The epidemiology of multiple sclerosis in Europe.

Multiple sclerosis (MS) is a chronic and potentially highly disabling disorder with considerable social impact and economic consequences. It is the major cause of non-traumatic disability in young adults. The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of immunomodulatory treatments and multidisciplinary health care. Available MS epidemiological estimates are aimed at providing a measure of the disease burden in Europe. The total estimated prevalence rate of MS for the past three decades is 83 per 100,000 with higher rates in northern countries and a female:male ratio around 2.0. Prevalence rates are higher for women for all countries considered. The highest prevalence rates have been estimated for the age group 35-64 years for both sexes and for all countries. The estimated European mean annual MS incidence rate is 4.3 cases per 100,000. The mean distribution by disease course and by disability is also reported. Despite the wealth of epidemiological data on MS, comparing epidemiological indices among European countries is a hard task and often leads only to approximate estimates. This represents a major methodological concern when evaluating the MS burden in Europe and when implementing specific cost-of-illness studies.

Polymorphisms in the interleukin-4 and IL-4 receptor genes and multiple sclerosis: a study in Spanish-Basque, Northern Irish and Belgian populations.

Cytokine gene polymorphisms are known to influence susceptibility and disease course of many autoimmune diseases. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. We analysed both the well-known intronic variable number of tandem repeat (VNTR) and +33 C/T single-nucleotide polymorphisms (SNP) in the IL-4 gene, as well as the functional Q551R SNP in the IL4-R gene in a cohort of three distinct populations comprising sporadic cases and controls from the northern Spanish Basque Country and Northern Ireland, as well as family trios from Belgium. The IL-4 +33 TT genotype was decreased in primary progressive (PP) versus relapsing-remitting (RR) patients in the Northern Irish population (OR = 0.14; 95% CI = 0.018-1.09). Two-marker haplotype distribution of the VNTR and +33 C/T SNP in PP patients differed from that seen in RR patients in Northern Ireland (P = 0.03). The R allele of the Q551R SNP was significantly under-transmitted in the Belgian trio families (P = 0.003), although this effect was not seen in the Northern Irish and Basque data sets. We did not identify IL-4-IL4-R gene-gene interaction in determining susceptibility or clinical parameters of MS. Disease or genetic heterogeneity or both may be responsible for the observed lack of reproduction in different populations. Our data reinforce recent findings for a role of IL4-R in susceptibility to MS.

The CTLA4 +49 A/G*G-CT60*G haplotype is associated with susceptibility to multiple sclerosis in Flanders.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. The cytotoxic T lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analysed the CTLA4 +49A/G and CT60 polymorphisms in a cohort of 120 MS trio families recruited from the Flanders region in Belgium. Both polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (RFLP). The +49 G-allele was significantly more transmitted to affected probands (P = 0.005). No transmission distortion was observed for the CT60 polymorphism. Haplotype analysis revealed significant overtransmission of the +49 A/G*G-CT60*G haplotype (P = 0.0025), and undertransmission of the +49 A/G*A-CT60*G haplotype (P = 0.015). The CTLA4 gene has been the focus of intense investigation in MS. Of 15 recently published papers, only six reported significant associations of various CTLA4 polymorphisms with MS, with the remainder being negative. Ours is the first report investigating the CT60 polymorphism in MS. Our data highlight a need for further scrutiny of the CTLA4 gene in MS.

Processing of cardiovascular allografts: effectiveness of European Homograft Bank (EHB) antimicrobial treatment (cool decontamination protocol with low concentration of antibiotics).

