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Contains fulltext : 88123.pdf (Publisher’s version ) (Closed access) In patients with relapsing remitting multiple sclerosis (RRMS), the effect of interferon-beta (INFb) on health-related quality of life (HR-QoL) is not firmly documented. The objective of this study is to assess HR-QoL during 2 years of treatment with intramuscular INFb and its correlation with disability. In 36 neurological practices in the Netherlands (17), Belgium (16), United Kingdom (2) and Luxemburg (1), 284 RRMS patients were treated with intramuscular INFb-1a. Physical and mental domains of HR-QoL were measured by the MS54 Quality of Life (MS54QoL) questionnaire, and disability was assessed by the Multiple Sclerosis Functional Composite (MSFC) (Timed 25-Foot Walk Test [Timed 25-FWT], 9 Hole Peg Test [9-HPT], Paced Auditory Serial Addition Test [PASAT]) at baseline and at months 3, 6, 12, 18 and 24. Expanded Disability Status Scale (EDSS) score was assessed at baseline and month 24. Pearson's correlation coefficients were determined and predefined factors were analyzed for relation to HR-QoL after baseline by stepwise regression analyses on physical and mental scores. 204 patients (71.8%) completed 2 years of treatment. Mean values for MS54QoL increased from 56.6 to 61.0 for physical (p < 0.05) and from 57.2 to 61.1 for mental domain (p = 0.07). Correlations between physical domain and MSFC was -0.40 (p < 0.05), and between mental domain and MSFC -0.24 (p < 0.05). MSFC and EDSS did not change. Increase of physical MS54QoL was associated with lower age, lower EDSS, less time for Timed 25-FWT, and higher PASAT score at baseline. Increase of mental MS54QoL was associated with higher PASAT and lower EDSS. Patients who discontinued INFb had lower physical or mental HR-QoL at baseline. In RRMS patients, 2 years of treatment with intramuscular INFb-1a is associated with an increase in HR-QoL, especially in younger patients with low disability. 01 april 2010

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.

We have completed a whole genome screen for association with multiple sclerosis (MS) in a Belgian population. The 6000 microsatellite markers provided through the Genetic Association of Multiple Sclerosis in EuropeanS (GAMES) collaborative were genotyped in case–control and family-based samples. The 20 most promising markers included three markers (D6S1615, D6S2444 and TNFa) from the classically established HLA class II cluster and one (D6S265) from the recently re-emphasized HLA class I cluster. In other highlighted regions, preliminary candidate genes from the immune system have been identified: e.g. the integrin ligand EDIL3, the high-mobility group box protein TOX, neutral sphingomyelinase activating factor (NSMAF) and the B-cell specific transcription factor POU2AF1.

We report on a neuropathological analysis of two cases of TSP/HAM originating from Brazil. These two cases had, respectively, an evolution of 13 and 40 years. The main neuropathological findings consisted of spinal cord atrophy, mainly the lower thoracic cord, diffuse degeneration of the white and grey matter, rare foci of mononuclear and perivascular cuffs, and hyaline hardening of arteriolae. The supraspinal structures were normal, excepting for a slight gliosis in the cerebellum. An analysis on the long evolutive cases as described in the literature is outlined in this study. Relatamos a análise neuropatológica de dois casos de PET/MAH originários do Brasil. Estes dois casos tinham, respectivamente, uma evolução de 13 e 40 anos. O principais achados neuropatológicos consistiam de atrofia da medula espinhal, principalmente da medula torácica baixa, degeneração difusa das substâncias branca e cinzenta, raros focos de infiltrado mononuclear e perivascular, e endurecimento hialínico das arteriolae. As estruturas supra-espinhais eram normais, exceto por uma ligeira gliose do cerebelo. Uma análise dos casos de longa evolução descritos na literatura é salientada neste estudo.

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

A type-specific serological survey among 1042 random nonneurological outpatients in two cities in the state of Ceara (northeastern Brazil) shows a low prevalence of HTLV-I (0.34% in Fortaleza; 0.44% in Crato) and of HTLV-II (0.34% in Fortaleza; 0% in Crato). Among 62 chronic myelopathic patients seen in Fortaleza 27 patients were found with clinical features of tropical spastic paraparesis (TSP); 10 of 27 were found HTLV-I seropositive (37%; 95% confidence limits, 19-58%). Proviral genome detection by polymerase chain reaction in 5 seropositive and 12 seronegative patients confirmed the serological findings. This excludes HTLV-I or -II infection as a cause in the seronegative TSP patients. The HTLV-positive and -negative patients did not differ clinically and by history, except that seropositives had a longer mean disease duration, a female predominance, and a higher proportion of white Caucasians. In this population with low HTLV-I and HTLV-II prevalences, HTLV-negative TSP is at least as frequent as the HTLV-I-associated TSP.

