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Background and purpose Evidence on regional changes resulting from neurodegenerative processes underlying primary progressive multiple sclerosis (PPMS) is still limited. We assessed brain region volumes and their relationship with disability progression and cognitive function in PPMS patients. Methods This was an MRI analysis of 43 patients from the prospective Understanding Primary Progressive Multiple Sclerosis (UPPMS) cohort study. MRI scans were performed within 3 months before enrollment and at month 12. Results Gray matter volume of declive and white matter volumes adjacent to left straight gyrus, right calcarine sulcus, and right inferior occipital gyrus significantly decreased from baseline to month 12. Baseline white matter volumes adjacent to right amygdala and left cuneus significantly differed between patients with and without disability progression, as well as baseline gray matter volumes of left cuneus, right parahippocampal gyrus, right insula, left superior frontal gyrus, declive, right inferior temporal gyrus, right superior temporal gyrus (pole), and right calcarine sulcus. Baseline gray matter volumes of right cuneus and right superior temporal gyrus positively correlated with 12‐month Selective Reminding Test and Word List Generation performance, respectively. Gray matter changes in right superior semilunar lobe and white matter adjacent to left declive and right cerebellar tonsil also positively correlated with Word List Generation scores, while white matter change in left inferior semilunar lobe positively correlated with Symbol Digit Modalities Test performance after 12 months. Conclusions White and gray matter volumes of specific brain regions could predict disability progression and cognitive performance of PPMS patients after one year., The data described in the present manuscript provide a detailed description of region volume changes exhibited by primary progressive multiple sclerosis patients over one year, including decreases in gray matter declive and white matter adjacent to left straight gyrus, right calcarine sulcus, and right inferior occipital gyrus. In addition, baseline volumes of white matter adjacent to right amygdala and left cuneus could also predict 1‐year disability progression in patients with primary progressive multiple sclerosis, as well as baseline grey matter volumes of left cuneus, right parahippocampal gyrus, right insula, left superior frontal gyrus, declive, right inferior temporal gyrus, right superior temporal gyrus (pole), and right calcarine sulcus. Furthermore, baseline volumes of certain regions such as grey matter of right cuneus and right superior temporal gyrus could also predict cognitive performance after one year, as well as volume changes in grey matter of right superior semilunar lobe and white matter of left inferior semilunar lobe and adjacent to left declive and right cerebellar tonsil were correlates of cognitive performance.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. MS is more prevalent in women and is estimated to affect some 2.3 million people across the world. There is unequivocal genetic susceptibility in MS. The most consistent genetic determinant identified is the major histocompatibility complex (MHC). The haplotypes more strongly related to susceptibility and protection for MS are HLA-DR2 and HLA-DR11, respectively. Some genes outside the MHC, such as IL2RA, IL7R and TNFRSF1A, have also been related to MS. There is a latitudinal gradient of MS prevalence, probably due to environmental factors on the genetic susceptibility. The most important MS risk factors are seropositivity against Epstein–Barr virus, infectious mononucleosis, and smoking. Other factors such as vitamin D or parasitic infections require further investigation. The clinical manifestations of relapsing forms of MS in initial stages are related to demyelination of the susceptible structures such as the optic nerves or spinal cord. In established MS, the clinical symptoms are related to the multisystemic affectation and neurodegeneration such as cognitive impairment or sphincter disorders. An unmet need exists for highly effective medications with low risk for deep immunosuppression and for the symptomatic relief of MS.