To assess the effectiveness of antimicrobial treatment by using cool decontamination protocol with low concentration of antibiotics during processing of cardiovascular allografts, 948 allografts processed during a 2-year period were analysed. Five hundred and fourty one donors aged <62 years were classified in: multiorgan donors (MOD) with non-transplantable hearts; recipients of cardiac transplantation (RHT); and non-beating heart cadavers with a warm ischemic time of less than 6 h (NBHD). During processing three samples for bacteriology testing were taken A (sampling before decontamination); B (sampling after decontamination); C (sampling on the final product). Samples A were positive in 348 cases (36.4%), respectively 36% for MOD, 21.6% for RHT and 78.1% for NBHD. All the allografts were immersed in a cocktail of four antibiotics at 4 degrees C. After exposure to antibiotics the rate of decontamination of those with A positive was 90.4, 92.5, 82.5% respectively for MOD, RHT, NBHD. At the end of processing, 57 allografts (6%) were positive in B and/or C, 15 allografts remained contaminated with the same bacteria as in A, 42 were contaminated during processing. The overall rate of sterility in the end of processing is 94% and for each group this is: 95.4% for MOD, 96.8% for RHT and 86.3% for NBHD. Analysis shows that there is no influence of time of exposure in AB in the rate of decontamination for MOD and RHT. The most predominant germ in contamination is Coagulase Negative Staphylococcus (CNS) (53.4% alone, 8.9% with other bacteria). 83.3% of MOD; 88.5% of RHT were contaminated with one germ, while 40.4% of NBHD were contaminated with more than one.

Dysphagia in multiple sclerosis.

OBJECTIVES: (1) To determine the prevalence of swallowing problems in MS patients and its relation to the overall disability. (2) To define the most frequent symptoms suggestive of dysphagia. (3) To describe the abnormalities on manofluoroscopy (MFS). METHODS: Three hundred and eight consecutive MS patients were asked whether they ever had swallowing problems. If so the questionnaire of the Johns Hopkins Swallowing Centre was applied to qualify the dysphagia. A MFS was performed in 30 patients with dysphagia covering the entire spectrum of MS. Overall disability was assessed using the Expanded Disability Status Scale (EDSS). RESULTS: Seventy-three of our 309 patients had permanent dysphagia (24%). Another 5% had a history of transitory swallowing problems only. Permanent dysphagia started to be a problem in mildly impaired patients (EDSS 2-3). Prevalence increased together with rising disability to reach 65% in the most severely disabled subjects (EDSS 8-9). Two alarming symptoms of patients with swallowing problems, coughing or choking during the meal and a history of pneumonia were present in 59%, respectively, 12% of these patients. MFS showed deficiency of the oral phase in all patients, while only the patients with an EDSS higher than 7.5 showed abnormalities of the pharyngeal phase. CONCLUSIONS: Permanent dysphagia may already develop in mildly impaired MS patients but becomes a rather frequent finding in MS patients with moderate or severe disability. MFS is a sensitive and useful ancillary examination. Important qualitative changes of the pharyngeal phase on MFS are seen in patients with an EDSS higher than 7.5.

Gelatinase B, PECAM-1 and MCP-3 gene polymorphisms in Belgian multiple sclerosis.

Polymorphic microsatellite markers in the genes for gelatinase B, PECAM-1 and MCP-3 have previously been analysed in Swedish and Sardinian individuals to test for association with multiple sclerosis (MS). Confirmation and comparison of genetic associations in various ethnic populations is mandatory and, therefore, we studied these three gene polymorphisms in 216 clinically definite MS patients and 193 normal controls, and in 148 simplex MS families, all of Belgian origin. No allelic associations were found between MS and the CA microsatellite marker in the promoter region of the gelatinase B gene, and the polymorphic CA repeat in the sixth intron of PECAM1. However, the two most abundant alleles of the CA/GA microsatellite polymorphism in the promoter-enhancer region of the MCP-3 gene, A2 (109 bp) and A3 (111 bp), were found to be significantly associated with disease in the case-control study [OR (95% CI)=0.68 (0.51-0.92), p (1 df)=0.015 and OR (95% CI)=1.62 (1.22-2.14), p (1 df)=0.0010, respectively], but not in the family study. These results are in agreement with previous findings in the Swedish and Sardinian populations and reinforce the possibility of a role for chemokines in MS pathogenesis.

HTLV-I negative tropical spastic paraparesis: a scientific challenge.

