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.

Human herpes virus 6 and multiple sclerosis: a Finnish twin study.

OBJECTIVE: To investigate the possible association of human herpes virus 6- (HHV6) infection and multiple sclerosis (MS). BACKGROUND: Despite intensive investigations of genetic and environmental factors, the etiopathogenesis of MS remains unknown. HHV6 is a possible candidate in that it is neurotropic, able to induce demyelination and become latent and be reactivated. We had access to The Finnish National Twin Cohort, which provided a unique opportunity to study the association between HHV6 and MS in genetically homogenous patients. METHODS: Thirty-four serum samples from 17 MS twin pairs and 12 cerebrospinal fluid (CSF) samples from six MS twin pairs were tested by PCR specific for HHV6. Immunoglobulin (Ig) G and M response against HHV6 in serum and CSF were analysed using ELISA method. The samples were collected during a remission of the disease. RESULTS: No HHV6 DNA was found in any serum (n=34) or CSF (n=12) samples. Eighty-eight percent of the twins with MS and 86% of the healthy twin siblings were positive for IgG in serum. One twin with MS was also positive for IgM in serum, whereas none of the healthy twins was IgM positive. All CSF samples were negative for IgG and IgM in both groups. CONCLUSIONS: During a clinical remission of MS the detection of antibodies against HHV6 in CSF and HHV6 DNA in serum, CSF supernatant or CSF leukocytes is unlikely. However, the results do not exclude a possibility of HHV6 reactivation during MS exacerbation or acute HHV6 infection being one of the triggering agents in development of MS long before its clinical manifestation.

Patient satisfaction with switching to Stalevo: an open-label evaluation in PD patients experiencing wearing-off (Simcom Study).

OBJECTIVES AND METHODS: This study investigated the ease with which 52 Parkinson's disease patients already receiving adjunct entacapone to traditional levodopa were switched to Stalevo (levodopa/carbidopa/entacapone). RESULTS: The switch to Stalevo was straightforward for most patients taking standard-release levodopa with 86% of these patients being able to replace their entire regimen without having to change the amount of levodopa taken. The majority of patients (54%, P = 0.162) preferred Stalevo; 31% preferred their prior treatment regimen; 15% had no preference. Patients found Stalevo more simple to dose (94%), more convenient to use (84%), easier to handle (84%), easier to remember (67%) and easier to swallow (59%), compared with their previous medication. CONCLUSIONS: Stalevo was well tolerated, with a low incidence of adverse events. The study shows that Stalevo is an effective, preferred and well-tolerated means of delivering levodopa/carbidopa/entacapone in one easy-to-use tablet.

Enteroviruses and the risk of MS in the Finnish Twin Cohort.

To investigate the possible association of enterovirus (EV) infection with the development of multiple sclerosis (MS). The role of various genetic and environmental factors has been intensively studied in the etiopathogenesis of MS but the cause of the disease has remained unknown. Enteroviruses are possible candidates because they are neurotropic and able to cause chronic infections. Serum and cerebrospinal fluid (CSF) were tested with reverse transcription-polymerase chain reaction specific for enteroviruses in 17 MS twin pairs. No enteroviral RNA was found in any serum (n = 34) or CSF (n = 12) sample. We found no evidence of enterovirus infection in twins with MS or their healthy siblings. To our knowledge this is a first study to assess the role of enterovirus infections in the risk of developing MS in twins.

Infections of the central nervous system of suspected viral origin: a collaborative study from Finland.

We studied 3231 patients with acute central nervous system (CNS) symptoms of suspected viral origin to elucidate the current etiologic spectrum. In 46% of the cases, a viral finding was observed. Varicella-zoster virus (VZV) was the main agent associated with encephalitis, as well as meningitis and myelitis. VZV comprised 29% of all confirmed or probable etiologic agents. Herpes simplex virus (HSV) and enteroviruses accounted 11% each, and influenza A virus 7%. VZV seems to have achieved a major role in viral infections of CNS. In encephalitis in our population, VZV is clearly more commonly associated with these neurological diseases than HSV. The increase in VZV findings may in part be a pseudophenomenon due to improved diagnostic methods, however, a true increase may have occurred and the pathogenetic mechanisms behind this should be elucidated.

Risk of Guillain-Barré syndrome after measles-mumps-rubella vaccination.

OBJECTIVE: To assess the postulated causal association between measles-mumps-rubella (MMR) vaccination and Guillain-Barré syndrome (GBS). STUDY DESIGN: Active retrospective study based on linkage of the nationwide hospital discharge register with individual vaccination records. All patients hospitalized for treatment of GBS in Finland between November 1982 and December 1986 were included in the study. RESULTS: During the study period, 189 patients were hospitalized for treatment of GBS, and approximately 630,000 vaccine recipients received 900,000 doses of MMR vaccine; 24 of the 189 patients represented the prevailing target population for MMR vaccination, of whom 20 were vaccinated. MMR vaccination did not cause any increase over the background incidence of GBS, and no clustering of cases of GBS occurred at any time point after administration of MMR vaccine. The interval between vaccination and onset of symptoms of GBS exceeded the designated risk period of 6 weeks in all cases, varying from 80 days to years. MMR vaccination after recovery from GBS did not cause relapses of the illness. Respiratory or gastrointestinal tract infection predated the onset of GBS by 3 to 30 days in 20 (83%) of the 24 patients. CONCLUSIONS: No causal association seems to prevail between MMR vaccination and GBS.

Nationwide oral poliovirus vaccination campaign and the incidence of Guillain-Barré Syndrome.

