Patient reported outcomes in a secondary progressive MS cohort related to cognition, MRI and physical outcomes.

BACKGROUND: Patient-reported outcomes (PROs) are increasingly being used as outcomes in secondary progressive multiple sclerosis (SPMS) trials. We examined how PROs reflect disease burden in SPMS. METHODS: In this observational prospective study, 65 SPMS patients were examined by five different PROs (Fatigue Scale Motor Cognition (FSMC), Multiple Sclerosis Impact Scale version 2 (MSIS-29v2), 36-Item Short Form Health Survey version 2 (SF-36v2), EQ-5D-5L and Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis version 2.0 (WPAI:MS)); two different rating scales, Multiple Sclerosis Impairment Scale (MSIS) and Expanded Disability Status Scale (EDSS); functional tests of mobility (Timed-25-Foot Walk (T-25FW), 6-Spot Step Test (6-SST) and (9-Hole Peg Test (9-HPT)); cognitive tests (Symbol Digital Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R)); and multimodal Magnetic Resonance Imaging (MRI). RESULTS: When the PROs were divided into physical and psychological subscores, the PRO physical subscores of FSMC, MSIS-29v2 and SF-36v2 correlated with physical rating scales (EDSS, MSIS) and physical measures of upper (9-HPT) and lower extremity function (T-25FW and 6-SST)) (p = 0.04-0.0001). 9-HPT correlated the least with physical subscores of PROs but showed the strongest correlation with activity impairment (subscore of WPAI:MS). In contrast, psychological PRO subscores of FSMC, MSIS-29v2 and SF-36v2 did not reflect the cognitive outcomes (SDMT and BVMT-R), although the cognitive scores correlated with disease burden indicated by MRI lesion volumes. The psychological PRO subscores did not correlate with fatigue, physical and MRI outcomes either. CONCLUSION: Correlation between PRO physical subscores and physical outcomes supports PROs as potentially useful clinical endpoints in SPMS. The results of this study indicate that patients with SPMS highly perceive their mobility on function of their lower extremities, while they perceive their daily activities highly dependent on function of the upper extremities. Psychological subscores of MS specific PROs may be less suitable as surrogate markers for the cognitive status and should be considered as a mental quality of life measurement independent of disease burden.

Treatment of MOG antibody associated disorders: results of an international survey.

INTRODUCTION: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. OBJECTIVE: To survey the current global clinical practice of clinicians treating MOGAD. METHOD: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019). RESULTS: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. CONCLUSION: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

Cladribine modifies functional properties of microglia.

Cladribine (CdA), an oral prodrug approved for the treatment of relapsing multiple sclerosis, selectively depletes lymphocytes. CdA passes the blood-brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. We examined if CdA modifies the phenotype and function of naive and activated primary mouse microglia, when applied in the concentrations 0·1-1 µM that putatively overlap human cerebrospinal fluid (CSF) concentrations. Primary microglia cultures without stimulation or in the presence of proinflammatory lipopolysaccharide (LPS) or anti-inflammatory interleukin (IL)-4 were treated with different concentrations of CdA for 24 h. Viability was assessed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Phagocytotic ability and morphology were examined by flow cytometry and random migration using IncuCyte Zoom and TrackMate. Change in gene expression was examined by quantitative polymerase chain reaction (qPCR) and protein secretion by Meso Scale Discovery. We found that LPS and IL-4 up-regulated deoxycytidine kinase (DCK) expression. Only activated microglia were affected by CdA, and this was unrelated to viability. CdA 0·1-1 µM significantly reduced granularity, phagocytotic ability and random migration of activated microglia. CdA 10 µM increased the IL-4-induced gene expression of arginase 1 (Arg1) and LPS-induced expression of IL-1ß, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS) and Arg1, but protein secretion remained unaffected. CdA 10 µM potentiated the increased expression of anti-inflammatory TNF receptor 2 (TNF-R2) but not TNF-R1 induced by LPS. This suggests that microglia acquire a less activated phenotype when treated with 0·1-1 µM CdA that putatively overlaps human CSF concentrations. This may be related to the up-regulated gene expression of DCK upon activation, and suggests a potential alternative mechanism of CdA with direct effect on CNS resident cells.