We reviewed the historical, clinical and etiological aspects of the progressive chronic spastic myelopathies of unknown etiology, disserting on the clinical similarities between HTLV-I seropositive and seronegative tropical spastic paraparesis (TSP), as well as focusing on the PCR studies of the seronegative TSP.

A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis.

A double-blind clinical trial of mitoxantrone versus methylprednisolone was performed in 49 patients with relapsing, secondary multiple sclerosis. Patients were randomized to receive 13 infusions of mitoxantrone 12 mg/m2 (n = 28), or 13 infusions of 1 g of methylprednisolone (n = 21), over 32 months. Twenty-four patients completed the trial. There were no statistical differences between the two groups of patients at study entry. A significant improvement in the Expanded Disability Scale Score (EDSS) was observed in the mitoxantrone group after one year of treatment (p < 0.0022). The total number of relapses, the mean number of relapses/patient/year, and the total number of gadolinium-enhanced lesions on bi-annual MRI scans were significantly decreased in the mitoxantrone group throughout the study period. Nausea, vomiting, and alopecia were more frequent in the mitoxantrone-treated patients. Mitoxantrone has a role in the treatment of MS patients with frequent exacerbations and rapid disease progression.

Mitochondrial mutations of Leber's hereditary optic neuropathy: a risk factor for multiple sclerosis.

Multiple sclerosis (MS) and Leber's hereditary optic neuropathy (LHON) have been found to occur in combination. Based on an extensive literature search and on a clinical analysis of 55 LHON pedigrees (103 patients) and 40 patients with definite MS, this study concludes that the association of LHON and MS is more than a coincidence, and that carrying a primary LHON mutation is a risk factor for developing MS. All three primary LHON mutations occurring in the European and North American populations have been found to be associated with an MS-like syndrome. The neurological characteristics of MS associated with LHON are indistinguishable from those of MS in general, but the severe and bilateral visual symptoms and signs justify considering these patients as a clinical subgroup of MS and screening them for LHON mutations. However, screening LHON patients for MS appears to be more rewarding.

A quantitative study of unpaid caregiving in multiple sclerosis.

Data on healthcare utilisation by MS patients of different grades of disability were collected using the method of a prospective diary. Professional care providers and unpaid caregivers noted during 4 weeks the time they spent and the types of support they provided. The total homecaring time of family and friends amounted to 4.6 and 12 h per day for the moderately and the severely disabled MS patients respectively. The time for unpaid core activities such as mobility help, nursing care and personal care of moderately and severely disabled patients amounted to 0.5 and 2 h per day, exceeding the time for professional medical and paramedical care at home. Eighty per cent of informal homecaring is provided by persons living with the patients, primarily the partner, who provides 60% of homecaring time. Severely disturbed bowel function and absence of a partner were associated with permanent institutionalisation. Multiple Sclerosis (2000) 6 274 - 279

Respiratory muscle weakness and respiratory muscle training in severely disabled multiple sclerosis patients.

