Minocycline added to subcutaneous interferon ß-1a in multiple sclerosis: randomized RECYCLINE study.

BACKGROUND AND PURPOSE: Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) ß-1a therapy. METHODS: This was a double-blind, randomized, placebo-controlled multicentre study. Within 3 months (±1 month) of starting sc IFN ß-1a 44 µg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN ß-1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying relapse. Secondary efficacy endpoints were the annualized relapse rate for qualifying relapses, the number of new/enlarging T2-weighted lesions and change in brain volume [magnetic resonance imaging (MRI) was performed only in a few selected centres]. In addition, a number of tertiary efficacy endpoints were assessed. RESULTS: One hundred and forty-nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log-rank = 0.50; P = 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo. CONCLUSION: Minocycline showed no statistically significant beneficial effect when added to sc IFN ß-1a therapy.

The progress of cognitive decline in newly diagnosed MS patients.

OBJECTIVES: Cognitive impairment occurs in multiple sclerosis already in the early stages of the disease. Less is known about the evolution of cognitive decline, especially in newly diagnosed MS patients. The results of existing studies are contradictory in that both cognitive preservation and progressive deterioration have been reported. The purpose of this study was to examine how cognitive impairment evolves over time in the early stages of MS. MATERIAL AND METHODS: At baseline, the participants were 36 newly diagnosed MS patients and 37 controls. A group of 30 patients were followed longitudinally at a mean test-retest interval of 6.1 years. The test battery covered attention, information processing, memory and learning, verbal and motor functions and reasoning. RESULTS: There was a significant decline in divided attention (dual task) and information-processing speed (SDMT) at follow-up, but no significant deterioration in overall cognitive performance. CONCLUSIONS: Overall cognitive functioning remained quite stable during the 6-year follow-up, whereas divided attention and processing speed deteriorated. However, deterioration in performance on the SDMT and the dual task does not seem to indicate more extensive cognitive deterioration. Given the impact of cognitive impairment on patients' quality of life, early detection of its occurrence in MS is extremely important.

Concordance and heritability of multiple sclerosis in Finland: study on a nationwide series of twins.

OBJECTIVES: To evaluate the changes in the multiple sclerosis (MS) concordance in twins, and the contribution of genetic and environmental factors to the aetiology of MS in Finland. BACKGROUND: Both genes and the environment contribute to the development of MS. A well-conducted twin study is an excellent means to assess the relative contribution of heritability and environmental factors. METHODS: Multiple sclerosis concordance was assessed for 10 Monozygotic and 14 dizygotic twin pairs using pairwise and probandwise concordance rates. The tetrachoric correlations in liability to disease for twin pairs were computed and a polygenic multifactorial model was used to estimate heritability. RESULTS: The pairwise concordance for MZ twins was 30% and for the DZ twins 14.3%, compared with 30% for MZ and 0% for DZ 20 years ago. The corresponding probandwise concordance rates were 46.2% and 25%. The genetic variance (heritability) was 15.3% (95% Cl 0.0-77.6), the common environmental variance 73.7% (95% Cl 14.1-93.9) and the unique environmental variance 11.1% (95% Cl 2.3-30.0). CONCLUSIONS: As the concordance of MS in DZ twins has increased during the past two decades and the heritability estimate is low, it seems that the reported increase in MS incidence in Finland is mainly caused by environmental factors.

Viral antibodies in multiple sclerosis. A nationwide co-twin study.

Serum viral antibody titers against 21 viruses were studied in 19 of 23 same-sex twin pairs with multiple sclerosis derived from the Finnish Twin Cohort. Thorough neurologic examinations showed two monozygotic pairs to be concordant, whereas all dizygotic pairs were discordant. Special attention was given to measles, mumps, and rubella viruses, against which the antibody levels were determined with the complement fixation, hemagglutination inhibition, hemolysis-ingel, and enzyme immunoassay methods. Epstein-Barr virus antibody levels were determined by enzyme assay. In pairwise comparisons, the measles, mumps, and Epstein-Barr virus-IgG antibody levels were more often elevated in the patients with multiple sclerosis, compared with the healthy co-twins. The same antibody levels were more often above the median in the diseased twin, compared with the healthy twin, but the difference was not significant. No human T-cell lymphotropic virus type I antibodies were found in any of the individuals examined. The total IgG, IgA, and IgM levels did not differ between the diseased and healthy subjects. The HLA types, severity of the disease, and cell-mediated immunity parameters did not influence antibody levels.

