Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria.

OBJECTIVE: To evaluate the efficiency of mitoxantrone in multiple sclerosis. METHODS: Forty two patients with confirmed multiple sclerosis, selected as having a very active disease on clinical and MRI criteria were randomised to receive either mitoxantrone (20 mg intravenously (IV) monthly) and methylprednisolone (1 g iv monthly) or methylprednisolone alone over six months. In the steroid alone group five patients dropped out due to severe exacerbation. RESULTS: Blinded analysis of MRI data showed significantly more patients with no new enhancing lesions in the mitoxantrone group compared with the steroid alone group, (90% v 31%, P < 0.001). In the mitoxantrone group there was a month by month decrease almost to zero in the number of new enhancing lesions, and in the total number of enhancing lesions, whereas both remained high in the steroid alone group. The differences were significant for both indices at all months from 1-6. Unblinded clinical assessments showed a significant improvement in change in EDSS at months 2-6 in the mitoxantrone group, with a final mean improvement of more than one point (-1.1 v + 0.3; P < 0.001). There was a significant reduction in the number of relapses (7 v 31; P < 0.01), and an increase in the number of patients free of exacerbation (14 v 7; P < 0.05). CONCLUSION: In this selected group of patients with multiple sclerosis with very active disease, mitoxantrone combined with methylprednisolone was effective in improving both clinical and MRI indices of disease activity over a period of six months whereas methylprednisolone alone was not. Further double blinded long term studies are needed to properly evaluate the effect of mitoxantrone on progression in disability.

TAP2 gene polymorphism contributes to genetic susceptibility to multiple sclerosis.

MS is an autoimmune demyelinating disease that has been known to be associated with the HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotype. TAP1 and TAP2, two genes encoded within the MHC class II region between HLA-DP and -DQ loci, display genetic variability and are involved in the transport of antigenic peptides from the cytoplasm to the endoplasmic reticulum. Comparison of 116 MS patients with Caucasoid controls did not reveal any significant correlation between the previously described alleles of the TAP1 and TAP2 genes and MS. We report here an additional TAP2 dimorphism at codon 386, called I and J, corresponding to a silent mutation. An increased frequency of the J variant was observed in the patient population. The J mutation was not found in linkage disequilibrium with the HLA-DRB1*1501 allele and can be considered an additional genetic susceptibility marker of the disease.

[Benign forms of multiple sclerosis]. / Les formes bénignes de sclérose en plaques.

It is still difficult, in 1991, to evaluate precisely the position occupied by benign forms of multiple sclerosis (MS) in the natural history of the disease. The reality hidden behind the adjective "benign" varies from one author to another, and the estimated frequency of these forms is not the same when one refers to epidemiological studies on whole populations or to clinical studies in major hospitals. There is, however, no doubt that benign MS does exist, since about 10% of MS patients will suffer, throughout the whole duration of the disease (over 30 years), from no more than moderate disablement with few repercussions on their social and professional life. These are patients in who MS began when they were 20 to 30 years' old and evolved by episodes rather than progressively and whose main symptoms are optic neuritis and sensory disorders without pyramidal or cerebellar deficit. Nevertheless, these cases are not easy to recognize a priori: there is no paraclinical examination that can predict a benign course in the long term, and an MS which has long been benign may become worse at any moment.

[A focus of multiple sclerosis in Bretagne: HLA markers and evaluation of consanguinity]. / Etude d'un foyer de sclérose en plaques en Bretagne: marqueurs HLA et évaluation de la consanguinité.

In a previous study, we established the overall prevalence of multiple sclerosis at 25 per 100,000 inhabitants in the French province of Brittany and found that the geographical distribution was uneven with four circumscribed high prevalence areas with more than 45 per 100,000. We conducted the present study to try to ascertain whether the existence of such clusters of MS could be explained by genetic factors, using two ways: the major histocompatibility markers and the frequency of intermarriage. Among the four areas of high prevalence, we examined the one with the highest prevalence, exempt from migratory movements over the last 100 years. We compared this studied population to a sample of 1005 healthy unrelated individuals coming from all over Brittany, designated as general Brittany population. A large sampling (about 25%) of the population accepted to take part in the study. Regarding HLA markers, we observed in the high prevalence area an increases percentage of B7, B8, B12, DR4 and a decreased percentage of B5, compared with the Brittany control population. The consanguinity coefficient in the population of high MS prevalence area was steadily much higher than the one in neighbouring areas with a low MS prevalence during a long period from 1896 to 1945. Under the reserve of non-randomized sampling of individuals for HLA marker study, our findings yielded a double argument in favor of genetic factors influencing the presence of clusters of MS cases: the particularities of HLA phenotype pattern and the increased consanguinity coefficient. The particularities of HLA polymorphism observed in the high prevalence area are likely to be the consequence of the intermarriage habits of this population.