OBJECTIVE: To evaluate the contribution of respiratory muscle weakness (part 1) and respiratory muscle training (part 2) to pulmonary function, cough efficacy, and functional status in patients with advanced multiple sclerosis (MS). DESIGN: Survey (part 1) and randomized controlled trial (part 2). SETTING: Rehabilitation center for MS. PATIENTS: Twenty-eight bedridden or wheelchair-bound MS patients (part 1); 18 patients were randomly assigned to a training group (n = 9) or a control group (n = 9) (part 2). INTERVENTION: The training group (part 2) performed three series of 15 contractions against an expiratory resistance (60% maximum expiratory pressure [PEmax]) two times a day, whereas the control group performed breathing exercises to enhance maximal inspirations. MAIN OUTCOME MEASURES: Forced vital capacity (FVC), inspiratory, and expiratory muscle strength (PImax and PEmax), neck flexion force (NFF), cough efficacy by means of the Pulmonary Index (PI), and functional status by means of the Extended Disability Status Scale (EDSS). RESULTS: Part 1 revealed a significantly reduced FVC (43% +/- 26% predicted), PEmax (18% +/- 8% predicted), and PImax (27% +/- 11% predicted), whereas NFF was only mildly reduced (93% +/- 26% predicted). The PI (median score, 10) and EDSS (median score, 8.5) were severely reduced. PEmax was significantly correlated to FVC, EDSS, and PI (r = .77, -.79, and -.47, respectively). In stepwise multiple regression analysis. PEmax was the only factor contributing to the explained variance in FVC (R2 = .60), whereas body weight (R2 = .41) was the only factor for the PI. In part 2, changes in PImax and PEmax tended to be higher in the training group (p = .06 and p = .07, respectively). The PI was significantly improved after 3 months of training compared with the control group (p < .05). After 6 months, the PI remained significantly better in the training group. CONCLUSIONS: Expiratory muscle strength was significantly reduced and related to FVC, cough efficacy, and functional status. Expiratory muscle training tended to enhance inspiratory and expiratory muscle strength. In addition, subjectively and objectively rated cough efficacy improved significantly and lasted for 3 months after training cessation.

Mid-term comparative follow-up after aortic valve replacement with Carpentier-Edwards and Pericarbon pericardial prostheses.

BACKGROUND: The first generation of pericardial valves had a high rate of premature deterioration. The aim of this study was to compare the outcome after aortic valve replacement with second generation pericardial prostheses (Pericarbon and Carpentier-Edwards). METHODS AND RESULTS: Between 1987 and 1994, 162 patients underwent aortic valve replacement with either a Pericarbon (n=81, 69+/-11 years) or a Carpentier-Edwards (n=81, 70+/-11 years) pericardial prosthesis. Mean follow-up was 4.4+/-2.7 years for Pericarbon and 4.8+/-2.4 years for Carpentier-Edwards valves (P=0. 27), giving a total follow-up of 745 patient-years. Thirty-day mortality and 5-year actuarial survival were, respectively, 6.2% and 63.2+/-5.7% in the Pericarbon group and 6.2% and 63.5+/-5.6% in the Carpentier-Edwards group. At 8 years, freedom from (and linearized rates per patient-year) thromboembolism, structural failure, and all valve-related events were, respectively, 91.8+/-3.6% (1.4%), 76. 9+/-8.7% (2.5%), and 58.4+/-9.3% (5.6%) in the Pericarbon group and 94.4+/-2.7% (1%), 100% (0%, P<0.01), and 88.8+/-3.7% (2%, P<0.05) in the Carpentier-Edwards group. There were 9 (11.1%) Pericarbon structural failures related predominantly to severe calcification and stenosis. The actual reoperation rate was 7.4% (1.6% per patient-year) in the Pericarbon group for fibrocalcific degeneration (n=3), periprosthetic leak (n=1), endocarditis (n=1), and aortic dissection (n=1). There was neither structural valve failure nor valve reoperation in the Carpentier-Edwards group. Echocardiographic review of 70 patients from 85 survivors (82.3%) found 4 additional Pericarbon valves with signs of early structural failure but no Carpentier-Edwards valve with such changes. CONCLUSIONS: Eight years after aortic valve replacement, Pericarbon pericardial prostheses compared unfavorably with Carpentier-Edwards pericardial prostheses, with a high incidence of structural valve failure and reoperation.

Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke.