Background Primary progressive multiple sclerosis (PPMS) has long been defined by progressive disability accrual in the absence of initial relapses. However, its underlying neurodegenerative process seems to be accompanied by central nervous system inflammation. A new classification defined multiple sclerosis courses according to clinical/radiological activity and progression. We provide further insight into PPMS activity according to this classification and other daily living aspects. Methods This was a multicentre, prospective, cohort study including 55 adult patients with PPMS according to 2010 McDonald criteria, within ten years from neurologic symptom onset and not receiving disease-modifying therapies during the past six months, who were followed up for 12 months. The primary study endpoint was the percentage of patients with active disease based on clinical relapses and/or magnetic resonance activity. Disability progression, cognitive function, physical/psychological impact, depression symptoms, stigma and employment were secondary endpoints. Results Eleven (25.6%) patients exhibited multiple sclerosis activity throughout the 12-month study follow-up. Fourteen showed non-active multiple sclerosis without progression, 11 non-active multiple sclerosis with progression, 6 active multiple sclerosis without progression and 4 active multiple sclerosis with progression; one patient with disease activity was not assessable for progression. Cognitive function scores remained unchanged or increased, disease physical impact was maintained and disease psychological impact significantly decreased. The proportion of patients with depression symptoms or stigma remained without significant changes as well as employment outcomes. Conclusion This study shows that one-fourth of PPMS patients may exhibit disease activity over one year, with disability progression in approximately one-third but without worsening of cognitive function, disease impact, depression, stigma or employment outcomes.

Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment. Materials and methods: Samples were obtained from relapsing-remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics. Results: Fingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod. Conclusion: MS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker. This work was mostly supported by grants from Novartis (PI110/13 JGM-INM2014-01) and Fondo de Investigación Sanitaria FIS PI12/02672 and PI15/02099 integrated in the Plan Nacional de I+D+I (2008–2011 and 2013–2016, respectively), supported by the ISCIII—subdirección General de Evaluación and co-financed by the Fondo Europeo de Desarrollo Regional (FEDER). The funding sources had no involvement in the study design, data collection, analysis, interpretation, preparation of the manuscript, and the decision to submit the article for publication. Sí

The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to clinically isolated syndrome and to multiple sclerosis in 75 patients with radiologically isolated syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically isolated syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to clinically isolated syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of clinically isolated syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to clinically isolated syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically isolated syndrome presenting positive oligoclonal bands converted faster to clinically isolated syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to clinically isolated syndrome and multiple sclerosis were more pronounced in radiologically isolated syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to clinically isolated syndrome and multiple sclerosis in radiologically isolated syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically isolated syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically isolated syndrome.

Since the introduction of interferon beta 1 b for the treatment of multiple sclerosis, there has been a progressive increase in the number of drugs available for this disease. Currently, 11 drugs have been approved in Spain, and their indications depend on specific clinical characteristics. The present article reviews these indications and also discusses other medications without official approval that have also been used in multiple sclerosis.

Refractory spasticity, central neuropathic pain and bladder dysfunction are common clinical problems in patients with multiple sclerosis (MS). None of the currently available oral medications has proven to be reliably effective and can be limited by toxicity. Cannabinoids have shown therapeutic effects on those MS-associated symptoms. Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) Sativex (nabiximols) is an oromucosal spray formulation that contains THC and CBD in an approximate 1:1 ratio and is described as an endocannabinoid system modulator. The efficacy of THC/CBD on MS-associated spasticity, pain and bladder dysfunction has been studied in clinical trials as well as in clinical practice studies. Adverse effects are usually mild or moderate and the low rate of drug discontinuation provides good evidence of long-term tolerability. This article focuses on the pharmacological properties, clinical efficacy and tolerability of THC/CBD in MS patients.

Stigma associated with neurological disorders may contribute to a poor health-related quality of life. However, limited information is available in primary progressive multiple sclerosis. We investigated the presence and impact of stigma in patients with primary progressive multiple sclerosis. A non-interventional, cross-sectional study was conducted. A total of 55 primary progressive multiple sclerosis patients were studied (mean age 55.8±9.5 years, 56.4% male). The median Expanded Disability Status Scale score was 5.5 (4.0–6.5). Stigma prevalence was 78.2% ( n=43). Twenty-four patients (43.6%) were classified as depressed. Scores on the eight-item Stigma Scale for Chronic Illness correlated with physical (rho=0.464, p