Randomized double-blind trial of injectable heptaminol for controlling spontaneous or bromocriptine-induced orthostatic hypotension in parkinsonians.

Heptaminol is a molecule with experimental cardiovascular analeptic properties. In this double-blind vs placebo trial, the potency, so far unproven, of the injectable form of a 626 mg dose of heptaminol chlorhydrate on spontaneous or induced orthostatic hypotension (OH), was assessed. Nineteen patients were included in the study: 7 displayed spontaneous OH, and in the other 12 OH was induced by bromocriptine, as monitored 103 min/after an oral intake of 6.6 mg on average. Neither spontaneous nor induced OH were recorded in 32% of the Parkinsonian population registered, with no obvious distinctive characteristics. Potency tilt-trials, performed 15, 30 and 45 min after parenteral administration of heptaminol, revealed a significant and expressive potency of the molecule on the systolic blood pressure after 15 min (P less than 0.05). Clinical and biological tolerance was excellent. Low plasma renin activity and the absence of response to orthostatism indicated, in this population of Parkinsonian extrapyramidal syndromes, a loss in positive tonus likely to be of sympathetic origin. The anti-hypotensive action of heptaminol does not seem to be related to any renal or even sympathetic interaction.

Randomized, double-blind trial of exifone versus cognitive problems in Parkinson's disease.

Exifone is a novel substance of the benzophenone group that possesses potent scavenging properties. Initial findings demonstrate beneficial effects on age-related cognitive disorders. In this double-blind clinical trial versus placebo, the efficacy of 2 dosages (600 and 1200 mg/d) was evaluated with regard to Parkinson's disease (PD)-related cognitive disorders, for which there is increasing suspicion of a free-radicals origin. Despite disparities between the treatment groups as assessed by validated scales and subtests, and a considerable placebo effect on main parameters, both dose levels of exifone produced statistically significant improvement of the cognitive items most commonly impaired by PD: immediate recall, naming of objects presented, spatiotemporal orientation, and calculation. These properties suggest a new slot for exifone in the range of therapeutics available.

[Long-term immunosuppression in multiple sclerosis: evaluation of treatments begun before 1972]. / Immunosupression au long cours dans la sclérose en plaques: évaluation des traitements commencés avant 1972.

Multiple sclerosis patients have been continuously treated by azathioprine. Only severe progressive forms were selected. The protocol of inclusion and follow-up is detailed. All cases started before 1972 have been reviewed, i.e. 102 cases. Of these 102, 35 stopped azathioprine during the first years and the reasons for this drop-out are analysed. Sixty seven treatments have been maintained for more than 5 years. An evaluation of these 67 patients through the Kurtzke scale shows that the 40 cases with a remittent progressive course have been stabilized as long as they were under treatment. Relapses were observed after discontinuing the therapy. In such cases azathioprine was restarted, leading again to stabilization. Twenty seven cases following a continuous progressive course at the time azathioprine was started showed no evidence of a benefit and kept on worsening. Complications related to treatment (as observed on 240 patients from 1967 to 1982) are detailed with special reference to infections, liver disease and malignancy. Even if the results observed on the course of severe remittent progressive forms of MS are in favor of continuous therapy by azathioprine, this should not be extended to all cases of MS at their first manifestation. It has to be limited to rapidly worsening cases, appreciated after a period of evaluation, when a threatening loss of autonomy may justify some limited risks.

[Urinary disorders in multiple sclerosis. Apropos of 47 cases]. / Les troubles urinaires dans la sclérose en plaques. A propos de 47 cas.