There are compelling data to indicate that the susceptibility to multiple sclerosis (MS) is inherited, at least in part. Particular HLA genotypes may be associated with MS and recently also polymorphisms in the T-cell receptor (TCR) genes have been reported to correlate with the disease; however, these data have been difficult to confirm. We investigated the TCRA and TCRB chain genes of HLA-typed Belgian CP MS patients employing four DNA restriction fragment length polymorphisms (RFLPs) detected with TCR constant (TCRAC1, TCRBC2) and variable (TCRBV8, TCRBV11) gene segments. Similar frequencies in patients and controls were observed for all RFLPs studied. Although the HLA DR2 genotype was significantly associated with MS, no interactive effects were seen with MS, DR2, TCRAC1, TCRBC2 and TCRBV alleles. We conclude that, while a clear association with HLA DR2 is observed, little convincing evidence exists for an association of CP MS with RFLPs of the TCRA or TCRB chain genes.

Gelatinases in inflammatory demyelinating diseases of the central nervous system (CNS) were studied using actively induced experimental autoimmune encephalomyelitis (EAE) in mice as a model system. Clinical disease scores correlated in time and in intensity with pathology parameters such as cytosis in the cerebrospinal fluid (CSF), inflammatory infiltrates, and demyelination in the CNS. Zymographic analysis was employed to measure gelatinases A and B in the CSF from individual animals. According to their apparent molecular weight (MW), gelatinases A and B appeared with a MW of 65 and 95 kDa, respectively. The 65 kDa form was present in all samples, even in those derived from non-induced animals, whereas the 95 kDa form was present only in samples from animals developing EAE. The levels of 95 and 65 kDa gelatinase correlated with the CSF cytosis. In vitro digestion of myelin basic protein (MBP) with gelatinase B and analysis of the cleavage products by protein sequence analysis pinpointed two cleavage sites in conserved regions of MBP. Gelatinase production within the CNS may constitute an important pathogenic mechanism for both the disruption of the blood-brain barrier and the destruction of myelin, as observed in several neuroinflammatory disorders.

A substrate conversion assay was used to detect gelatinase activity in the cerebrospinal fluid (CSF) of patients with various neurological disorders. Two main forms of gelatinase with an apparent molecular mass of 65 and 85 kDa, respectively, could be discerned. The high molecular mass gelatinase was detectable only in samples of patients with multiple sclerosis or other inflammatory neurological disorders. A statistically significant correlation was found between the level of the 85-kDa gelatinase and the CSF cytosis. This protease could play a role in the process of demyelination and breakdown of the blood-brain barrier in certain neurological disorders, such as multiple sclerosis.

We report a 39-year-old female patient with systemic lupus erythematosus under immunosuppressive therapy who developed persistent neutrophilic meningitis, for which no infectious agent could be identified. Intensifying the immunosuppressive therapy induced a short amelioration of the clinical picture. At autopsy, basal meningitis was found to be due to Aspergillus sp.

Axial and sagittal proton density and T2-weighted MR images (TR 2,500-3,000 ms, TE 15-22 and 85-90 ms) were performed in 50 patients with multiple sclerosis (MS) on a 1.5 T superconductive system. The number of plaques on the axial and sagittal images in the periventricular white matter, the corpus callosum, the brain stem, the cerebellum, and the basal ganglia were counted separately by two independent observers. A total of 858 lesions (mean 17.40 +/- 21.57) were seen on the axial series and 1,196 (mean 24.32 +/- 26.22) on the sagittal scans. More lesions were visualized on sagittal images in the periventricular region (mean 18.79 +/- 21.69 versus 13.34 +/- 16.45; p less than 0.001) and the corpus callosum (mean 3.00 +/- 2.72 versus 0.57 +/- 1.19; p less than 0.001). In the brain stem more lesions were visualized on the axial images (mean 1.55 +/- 2.55 versus 0.87 +/- 1.20; p less than 0.05). In the cerebellum and basal ganglia, scans in the two planes were equivalent (p greater than 0.5). In three patients lesions were seen on the sagittal series, while the axial scans were normal. Sagittal T2-weighted images appear to demonstrate significantly more MS plaques than transverse images, especially in the periventricular region and the corpus callosum. This is explained by partial volume averaging, by the orientation of some cerebral structures (e.g., corpus callosum) with regard to the section plane, and by the longer diameter of the lesions in the axial plane.