Spasticity is a disabling complication of multiple sclerosis. Some commonly used oral medications include baclofen, tizanidine, anticonvulsants and benzodiazepines, but their benefits are modest. Sativex® (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) is a unique cannabinoid-based medicine with two main active ingredients; 9-δ-tetrahydrocannabinol, which acts mainly on cannabinoid 1 receptors in the CNS and plays a key role in the modulation of spasticity and spasms, and cannabidiol, which has different properties, including minimization of the psychoactivity associated with 9-δ-tetrahydrocannabinol. Sativex is indicated for symptomatic improvement in adult patients with moderate-to-severe multiple sclerosis-related spasticity who have not responded adequately to other first- or second-line antispasticity medications, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Over the past couple of years, Sativex has been approved for use in a number of European countries and ongoing postmarketing studies are evaluating the possible risks associated with Sativex treatment by systematically collecting all suspected adverse reactions that occur in patients from the start of treatment. Interim data from the UK as well as Spanish Sativex safety registries confirm that clinical benefit is maintained over the longer term despite the expected trend for deterioration owing to disease progression. Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex, including no evidence of driving impairment and no relevant incidence of falls or other adverse events of concern, such as psychiatric or nervous system events. Sativex appears to be a well-tolerated and useful add-on therapy in patients who have not achieved an adequate response with traditional antispastic agents.

The therapeutic utility of the anti-CD20 monoclonal antibodies (mAbs) is currently being evaluated in multiple sclerosis (MS) in line with the better understanding of the role of B lymphocytes in MS pathogenesis. Area covered: We conducted a literature search using Medline/Pub Med database of basic research and available controlled trials about anti-CD20 mAbs in MS. Additionally, ongoing studies were identified in the ClinicalTrials.gov database. B cells exert multiple inflammatory and regulatory functions playing an important role in MS pathogenesis as is demonstrated by the production of autoantibodies, infiltration of B cells in MS lesions and the formation of ectopic B cell follicle-like structures in meninges, among others. B-cell depletion by anti-CD20 mAbs has been shown to have an impact on these pathogenic mechanisms. The efficacy of three of them, rituximab, ocrelizumab and ofatumumab in MS has been confirmed by placebo-controlled clinical trials demonstrating a significant reduction of the annualized relapsing rate (ARR), new gadolinium-enhancing (GdE) and T2 lesions. There have been no significant safety problems so far but the overall benefit to risk profile is still to be determined. Expert commentary: After recent good results of these agents in MS therapy, questions related to maintenance therapy, markers of response and control of B cells values remain unanswered.

Introduction Cladribine is a prodrug, a synthetic analogue of deoxyadenosine, approved for use as selective immune reconstitution therapy in very active recurring multiple sclerosis in adults. Aims To review the development of the drug, its mechanism of action and the efficacy and safety data obtained to date, as well as to establish recommendations of Spanish experts for its use in clinical practice. Development The treatment of multiple sclerosis has been simplified with cladribine tablets, and two short courses of administration for two consecutive years (maximum 20 days) are needed to maintain an efficacy of up to four years after the first dose. Results of clinical trials have demonstrated the safety, tolerability and long-term efficacy of cladribine tablets in patients with recurring multiple sclerosis. Thus, patients treated with cladribine presented a significant reduction in the rate of flare-ups, in the risk of disability progression and in the development of new lesions in magnetic resonance imaging compared to those treated with placebo. In terms of safety, the treated patients had a higher frequency of lymphopenia, in relation to its mechanism of action, and of infections by herpes zoster virus. Long-term results with eight years' follow-up have shown that treated patients are not at greater risk of developing serious events, such as malignant neoplasms or opportunistic infections. Conclusions Cladribine is the first short-course oral therapy that has been shown to be effective and safe in patients with very active recurring multiple sclerosis, and with a sustained effect over time. The recommendations of Spanish experts on its usage are a fundamental complement to the considerations described by the regulatory agencies.