Genetic susceptibility to multiple sclerosis. A co-twin study of a nationwide series.

The problems of differentiation between environmental and genetic influences on the development of multiple sclerosis are well known. Twin studies may provide valuable information on this question. However, most published twin series are selected and no through clinical twin studies based on epidemiologic series have been carried out. In this study, all available same-sex twin pairs with clinically definite multiple sclerosis derived from the Finnish Twin Cohort of 15815 pairs were studied by clinical evaluation, magnetic resonance imaging, and visual and auditory evoked responses. The mean length of follow-up of the pairs after the onset of symptoms of multiple sclerosis was 20 years. Two of the seven monozygotic pairs were concordant; one was definitely so, and in the other, the co-twin of the index case had, in addition to clinical findings, white matter changes suggestive of multiple sclerosis in magnetic resonance imaging and abnormal visual evoked responses. All six dizygotic pairs were discordant. The frequency of the HLA antigen DR2 in probands (69%) was significantly increased, but the distribution among the healthy subjects and patients showed nonsignificant differences. The results indicate a genetic influence on the susceptibility to multiple sclerosis, although still unknown genetic determinants are possible involved.

Multiple sclerosis in Finland: evidence of increasing frequency and uneven geographic distribution.

For the present incidence study of multiple sclerosis (MS) in Finland, reliable data since 1964 were available. The mean annual incidence rate of MS was significantly higher in the western part (3.3 per 100,000) than in the southern part of the country (2.2 per 100,000). The mean annual incidence for all MS patients was highest during the second of the three 5-year periods from 1964 to 1978. However, the incidence for women in the western part increased also thereafter. At the same time, the female-to-male incidence ratio changed from 1.0 to 2.2. The results confirmed an uneven distribution with a stable cluster of MS in the western part of the country.

Multiple sclerosis in a nationwide series of twins.

A nation wide Finnish Twin Cohort was linked with sickness insurance and hospital discharge registers on the basis of the unique identification number assigned to each Finnish citizen. The study series consisted of 4,063 monozygotic (MZ) and 9,001 dizygotic (DZ) same-sexed twin pairs born before 1958 and alive in 1981. Altogether, 22 subjects representing 11 MZ pairs and 10 DZ pairs showed clinically definite multiple sclerosis (MS). In one MZ pair both members had the disease. The frequency of MS among DZ twins corresponded to the figure in the Finnish population, but the prevalence was higher in MZ twins than in DZ twins.

Guillain-Barré syndrome: quantitative measurement of plasma exchange therapy.

A prospective, controlled study with quantitative measurement of hand muscle-force for plasma exchange treatment in acute Guillain-Barré polyradiculitis was done. Of the 29 patients with severe symptoms, every second patient was selected to the plasma exchange group and all others to the control group. The muscle forces increased and CSF protein decreased significantly more in the plasma exchange group than in the control group, but there were no differences in hospitalization or recovery periods.

Incidence of Guillain-Barré syndrome during a nationwide oral poliovirus vaccine campaign.

Concomitant with a nationwide oral poliovirus vaccine (OPV) campaign in Finland in 1985, an unexpected rise in the number of patients hospitalized with the Guillain-Barré syndrome (GBS) occurred. An analysis based on hospital records covering a population of 1.17 million and 6 years revealed a significantly increased incidence of GBS coinciding with the OPV campaign. We carefully examined 10 cases with onset of GBS within 10 weeks after immunization. Only 4 patients could recall recent symptomatic infection, and we found no specific agent in these cases. Our study suggests that live-attenuated polioviruses may, like other infectious viruses, sometimes trigger the GBS.

Increased occurrence of free immunoglobulin light chains in cerebrospinal fluid and serum in human immunodeficiency virus-1 infection.

The presence of free immunoglobulin light chains (FLCs) in the cerebrospinal fluid (CSF) and sera of patients with human immunodeficiency virus-1 (HIV-1) infection, multiple sclerosis (MS), and neurologically healthy control individuals was investigated by paying special attention to ensure that only truly free light chains would be detected. The FLCs were extracted by specifically binding them to Sepharose-coupled anti-FLC monoclonal antibodies, and thereafter they were electrophoresed and immunoblotted with monoclonal antibodies to both light chain (LC) isotypes. A frequent occurrence of kappa and lambda FLCs was found in both CSF and sera of HIV-1 infected patients. In HIV-1 infection and in MS, the frequency of FLCs of the CSF was equal. In healthy controls, only occasional weak FLCs were observed in either CSF or serum. FLC bands of the CSF from patients with HIV-1 infection tended to be more intensive than those of the appropriately diluted sera. Both intrathecal synthesis of FLCs and their transudation from sera through the impaired blood-brain barrier (BBB) may contribute to this. Increasing severity of general HIV-1 infection was accompanied by an increase of FLC intensity in sera. A qualitative demonstration of FLC in the CSF may be meaningful only in the absence of altered BBB function.