Localized proton spectroscopy of the brain was performed on MS patients (n = 18) and the results are compared with those of a control group (n = 17). The experiments were performed in a 1.5-T Siemens Magnetom using the stimulated echo method and selective water suppression. Acquisition parameters were TR/TE/TM = 3000/270/30 ms, NA = 256, and Acq = 13 min. Localized volumes ranged from 8 to about 80 cc. The patients (ages 25 to 66) were at various stages of the disease. Three of the eighteen patients did not show any plaques on the MR images. VOIs were chosen to contain as much plaque volume as possible in the cerebrum white matter. In the controls and in the patients with no plaques, the VOI were localized in similar white matter regions. All spectra were characterized by the presence of Cho (3.2 ppm), PCr + Cr (3.0 ppm), and NAA (2.0 ppm). The ratios NAA/Cho and NAA/(PCr + Cr) were calculated for both the MS and the control group. The results for the three MS patients with no detectable plaques did not differ significantly from the results of the control group. The former group is, however, too limited to draw any conclusion for the moment. For the MRI positive patients, the following values were found (means ± 1 SD): NAA/Cho = 1.98 ± 0.33 and NAA/(PCr + Cr) = 2.16 ± 0.14. In the normals, these values were NAA/Cho = 2.54 ± 0.39 and NAA/(PCr + Cr) = 2.76 ± 0.25. The results quoted are TR and TE dependent. It is concluded that these ratios are significantly lower in the MS patients (p < 0.001). The decrease is attributed to a decrease in the NAA peak intensity. This is supported by the fact that the NAA/Cho and the NAA/Cr ratios are reduced by the same amount (0.78) in the MS patients. Also, this decrease in metabolite ratios is not significantly affected by the MS plaque density and the stage and duration of the disease. © 1991 Academic Press. Inc.

Two patients developed acute sensorimotor polyneuropathy after intoxication with lithium carbonate. Nerve conduction studies, electromyography, and sural nerve biopsy proved it to be an axonal neuropathy. Recovery of muscle strength, reflexes, and sensory function started weeks after discontinuation of lithium therapy. One patient fully recovered within a year. In the literature we found nine other cases of lithium polyneuropathy.

After the first description of TSP/HAM in 1985 and the elaboration of WHO's diagnostic criteria in 1988, the experience of the professionals in this field has increased so that a critical reappraisal of these diagnostic guidelines was considered timely. Brazilian neurologists and observers from other countries met recently to discuss and propose a modified model for diagnosing TSP/HAM with levels of ascertainment as definite, probable, and possible, according to myelopathic symptoms, serological findings, and/or detection of HTLV-I DNA and exclusion of other disorders.

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.

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.

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.

Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM) is clinically characterized by chronic insidious spastic paraparesis associated with variable sensory impairment and sphincter symptoms. Neuropathological studies of this condition are based on a few autopsied cases, and on experimental animal models. However, divergent aspects exist between human and experimental animal neuropathology of TSP/HAM, namely, the site of lesions in the spinal cord, the involvement of peripheral nerves and roots, the nature of histological abnormalities, and the cellular reactions. Moreover, unanswered questions as to the preferential site of spinal affection, the temporal inflammatory picture, the selective damage of the corticospinal tract, the sparing of lower motor neurons, the inconsistent affection of sensory tracts, and the involvement of the brain, are outlined. A long-term, chronological, correlated clinical and neuropathological study in HAM experimental animals is suggested.

A case of HTLV-1 associated tropical spastic paraparesis is described in a Belgian nun who had been working as a midwife in Central Africa. Occupational exposure was the only risk factor identified. Among 2,482 Belgian expatriates in tropical countries, 92% of whom had resided in sub-Saharan Africa for an average of 15.5 years, only one Belgian-born man was found seropositive for HTLV-1. He was married to an African woman and living in Central Africa for 23 years. The risk of HTLV-1 infection is low in Belgian expatriates and on its own does not support generalised anti-HTLV screening in autochthonous Belgian blood donors.