The authors report a series of 47 patients suffering from disseminated sclerosis who required neuro-urological management because of micturition disturbances. They were in general young (mean age 43 years) and had been suffering from disseminated sclerosis for 10 years (on average). The neurological disease was in general severe since it was progressive in 32 cases and pure remittent in 13 only. Two-thirds of the patients were autonomous from a locomotor standpoint. Micturition disturbances developed in the first five years of the disease in 2/ 3rds of the patients and became really troublesome only after disseminated sclerosis had been progressive for five years. Dysuria, frequency and incontinence with urgency were the commonest symptoms. Persistent or transient retention of urine remained relatively common. Nocturnal urine loss was rarer. Sphincter incompetence was marked in half of the patients but this did not necessarily go hand in hand with locomotor incapacity. Symptoms and signs were grouped as irritative, obstructive and mixed syndromes. From a urodynamic standpoint, the detrusor was sometimes normal but more often behaved pathologically, being either hyperactive or hypoactive. Hypoactivity of the detrusor was accompanied in 9 cases out of 10 by spasticity of the striate sphincter. Spasticity of the striate sphincter was the commonest type of behaviour, although normal striate sphincter electromyography was possible and; rarely, results were of peripheral neurogenic type. There was no evidence of any correlation between the type of micturition syndrome, detrusor function and striate sphincter function. Similarly, no correlation could be established between the type of detrusor dysfunction and the period for which disseminated sclerosis had been present.(ABSTRACT TRUNCATED AT 250 WORDS)

[Complement markers Bf and C4 in multiple sclerosis]. / Les marqueurs Bf et C4 du complément dans la sclérose en plaques.

Some immunogenetic HLA markers are significantly correlated with multiple sclerosis, e.g.: the antigens B7, DR2, and the associations B7-DR2, A3-B7-DR2. In addition, the polymorphism of the allotypes Bf and C4 is also controlled by chromosome 6; a study of these markers is therefore of interest. The study of Bf and C4 in multiple sclerosis included a population of genotyped unrelated patients: 50 patients for Bf markers and 41 for C4A and C4B markers. This study revealed an over-representation of allotype S and homozygous BfSS in multiple sclerosis. BfSS homozygote was significantly more frequent in the B7 negative and/or DR2 negative patients, i.e. when the risk markers per se were absent. No correlation could be evidenced with the remittent or progressive character of the disease. These data, obtained from the study of C4, are still preliminary ones. The results found with the Bf markers confirm the existence of a genetic factor in multiple sclerosis and suggest that the susceptibility gene of the disease could be closer to locus Bf than to locus DR.

[Epidemiology of multiple sclerosis in Brittany]. / Epidémiologie de la sclérose en plaques en Bretagne.

In the period 1976-1978 a study of the prevalence of multiple sclerosis in Brittany was conducted using data collected from hospital neurology units, Social Security offices and institutions for chronic patients. After elimination of double entries, analysis of these data showed a prevalence of 25 for 100 000 people. This was less than expected from estimates for northern France and from the known prevalences in the southern part of the British isles. When broken down according to the patients' place of residence, the figures were found to vary from one district to another, with four main foci: two near the coast, one inland and one in the town of Fougères. Disease-free areas were present near these foci.

HLA profiles in multiple sclerosis suggest two forms of disease and the existence of protective haplotypes.

261 multiple sclerosis (MS) patients were HLA-A and -B typed and 94 were HLA-D typed. The results were compared to those of controls typed for HLA-A; HLA-B (356) and HLA-D (113). We confirm and extend earlier findings (Oger et al. 1980b) that some phenotypes could modulate the expression of the MS susceptibility gene linked to B7-DR2: DR3 was found together with DR2 in 12/94 MS and only 3/113 controls and could be marker for an "augmentor" gene. In contrast, B35 and DR1 as well as B12 and DR7 could be markers of protector genes. We compared typing results of patients subgrouped on clinical features. 61 patients with progressive evolution showed increased A1, A1-B8, B8-DR3 and A1-B8-DR3 when compared to 200 patients with remitting evolution. When compared to controls both groups showed increased B7 but only the remitting group showed increased DR2. 71 patients with "benign MS" showed increased B7-DR2 and A3-B7-DR2. 54 patients with "severe disease" showed increased DR3 and A1-B8-DR3 when compared to controls. Both groups showed increased B7 (49.2% and 44.4% versus 25.5% for controls). 120 patients treated greater than 5 years with azathioprine were divided into "no progression" and "progression" while treated. Both groups showed increased B7 when compared to controls. DR2 was increased only in the "no progression" group. B8-DR3 and A1-B8-DR3 were found increased in the "progression" group only. We conclude that two forms of MS exist with different HLA profiles.

[Recurrent familial neuropathy: report of one family]. / Neuropathie recurrente familiale a propos d'une famille.

The authors report a case of a family with hereditary compression of peripheral nerves. The disease is traced through five generations. Six members were proved to be affected. 14 patients were examined. The review of the literature and the family studied suggest that the disorder is transmitted by an autosomal dominant gene with variable expressivity.