BACKGROUND AND PURPOSE: Diaspirin cross-linked hemoglobin (DCLHb) is a purified, cell-free human hemoglobin solution. In animal stroke models its use led to a significant reduction in the extent of brain injury. The primary objective of this study was to evaluate the safety of DCLHb in patients with acute ischemic stroke. METHODS: DCLHb or saline was administered to 85 patients with acute ischemic stroke in the anterior circulation, within 18 hours of onset of symptoms, in a multicenter, randomized, single-blind, dose-finding, controlled safety trial, consisting of 3 parts: 12 doses of 25, 50, and 100 mg/kg DCLHb over 72 hours. RESULTS: DCLHb caused a rapid rise in mean arterial blood pressure. The pressor effect was not accompanied by complications or excessive need for antihypertensive treatment. Two patients in the 100 mg/kg group had adverse events that were possibly drug related: one suffered fatal brain and pulmonary edema, the other transient renal and pancreatic insufficiency. Multivariate logistic regression analysis showed that a severe stroke at baseline and treatment with DCLHb (OR, 4.0; CI, 1.4 to 12.0) were independent predictors of a worse outcome (Rankin Scale score of 3 to 6) at 3 months. CONCLUSIONS: Outcome scale scores were worse in the DCLHb group, and more serious adverse events and deaths occurred in DCLHb-treated patients than in control patients. We recommend that additional safety studies be performed, preferably with a second generation, genetically engineered hemoglobin.

Gelatinase B in multiple sclerosis and experimental autoimmune encephalomyelitis.

The matrix metalloproteases (MMPs) are a family of structurally related proteolytic enzymes, that are involved in various physiological and pathological processes. In the central nervous system, MMPs may contribute to proteolysis of basement membranes, extracellular matrix molecules, cytokine precursors, zymogens, cell surface molecules, and myelin components. Clipping of the latter increases the local antigenic epitope load. We explain the REGA model (Remnant Epitopes Generate Autoimmunity), which may be applied to the pathophysiology of many autoimmune diseases, including multiple sclerosis, and which consists of a tight control of the enzymatic activity of the MMPs at several levels: MMP gene transcription and MMP secretion, that are regulated by cytokines and chemokines, activation of latent zymogens by proteolysis, inhibition of enzyme activity by specific inhibitors, and glycosylation. Gelatinase B, a rather complex protease, is discussed as a prototypic MMP example. Possible applications of our understanding about the regulation of MMP activity and of the influence on disease-promotion or -limitation are reviewed.

Utilisation and cost of professional care and assistance according to disability of patients with multiple sclerosis in Flanders (Belgium)

OBJECTIVES: To assess the utilisation of medical services and social (community) assistance in patients with multiple sclerosis of different disability and to calculate the direct healthcare costs to society. METHODS: (1) One hundred and eighty four patients with multiple sclerosis were classified into four grades of disability according to a simplified Kurzke disability status scale. (2) Patients were interviewed with a structured questionnaire containing questions on their sociodemographic status, the use of inpatient and outpatient medical services and pharmaceutical products during the previous year, the use of social assistance, and the purchase of prosthetics and charges for house adaptations during the previous five years. (3) Data were also prospectively collected by means of four week diary annotations of all medical and social acts and their duration. RESULTS: After correction for the disability distribution the yearly costs for the 5500 patients with multiple sclerosis in Flanders was estimated to be ECU 13106000 for ambulatory care including rehabilitation and district nursing and ECU 3234000 for pharmaceutical products. To these direct medical costs ECU 3491000 for social assistance and ECU 4938000 for prosthetics and adaptations should be added. The yearly costs for admissions to hospital including permanent residence in an institution and pharmacy was ECU 26581000 . Home nursing and long term or permanent residence in an institution of the most severely disabled, 17% of the multiple sclerosis population, are responsible for 50% of the total direct healthcare costs and care for the 6.5% institutionalised patients accounts for 23%. Direct costs for medical care and social assistance for patients with multiple sclerosis, who account for about 0.1 % of the total population, amounts to 1% of the total healthcare budget in Flanders. CONCLUSION: This information on utilisation of medical services and social assistance can be used for good healthcare planning and cost effectiveness studies.

Bladder cancer in patients with multiple sclerosis treated with cyclophosphamide.

