Placebo-Controlled Clinical Trials In Multiple Sclerosis: Ethical Considerations
National Multiple Sclerosis Society (USA) Task Force On Placebo-Controlled Clinical Trials In MS
Lublin FD, Reingold SC
Ann Neurol 2001 May;49(5):677-81
Mount Sinai School of Medicine, Dept of Neurology, New York 10029-6574, USA
PMID# 11357961; UI# 21256464
The availability of partially effective therapies for some forms of Multiple Sclerosis (MS) raises practical and ethical issues for future placebo-controlled clinical trials.
An international Task Force of clinicians, statisticians, ethicists and regulators was convened to discuss these issues and develop consensus.
The Task Force concluded that placebo-controlled clinical trials in forms of MS for which partially effective therapies exist were ethical.
So long as study subjects were fully apprised of the availability of such therapies and were encouraged to pursue them outside of a clinical trial.
Patients who decline to utilize available treatments, after proper education and counseling, or those that fail all therapies can be considered to have no treatment alternatives and thus may participate in a placebo-controlled trial.
Analysis Of The NRAMP1 Gene Implicated In Iron Transport: Association With Multiple Sclerosis And Age Effects
Kotze MJ, de Villiers JN, Rooney RN, Grobbelaar JJ, Mansvelt EP, Bouwens CS, Carr J, Stander I, du Plessis L
Blood Cells Mol Dis 2001 Jan-Feb;27(1):44-53
Faculty of Medicine, Dept of Human Genetics, Tygerberg, South Africa
PMID# 11358358; UI# 21257662
Multiple Sclerosis (MS) is believed to be an AutoImmune process occurring in Genetically susceptible individuals after an appropriate environmental exposure.
We have exploited the homogeneous Afrikaner population of European ancestry to investigate the likelihood that Iron dysregulation, in association with infectious and/or AutoImmune Disease susceptibility, may underlie the MS phenotype in a subgroup of patients.
The functional Z-DNA forming repeat polymorphism of the Natural Resistance-Associated Macrophage Protein-1 (NRAMP1) Gene was analyzed in 104 patients diagnosed with MS and 522 Caucasian controls.
A family-based control group consisting of 32 parental alleles not transmitted to MS offspring was additionally studied to exclude the likelihood of population substructures.
Statistically significant differences in allelic distribution were observed between the patient and control samples drawn from the same population (P < 0.01).
Evidence is furthermore provided that alleles considered to be detrimental in relation to AutoImmune disease susceptibility may be maintained in the population, as a consequence of improved survival to reproductive age following infectious disease challenge.
Although it remains to be determined whether the disease phenotype in MS patients with allele 5 of the NRAMP1 promoter polymorphism is directly related to dysregulation of Iron.
Or modified susceptibility to Viral infection and/or AutoImmunity, a combination of these processes most likely underlies the disease phenotype in these patients.
In view of the emerging role of polymorphic variants in complex diseases and minimizing of possible confounding factors in this association study.
We conclude that allelic variation in the NRAMP1 promoter may contribute significantly to MS susceptibility in the South African Caucasian population.
Copyright 2001 Academic Press.
Bakshi R, Ariyaratana S, Benedict RH, Jacobs L
Arch Neurol 2001 May;58(5):742-748
Buffalo General Hospital, NeuroScience Center, E-2, 100 High St, Buffalo, NY 14203
Autopsy studies showed Cortical and JuxtaCortical Multiple Sclerosis (MS) plaques.
Fluid-Attenuated Inversion Recovery (FLAIR) is an advanced Magnetic Resonance Imaging sequence that reveals tissue T2 prolongation with CerebroSpinal Fluid suppression, allowing detection of superficial Brain lesions.
To assess FLAIR, T1-weighted, and T2-weighted images for detecting lesions in or near the Cerebral Cortex in patients with MS and to explore the relation between Cortical lesions and Cortical Atrophy.
Design, Setting, And Patients
Cross-sectional study in a Univ MS clinic of 84 patients with MS and 66 age-matched healthy controls receiving 1.5-T fast FLAIR, T2-weighted, and T1-weighted images.
Main Outcome Measures
Regional Cortical Atrophy was rated vs controls. Cortical and JuxtaCortical lesions were ovoid HyperIntensities involving the Cortex and/or Gray-White junction.
A total of 810 Cortical and JuxtaCortical lesions were seen by FLAIR in patients (mean, 9.6 per patient), most commonly in the Superior Frontal Lobe.
Cortical and JuxtaCortical lesions were identified in 72 patients and 6 controls. Fourteen percent of Cortical and JuxtaCortical lesions were seen on T1-weighted images and 26% were seen on T2-weighted images.