A population-based epidemiological study of neuromyelitis optica spectrum disorder in Hungary.

BACKGROUND AND PURPOSE: The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO Diagnosis (IPND) criteria. METHODS: A retrospective population-based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re-evaluation from multiple sources. Crude and sex- and serostatus-specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person-years) from 2006 to 2015 were estimated and age-adjusted rates were determined. RESULTS: Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 [95% confidence interval (CI) 1.52-2.28] per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person-years provided an incidence rate of 1.32 (95% CI 1.08-1.61) per 1 000 000 person-years. Age-adjusted prevalence was 1.87 (95% CI 1.56-2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98-1.46) per 1 000 000 person-years. CONCLUSIONS: In this first report of a large population-based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations.

Autoimmune encephalitis associated with voltage-gated potassium channels-complex and leucine-rich glioma-inactivated 1 antibodies - a national cohort study.

BACKGROUND AND PURPOSE: The aim of this study was to describe clinical and paraclinical characteristics of all Danish patients who tested positive for anti-voltage-gated potassium channels (VGKC)-complex, anti-leucine-rich glioma-inactivated 1 (LGI1) and anti-contactin-associated protein-2 antibodies in the serum/cerebrospinal fluid between 2009 and 2013 with follow-up interviews in 2015 and 2016. METHODS: We evaluated antibody status, symptoms leading to testing, course of disease, suspected diagnosis and time of admission as well as diagnosis and treatment. All magnetic resonance imaging, electroencephalography and 18 F-fluorodeoxyglucose positron emission tomography scans were re-evaluated by experts in the field. RESULTS: A total of 28/192 patients tested positive for VGKC-complex antibodies by radioimmunoassay and indirect immunofluorescence; 17 had antibodies to LGI1 and 6/7 of the available cerebrospinal fluids from these patients were seropositive. These 17 patients all had a clinical phenotype appropriate to LGI1 antibodies. The remaining 11 were LGI1 negative (n = 4) or not tested (n = 7). Of these, two had a phenotype consistent with limbic encephalitis. The remaining phenotypes were Guillain-Barré syndrome, Creutzfeldt-Jakob disease, neuromyotonia and anti-N-methyl-D-aspartate receptor encephalitis. Magnetic resonance imaging abnormalities were demonstrated in 69% of the LGI1-positive patients. Two patients with normal magnetic resonance imaging demonstrated temporal lobe hypermetabolism using 18 F-fluorodeoxyglucose positron emission tomography. Abnormal electroencephalography recordings were found in 86% of the patients. Upon follow-up (median 3.2 years), the median modified Rankin Scale score of anti-LGI1-positive patients was 2 and only two patients reported seizures in the past year. CONCLUSIONS: Patients diagnosed with anti-LGI1 autoimmune encephalitis increased significantly from 2009 to 2014, probably due to increased awareness. In contrast to seropositive anti-VGKC-complex patients, all anti-LGI1-positive patients presented with a classical limbic encephalitis. The majority of patients recovered well.

Identification of a novel HLA-B allele, HLA-B*08:177, in a Hungarian patient and her HLA identical sibling.

The newly detected HLA-B*08:177 differs from HLA-B*08:01:01:01 by 1 single nucleotide substitution at position 365 of exon 3.

Teriflunomide for multiple sclerosis in real-world setting.

OBJECTIVES: Teriflunomide 14 mg is a once-daily oral disease-modifying treatment for relapsing-remitting multiple sclerosis. We examined adverse event (AE) profile and efficacy in real life. MATERIALS AND METHODS: In this observational cohort study, we retrospectively examined 1521 blood samples and data of 102 patients followed for up to 28 months. RESULTS: The number of female patients starting teriflunomide peaked in the fifth decade, 10 years later compared to male patients (P<.001), reflecting pregnancy concerns. Seventy-six percentages of patients shifted to teriflunomide from treatment with interferon-beta. Expanded disability status scale improved in 11% of patients (18.2±3.6 months follow-up) and remained constant in 67.5% (15±5.3 months follow-up). Of ten relapses, three occurred within 6 months after starting treatment. Seventeen patients (16.5%) discontinued teriflunomide: 53% because of AEs and 29% because of relapse. Levels of alanine aminotransferase (ALT) remained normal in 95.3% of the blood samples and remained below 1.5 times the upper limit of normal in 91% of the 4.7% abnormal samples. One-third of the patients had abnormal ALT values at least once. Haematological abnormalities were found in <4% of the blood samples, but at least one abnormal value was observed in up to 21% of the patients. CONCLUSIONS: Efficacy and safety of teriflunomide in real-life setting support data obtained by the pivotal trials. Laboratory abnormalities are rare among the large number of samples, but patients may commonly have a single mild, abnormal value if frequently tested.

l-Arginine Pathway Metabolites Predict Need for Intra-operative Shunt During Carotid Endarterectomy.

