Consensus Statement on medication use in multiple sclerosis by the Spanish Society of Neurology's study group for demyelinating diseases.

Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment.

Spanish consensus on the use of natalizumab (Tysabri(®))--2011.

INTRODUCTION: Natalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients. DEVELOPMENT: At an initial meeting of experts on multiple sclerosis (the authors of this consensus), the relevant topics of the consensus were determined and assigned for further elaboration. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefits/risks, and how to monitor patients during treatment and after discontinuing treatment. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review sessions and meetings, the final draft was produced. CONCLUSIONS: Although natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory tests and magnetic resonance imaging (MRI) should be available for future comparisons in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to presence or absence of anti-JC virus antibodies, prior immunosuppressive therapy, and treatment duration. The follow-up, and frequency of MRI scans in particular, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy. This is a consensus that establishes general recommendations, but neurologists must use their clinical expertise to monitor patients individually.

Association of HLA-DRB1*15 allele and CSF oligoclonal bands in a Spanish multiple sclerosis cohort.

BACKGROUND AND OBJECTIVE: The HLA-DRB1*15 allele is consistently associated with multiple sclerosis (MS) susceptibility in most studied populations. This study investigated the association between HLA-DRB1 alleles and the presence of oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid (CSF) in a Spanish population with MS. METHODS: The HLA-DRB1 typing was performed in 268 patients with sporadic MS and the detection of OCB in CSF. HLA-DRB1 allelic frequencies were compared between OCB-positive and OCB-negative patients, and both groups were also compared with 1088 unrelated healthy controls. Moreover, we correlated the various HLA-DRB1 genotypes, considering all the combinations of both parental alleles found with the presence or absence of OCB. RESULTS: We found 206 OCB-positive and 62 OCB-negative patients. The HLA-DRB1*15 allele in OCB-positive patients had a higher frequency when compared with OCB-negative patients (39.3% in OCB-positive vs. 16.1% in OCB-negative, OR = 1.38 95% CI = 1.18-1.61, P < 0.001). The other alleles did not show differences. When we compared with controls, the HLA-DRB1*15 allele was associated with the disease only in the OCB-positive patients group. None of the 55 genotypes found showed any association with the presence or absence of OCB. CONCLUSIONS: HLA-DRB1*15 allele is associated with OCB-positive patients with MS when studying a Spanish MS population.

HLA-DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population.

BACKGROUND AND OBJECTIVE: The association of HLA-DRB1*15 with susceptibility to multiple sclerosis (MS) has been consistently reported although its effect on the clinical phenotype is still controversial. The objectives of this study are to investigate the influence of the HLA-DRB1 alleles on the genetic susceptibility to MS and to study their impact on disability progression in a Spanish population. METHODS: HLA-DRB1 typing was performed by PCR-SSP in 380 patients with sporadic MS and 1088 unrelated healthy controls. Allelic frequencies were compared between groups. We studied the correlation between the different alleles and the progression of MS. RESULTS: The HLA-DRB1*15 allele in patients with MS had a statistically significant higher frequency when compared with controls (18.9% in patients vs. 10.1% in controls, Odds ratio (OR)=2.07, 95% CI=1.64-2.60, P<0.001). In the univariate analysis, the DRB1*01 and DRB1*04 alleles were associated with a worse prognosis when considering the time to reach an EDSS of 6, whereas the DRB1*03 was correlated with a better outcome. In the multivariate analysis, the alleles*01 and *04 were demonstrated to be independent factors to have a worse prognosis. CONCLUSIONS: HLA-DRB1*15 is associated with MS when comparing patients with unrelated healthy controls in a Spanish population. The HLA-DRB1*01 and HLA-DRB1*04 alleles are related to a worse prognosis when considering the time taken to reach severe disability.

Multiple sclerosis and cognitive decline: is ApoE-4 a surrogate marker?