A retrospective analysis of the incidence of Guillain-Barré syndrome (GBS) in Finland in 1981-1986 was carried out by careful examination of medical records identified from nationwide Hospital Discharge Register data based on a mean total population of 5 million people. Records from 247 patients fulfilled the accepted criteria of GBS corresponding to a mean annual incidence of 0.82 per 100,000 population. Monthly rates showed an increased incidence of GBS in March 1985, following by a few weeks the onset of the nationwide oral poliovirus vaccine campaign and partly overlapping it. Analysis of the time series in depth suggested, however, that a change point in the occurrence of GBS had already taken place before the oral poliovirus vaccine campaign. Widespread circulation of wild-type 3 poliovirus in the population immediately preceded the oral poliovirus vaccine campaign and the peak occurrence of GBS. These results demonstrate a temporal association between poliovirus infection, caused by either wild virus or live attenuated vaccine, and an episode of increased occurrence of GBS, but they cannot prove the suspected cause-effect relation between GBS and oral poliovirus vaccine administration.

Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients.

We describe 36 patients (six were apparently sporadic cases and 30 were cases from nine families) with amyotrophic lateral sclerosis (ALS) characterized by a distinct phenotype associated with homozygosity for an Asp90Ala mutation in the CuZn-superoxide dismutase gene. The presenting motor manifestation in all patients was paresis in the legs, with slow progression to the upper extremities and finally to the bulbar muscles. The age of ALS onset varied from 20 to 94 years, with a mean of 44 years. Mean survival time was 13 years for the 11 deceased patients. However, this is probably biased and untypical (low) when compared with the disease duration in the surviving patients, and when considering other medical complications in the deceased patients. The rate of progression was highly variable, even within families. All patients showed signs of involvement of both upper and lower motor neurons. Other neurological features included painful muscle spasms and paraesthesiae in the lower extremities. Two-thirds of patients experienced difficulty with micturition. Electrophysiological studies confirmed the slow progression and spatial distribution of clinical symptoms in the peripheral motor system. Furthermore, [corrected] potentials evoked by transcranial magnetic stimulation (MEP) were compared with those evoked by cervical or lumbosacral electrical stimulation and often revealed marked slowing of transmission in central motor pathways. In Sweden and Finland ALS patients homozygous for the Asp90Ala mutation constitute a phenotypically characteristic subset of motor neuron disease.

Co-twin control study on cerebral manifestations of systemic lupus erythematosus.

All available twin pairs systemic lupus erythematosus (SLE) derived from the Finnish Twin Cohort were studied by clinical evaluation, magnetic resonance imaging (MRI), anticardiolipin (aCL), and antineurofilament (ANFA) antibodies. One of the five monozygotic and one of the eight dizygotic pairs were concordant for SLE. 10 of the 15 patients showed clinical neurological abnormalities, and 11 had abnormal MRI of the brain. Altogether, 12 patients were considered to have neuropsychiatric lupus (NPSLE). Seven of the 11 patients with long-term corticosteroid treatment had either central or cortical atrophy. High or moderate aCL level was found in eight patients and two co-twins. Of them, six patients had at least two manifestations of the antiphospholipid syndrome. ANFAs were found in five patients and four co-twins. Five co-twins fulfilled some of the SLE criteria. Of them, three MZ twins and one additional DZ co-twin with no ARA criteria had findings suggesting central nervous system (CNS) involvement. The results indicate that the majority of SLE patients has cerebral abnormalities either as a result of SLE, or concomitant risk factors. The co-twins without clinical SLE often have minor signs of SLE, and even they may have neurological and MRI abnormalities. However, their aCL and ANFA levels seem not to correlate with MRI abnormalities.

Effects of recombinant alpha-2b-interferon therapy in patients with progressive MS.

The effects of systemic recombinant interferon-alpha-2b were studied in 6 carefully selected patients with progressive multiple sclerosis. 3.0 million IU were given as daily subcutaneous injections for 6 months, 5 patients showed worsening disability, and in 4 of them new or enlarged lesions were detected in MRI. In one patient no change in disability was found; his MRI showed regressed changes. The mean progression index during the treatment was significantly higher (p < 0.02) than during the previous 2 to 3 years' period of continuous progression. The frequency of peripheral blood natural killer (CD16+) cells declined significantly 3 months during the treatment, but returned to the pretreatment values after termination the treatment. An increase of intrathecal IgG synthesis and oligoclonal bands was demonstrated in 4 and 3 patients, respectively. Our experience suggests that long-term recombinant IFN-alpha-2b treatment may activate the immunological process of MS.

Cerebrospinal fluid and MRI findings in three patients with multiple sclerosis and systemic lupus erythematosus.

Three patients fulfilling the diagnostic criteria of both multiple sclerosis (MS) and systemic lupus erythematosus (SLE) were examined clinically, immunologically and by magnetic resonance imaging (MRI). In all three patients MRI showed several high-signal lesions compatible with MS and, additionally, non-specific small white matter lesions suggesting small vessel occlusion were seen. In CSF the cytoimmunological abnormalities were variable and showed only slight to moderate immunoactivation within the CNS at the time of sampling.

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.

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.

Survey of Guillain-Barré syndrome in southern Finland.

All acute Guillain-Barré syndrome (GBS) cases identified in the county of Uusimaa in southern Finland from 1981-1985 were analyzed. The incidence varied from 0.5 to 2.1 per 100,000 population. An antecedent event of possible etiologic significance was reported in 10% of the cases. Plasma exchange therapy was introduced during these years. Less children than expected fell ill, perhaps because of vaccinations, but a rise in the incidence of GBS in 1985 occurred during a nation-wide oral poliovirus vaccination campaign. A total of 19.4% of the patients needed respirator treatment, and plasma exchange therapy was given to 27.4% of these patients, among whom the time in respirator was shortened compared to equally affected individuals not given plasma exchange. The mortality was lower in the recent compared to the earlier period. This may be due to plasma exchange therapy.