Abnormal apoptosis has been reported in circulating T lymphocytes in patients with multiple sclerosis. The effects of 12 months of IFNbeta treatment in T and B lymphocyte spontaneous ex vivo apoptosis were studied in patients with MS. Peripheral blood mononuclear cells were obtained from 48 patients before and at 1, 6 and 12 months after treatment with IFNbeta. Spontaneous ex vivo apoptosis was quantified by four-color flow cytometry. A significant reduction and normalization of the percentage of apoptotic cells was found in all T lymphocyte subsets. B cell apoptosis values were unaffected by therapy; Relapses of the clinical activity of the disease were associated to transitory upturns of lymphocyte apoptosis. In conclusion, IFNbeta therapy progressively normalizes the increased ex vivo T lymphocyte apoptosis observed in MS. However, it is not clear if this reduction in spontaneous T lymphocyte apoptosis is due to direct effect of IFNbeta or secondary to decreased clinical and sub-clinical activity.

Many reports have shown that cannabinoids might be beneficial in the symptomatic treatment of multiple sclerosis (MS). We have investigated the therapeutic properties of the non-selective cannabinoid receptor agonist WIN-2 as a suppressive drug in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the passive variety of EAE, induced in Lewis rats by adoptive transfer of myelin-reactive T cells, WIN-2 ameliorates the clinical signs and diminishes the cell infiltration of the spinal cord. Due to the involvement of cannabinoids in the regulation of cell death and survival, we investigated the effects of WIN-2 on the encephalitogenic T cell population. WIN-2 induced a profound increase of apoptosis in a dose- and time-dependent manner. The potential involvement of cannabinoid receptors (CB) was investigated by encephalitogenic T cell stimulation in the presence of the CB(1) (SR141716A) and CB(2) (SR144528) antagonists, pertussis toxin (PTX) and the inactive enantiomer WIN-3. WIN-2-induced apoptosis was partially blocked by SR144528 and PTX, whereas, WIN-3 only exerted a mild effect on cell viability. These results point to the partial involvement of CB(2) receptor together with other receptor-independent mechanism or by yet unknown cannabinoid receptors. Moreover, WIN-2 induced the extrinsic pathway of apoptosis, as shown by caspase-10 and -3 activation. These results suggest that cannabinoid-induced apoptosis of encephalitogenic T cells may cooperate in their anti-inflammatory action in EAE models. The partial involvement of CB(2) receptors in WIN-2 action may open new therapeutic doors in the management of MS by non-psychoactive selective cannabinoid agonists.

Evidence exists for a potential modulation of inflammasome activity by interferon beta. Here, we investigated the roles of inflammasomes [absent in melanoma 2 (AIM2); NLR family, CARD domain containing 4 (NLRC4); NLR family, pyrin domain containing 1 and 3 (NLRP1 and NLRP3)] and related cytokines (IL1B, IL10, IL18) in the response to interferon beta in patients with relapsing-remitting multiple sclerosis. Ninety-seven patients treated with interferon beta were classified into responders and non-responders according to clinical criteria after 24 months and clinical-radiological criteria after 12 months of treatment. Messenger RNA expression levels of inflammasomes and cytokines were determined by real-time polymerase chain reaction in peripheral blood mononuclear cells collected before treatment with interferon beta. In a subgroup of patients, NLRP3 and IL1B expression was also determined after 3 months (n = 32) and 12 months (n = 20) of interferon beta treatment. A polymorphism located in the NLRP3 gene, rs35829419, was genotyped in 789 multiple sclerosis patients treated with interferon beta. Baseline mRNA expression levels for NLRP3 and IL1B were increased in peripheral blood mononuclear cells from non-responders compared to responders classified according to clinical criteria after 24 months (P = 0.02 and P = 0.001, respectively). No significant differences were observed for other inflammasomes and related cytokines. Differences in NLRP3 and IL1B expression remained significant following a clinical-radiological classification after 12 months (P = 0.007 and P = 0.02, respectively). After treatment with interferon beta, NLRP3 and IL1B expression was increased in responders but unchanged in non-responders. A trend for association was observed between rs35829419 and interferon beta response (pM-H = 0.08). These results point to a role of the NLRP3 inflammasome and its related cytokine IL1B in the response to interferon beta in patients with relapsing-remitting multiple sclerosis.