BACKGROUND - The role of the apolipoprotein E (ApoE) polymorphism has been well demonstrated in neurodegenerative disorders such as Alzheimer. However, its role in multiple sclerosis (MS) remains unclear. AIMS - The aims of our study were as follows: (i) to assess whether ApoE-4 might be a surrogate marker of cognitive decline in MS; (ii) to confirm the presence of cognitive impairment in mildly disabled patients treated with interferon-beta; and (iii) to analyse the correlation between cognitive disturbances and clinical variables. MATERIAL AND METHODS - Fifty relapsing-remitting MS patients underwent a battery of neuropsychological tests and were genotyped for ApoE. Their scores were compared with those of 35 controls. RESULTS - No association was found between ApoE-4 and cognitive impairment. Significant differences in most domains were observed between MS and the control group. Cognitive decline was not related to disability progression. CONCLUSION - No association between cognitive impairment and ApoE-4 or clinical markers was detected in our MS patients.

Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study.

BACKGROUND: Laquinimod, an oral novel immunomodulator, was shown to reduce MRI-measured disease activity in relapsing-remitting MS (RRMS) patients. OBJECTIVES: To determine whether the safety and efficacy profile of laquinimod, as shown in a placebo-controlled 36-week trial (LAQ/5062), is sustained and reproducible. METHODS: Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase. Clinical assessments were performed at weeks 4, 12 and every 12 weeks thereafter. RESULTS: Two hundred and thirty nine (93%) patients completed the extension phase and 222 (86.3%) had a final scan available. Gadolinium-enhanced (GdE) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses (52%, p = 0.0006). In patients initially randomized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase (p = 0.01). The most prominent safety signal was elevations of liver enzymes, reversible in all cases. CONCLUSIONS: The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study.

Anticipation of age at onset in familial multiple sclerosis.

BACKGROUND AND OBJECTIVE: Anticipation of age at onset in the younger generations is a widely known characteristic of many diseases with genetic inheritance. This study was performed to assess whether there is anticipation of age at onset in younger generations of familial multiple sclerosis (MS) in a Spanish population and to compare clinical characteristics of familial and sporadic MS. METHODS: We studied a cohort of 1110 patients diagnosed with MS and followed-up in our MS Unit. Patients were considered as familial MS if they had in their family at least one relative of first or second degree diagnosed with MS. Otherwise, patients were considered to have sporadic MS. We compared the age at onset between relatives from different generations, and we also compared the age at onset of familial and sporadic MS. RESULTS: A lower age at onset in the younger generations was found (median 22 years vs. 30 years, P < 0.001) and a significant lower age at onset of the disease in familial MS comparing to sporadic MS (median 25 years vs. 29 years, P = 0.042). CONCLUSIONS: There is an anticipation of the age at onset of MS in the younger generations of patients with familial MS. There is also a lower age at onset in familial versus sporadic MS.

Anticipation of age at onset in multiple sclerosis: methodologic pitfalls.

BACKGROUND/AIM: There are several reports that claim anticipation in complex or polygenic diseases such as multiple sclerosis (MS), Crohn disease or schizophrenia. The aim of the present study was to assess age at onset of MS during the last 60 years in the region of Costa de Ponent (Barcelona, Spain) showing how apparent changes in age at onset between generations can be an artefact of analysis based on cohorts that have not been followed enough time. METHODS: The study comprised 1100 patients diagnosed of MS. The method used to correct for follow-up time bias involves constructing comparison cohorts that had been observed for the same amount of time. To ensure equal follow-up times, we restricted our analysis to patients whose onset was by 37 years of age (percentile 75) and were at least 37 years old. We analysed differences in age at onset using log-rank test to compare survival curves estimated by Kaplan-Meier method. RESULTS: Age at onset decreases progressively from older to younger generations. However, when adjustment to equal follow-up time was done, anticipation in age at onset was not found. CONCLUSION: Anticipation of age at onset is undetectable when adjusted for follow-up time.

Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study.