OBJECTIVE/BACKGROUND: Asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthesis and is a marker of atherosclerosis. This study examined the correlation between pre-operative l-arginine and ADMA concentration during carotid endarterectomy (CEA), and jugular lactate indicating anaerobic cerebral metabolism, jugular S100B reflecting blood-brain barrier integrity, and with factors of surgical intervention. METHODS: The concentration of l-arginine, ADMA, and symmetric dimethylarginine was measured in blood taken under regional anaesthesia from the radial artery of 55 patients prior to CEA. Blood gas parameters, concentration of lactate, and S100B were also serially measured in blood taken from both the radial artery and the jugular bulb before and after carotid clamping, and after release of the clamp. To estimate anaerobic metabolism, the jugulo-arterial ratio of CO2 gap/oxygen extraction was calculated. RESULTS: Positive correlation was found between pre-operative ADMA levels and the ratio of jugulo-arterial CO2 gap/oxygen extraction during clamp and reperfusion (p = .005 and p = .01, respectively). An inverse correlation was found between the pre-operative l-arginine concentration and jugular lactate at each time point (both p = .002). The critical pre-operative level of l-arginine was determined by receiver operator curve analysis. If l-arginine was below the cutoff value of 35 µmol/L, jugular S100B concentration was higher 24 h post-operatively (p = .03), and jugular lactate levels were increased during reperfusion (p = .02). The median pre-operative concentration of l-arginine was lower in patients requiring an intra-operative shunt than in patients without need of shunt (median: 30.3 µmol/L [interquartile range 24.4-34.4 µmol/L] vs. 57.6 µmol/L [interquartile range 42.3-74.5 µmol/L]; p = .002). CONCLUSION: High pre-operative ADMA concentration predicts poor cerebral perfusion indicated by elevated jugulo-arterial CO2 gap/oxygen extraction. Low pre-operative l-arginine concentration predicts the need for a shunt. The inverse correlation between pre-operative l-arginine concentration and both jugular lactate and S100B during carotid clamping suggests a protective role of the NO donor l-arginine.

HLA genetic diversity in Hungarians and Hungarian Gypsies: complementary differentiation patterns and demographic signals revealed by HLA-A, -B and -DRB1 in Central Europe.

Systematic analyses of human leukocyte antigen (HLA) profiles in different populations may increase the efficiency of bone marrow donor selection and help reconstructing human peopling history. We typed HLA-A, -B, and -DRB1 allele groups in two bone marrow donor cohorts of 2402 Hungarians and 186 Hungarian Gypsies and compared them with several Central-European, Spanish Gypsy, and Indian populations. Our results indicate that different European Gypsy populations share a common origin but diverged genetically as a consequence of founder effect and rapid genetic drift, whereas other European populations are related genetically in relation to geography. This study also suggests that while HLA-A accurately depicts the effects of genetic drift, HLA-B, and -DRB1 conserve more signatures of ancient population relationships, as a result of balancing selection.

Low occurrence of the HLA-C*04:09N allele in a large Hungarian cohort.

The presence of null alleles may affect the outcome of stem cell transplantation. HLA-C*04:09N was defined as 'common' with a frequency of 2-5/1000 in Caucasians, and its presence is routinely tested as part of haplotypes HLA-A*02:01/A*23:01-B*44:03-DRB1*07:01-DQB1*02:01. We aimed to investigate HLA-C*04:09N in a representative Hungarian cohort. HLA-typing data of 7345 unrelated persons were analyzed. The presence of HLA-C*04:09N was excluded in 157 chromosomes with either serology typing or with an allele-specific polymerase chain reaction for HLA-C*04:09N. HLA-C*04:09N was identified in a single chromosome with HLA-A*02, B*44, C*04, DRB1*07 resulting in a HLA-C*04:09N allele frequency of 0.0068% (1/14,690). This is approximately a 10- to 40-fold lower frequency compared with the previous data. Our results emphasize the need of precise local population-specific HLA-data, allowing appropriate modifications of local HLA-typing protocols.

