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.

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.

Myasthenic syndrome caused by direct effect of chloroquine on neuromuscular junction.

Chloroquine induced a myasthenic syndrome in a patient taking the drug for presumable reticular erythematous mucinosis. Clinical features and results of single-fiber electromyography were typical for a failure of neuromuscular transmission, while peripheral nerves and muscles were intact on clinical, biochemical, electrophysiologic, and pathologic investigation. The time course of the clinical and electrophysiologic findings during provocation with chloroquine and the absence of autoantibodies indicate that the syndrome was due to a direct effect of the drug on the neuromuscular junction. While not taking chloroquine, the patient showed a decremental response on a modified double-step nerve stimulation test and a mean consecutive difference on single-fiber electromyography that was at the upper limit of normal, indicating a subclinical impairment of neuromuscular transmission. These findings can explain the apparent rarity of the syndrome described, as a direct effect of chloroquine on the neuromuscular junction may only have clinical relevance in patients with a reduced neuromuscular safety factor.

Progressive pontobulbar palsy with deafness: clinical and pathological study of two cases.

Among the hereditary affections of the nervous system associated with deafness, a rare condition called "progressive pontobulbar palsy with deafness" has been described. In this slowly progressive condition, hearing loss and vestibular are-flexia are almost always the first symptoms, occurring in late childhood or early adulthood. Only 18 cases-some sporadic, several familial-have been published without a full report of pathological findings. The clinical and pathological data of two new cases-one familial, one sporadic-are described here. There are differences from other forms of bulbar paralysis, lower motor neuron diseases, and some spinocerebellar hereditary affections. In view of the homochrony and homotypy in familial cases and the pathological findings, progressive pontobulbar palsy with deafness appears to be an abiotrophic process wih autosomal recessive inheritance.

Human retroviruses HTLV-I, HIV-1, and HIV-2 and neurological diseases in some equatorial areas of Africa.

HTLV-I is associated with tropical spastic paraparesis (TSP) in the Caribbean area and with certain chronic myelopathies termed HAM (HTLV-I-associated myelopathy) in Japan. In order to investigate the situation in Africa, we tested for HTLV-I, but also for HIV-1 and HIV-2 antibodies, 94 patients with epidemic spastic paraparesis (ESP) from Zaire and Tanzania, 26 cases of sporadic spastic paraparesis (SSP) and 21 cases of tropical ataxic neuropathy (TAN), both from Ivory Coast, and 319 unselected neurological patients from Ivory Coast, Congo, and Tanzania. While none of the 94 ESP cases nor any of the 21 TAN patients exhibited antibodies to any retrovirus, 4 of the 26 sporadic spastic paraparesis patients had high HTLV-I antibodies in their sera and cerebrospinal fluid (CSF). Three of those were clinically and immunologically identical to TSP, as observed in persons from the Caribbean region, and the fourth case, a poorly explored chronic pyramidal syndrome, could also represent a TSP. Only one of these four cases originally had HIV-1 antibodies. Among the 319 unselected patients, only 5 (1.6%) had HTLV-I antibodies, but 32 (10%) had HIV-1 antibodies and 14 (4.4%) had HIV-2 antibodies, with a number of combined infections, indicating that retroviruses represent potentially important etiological agents for African neurological diseases.

Globoid cell leukodystrophy: a family with both late-infantile and adult type.

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.

Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological 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.

Leu-3+ lymphocytes account for increased CSF cellularity.

Inflammatory conditions of the central nervous system (CNS) are often marked by an increase in lymphocyte number in the cerebrospinal fluid (CSF). In order to determine if changes in CSF cell numbers can alter T-lymphocyte subset composition in CSF or in blood, cell surface markers were evaluated in 25 CSF and paired blood samples from a variety of neurologically affected patients. T-cell subset levels in peripheral blood did not reflect subset levels in paired CSF samples. However, CSF samples with elevated cell numbers (greater than 3 cells/mm3) had significantly increased levels of Leu-3+ T-cells (P less than 0.001), but not Leu-2+ T-cells relative to CSF samples with low cell counts. These data suggest a selective increase in the Leu-3+ T-lymphocyte subset in CSFs with increased cellularity in patients with acute neurologic signs.

HLA and T-cell receptor polymorphisms in Belgian multiple sclerosis patients: no evidence for disease association with the T-cell receptor.

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.

Importance of HLA-DRB1 and DQA1 genes and of the amino acid polymorphisms in the functional domain of DR beta 1 chain in multiple sclerosis.

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.

Familial transmission and minimal sequence variability of human T-lymphotropic virus type I (HTLV-I) in Zaire.

