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Objective Evaluate the effect of subcutaneous interferon β-1a (sc IFN β-1a) versus placebo on the evolution of T1-weighted MRI lesions and central brain atrophy in in patients with a first clinical demyelinating event (FCDE). Methods Post hoc analysis of baseline-to-24 month MRI data from patients with an FCDE who received sc IFN β-1a 44 μg once- (qw) or three-times-weekly (tiw), or placebo, in REFLEX. Patients were grouped according to treatment regimen or conversion to clinically definite MS (CDMS) status. The intensity of new lesions on unenhanced T1-weighted images was classified as T1 iso- or hypo-intense (black holes) and percentage ventricular volume change (PVVC) was assessed throughout the study. Results In patients not converting to CDMS, sc IFN β-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P P = 0.005) and new T1 iso-intense lesions (P P = 0.002) after 24 months; only sc IFN β-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P P Conclusions In patients with an FCDE, treatment with sc IFN β-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

BackgroundThe visual system could be included in the diagnostic criteria for multiple sclerosis (MS) to demonstrate dissemination in space (DIS) and dissemination in time (DIT).ObjectiveTo investigate the diagnostic value of retinal asymmetry in MS.MethodsA prospective, longitudinal study in individuals with MS (n=151) and healthy controls (n=27). Optical coherence tomography (OCT) was performed at 0, 2 and 4 years. Macular ganglion cell and inner plexiform layer (mGCIPL) thickness was determined as well as measures for retinal asymmetry: the inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD). Receiver operator characteristics curves were plotted and the area under the curve (AUC) was calculated for group comparisons of the mGCIPL, IEPD, IEAD and atrophy rates.ResultsThe diagnostic accuracy of both the IEPD and IEAD for differentiating bilateral and unilateral MS optic neuritis was high and stable over time (AUCs 0.88–0.93). The IEPD slightly outperformed the IEAD. Atrophy rates showed low discriminatory abilities for differentiating MS from controls (AUC 0.49–0.58).ConclusionThe inter-eye differences of the mGCIPL have value for demonstration of DIS but in individuals with longstanding MS not for DIT. This may be considered as a test to detect DIS in future diagnostic criteria. Validation in a large prospective study in people presenting with symptoms suggestive of MS is required.

Background Brain tumour patients often have neurocognitive deficits which can result in problems with activities in daily living that are cognitively complex. Currently, no valid and reliable brain tumour-specific instrument to measure these instrumental activities of daily living (IADL) is available, but such an instrument is being developed. This study aimed to validate the EORTC IADL-BN32 questionnaire, comprising five multi-item and two single item scales, in a large set of international brain tumour patients. Material and Methods This international study was conducted in 10 countries worldwide. Primary and metastatic brain tumour patients and their proxies were requested to complete the EORTC IADL-BN32 and a subjective cognitive questionnaire (MOS COG-R) at multiple time points. Several psychometric properties were evaluated with baseline data, including the structural validity (bi-factor confirmatory factor analysis [CFA]), reliability (internal consistency), construct validity (known groups comparisons) and patient-proxy congruency (intra-class correlation coefficients [ICC], Spearman's correlation). Results At baseline, 326 patients ( 30% low-grade glioma, 37% high-grade glioma (HGG) and 33% brain metastases) and 311 proxies completed the EORTC IADL-BN32. The bi-factor CFA was found to have a satisfactory model fit (CFI=0.92 and TLI=0.90), and other parameters indicated a good fit (RMSEA=0.08 and SRMR=0.05), thereby validating the preliminary scale structure, but also an IADL sum score. The multi-item scales showed good (0.9>α≥0.8) to excellent (α≥0.9) internal consistency (range α=0.86-0.97). Known groups comparisons analyses regarding patient’s cognitive status (indications vs. no cognitive impairment), subjective cognitive complaints (MOS COG-R ≤30 vs. >30), basic ADL (Barthel Index Conclusion The evaluated psychometric properties support the current scale structure of the EORTC IADL-BN32. Additional psychometric properties with longitudinal data are needed, such as test-retest reliability and responsiveness, to further validate the EORTC-IADL BN32 questionnaire.