Lymphocyte activation in discordant multiple sclerosis twin pairs.

Phytohemagglutinin-induced lymphocyte activation sequence was studied in monozygotic and dizygotic discordant multiple sclerosis (MS) twin pairs in a quiescent disease phase. The study group included all available 11 pairs listed in a nation-wide twin register. Lymphocyte activation markers, DNA synthesis and gamma-interferon secretion were studied using avidin-biotin-peroxidase complex (ABC) stainings, [3H]thymidine incorporation, and a solid-phase double-antibody immunoradiometric assay (IRMA), respectively. The level and kinetics of interleukin-2 receptor expression, DNA synthesis, gamma-interferon secretion, and major histocompatibility complex (MHC) locus II antigen expression were similar (Wilcoxon's test for paired samples) in both the diseased and healthy monozygotic and dizygotic twins. Our results suggest that the cell-mediated immune system may not be primarily at fault, but rather that both MS itself and its exacerbations are caused by an unknown triggering stimulus facing a properly functioning immune system.

Pleuropulmonary involvement during bromocriptine treatment.

The use of bromocriptine in the treatment of Parkinson's disease is increasing. More than 20 cases of suggested drug-induced pleuropulmonary disorders during bromocriptine therapy have been reported. We describe four male parkinsonian patients taking bromocriptine in whom pleuropulmonary abnormalities were discovered in a pulmonary hospital during a one-year period. In only one case were the roentgenographic changes reversible after withdrawal of the drug. Pleural fluid from two patients was analyzed and showed lymphocyte-predominant chronic inflammatory changes. Raised erythrocyte sedimentation rate (ESR) and C-reactive protein values decreased after cessation of bromocriptine. Lung function studies demonstrated volume restriction with normal or high CO transfer coefficient. The frequency of pleuropulmonary changes during bromocriptine therapy may be greater than assumed, and such patients may initially present with nonrespiratory symptoms. Follow-up of patients during bromocriptine treatment by ESR, C-reactive protein, and chest roentgenogram is recommended.

The significance of cerebrospinal fluid routine screening for neurosyphilis.

From 1980 to 1985 the cerebrospinal fluid microhaemagglutination assay for Treponema pallidum antibodies (MHA:TP-CSF) was routinely examined from 10 386 consecutive CSF samples of more than 10,000 patients admitted to a large neurological unit in Helsinki. Twenty one patients were considered to have neurosyphilis on the basis of clinical, serological and CSF findings. The MHA:TP-CSF test was positive in 14 patients, in 4 patients the result was undefined, and in 3 patients negative. No false-positive results were obtained. Ten of the patients had no previous history of syphilis demonstrating the value of this type of routine screening, and in only 2 of these patients the diagnosis was suspected by clinicians before the CSF examination. The serum MHA:TP was positive in all examined 18 neurosyphilis patients indicating its value for the routine screening method instead of the CSF examination.

Myasthenia gravis associated with multiple sclerosis. Epidemiological survey and immunological findings.

Patient registers on myasthenia gravis (94 patients) and multiple sclerosis (991 patients) from a population of 1.5 million were reviewed to find patients with both diseases. Seven potential candidates were found, but both diagnoses were confirmed in 2 women only. The first patient had also iritis, the second patient had, besides MG and MS, bronchial asthma and polyarthritis. Both neurological diseases had a relatively mild clinical course. Thymectomy relieved MG symptoms in both patients. Cerebrospinal fluid studies during the follow-up indicated immunoactivation within the central nervous system. Changes in cellular immunity were also noted. The HLA types were different. The combination of these two diseases appears to be more common than expected.

Histocompatibility antigens in familial multiple sclerosis in a high-risk area of the disease.

Fourteen Finnish families, each with two or more cases of multiple sclerosis (MS), were analysed for HLA antigens. Seventy family members were studied. They were all born in a high-risk area of MS and came from families with an unusually high frequency of MS. The frequencies of B7, B12 and DR2 were increased both in patients and their healthy relatives, whereas A1, B8 and DR1 were decreased in patients. MS patients shared the HLA haplotypes more often than expected.