Many studies have demonstrated that the endocannabinoid system (ECS) is altered in different tumor types, including colon cancer. However, little is known about the role of the ECS in tumor progression. Here we report the correlation between CB 2 expression and pathological data in a series of 175 colorectal cancer patients, as well as the response of the HT29 colon cancer-derived cell line upon CB 2 activation. CB 2 mRNA was detected in 28.6% of samples tested. It was more frequent in N+ patients and predicts disease free survival and overall survival in colon cancer. In positive samples, CB 2 was expressed with great intensity in tumor epithelial cells and correlated with tumor growth. Treatment of HT29 with CB 2 agonist revealed membrane loss of E-cadherin and SNAIL1 overexpression. A direct correlation between CB 2 and SNAIL1 expression was also found in human tumors. CB 2 receptor expression is a poor prognostic marker for colon cancer and the activation of this receptor, with non-apoptotic doses of agonists, could be collaborating with disease progression. These results raise the question whether the activation of CB 2 should be considered as anti-tumoral therapy. This study was supported by AECC; ISCIIIPI10/00879 (Plan Nacional de I+D+I 2008-2011, FEDER funds co-financed), and ISCIII-RETIC RD12/0036/0041/n(Plan Estatal de I+D+I 2013-2016, FEDER funds cofinanced). JMG and EMM are supported by ISCIII, CP08/00217 and FI11/00696 respectively, (Plan Nacional/nde I+D+I 2008-2011, FEDER funds co-financed).

A 34-year-old man, recently diagnosed as diabetic, presented an acute painful neuropathy. He reported a profound weight loss during the months preceding onset. There were no motor symptoms, and only mild neurological signs were observed on examination. Improvement was related to a good glycemic control and weight gain. Acute painful diabetic neuropathy is a condition that may affect diabetic patients shortly after development of the disease. The pathogenetic roles played by different factors are reviewed.

Background A debate surrounding multiple sclerosis epidemiology has centred on time-related incidence increases and the need of monitoring. The purpose of this study is to reassess multiple sclerosis incidence in the European Economic Area. Methods We conducted a systematic review of literature from 1965 onwards and integrated elements of original research, including requested or completed data by surveys authors and specific analyses. Results The review of 5323 documents yielded ten studies for age- and sex-specific analyses, and 21 studies for time-trend analysis of single data sets. After 1985, the incidence of multiple sclerosis ranged from 1.12 to 6.96 per 100,000 population, was higher in females, tripled with latitude, and doubled with study midpoint year. The north registered increasing trends from the 1960s and 1970s, with a historic drop in the Faroe Islands, and fairly stable data in the period 1980-2000; incidence rose in Italian and French populations in the period 1970-2000, in Evros (Greece) in the 1980s, and in the French West Indies in around 2000. Conclusions We conclude that the increase in multiple sclerosis incidence is only apparent, and that it is not specific to women. Monitoring of multiple sclerosis incidence might be appropriate for the European Economic Area.

Antibodies of the IgM, IgG and IgA class against GM1, asialo-GM1, GD1b and GM2 gangliosides were determined in the sera of patients with motor neuron disease (MND), peripheral neuropathy, other neurological diseases (OND) and healthy individuals. Antibodies of the three immunoglobulin classes were present in healthy persons. MND patients did not differ from OND or controls in anti-GM1 titers of the three isotypes. In the group of peripheral neuropathy, no elevations of antibody titers were observed in patients with sensory or sensory-motor neuropathy; however, four out of 12 patients with the motor variety had very high levels of IgM or IgG antibodies. Two of these four patients also had increased titers of IgA antibodies, but no patients exhibited high titers restricted to this isotype.

There is evidence suggesting the involvemnt of the platelet-activating factor (PAF) in central nervous system (CNS) functions. The possibility exists that PAF may be relevant in eliciting cell-mediated autoimmune phenomena in CNS. Toe assess the role of PAF in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), male Lewis rats were primed with whole spinal cord from guinea pig, emulsified in Freund's adjuvant supplemented with 10 mg/ml of Mycobacterium tuberculosis , H37Ra strain. Treatment with two different PAF antagonist (PCA 4248, WEB 2170) was applied starting from day 1 or day 5 postinoculation on a twice-daily basis. Neither PCA 4248 nor WEB 2170 suppressed the clinical signs of EAE. PAF concentration was measured in CNS tissue from the 9th day after inoculation to the 15th day, and no differences were found between control and EAE animals. These results suggest that PAF is not involved in the mediation of EAE.