BACKGROUND: A 24-week phase II trial has shown that 0.3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of active lesions. We assessed the effect of oral daily 0.3 and 0.6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind, placebo-controlled phase IIb study. METHODS: The study was done in 51 centres in nine countries. Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing (GdE) lesion on screening MRI. Of 720 patients screened, 306 eligible patients were enrolled. Patients, aged 18-50 years, were randomly assigned to placebo (n=102), laquinimod 0.3 mg a day (n=98), or 0.6 mg a day (n=106). Brain MRI scans and clinical assessments were done at week -4, baseline, and monthly from week 12 to week 36. The primary outcome was the cumulative number of GdE lesions at weeks 24, 28, 32, and 36. The principal analysis of the primary endpoint was done on the intention-to-treat cohort. This study is registered with ClinicalTrials.gov, number NCT00349193. FINDINGS: Compared with placebo, treatment with laquinimod 0.6 mg per day showed a 40.4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4.2 [SD 9.2] vs 2.6 [5.3], p=0.0048); treatment with 0.3 mg per day showed no significant effects (3.9 [5.5] vs placebo, p=0.6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd-Chiari syndrome-ie, a thrombotic venous outflow obstruction of the liver-occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0.6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation. INTERPRETATION: In patients with relapsing-remitting multiple sclerosis, 0.6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated.

Effect of glatiramer acetate (Copaxone) on the immunophenotypic and cytokine profile and BDNF production in multiple sclerosis: a longitudinal study.

We assessed the effect of glatiramer acetate (GA) on the immunophenotypic and cytokine profile and the BDNF production by peripheral blood mononuclear cells, and their association with the clinical response in 19 naïve-treated MS patients prospectively followed-up after GA therapy. Two patients withdrew the therapy. After a median follow-up of 21 months, twelve were considered responders and five as non-responders. Non-responder patients had significant longer disease duration and a higher EDSS score at baseline. In the responder group, a significant decrease in the percentage of INF-gamma producing total lymphocytes, CD4+ and CD8+ T cells, and reduced percentage of IL-2 producing CD4+ and CD8+ T cells were observed at 12, 18 and 24 months. These changes were associated with a significant increase in the percentage of CD3+, CD4+ and CD4(+) CD45RA(+) T cells, and BDNF production from month 6 that remained significant throughout the study. We did not observe significant changes in the nonresponder group for any of the parameters studied. Our data suggest that GA treatment induces a downmodulation of proinflammatory cytokines associated with the regulation of the peripheral T cell compartment and with increased production of BDNF that might be related to the clinical response.

Paraneoplastic cerebellar degeneration. III. Cerebellar degeneration, cancer, and the Lambert-Eaton myasthenic syndrome.

We studied nine patients with a subacute onset of a pancerebellar syndrome. Six had known cancer (three small-cell carcinoma of the lung [SCLC], one metastatic small-cell carcinoma, one small-cell carcinoma of the prostate, and one non-Hodgkin's lymphoma). Six of eight who had neurophysiologic testing, including the three patients without detectable cancer, had coexistent Lambert-Eaton myasthenic syndrome (LEMS). In two of the patients, LEMS was discovered only by neurophysiologic testing. We looked for anti-Purkinje cell autoantibodies in all patient's sera and in four patients' CSF. We also looked for autoantibodies to voltage-gated calcium channels (VGCCs) in seven patients' sera and two patients' CSF, using the 125I-omega-conotoxin radioimmunoassay. We were unable to detect anti-Purkinje cell autoantibodies in any patients' serum or CSF. However, there were raised titers of anti-VGCC autoantibodies in five of seven patients' serum, including one patient with SCLC who did not have LEMS, and in the CSF of one of two patients. We conclude that the frequency of presentation of a pancerebellar syndrome with LEMS is higher than expected by chance and is usually associated with cancer. In some of these patients, LEMS may be clinically occult. The presence of LEMS and raised titers of anti-VGCC autoantibodies in some patients with subacute cerebellar degeneration is suggestive of an autoimmune etiology even though anti-Purkinje cell antibodies could not be detected. Anti-VGCC autoantibodies are not confined to LEMS. They may be found at high titer in CSF as well as serum.

14-3-3 protein in the CSF as prognostic marker in early multiple sclerosis.