Gosselink R, Kovacs L, Ketelaer P, Carton H, Decramer M. Respiratory muscle weakness and respiratory muscle training in severely disabled multiple sclerosis patients. Arch Phys Med Rehabil 2000;81:747-51. 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 ( R 2 =.60), whereas body weight ( R 2 =.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 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. © 2000 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

In Lisala (Equateur region, Zaire), where a cluster of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) was described, 28 200 (14%) out-patients and hospital personnel were HTLV antibody positive. No differences in prevalences were observed between out-patients and hospital personnel or between ethnic groups. The annual attack rate of TSP/HAM is estimated at 0·15-0·3 per 1000 infected. The ethnic and familial clustering of TSP/HAM together with the high attack rate suggests the presence of co-factors for the progression to disease. This high prevalence of HTLV antibodies contrasts with the low prevalence in another part of the Equateur region.

Interleukin 6 (IL6) is one of the major inflammation-associated cytokines. Elevated serum or tissue levels of IL 6 have been reported to occur in several human diseases, including infections of the central nervous system (CNS), but not in non-infectious CNS inflammation, e.g. multiple sclerosis. While studying experimental autoimmune encephalomyelitis (EAE) as an animal model for autoimmune inflammation of the CNS, we found increased IL 6 levels in the CNS of mice suffering from a lethal form of the disease. IL 6 levels in the spleens and sera were not significantly increased. These findings are indicative of local production of IL6 in the CNS during EAE, and represent the first demonstration of IL6 production in non-infectious CNS inflammatory disease.

Objectives—To assess the utilisation of medical services and social (community) assistance in patients with multiple sclerosis of diVerent 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 13 106 000 for ambulatory care including rehabilitation and district nursing and ECU 3 234 000 for pharmaceutical products. To these direct medical costs ECU 3 491 000 for social assistance and ECU 4 938 000 for prosthetics and adaptations should be added. The yearly costs for admissions to hospital including permanent residence in an institution and pharmacy was ECU 26 581 000 . 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 eVectiveness studies. (J Neurol Neurosurg Psychiatry 1998;64:444‐450)

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 efficaceous protease inhibitors than those used in the combination therapy described here.

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 26 225 first, second, and third degree relatives. Full medical information to allow documentation of multiple sclerosis status was available for 21 351 (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.

The in vitro activity of gelatinase B, an enzyme whose appearance in the cerebrospinal fluid is associated with inflammatory diseases of the central nervous system, was dose-dependently inhibited by the antirheumatic D-penicillamine. Inhibition of gelatinase B in electrophoretically pure preparations and in cell culture supernatants and human body fluids was obtained at dosages reached in the circulation of patients treated with a peroral dosis of 750 mg D-penicillamine per day. In mice, developing acute demyelination, D-penicillamine significantly reduced the mortality and morbidity rates of experimental allergic encephalomyelitis (EAE). In chronic relapsing EAE in Biozzi AB/H mice, an animal model for relapses in multiple sclerosis (MS), it attenuated the exacerbations, even when the treatment was started after the primary full-blown disease had developed. We infer protease inhibition as the mechanism of action of D-penicillamine and suggest that its use may be effective as peroral treatment for MS.

In a retrospective study of 72 patients with developmental venous anomalies (DVA) diagnosed by MRI and/or angiography, 33 associated lesions were found in 32 patients (44%). Study of the clinical files allowed classification of the patient population into three groups. In group 1 (11 patients: 34%) the symptoms were attributed with certainty to the associated lesions (1 brain infarction, 2 multiple sclerosis patients, 1 case of meningitis, and 7 patients with tumors). In group 2 (9 patients: 28%) the symptoms were probably caused by the associated lesion and not by the associated DVA (1 contusion, 1 Sturge-Weber angiomatosis, and 7 hemorrhagic DVA). In group 3 (12 patients: 38%) the symptoms were nonspecific (10 cavernous angiomas, 1 varix with sinus pericranii, and 1 ectasia of the middle cerebral artery. These findings sustain the theory that DVA is a congenital anomaly of the venous drainage of the brain, without pathological significance, and must be considered as an incidental finding.