Immunological studies on patients with optic neuritis without evidence of multiple sclerosis.

We studied 6 patients with idiopathic optic neuritis (ON) after a mean follow-up period of 12 years. No evidence of multiple sclerosis (MS) was found on clinical grounds, nor by magnetic resonance imaging (MRI) or evoked responses. Levels of spontaneous proliferation, serum gamma-interferon (IFN-gamma) and lymphocyte MHC locus II antigen were similar in ON and in 6 patients with progressive MS, but different in healthy controls. This suggests that similar immunological conditions in vivo prevail after an idiopathic ON and in MS. A normal PHA-induced interleukin-2 receptor expression and lymphocyte proliferation but a low IFN-gamma secretion and MHC locus II antigen expression were observed. This suggests that an ON and MS defect is expressed after an interleukin-2 receptor ligand but before IFN-gamma secretion. Our findings also suggest that immunological factors do not explain the neuropathological confinement of the lesions in ON but the protective influence may rather be exerted by some as yet undefined genetic influence or may be explained by the different etiology of ON and MS.

Serum selenium concentration, glutathione peroxidase activity and lipid peroxides in a co-twin control study on multiple sclerosis.

Serum selenium concentration, glutathione peroxidase activity and lipid peroxides were determined in patients with multiple sclerosis (MS). The series consisted of 13 same-sexed twin pairs derived from the Finnish Twin Cohort of 15,815 pairs. Fourteen subjects had a definite and 1 a probable MS, and their 11 co-twins showed no evidence of central nervous system disease. No statistical differences were observed, but the 3 patients with active progressive MS had a higher mean level of lipid peroxides than the rest of the patients. We suggest that serum lipid peroxidation may be involved in the activity of MS.

Activated T lymphocytes in patients with multiple sclerosis in clinical remission.

Activation state and proliferation of lymphocytes of 6 patients with definite multiple sclerosis in clinical remission were studied. Lymphocytes carrying MHC class II coded Ia antigen, glycoprotein gp 40/80 and interleukin-2 receptor were significantly higher in patients with MS in remission than in normal healthy controls. The entrance of T cells into the G1 and S phase of the cell cycle was studied using [3H]thymidine autoradiography in combination with immunocytochemistry (cell markers). The proportion of T cells in the S phase of the cell cycle in the peripheral blood was similar in the MS patient and in the control group.

Low-field MRI in the evaluation of rheumatoid cervical spine. Comparison with neurological findings and routine plain radiography.

The usefulness of a low-field magnetic resonance imaging (MRI) instrument in the evaluation of cervical spine abnormalities was studied in 20 patients with rheumatoid arthritis and known anterior atlantoaxial subluxation (AAS) (16 patients) or other cervical spine abnormalities (4 patients). The MRI results were compared with routine plain radiographs and with neurological findings. Three patients had a clinical suspicion of cervical spinal cord compression. This was confirmed by MRI, which additionally detected one more patient with compressive myelopathy. Anterior AAS in MR images was seen in 4 patients, but proper flexion images were not obtained. Atlantoaxial impaction was detected by a recent method of Sakaguchi-Kauppi in 16 patients as compared to 9 patients by the McGregor method and 4 patients by MRI. Most of the clinically important consequences of rheumatoid cervical spine are seen with a low-field MR imager, but detailed bony changes and precise measurements are better evaluated with plain X-rays.

Can severe cardiorespiratory dysregulation induced by clozapine monotherapy be predicted?

Severe orthostatic and cardiorespiratory dysregulation may occur during institution of clozapine therapy both during concomitant benzodiazepine medication and on reinstitution of clozapine after a washout period. Extensive medical and neurological workup before and after the trials can nevertheless be normal. The absence of similar previous reactions to other drugs, adhering to monotherapy with clozapine, increasing dosage slowly or performing a single test for orthostatic reactions after initiating clozapine are insufficient precautionary measures. Cardiorespiratory complications can occur without the challenge of assuming an erect position but appear to otherwise run an initial course similar to that of severe orthostatic reactions. A significantly abnormal response to testing for orthostatic reactions may be established, but only during the period of vulnerability to cardiorespiratory dysregulation. Repeated testing for this predisposition during the first weeks of clozapine therapy is suggested.