Axonal damage probably occurs early in the evolution of MS. Five of 38 (13%) patients had a positive assay for the neuronal 14-3-3 protein in the CSF obtained at the first clinically isolated syndrome suggestive of MS. A positive 14-3-3 assay was the only independent predictor for a shorter time to conversion to clinical definite MS (risk ratio 4.1; 95% CI 1.1 to 15) and to reach an Expanded Disability Status Scale (EDSS) > or =2 at the end of follow-up (odds ratio 14.8; 95% CI 2.86 to 76.8). The detection of the 14-3-3 protein in the CSF at the first neurologic event suggestive of MS may be a useful predictor of short-term evolution.

MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS.

OBJECTIVE: To analyze the MRI and CSF oligoclonal bands (OB) changes in patients with MS who underwent an autologous hematopoietic stem cell transplantation (AHSCT). BACKGROUND: AHSCT is evaluated as an alternative therapy in severe MS. In previous series of AHSCT for MS, data on MRI or OB outcome were limited or not provided. METHODS: Five patients with a median Kurtzke's EDSS score of 6.5, more than two attacks, and confirmed worsening of the EDSS in the previous year received an AHSCT. Hematopoietic stem cells were mobilized with cyclophosphamide (3 g/m2) and granulocyte colony-stimulating factor (5 microg/kg/d). The graft was T cell depleted by positive CD 34+ selection. Conditioning regimen included BCNU (300 mg/m(2)), cyclophosphamide (150 mg/kg in 3 days), and antithymocyte globulin (60 mg/kg in 4 days). MRI scans were scheduled at baseline and 1, 3, 6, and 12 months and OB analysis at baseline and 3 and 12 months post-AHSCT. RESULTS: Four patients had a stable or improved EDSS after a median follow-up of 18 months (range, 12 to 24 months). The fifth patient's condition deteriorated during AHSCT. She partially improved and remained stable after month 3 after AHSCT. The baseline CSF OB persisted 1 year after AHSCT. MRI studies after AHSCT showed no enhanced T1 lesions and no new or enlarging T2 lesions. The median percentage change of T2 lesion load was -11.8% (range, -26.6 to -4.0%). All patients had a decrease of corpus callosum area at 1 year (median, 12.4%; range, 7.8% to 20.5%) that did not progress in the two patients evaluated at 2 years after AHSCT. CONCLUSIONS: Although the persistence of CSF OB suggests the lymphocytes were not eliminated from the CNS, the follow-up MRI studies showed no enhanced T1 brain lesions and a reduction in the T2 lesion load that correlated with the clinical stabilization of MS after AHSCT.

Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease.

We studied an autoantibody (called anti-Tr), found in the serum and CSF of five patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD). Anti-Tr antibodies labelled the cytoplasm of Purkinje cells of human and rat cerebellum. The molecular layer of rat cerebellum showed a characteristic dotted pattern suggestive of immunoreactivity of dendritic spines of Purkinje cells. Patients with cerebellar disorders without HD (159) or HD without PCD (30) did not harbor anti-Tr antibodies. Immunoblots of human Purkinje cells or rat and mouse cerebellum were negative. Anti-Tr antibodies, as defined in this study, appear specific for HD-associated PCD. The immunohistochemical pattern described in the rat cerebellum coupled with the absence of reactivity in the immunoblot may be used to identify anti-Tr antibodies.

A golgi and ultrastructural study of a dominant form of Kufs' disease.

A cerebral biopsy from a patient with inherited dominant autosomic Kufs' disease was studied with Golgi's method and ultrastructurally. A marked PAS positive, sudanophile, autofluorescent deposit was observed in the cytoplasm and in the proximal region of the axon of neurons from the third layer. Ultrastructurally this is a granular, membrane-bound product, sometimes with with a dense, compact rectilinear pattern in which the typical clear component of adult lipofuscin is scanty. Sections stained with Golgi's method show a prominent, sometimes double, axon hillock swelling without dendritic spines. These facts are compared with additional samples of Alzheimer's disease and Huntington's chorea processed in a similar way.

Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease.