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein-Barr nuclear antigen 1 and its aa35-58 or aa398-404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis.

Several studies suggest that infection by Epstein-Barr virus (EBV) might be one of the environmental factors which facilitates the development of autoimmune disorders in genetically susceptible individuals. Recent data indicate that high anti-Epstein-Barr nuclear antigen 1 (EBNA)-1 immunoglobulin (Ig)G titre is a strong risk factor for multiple sclerosis (MS) in patients both with and without the main genetic predisposing trait, human leucocyte antigen (HLA)-DRB1*15:01. Because no similar studies have been published in systemic lupus erythematosus (SLE) patients, we determined the HLA-DRB1*15:01 carrier state and the serum titres against the whole EBNA-1 and its small fragments aa35-58 and aa398-404 in 301 SLE patients, 135 MS patients and in 345 healthy controls. The carrier state of the HLA-DRB1*15:01 allele was deduced from genotyping of a tagSNP (rs3135388) by applying a Taqman-based assay. The serum concentrations of antibodies to EBNA-1 and its aa35-58 or aa398-404 fragments were determined using a commercial assay (ETI-EBNA-G) and home-made enzyme-linked immunosorbent assays, respectively. The serum concentration of anti-EBNA-1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA-DRB1*15:01 carriers and non-carriers. Furthermore, titres of antibodies against the aa35-58 EBNA-1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398-404 EBNA-1 antibodies were elevated significantly only in the SLE patients. These findings indicate that high anti-EBNA-1 IgG titres are HLA-DRB1*15:01-independent risk factors not only for MS, but also for SLE, while high antibody titres against the aa398-404 fragment are characteristic for SLE.

Antibody response against gastrointestinal antigens in demyelinating diseases of the central nervous system.

BACKGROUND: Antibodies against gastrointestinal antigens may indicate altered microbiota and immune responses in the gut. Recent experimental data suggest a connection between gastrointestinal immune responses and CNS autoimmunity. METHODS: Antibodies against gliadin, tissue transglutaminase (tTG), intrinsic factor (IF), parietal cells (PC) and Saccharomyces cerevisiae (ASCA) were screened in the sera of 45 patients with AQP4-seropositive neuromyelitis optica (NMO) and NMO spectrum diseases (NMO/NMO-SD), 17 patients with AQP4-seronegative NMO, 85 patients with clinically definite multiple sclerosis (MS), and 48 healthy controls (HC). RESULTS: Thirty-seven percentages of patients with AQP4-seropositive NMO/NMO-SD and 28% of patients with MS had at least one particular antibody in contrast to 8% of HC (P < 0.01, respectively). Antibodies were most common (46%) in AQP4-seropositive myelitis (P = 0.01 versus HS, P = 0.05 versus MS). Anti-gliadin and ASCA were more frequent in the AQP4-seropositive NMO-spectrum compared to controls (P = 0.01 and P < 0.05, respectively). CONCLUSION: Antibody responses against gastrointestinal antigens are common in MS and AQP4-seropositive NMO/NMO-SD, especially in longitudinally extensive myelitis.

Decrease in cold ischemic times as a result of protocol changes of urgent immunogenetic testing during cadaveric kidney transplantation in Hungary.

