain magnetic resonance imaging (MRI) after the injection of a standard dose (SO) and a triple dose (TO) of gadolinium‐OTPA (Gd) in patients with primary progressive multiple sclerosis (PPMS). Every 4 weeks for 3 months and in two separate sessions, MRI scans were obtained from 5 patients with PPMS, 5 (early) and 20 minutes (delayed) after SO (0.1 mmol/kg) or TO (0.3 mmol/kg) Gd injection. In 2 patients, T1‐weighted scans with a magnetization transfer pulse (MT) after SD and TD injection were also obtained. There were 13 enhancing lesions (5 of which were new) on the early SO scans, 15 (5 new) on the delayed SD scans, 17 (6 new) on the early TO scans and 18 (7 new) on the delayed TO scans. TO MRI scans detected more enhancing lesions than SO scans in 3 patients (two of them were those with the lowest disability). The application of the MT pulse did not change the numbers of enhancing lesions seen after the injection of SO and TO of Gd in the remaining two patients. No side effects were reported and no significant changes in blood test parameters were found throughout the study. Our results suggest that serial monthly TO MRI, delayed scanning, MT T1‐weighted scans or their combination, although safe, have a limited role for monitoring disease evolution in patients with PPMS.

The authors assessed the ability of diffusion tensor MRI to grade cervical cord damage in 10 patients with neuromyelitis optica, 10 patients with multiple sclerosis, and 10 healthy controls. The three groups differed in terms of average mean diffusivity (p0.008) and average fractional anisotropy (p0.04). There was a correlation between the Expanded Standard Disability Status Scale score and cord average mean diffusivity (r0.52, p0.02).

In this study, we evaluated the effect of imprecision in patient repositioning encountered in real life on multiple sclerosis (MS) lesion volumes measured from MRIs. We also evaluated two putative methods for reducing the variability in these lesion volume measurements: first, a reduction of slice thickness (from the conventional 5 mm to 3 mm) and second, the application of a new repositioning technique based on the use of head immobilization shells. We evaluated the errors in lesion volume by scanning 10 patients a total of four times using the two slice thicknesses and two repositioning methods (conventional and using a head immobilization shell). The mean absolute percentage difference between two corresponding scans was 6.8% (range, 1.24 to 11%) using conventional slice thickness and repositioning, 4.1% (range, 0.7 to 5.56%) using conventional slice thickness and head immobilization shells, 2.6% (range, 0.8 to 6.66%) using the conventional repositioning technique and 3-mm slice thickness, and 1.4%(range, 0.2 to 6.14%) using slice thickness of 3 mm and head immobilization shells. These mean absolute differences were significantly different(p= 0.0008). Our results indicate that the effect of repositioning errors of the order of those that can be encountered in the daily life situation of clinical trials affects significantly lesion load measurements in MS and that the combined use of thinner slices and more accurate repositioning techniques can markedly improve the reproducibility of such measurements.

In 1967 Shealy first used electrical stimulation of the spinal cord to treat spasticity and pain. This therapy proved to be effective for bladder dysfunction too. The effect of electrical stimulation of the spinal cord at thoracic level has been evaluated in 18 neurogenic patients suffering from hyperreflexia with detrusor-sphincter dyssynergia. Bladder function improved significantly in 13 (73%). Partial or complete relief of bladder hyperreflexia, marked increased of bladder capacity and reduction of residual urine were recorded. The beneficial effect of stimulation indicates that it is a safe and effective alternative treatment for the neuropathic bladder and careful trials with further investigations should be carried out.

Two of four sisters have multiple sclerosis (MS), lamellar ichthyosis, beta thalassaemia minor and a quantitative deficit of factor VIII-von Willebrand complex. The mother and the other sisters have only beta thalassaemia minor. The association of MS and a cluster of genetically determined diseases is rare. Such families could offer a new approach to the investigation of the polygenetic background of MS.

Multiple sclerosis progressively impairs patients’ ability to independently perform activities of daily living, reduces working capacity, and negatively affects social interactions and relationships, imposing a cost for the society. The aim of this study was to explore the impact on society of treatment of multiple sclerosis with natalizumab in Italian clinical practice. A prospective, observational study was conducted in 24 specialized centers throughout Italy. Direct and indirect costs, as well as the health-related quality of life of patients undergoing treatments, were estimated, while societal impacts were determined using a cost-utility approach. Non-medical direct and indirect costs accounted for 55.7% of the total cost prior to treatment and up to 47.5% after treatment with natalizumab. From the social perspective, greater medical direct costs for second-line drug treatment are nearly offset by savings on non-medical direct costs and by greater productivity, resulting in a +0.5% incremental cost. Assuming a societal perspective, the first year of treatment with natalizumab in real-world clinical practice results in an incremental cost of €2814.8/quality-adjusted life year gained. Multiple sclerosis imposes a considerable burden on patients, their families, and caregivers, stressing the importance of considering the societal perspective in the appraisal process. Treatment with natalizumab shows a noteworthy benefit in social terms.

Without Abstract:

TO THE EDITOR. —Greenberg et al1 recently reported that elevated levels of a soluble form of the interleukin 2 receptor (sIl-2r) released by activated lymphoid cells2 are found in the serum samples of patients affected by chronic progressive multiple sclerosis. An increased expression of membrane-bound interleukin 2 receptor on peripheral blood lymphocytes in patients with a relapsing-remitting form of multiple sclerosis has also been described.3 Therefore, we have measured the levels of sIl-2r in the serum samples obtained from 34 patients with clinically defined4 relapsing-remitting multiple sclerosis using an enzyme-linked immunosorbent assay (Tcell Science, Cambridge, Mass). Nine patients (7 females, 2 males; mean age, 29.2 years) were studied during an acute exacerbation, while 25 patients (17 females, 8 males; mean age, 38.9 years) were studied in a period of clinical remission of at least 6 months' duration. None of the patients had taken steroids during the