Neuropsychological test scores in people with MS (PwMS) do not fully reflect cognitive functioning in daily life. Therefore, we developed a questionnaire based on instrumental activities of daily living (IADL), using the Amsterdam IADL-Q© for Alzheimer’s disease as starting point. Forty-eight items were evaluated on relevance and clarity by (inter)national experts (n = 30), PwMS (n = 61) and proxies (n = 30). Consequently, four items were omitted, two items were merged and seven items were added. Fifty items were included in the IADL questionnaire specific to cognitive functioning in MS (the MS-IADL-Q). Future studies are warranted to assess the psychometric properties of the MS-IADL-Q.

Aim: In active relapsing remitting multiple sclerosis (RRMS) patients requiring second-line treatment, the Dutch National Health Care Institute (ZiN) has not stated a preference for either alemtuzumab, fingolimod, or natalizumab. The aim was to give healthcare decision-makers insight into the differences in cost accumulation over time between alemtuzumab—with a unique, non-continuous treatment schedule—and fingolimod and natalizumab for second-line treatment of active RRMS patients in the Netherlands. Methods: In line with ZiN’s assessment, a cost-minimization analysis was performed from a Dutch healthcare perspective over a 5-year time horizon. Resource use was derived from hospital protocols and summaries of product characteristics, and validated by two MS specialists. Unit costs were based on national tariffs and guidelines. Robustness of the base case results was verified with multiple sensitivity and scenario analyses. Results: Alemtuzumab results in cost savings compared to fingolimod and natalizumab from, respectively, 3.3 and 2.8 years since treatment initiation onwards. At 5 years, total discounted costs per patient of alemtuzumab were €79,717, followed by fingolimod with €110,044 and natalizumab with €122,238, resulting in cost savings of €30,327 and €42,522 for alemtuzumab compared to fingolimod and natalizumab, respectively. Key drivers of the model are drug acquisition costs and the proportions of patients that do not require further alemtuzumab treatment after either two, three, or four courses. Limitations: No treatment discontinuation and associated switching between treatments were incorporated. Consequences of JC virus seropositivity while continuing natalizumab treatment (e.g. additional monitoring) were omitted from the base case. Conclusion: The current cost-minimization analysis demonstrates that, from the Dutch healthcare perspective, treating active RRMS patients with alemtuzumab results in cost savings compared to second-line alternatives fingolimod and natalizumab from ∼3 years since treatment initiation onwards. After 5 years, alemtuzumab’s cost savings are estimated at €30k compared to fingolimod and €43k compared to natalizumab.

Background and purposeJohn Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab‐associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab‐treated relapsing−remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab‐treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing.Methods and resultsIn our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti‐JCV antibody indices were measured in 933 available samples. Eighty‐six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow‐up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow‐up duration. No significant increase was seen in the anti‐JCV antibody index in the non‐converting patients during the follow‐up.ConclusionThe annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.

Disease progression in multiple sclerosis occurs within the interface of glial activation and gliosis. This study aimed to investigate the relationship between biomarkers of different glial cell responses: (i) to disease dynamics and the clinical subtypes of multiple sclerosis; (ii) to disability; and (iii) to cross-validate these findings in a post-mortem study. To address the first goal, 51 patients with multiple sclerosis [20 relapsing remitting (RR), 21 secondary progressive (SP) and 10 primary progressive (PP)] and 51 neurological control patients were included. Disability was assessed using the ambulation index (AI), the Expanded Disability Status Scale score (EDSS) and the 9-hole PEG test (9HPT). Patients underwent lumbar puncture within 7 days of clinical assessment. Post-mortem brain tissue (12 multiple sclerosis and eight control patients) was classified histologically and adjacent sites were homogenized for protein analysis. S100B, ferritin and glial-fibrillary acidic protein (GFAP) were quantified in CSF and brain-tissue homogenate by ELISA (enzyme-linked immunosorbent assay) techniques developed in-house. There was a significant trend for increasing S100B levels from PP to SP to RR multiple sclerosis (P0.05). S100B was significantly higher in RR multiple sclerosis than in control patients (P0.01), whilst ferritin levels were significantly higher in SP multiple sclerosis than in control patients (P0.01). The S100B : ferritin ratio discriminated patients with RR multiple sclerosis from SP, PP or control patients (P0.05, P0.01 and P0.01, respectively). Multiple sclerosis patients with poor ambulation (AIor =7) or severe disability (EDSS6.5) had significantly higher CSF GFAP levels than less disabled multiple sclerosis or control patients (P0.01 and P0.001, respectively). There was a correlation between GFAP levels and ambulation in SP multiple sclerosis (r = 0.57, P0.01), and between S100B level and the 9HPT in PP multiple sclerosis patients (r = -0.85, P0.01). The post-mortem study showed significantly higher S100B levels in the acute than in the subacute plaques (P0.01), whilst ferritin levels were elevated in all multiple sclerosis lesion stages. Both GFAP and S100B levels were significantly higher in the cortex of multiple sclerosis than in control brain homogenate (P0.001 and P0.05, respectively). We found that S100B is a good marker for the relapsing phase of the disease (confirmed by post-mortem observation) as opposed to ferritin, which is elevated throughout the entire course. GFAP correlated with disability scales and may therefore be a marker for irreversible damage. The results of this study have broad implications for finding new and sensitive outcome measures for treatment trials that aim to delay the development of disability. They may also be considered in future classifications of multiple sclerosis patients.