BACKGROUND: Based on national ethics committee permission, the procedure of urgent immunogenetics testing prior to cadaveric kidney transplantation was changed in Hungary from January 1, 2011 allowing HLA typing of the donor and prospective crossmatching using peripheral blood samples from the donor prior to the definitive declaration of brain death. The aim of the current study was to compare key indicators of transplantation primarily cold ischemic time [CIT], between time periods with outcomes. METHODS: The following indicators were systematically collected prospectively and retrospectively for each deceased heart-beating donor transplantation between January 1, 2010 and October 31, 2010 (n = 114) versus January 1, 2011 and October 31, 2011 (n = 91): CIT for the first and second kidney; laboratory turnaround times (TAT), and time for final preparation of the selected recipient. RESULTS: As a result of the new procedure, the CIT for the first kidney decreased from 16.5 ± 3.5 to 12.4 ± 3.2 hours (P < .001). Similarly, for the second kidney the parameters were a 19.8 ± 3.4 versus 16.0 ± 3.8 hours (P < .001). As a consequence of more hands-on time in the laboratory, the TAT increased from 5.6 ± 0.8 hours to 7.2 ± 1.1 hours (TAT1) followed by an additional 4.2 ± 1.0 hours (TAT2). We also compared the times necessary for preparation of immunologically suitable recipients for transplantation, namely, 9.5 ± 2.3 hours in the earlier system, increasing to 15.5 ± 4.3 hours during the new procedure. CONCLUSION: As a consequence of the procedural change, the CIT parameter decreased significantly for both kidneys, which may have contributed to improved short-term outcomes of transplantation. The time available for final preparation of selected recipients was increased allowing improvements in CIT.

High anti-EBNA-1 IgG levels are associated with early-onset myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acethylcholine receptor (AchR) of the neuromuscular junction in the majority of patients. METHODS: Here, we examined IgG antibodies against the type 1 nuclear antigen of Epstein-Barr virus (EBNA-1) in the sera of 158 patients with MG compared to 184 healthy controls. RESULTS: Although serum concentration in the sera was not different, high anti-EBNA-1 IgG titers (above 90th percentile of the normal values) were more common in the patients (26.6 vs. 16.3%, P=0.024). In addition, high EBNA-1 IgG levels occurred more frequently amongst the 94 patients with early-onset myasthenia gravis (EOMG, 30.8%) as compared to the 64 patients with late-onset disease (LOMG, 14.1%) (P=0.021). Using multiple logistic regression, high serum concentration of the anti-EBNA-1 IgG antibodies was significantly associated with EOMG (OR: 3.17, P=0.027), even after adjustment for sex, presence/absence of anti-AchR antibodies and presence/absence of anti-Titin antibodies. Out of 39 patients with EOMG, who underwent thymectomy, 18 patients (46%) had thymoma, 6 had thymic hyperplasia (15%), and 15 patients had thymic atrophy (39%); there was no difference comparing EBNA-1 antibody titers in the sera. As no correlation was found between the titers of anti-AchR, anti-Titin, and EBNA-1 antibodies, a dysregulated heterogeneous B-cell response was unlikely to be responsible for the elevated levels of EBV-associated antibody in patients. CONCLUSIONS: In summary, our data suggest that high levels of EBNA-1 antibodies are more common in MG compared to healthy controls and are especially associated with EOMG.

EFNS guidelines on diagnosis and management of neuromyelitis optica.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge. SEARCH STRATEGY: Evidence for this guideline was collected by searches for original articles, case reports and meta-analyses in the MEDLINE and Cochrane databases. In addition, clinical practice guidelines of professional neurological and rheumatological organizations were studied. RESULTS: Different diagnostic criteria for NMO diagnosis [Wingerchuk et al. Revised NMO criteria, 2006 and Miller et al. National Multiple Sclerosis Society (NMSS) task force criteria, 2008] and features potentially indicative of NMO facilitate the diagnosis. In addition, guidance for the work-up and diagnosis of spatially limited NMO spectrum disorders is provided by the task force. Due to lack of studies fulfilling requirement for the highest levels of evidence, the task force suggests concepts for treatment of acute exacerbations and attack prevention based on expert opinion. CONCLUSIONS: Studies on diagnosis and management of NMO fulfilling requirements for the highest levels of evidence (class I-III rating) are limited, and diagnostic and therapeutic concepts based on expert opinion and consensus of the task force members were assembled for this guideline.