The association of some HLA class II alleles with multiple sclerosis (MS) has been amply documented. In the present study the role of HLA class II haplotypes and genotypes and of polymorphic amino acids at the DR beta 1 locus, located in the antigen binding groove and the CD4 binding domain of the DR beta 1 chain, were studied in 78 unrelated Caucasian chronic progressive MS (CP MS) patients and 204 controls. The results confirmed the positive association of the DRB1*1501 allele and through linkage also of the DRB1*1501-DQA1*0102 haplotype with MS. In addition, the results showed that the DRB1*1501/DRB1*0400 or DR beta 1Ala71+ His13+ genotype conferred the highest relative risk for MS (RR = 9.14). Alleles encoding for DR beta 1Phe47+, DR beta 1Asp70+ and DR beta 1Thr140+, DQ alpha 1Phe25+, DQ alpha 1Leu69+ residues were protective and the highest protection (RR = 0.24) was provided by the DR beta 1(Phe47+)-DQ alpha 1Phe25+ and DR beta 1(Ser13+)-DQ alpha 1Phe25+ haplotypes. Our results suggest that both DQ and DR alpha beta heterodimers might contribute to the increased or decreased risk to develop MS by the shape of their antigen-binding groove.

We demonstrate focal leptomeningeal enhancement along the chiasm on MRI in a 28-year-old man presenting with blurred vision and bitemporal visual field defects. The diagnosis of clinically definite multiple sclerosis was confirmed by laboratory investigations and brain MR findings.

We studied 200 female patients with multiple sclerosis (MS) to investigate whether pregnancy after the onset of disease influences long term disability. As an index of progression, we used the time between disease onset and wheelchair dependence. Patients who had at least one pregnancy after onset were wheelchair dependent after 18.6 years, versus 12.5 years for the other women (P < 0.0001). This difference remains statistically significant after correction for age at onset of disease.

The magnetic resonance imaging (MRI) findings in eight patients with herpes simplex meningoencephalitis were reviewed: 14 examinations were analysed. The most striking finding was high signal intensity in the temporal lobe(s) with the typical configuration known from CT. Meningeal enhancement after Gd-DTPA administration was clearly seen in four patients. Haemorrhagic changes are much better seen on MRI than on CT. When adequate motion control can be achieved, MRI becomes the examination of choice in the diagnosis and follow-up of herpes simplex encephalitis. Localized 1H MR spectroscopy also proved promising in the study of neuronal loss.

In a combined retrospective and prospective study, we tried to define the prevalence of antinuclear antibodies (ANA) and its clinical relevance in neurological patients. Three hundred twenty-seven neurological patients who had ANA determined because of suspicion of connective tissue disease (CTD), were retrospectively studied. Thirty (9.2%) were ANA positive, 20 (66%) of whom had CTD. Of 327 consecutively admitted patients, prospectively studied, 18 (5.5%) were ANA positive, 5 (28%) of whom had evidence of CTD. Systemic lupus erythematosus (SLE) was the most frequently diagnosed CTD. In a prospective study of 48 multiple sclerosis (MS) patients, only 1 had detectable ANA at a dilution of 1:40. Lupus anticoagulant (LA) was prospectively detected in 2 patients but was not associated with a vascular or autoimmune systemic disease.

The MR findings in an adult patient with globoid cell leucodystrophy (GLD) or Krabbe's disease are presented. MRI showed a bilateral periventricular hyperintensity of the parieto-occipital white matter on the T2-weighted images. A hyperintense signal was seen bilaterally along the corticospinal tract. There was no immediate nor delayed contrast enhancement. The MR findings in this case of GLD are rather atypical.

Eleven patients with a relapsing-remitting form of multiple sclerosis (MS) were examined clinically and with magnetic resonance imaging scans 3 weeks before, at the day of vaccination with killed influenza virus and 3 weeks afterwards. No exacerbations were noted in the pre- or postvaccination period. Eight contrast-enhanced or active lesions were present at the onset of the study. Three new active lesions appeared at the end of the prevacci-nation period while only 1 new active lesion was found at the end of the postvaccination period. We conclude that vaccination with killed influenza virus has no clinical or subclinical short-term effect on the activity of MS.