BMJ 2000;321:490-4 Multiple sclerosis is the most common cause of chronic neurological disability in young adults, with a prevalence of about 1 in 1000. About 50% of patients are unable to walk without assistance 15 years after onset As yet, no treatment can halt the accumulation of disability. In recent years, however, there has been substantial progress in understanding the pathogenetic mecha nisms of the disease and in developing techniques to monitor treatment Based on this progress treatments were developed that have a favourable impact on the natural course of the disease (disease modifying drugs). We discuss the evidence available from large ran domised, placebo controlled studies, and we address several questions that still generate wide interest in rela tion to treatment with disease modifying drugs. Treatment of symptoms and rehabilitation, which still remain the mainstay of treatment for most patients with multiple sclerosis, are not reviewed here.

We examined the value of spinal cord magnetic resonance imaging (MRI) in the diagnostic work-up of multiple sclerosis (MS). Forty patients suspected of having MS were examined within 24 months after the start of symptoms. Disability was assessed, and symptoms were categorized as either brain or spinal cord. Work-up further included cerebrospinal fluid analysis and standard proton-density, T2-, and T1-weighted gadolinium-enhanced brain and spinal cord MRI. Patients were categorized as either clinically definite MS (n = 13), laboratory-supported definite MS (n = 14), or clinically probable MS (n = 4); four patients had clinically probable MS, and in nine MS was suspected. Spinal cord abnormalities were found in 35 of 40 patients (87.5 %), consisting of focal lesions in 31, only diffuse abnormalities in two, and both in two. Asymptomatic spinal cord lesions occurred in six patients. All patients with diffuse spinal cord abnormality had clear spinal cord symptoms and a primary progressive disease course. In clinically definite MS, the inclusion of spinal imaging increased the sensitivity of MRI to 100 %. Seven patients without a definite diagnosis had clinically isolated syndromes involving the spinal cord. Brain MRI was inconclusive, while all had focal spinal cord lesions which explained symptoms and ruled out other causes. Two other patients had atypical brain abnormalities suggesting ischemic/vascular disease. No spinal cord abnormalities were found, and during follow-up MS was ruled out. Spinal cord abnormalities are common in suspected MS, and may occur asymptomatic. Although diagnostic classification is seldom changed, spinal cord imaging increases diagnostic sensitivity of MRI in patients with suspected MS. In addition, patients with primary progressive MS may possibly be earlier diagnosed. Finally, differentiation with atypical lesions may be improved.