More Cortical and JuxtaCortical lesions were present in Secondary/Progressive than Relapsing/Remitting disease.
The total number of Cortical and JuxtaCortical lesions correlated significantly with disease duration and the regional number correlated with the degree of Regional Atrophy.
After taking into account NonCortical (White Matter) Lesions, only the Cortical and JuxtaCortical lesion count predicted Atrophy in that region.
FLAIR can detect many Cortical and JuxtaCortical lesions in MS, which were appreciated previously in autopsy studies but usually missed by Magnetic Resonance Imaging during life.
Cortical and JuxtaCortical plaque formation may contribute to Cortical Atrophy in MS.
Lawrenson R, Wyndaele JJ, Vlachonikolis I, Farmer C, Glickman S
NeuroEpidemiology 2001 May;20(2):138-43
Univ of Surrey, Postgraduate Medical School, Stirling House, Guildford, Surrey, UK
PMID# 11359083; UI# 21258163
People with Multiple Sclerosis, Paraplegia and Neural Tube defects typically have Neurogenic Lower Urinary Tract Dysfunction (NLUTD). This encompasses Detrusor HyperReflexia with or without Detrusor Sphincter DysSynergia and Hypo- or Acontractility.
Their effects undermine safe, effective and controlled storage and voiding of Urine and predispose to Reflux Nephropathy. Therefore, patients in these diagnostic groups with NLUTD would be expected to have increased risk of Renal failure.
The aim of this study was to quantify this risk using the General Practice Research Database (GPRD). All patients registered in the database between 1994 and 1997 and aged 10-69 were included in the study.
The prevalence and incidence of Renal failure and Renal replacement therapy in the general population was ascertained, as was the prevalence of Multiple Sclerosis, Paraplegia and Neural Tube defects.
The prevalence of Renal failure in each of the special populations was then compared with the prevalence in the unaffected general population.
The age-standardized prevalence of Renal failure in the GPRD population aged 10-69 years was 14 per 10,000.
The rate ratio of Renal failure compared with the general population in each of the years 1994-1997 for Neural Tube defects ranged between males (M) 6.8-9.0 and females (F) 9.2-11.5.
For Paraplegia M 4.1-9.0, F 4.0-7.0, and for Multiple Sclerosis M 0.4-1.3, F 0.5-2.2. As expected, people with Paraplegia or Neural Tube defects were found to have a substantially increased risk of Renal failure compared with the general population.
We could not demonstrate an increased risk of Renal failure in people with Multiple Sclerosis. We believe this finding requires further study, but may reflect a problem in the recognition of Renal failure in this group of patients.
We recommend that all three patient groups should be regularly screened so that Renal impairment may be detected prior to the development of Renal failure.
Copyright 2001 S. Karger AG, Basel
Frequency Of Multiple Sclerosis In Menorca, Balearic Islands, Spain
Casquero P, Villoslada P, Montalban X, Torrent M
NeuroEpidemiology 2001 May;20(2):129-33
Hospital Verge del Toro, Neurology Unit, Mahon, Spain
PMID# 11359081; UI# 21258161
To establish prevalence and incidence of Multiple Sclerosis (MS) in Menorca (Balearic Islands, Spain; population: 67,009).
An extensive Epidemiological study was undertaken using all available information sources. Patients were classified according to Poser's Criteria.
The prevalence rate of Definite and Probable MS was 68.6/100,000 (95% confidence interval 50.3-91.6).
The incidence rate was 3.4/100,000/year (95% CI 2.2-5.3).
The time lag between the first symptom and diagnosis was 10.2 years for patients with disease onset before 1987 and 2.1 years for patients with onset between 1987 and 1996.
Menorca's population has a moderately high MS risk, with a prevalence rate the highest reported for a Spanish region.
Copyright 2001 S. Karger AG, Basel
T1 HypoIntensities And Axonal Loss
Barkhof F, Karas GB, van Walderveen MA
NeuroImaging Clin N Am 2000 Nov;10(4):739-752
Multiple Sclerosis MRI Research Centre Amsterdam, Vrije Universiteit Hospital, Dept of Radiology, Amsterdam, The Netherlands
PMID# 11359722; UI# 21260119
T1 HypoIntensities are lesions that are HypoIntense on moderately T1-weighted conventional Spin-Echo sequences and serve as markers of matrix destruction and Axonal loss.
They correlate better with clinical disability than T2-weighted images, are found in patients with Progressive Multiple Sclerosis, and can be used as surrogate outcome measures in treatment trials.