Many different mutations, causative of Alzheimer's disease, have been found in the presenilin-1 gene (PS-1). We have developed a screening method based on denaturing gradient gel electrophoresis (DGGE), which allows the mutational analysis of the whole exon 9 of PS-1. Upon the screening of a Spanish sample of early onset familial Alzheimer disease cases, we have found a novel mutation in the PS-1 gene. The mutation (a T to G transition) results in a change of the amino acid at position 282 of the presenilin protein from leucine to arginine. This mutation is located in the hydrophobic domain number 7 (exon 9) close to the site of physiological cleavage processing. The average of onset of the affected members of this family is 43+/-5 years, and the average age of exitus of affected members is 56+/-3 years. The possibility to determine the specific pathologic mechanisms of this mutation is now open.

A family with adult spinal and bulbar muscular atrophy, X-linked inheritance and associated testicular failure.

A family with adult spinal and bulbar muscular atrophy with X-linked recessive inheritance (Kennedy's disease) is described. Affected members presented at age 20 with muscle cramps followed insidiously by gynaecomastia, partial loss of secondary sexual traits, loss of libido and inability to maintain an erection. Three had also testicular atrophy and severe oligospermia was found in two patients. Testicular biopsy in one case showed germinal failure with almost normal Leydig cells. Hormonal tests were suggestive of a primary testicular failure. Etiologic possibilities are considered.

[Pellagroid encephalopathy in chronic alcoholism. Clinicopathological study (author's transl)]. / Encefalopatía pelagroide en el contexto del alcoholismo crónico. Estudio clinicopatológico.

Pathological findings from two patients with clinical symptoms of diffuse encephalopathy who died due to a bronchopneumonia are studied. Postmortem examination of the central nervous system revealed neuronal changes which suggested the diagnosis of pellagroid encephalopathy. The differential diagnosis between several diseases characterized by encephalopathy, alcohol ingestion and malnutrition are discussed (chronic alcoholism, acquired hepatocerebral degeneration, Marchiafava-Bignami's syndrome, Morel's lamilar sclerosis, Wernicke-Korsakoff's syndrome and pellagroid encephalopathy). Alcoholic encephalopathy should be considered a medical emergency, which requires early correction of the basal parameters and prompt administration of thiamin and nicotinamide-nicotinic acid in doses of 500 mg per day i.v. followed by 200-300 mg per day of niacinamide by mouth.

[Peripheral neuropathy and insulinoma (author's transl)]. / Neuropatía periférica e insulinoma.

A case of insulinoma is reported with disease of the peripheral nervous system and pathological demonstration of a primary nerve lesion. On admission the female patient gave a history of hypoglycemic episodes and paresthesias and loss of strength in both hands. Physical examination disclosed loss of strength and atrophy of the distal musculature of the extremities, predominating in the upper ones and without fasciculations. Muscle biopsy demonstrated changes suggestive of neurogenous atrophy, and biopsy of the sural nerve showed reduction of the myelin fibers with axonal degeneration, important signs of demyelinization, and remyelinization figures. The neuropathy was unchanged two months after removal of the insulinoma. The exact location of the nerve lesion in insulinoma is controversial, some authors placing it in the peripheral nerve while others believe the motor neurons of the anterior horns to be diseased. The pathological findings in the present case suggest primary nerve disease, but an associated lesion of the anterior horns could also be present.

[Skin reactions to interferon alpha in a series of 92 patients with multiple sclerosis]. / Reacciones cutáneas por interferón beta en una serie de 92 pacientes con esclerosis múltiple.

BACKGROUND: A significant proportion of multiple sclerosis patients develop cutaneous reactions by interferon beta 1b (IFN-beta). The am of this study was to describe clinically and histologically the cutaneous reactions by IFN-beta. PATIENTS AND METHODS: A series of 92 patients with multiple sclerosis in treatment with IFN-beta was followed. Cutaneous biopsy was performed in cases with persistent lesions. RESULTS: 9 out of 92 patients presented eritematous plaques, 4 cutaneous ulcers and 1 sclerodermiform plaques. Vascular thrombosis was demonstrated in 2 cases. CONCLUSIONS: In patients with multiple sclerosis treated with IFN-beta the persistent skin lesions are more frequent in female patients. Generally is not necessary to stop the treatment.