Our group previously reported a strong familial clustering of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Zaire, suggesting a familial transmission of the virus together with the presence of cofactors. In the present study among 84 relatives of 16 HTLV-I-positive or HAM/TSP index cases, we found that all 15 seropositive children had a seropositive mother and that all 15 children with a seropositive father but a seronegative mother were seronegative. Lymphocytes of 17 relatives from 2 families with a familial HTLV-I-associated neuropathy were tested in 2 polymerase chain reaction (PCR) assays amplifying pol and tax/rex gene fragments. The 10 seropositive individuals were PCR positive for HTLV-I and the 7 seronegatives were negative in both PCR assays. The PCR results showed no evidence for a long lag period between infection with HTLV-I and seroconversion. The HTLV-I long terminal repeat (LTR) of these 10 individuals, related in the first to the fourth degree, was amplified and sequenced. Identical sequences were found within the families except for one woman infected with two variants, one being the familial strain and the other a mutated one with a single nucleotide substitution in the 755 sequenced nucleotides of the LTR region. The family strain and the mutant were both present in two samples taken 1 year apart. Together, the HTLV-I serology, PCR, and sequencing results point toward mother-to-child transmission as the main mode of HTLV-I infection in this population. Comparison of the LTR sequences of the two families with other HTLV-I strains from different geographical regions shows that the Zairean HTLV-I strains form a separate cluster.(ABSTRACT TRUNCATED AT 250 WORDS)

HTLV-negative and HTLV type I-positive tropical spastic paraparesis in northeastern Brazil.

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.

Apparent late-onset Cockayne syndrome and interstitial deletion of the long arm of chromosome 10 (del(10)(q11.23q21.2)).

We present the history and data on a 24-year-old man with clinical and neurological symptoms similar to the findings in patients with late-onset Cockayne syndrome. Prometaphase chromosome studies documented an interstitial 10q211 deletion in all cells. This finding may indicate that the gene for late Cockayne syndrome is at 10q211.

Clinical and ultrastructural study of a sporadic case of hereditary sensory neuropathy. Morphological evidence for a slow rate fiber degeneration.

A sporadic case of hereditary sensory neuropathy, with a clinical course and severe trophic and sensory alterations typical for type II, is presented. There was a severe loss of myelin in the sural nerve biopsy taken from the ankle. The most impressive microscopic feature was the number of rudimentary onion bulbs with an empty core which contained nude axons in the peripheral schwann cell layers; they were interpreted as vestigial structures left by the former myelinated fibers. Electron microscopy also revealed a definite involvement of unmyelinated fibers with attempted regeneration, which was confirmed by the overrepresentation of small axons on their frequency distribution curve. The whole ultrastructural picture suggested the protracted nature of the fiber involvement. This may be considered as agreeing with the slow course proposed for a system degeneration.

Clinical parameters and intrathecal IgG synthesis as prognostic features in multiple sclerosis. Part I.

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.

Biochemical findings in multiple sclerosis. V. Transformation of lymphocytes from patients with multiple sclerosis by human basic protein.

Lymphocyte stimulation tests with human basic protein of myelin were performed on patients with multiple sclerosis, with other neurological diseases and on normal subjects. In both MS and OND group, a hypersensitization to basic protein was seen in about one third of the cases. All normal subjects, except one, had negative responses. In the MS group, a positive correlation could be found with some features of the disease: significantly more positive responses were found in independent patients with a short duration of illness and in those with an oligoclonal distribution in the CSF. The authors compare their results with those of the literature. The possible role of BP in pathogeny of MS and OND is discussed.

Short-term intensive cyclophosphamide treatment in multiple sclerosis. A retrospective controlled study.

The effect of short-term intensive cyclophosphamide therapy upon 21 patients with moderately advanced multiple sclerosis is compared with a non-treated control group of 21 patients retrospectively matched for global disability. The progression of the disease was evaluated by regular disability scoring, and the results were analyzed by non-parametric statistical tests. No significant differences in the progression of the disability could be detected during a follow-up period of 2 years.

HLA antigens and progression of multiple sclerosis. Part II.

The HLA-A, -B, -C and -D were determined in 200 multiple sclerosis (MS) patients, 64 of whom underwent a CSF examination. Their frequencies were correlated with the rate of disease progression and with factors thought to influence disease progression, including onset age, type of clinical course and intrathecal IgG synthesis. No correlation was found between HLA haplotypes and progression rate or type of disease course. Patients starting MS after age 31 years carried the DR2 determinant more frequently (P = 0.016) than patients with onset before this median age. Although the greatest proportion of patients with an IgG index greater than 1.5 or more than 15 oligoclonal bands in their CSF were DR2 carriers, no statistical difference was found in the intrathecal IgG synthesis of HLA-DR2 (+) and (-) patients.

Magnesium deficiency as a cause of acute intractable seizures.

Clinical and experimental investigations have shown that magnesium depletion causes a marked irritability of the nervous system, eventually resulting in epileptic seizures. Although magnesium deficiency as a cause of epilepsy is uncommon, its recognition and correction may prove life-saving. Two case reports are presented which emphasize the importance of recognizing hypomagnesaemia in patients with acute intractable seizures.

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.