We present a patient with adult-onset globoid cell leukodystrophy (GBL) who had almost complete deficiency of galactosylceramide beta-galactosidase. A brother of the index patient deteriorated neurologically and died at the age of 4, probably from the late-infantile form of the disease. In this family, two clinical types of GBL are probably different expressions of an identical genotype.

Epidemiological findings of twenty sporadic cases of epidemic spastic paraparesis (buka-buka) in three areas of Bandundu (Zaire) are reported. These findings suggest the involvement of an infectious agent and do not support the hypothesis of a dietary cyanide intoxication, which has been advanced to explain the outbreak of a very similar disease (Mantakassa) in Mozambique.

The authors present a case report of early onset myophosphorylase deficiency (Mc Ardle's disease) with absence of myophosphorylase protein on SDS-electrophoresis. The different varieties of myophosphorylase deficiency and the clinical investigations which may lead to the diagnosis are reviewed. In particular, the relevance and possible dangers of an ischemic forearm exercise test and the suggestion of using a needle biopsy as a preliminary screening in similar cases of metabolic myopathies are discussed.

Morphometric analysis of the innervation pattern of the stromal layer of the urinary bladder was done on biopsies from 88 patients with definite multiple sclerosis (MS). The biopsies were stained for acetylcholinesterase and for S100 protein, and a semiquantitative score was assigned. Nearly 30% of the samples showed increased immunoreactivity for S100, indicating Schwann cell hyperplasia. In 16% a decreased S100 immunoreactivity was found, the significance of which is unclear. More than 90% had normal acetylcholinesterase activity. No correlation could be demonstrated for age, sex, severity and duration of the disease, the presence of cystitis and type of detrusor dysfunction. The finding of altered S100 immunoreactivity in MS bladders could indicate that MS also affects the peripheral nervous system and is not limited to the central nervous system as classically described. This finding warrants further investigations.

In a search for early prognostic features in multiple sclerosis, the progression rate was calculated in 200 consecutive multiple sclerosis patients who had had a lumbar puncture, and correlated with age at onset, type of disease course, the patient's sex, as well as with indices of blood-brain barrier breakdown and intrathecal IgG synthesis. The present study demonstrates that age at onset plays a role in determining whether the disease will be remitting-relapsing or chronic progressive. Age at onset is also a factor determining the rate of progression of the remitting-relapsing form, but is without influence on the progression of the chronic progressive form. A chronic progressive disease course per se (independent of age at onset) is also associated with a more rapid deterioration. The patient's sex does not appear to be a differentiating factor. Only inconsistent correlations were found between IgG index or number of oligoclonal bands in the CSF and disease progression.

The addition of indomethacin to concanavalin A (Con A)-induced cultures of human peripheral blood leukocytes (PBL) caused an increase in interferon response, regardless of whether the PBLs were derived from multiple sclerosis (MS) patients or from control donors. Specifically the response rates increased from 71 to 100% in controls and from 24 to 53% in MS patient-derived cultures. The amounts of interferon produced also increased in both groups by 0.8 log U/ml. However, interferon yields of nonresponsive cultures becoming interferon-producing only after indomethacin treatment remained relatively low. In control cultures, maximal increases of interferon production were obtained with doses of 0.05 to 0.1 microgram/ml indomethacin; for MS patients higher doses were needed--0.1 to 0.5 microgram/ml. Conversely, a relatively low dose (0.05 microgram/ml) of exogenous prostaglandin E2 (PGE2) was able to inhibit interferon production completely in MS patient-derived cultures, whereas in control cultures higher doses were needed (0.1 to 1.0 microgram/ml). Analysis of endogenous PGE2 levels in the PBL cultures revealed that PGE2 production was similar in nonresponder MS cultures and responder control cultures but that MS leukocytes were more sensitive to the inhibitory effect of PGE2 on interferon production. We conclude that in a minor percentage of MS patient-derived PBL cultures, the deficiency in interferon-gamma (IFN-gamma) production can be (partially) overcome by treatment of the cells with indomethacin. However, in the major part of nonresponder MS cultures, indomethacin has no effect, indicating that the PG system is not the major cause for the defective interferon response in MS.

Summary Hypothermia, defined as a core temperature less than 35°C has multiple causes and several neurological consequences. The cases of three patients with definite multiple sclerosis since more than a decade are reported, who presented with several episodes of coma and hypothermia. Systematic neuropathologic examination of the hypothalamus in one case did not reveal any abnormality.