Two patients, one of them with myasthenia gravis, presented symptoms of continuous muscle fiber activity syndrome before discovery of a thymoma. Peripheral neuropathy was present in both patients, with axonal and demyelinating lesions in sural nerve biopsy. The syndrome remained unchanged or worse after thymectomy. Both patients died of associated complications.

Temporal variation in Guillain-Barre syndrome (GBS) warrants monitoring in certain situations. This study sought to describe a public-health-based GBS surveillance service in Spain and conduct pilot surveillance in the period 1998-1999. Neurologists from 11 hospitals countrywide, serving a population of 3.9 million, reported all patients, ages 20 years or over, admitted to hospital with suspected GBS. Cases that did not belong to the designated hospital catchment area or failed to fulfill diagnostic criteria after follow- up were excluded. Reported monthly incidence was compared against predicted incidence obtained from retrospective data (1985-1997) using a reported method based on 97.5% percentile values. Alarm thresholds for 2000 onwards were obtained by applying the same method to the updated 1985-1999 series. During the 2-year period, 98 GBS cases were reported, yielding an overall age-adjusted incidence of 1.26 per 100 000 population, with a breakdown by sex of 1.83 for males and 0.76 for females. Monthly incidence remained below or was similar to the corresponding threshold limit value. Seasonality with highest incidence in winter was more pronounced in the elderly. Preceding events, mainly respiratory infections, were identified in 71% of patients. Pilot two-year GBS surveillance in Spain resulted neither in alarm nor in preventive measures. Adult GBS incidence in Spain might be monitored by a surveillance system set up at short notice when a possible threat is perceived. A monthly incidence of over 3 per 100 000 person-years in the population aged 20 years or older would exceed threshold values.

Retrospective demographic information and hospital record data were collected for 337 patients resident in Spain who had validated Guillain-Barré syndrome (GBS) diagnoses and clinical onset during the period 1985–1997 and had been admitted to 11 centres, covering a population of 3.9 million. The European age-adjusted GBS incidence per 100,000 for 1985–1997 among the population aged 20 and over was 0.85, with a breakdown of 1.14 in men and 0.58 in women. Incidence increased with age and time, with occasional rises that mimicked outbreaks and occurred at irregular 2- to 4-year intervals, mainly in winter. Spatial variation was modest. Respiratory and gastrointestinal infections respectively constituted 49.3 and 19.3% of recorded preceding events. The 97.5% intercentile limit, obtained from the 1985–1997 monthly incidences using predictions from a Poisson model, was proposed as the threshold value for pilot epidemiological surveillance of GBS in 1998–1999.

The case of a 22-year-old patient is described, who developed a clinical picture of pseudotumor cerebri in the course of typhoid fever, an association not previously described. The patient progressed favorably after treatment with amoxicillin. The etiopathogenesis of pseudotumor cerebri is briefly discussed, as is the need to study the possible existence of this disorder in cases of typhoid fever patients with headaches and/or visual deficits which are not readily explained.

INTRODUCTION Demonstration of the efficacy of interferon beta IB in the reduction of outbreaks of multiple sclerosis has led to it being used in Spain. DEVELOPMENT Discussion of the current situation regarding the use of interferon beta IB in Spain, diagnostic criteria, side-effects and future outlook. CONCLUSIONS Use of interferon beta IB in Spain has followed criteria established by a Committee of Experts, and there is a lower rate of non-completion of treatment than in the U.S.A. New possibilities arise with the appearance of new drugs which are still awaiting evaluation.

Excerpt To the editor: A recent article by Moore and colleagues (1) concerns neurologic dysfunction in the idiopathic hypereosinophilic syndrome. We report our own case, because some of its peculia...