PURPOSE: We define the risk of bladder cancer in multiple sclerosis related to the use of indwelling catheters and cyclophosphamide administered as an immunomodulating agent. MATERIALS AND METHODS: We retrospectively reviewed the records of 2,351 patients with multiple sclerosis referred to the National Center for Multiple Sclerosis. RESULTS: Of the 2,351 patients 2 women and 5 men (0.29%) had bladder cancer. Of the 850 chronically catheterized patients the incidence was 0.7%. One patient with cancer performed intermittent catheterization for a rate of 0.23% in this group. In a subgroup of 70 patients treated with cyclophosphamide 5 chronically catheterized patients (5.7%) had bladder cancer. Hematuria was the most common presenting symptom. These data were compared with those in the literature on bladder cancer in spinal cord injury. CONCLUSIONS: These data suggest a possible synergistic role of cyclophosphamide and chronic catheterization in the induction of secondary bladder cancer. Regular cystoscopy is warranted in these patients to allow early detection of bladder tumors. Nitric oxide metabolism may be an important factor in the carcinogenesis of this type of bladder cancer.

Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis.

The serine proteinase tissue-type plasminogen activator (t-PA) and the metalloproteinase gelatinase B (MMP-9) have recently been demonstrated in MS lesions. Both enzymes are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in vitro experiments to inhibit gelatinase B. The combination of peroral D-penicillamine plus metacycline was evaluated in a double-blind placebo-controlled way in two groups of 10 patients suffering from secondary progressive multiple sclerosis. The major objectives of this pilot trial were to examine the safety of this combination and the possibility of blinding, while the effect on disease progression was considered as a secondary endpoint. Over a follow-up period of 1 year and in this selected patient group, there was no significant improvement in the Expanded Disability Status Scale score (EDSS) as compared with that of the placebo-control group. Toxicity was too high to consider additional trials with this combination of metalloproteinase inhibitors. Although peroral treatment is by most MS patients acknowledged as a major improvement in treatment compliance, one has to await the development of more selective and efficacious protease inhibitors than those used in the combination therapy described here.

Risks of multiple sclerosis in relatives of patients in Flanders, Belgium.

OBJECTIVES: To calculate age adjusted risks for multiple sclerosis in relatives of Flemish patients with multiple sclerosis. METHODS: Lifetime risks were calculated using the maximum likelihood approach. RESULTS: Vital information was obtained on 674 probands with multiple sclerosis in Flanders and a total of their 26225 first, second, and third degree relatives. Full medical information to allow documentation of multiple sclerosis status was available for 21351 (81.4%) relatives. The age adjusted risk for parents was 1.61 (SEM 0.35)%, for siblings 2.10 (SE 0.36)%, and for children 1.71 (SEM 0.70)%. For aunts and uncles, the risk was 0.66 (SEM 0.13)%. CONCLUSIONS: The risk for first degree relatives of patients with multiple sclerosis in Flanders is increased 10-fold to 12-fold; for second degree relatives, it is increased threefold. This information can be used for risk counselling in families and provides additional support for the role of more than one locus contributing to the susceptibility of multiple sclerosis.

Positron emission tomography, magnetic resonance imaging and proton NMR spectroscopy of white matter in multiple sclerosis.

OBJECTIVE: To assess characteristics of MS lesions and normal appearing white matter (NAWM) with various imaging modalities. Glucose metabolism was investigated with FDG-PET, metabolite concentration with proton NMR spectroscopy, and lesion detection with routine brain MRI. METHODS: Thirteen patients were studied in a stable phase of their disease, and two during an acute episode. Nine healthy volunteers served as controls. RESULTS: Three patients had a normal brain MRI, 12 had typical lesions. MR images were registered to the PET planes. Lesions and contra-lateral control areas were analyzed, 10/15 lesions showed relative hyper-metabolism and 2 hypo-metabolism. NAA concentration was significantly decreased in both lesions and NAWM. CONCLUSION: In stable MS, most large lesions have a relatively increased glucose utilization and decreased NAA concentration. NAWM showed a significantly decreased NAA concentration compared to healthy subjects, but no difference in glucose metabolism. Active lesions in acute MS are also hyper-metabolic. This finding opens a new window on the classification of white matter lesions based on glucose utilization.