Social cognition and Theory of Mind in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Theory of Mind (ToM) is an ability to understand and interpret another person's beliefs, emotions, and intentions. ToM requires both cognitive and emotional perspective taking and is deficient in several neuropsychiatric disorders all connected with impaired social functioning. Cognitive and mood dysfunctions have been recognized as common symptoms in multiple sclerosis (MS). METHODS: We investigated social cognition in 40 ambulatory patients with MS compared to 35 healthy controls by using verbal and non-verbal ToM tests (Faux Pas, Baron-Cohen's Adult Eyes and Faces test) and Baron-Cohen's Empathy questionnaire. The effect of disability and disease duration on social cognition was also analyzed by multiple logistic regression analysis after adjusting for confounding factors of age, gender, intelligence, depression, and anxiety. RESULTS: Even when adjusted, patients with MS made significantly more mistakes in non-verbal test (adult Eyes Test), and more disabled patients performed worse in both verbal and non-verbal ToM tests (Eyes Test and Faux Pas) compared to controls. Patients with a shorter disease course described themselves as more empathetic. DISCUSSION: In the absence of marked cognitive decline and disability, patients with ambulatory MS had a deficit interpreting social situations and performing in interpersonal contexts.

Long-lasting airplane headache in a patient with chronic rhinosinusitis.

The authors report long-lasting airplane headache in a patient with non-allergic, chronic rhinosinusitis. Association of mucosal inflammation with compromised sinonasal ventilation and sinus barotrauma created a base for not only the pain but also for the prolongation of symptoms. Effective therapy with antihistamine and nasal decongestant supports the theory that sinonasal barotrauma plays a triggering role in the pathophysiology of airplane headache.

Long-term effects of combined immunosuppressive treatment on myasthenic crisis.

BACKGROUND AND PURPOSE: We studied the long-term crisis-preventing effect of combined prednisolone-azathioprine (PR-AZA) treatment in myasthenia gravis (MG). METHODS: Case-control study with a median follow-up of 64 months in the treated group, and 80 months in the non-treated group. Sixty-nine patients with episodes of myasthenic crisis (MC) were treated and followed prospectively in 1990-2004. Twenty-seven patients had MC between 1990 and 1996, and were not treated with immunosuppressants on long-term. Long-term PR-AZA treatment was introduced in another 42 patients, who developed MC in 1997-2004. The difference in the frequency of repeated MCs between the treated and the non-treated group during long-term follow-up was investigated. As secondary end-points, we analyzed the number of admittances to the ICU; the number of mechanical ventilation episodes; the duration of ICU treatment; the characteristics of the applied treatment; and the functional outcome of the patients 1 month after the onset of the crisis. RESULTS: Recurrent MCs occurred in 74% of the non-treated and 19% of the treated group (P < 0.001). The number of ICU admissions (P = 0.005) and mechanical ventilation events (P = 0.002) were also reduced. The highly significant MC preventing effect of PR-AZA was evident after 6 months. CONCLUSIONS: After the initial 6 months of therapy, PR-AZA is effective in preventing MC.

Deficient leucocyte antisedimentation is related to post-stroke infections and outcome.

BACKGROUND: Patients with stroke are more susceptible to infections, suggesting possible deficiencies of early immune responses, particularly of leucocytes. AIMS: To serially examine leucocyte antisedimentation rate (LAR), a simple test to detect activation of leucocytes, and correlate it with S100beta, procalcitonin and outcome in patients with acute ischaemic events. METHODS: Venous blood samples were taken from 61 healthy volunteers and 49 patients with acute ischaemic events (acute ischaemic stroke (AIS), n = 38; transient ischaemic attack (TIA), n = 11) within 6 hours, at 24 and 72 hours after onset of symptoms. RESULTS: LAR was significantly higher in acute ischaemic events compared to controls within 6 hours after onset of stroke regardless of post-stroke infections. In addition, the increase of LAR was delayed and attenuated in TIA in contrast to AIS. A deficiency in early increase of LAR was associated with post-stroke infections and a poor outcome, measured by the Glasgow Outcome Scale in AIS. There was a positive correlation between LAR and S100beta at 72 hours after the onset of ischaemic stroke. Increased levels of S100beta at 24 and 72 hours after stroke were associated with poor outcome. CONCLUSIONS: An early activation of leucocytes indicated by an increase of LAR is characteristic of acute ischaemic cerebrovascular events. A delayed and ameliorated leucocyte activation represented by LAR is characteristic of TIA in contrast to stroke. Deficient early activation predisposes to post-stroke infections related to poor outcome. In addition, the extent of tissue injury correlates with the magnitude of innate immune responses.