Background: Provocative clinical tests are often performed in the diagnosis of ulnar neuropathy at the elbow (UNE) although the evidence for the usefulness of these tests is limited. The aim of this study was to determine the diagnostic value of provocative clinical tests in the diagnosis of UNE in a relevant spectrum of patients and controls. Methods: A prospective cohort study was performed in consecutive patients clinically suspected of having UNE. All patients underwent a neurological examination and four commonly used provocative clinical tests (Tinel’s test, flexion compression test, palpating for local ulnar nerve tenderness and nerve thickening). Subsequently, in all patients a reference standard test comprising electrophysiological studies and neurosonography was independently assessed. Results: 192 eligible patients completed the study protocol. UNE was diagnosed in 137 and an alternative diagnosis was made in 55 patients. The sensitivity, specificity, and positive and negative predictive values were as follows: Tinel’s test 62%, 53%, 77% and 30%; flexion compression test 61%, 40%, 72% and 29%; palpating for nerve thickening 28%, 87%, 84% and 33%; and palpating for nerve tenderness 32%, 80%, 80% and 32%. Logistic regression and receiver operating characteristic curves showed that the added value of one or more provocative tests over routine clinical examination is minimal. Conclusion: The diagnostic value of provocative clinical tests in UNE is poor.

Background: Carpal tunnel syndrome is a common disorder for which several surgical treatment options are available. Objectives: To compare the efficacy of the various surgical techniques in relieving symptoms and promoting return to work or activities of daily living and to compare the occurrence of side-effects and complications in patients suffering from carpal tunnel syndrome. Search strategy: We updated the searches in 2006. We conducted computer-aided searches of the Cochrane Neuromuscular Disease Group Trials Register (searched in June 2006), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 2), MEDLINE (January 1966 to June 2006), EMBASE (January 1980 to June 2006) and also tracked references in bibliographies. Selection criteria: Randomised controlled trials comparing various surgical techniques for the treatment of carpal tunnel syndrome. Data collection and analysis: Two review authors performed study selection, assessment of methodological quality and data extraction independently of each other. Main results: Thirty-three studies were included in the review of which 10 were newly identified in this update. The methodological quality of the trials ranged from fair to good; however, the use of allocation concealment was mentioned explicitly in only seven trials. Many studies failed to present the results in sufficient detail to enable statistical pooling. Pooling was also impeded by the vast variety of outcome measures that were applied in the various studies. None of the existing alternatives to standard open carpal tunnel release offered significantly better relief from symptoms in the short- or long-term. In three studies with a total of 294 participants, endoscopic carpal tunnel release resulted in earlier return to work or activities of daily living than open carpal tunnel release, with a weighted mean difference of -6 days (95% CI -9 to -3 days). Authors' conclusions: There is no strong evidence supporting the need for replacement of standard open carpal tunnel release by existing alternative surgical procedures for the treatment of carpal tunnel syndrome. The decision to apply endoscopic carpal tunnel release instead of open carpal tunnel release seems to be guided by the surgeon's and patient's preferences.

To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study.In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to 12 months in the follow up study reported here.Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease.These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-α in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS. © 2003 Elsevier Science B.V. All rights reserved. Chemicals/CAS: cannabis, 8001-45-4, 8063-14-7; dronabinol, 7663-50-5; Adjuvants, Immunologic; Cannabinoids; Plant Extracts; Tetrahydrocannabinol, 1972-08-3

The expression of chemokine receptors CCR5 and CXCR3 on CD4 and CD8 positive T cells in blood, measured by flow cytometry, was studied in 124 patients with different clinical subtypes of multiple sclerosis (MS) and 22 healthy controls. In a subgroup of patients (n=69) from whom MRI was available, chemokine receptor expression was correlated to the annualised changes in T1 and T2 lesion load. It was found that CCR5 and CXCR3 on both cell types might have impact on annualised increase in T2 lesion load, but not on T1 lesion load. Our results suggest that chemokines may play a more important role in the development of new lesions in MS than in the long-term outcome of those lesions.

Moderate doses of cyclophosphamide can cause effects on lymphocytes that may last for some time after discontinuation of the treatment. Since cyclophosphamide is also often used at high doses, we studied the short- and long-term effects of such a high dose (8 grams in 20 days) in 50 patients with chronic progressive multiple sclerosis with the use of monoclonal antibodies. The treatment caused a depletion of lymphocytes, especially CD4+ cells resulting in a significant decrease of the CD4/CD8 ratio. These changes can still be found up to 13.5 years after treatment. Although there was some recovery in the first few years after treatment this was only partial. Therefore, some of the effects of high dose cyclophosphamide on cellular immunity may be permanent. These changes should be taken into account when studying immune parameters or considering new treatments in these patients.

We have developed a new indirect immune fluorescence micro method for the determination of lymphocytes in CSF.