The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT).

OBJECTIVE: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. METHODS: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data. RESULTS: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). DISCUSSION: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective.

Prognostic Role of Visual Evoked Potentials in Non-Neuritic Eyes at Multiple Sclerosis Diagnosis.

Introduction: This study aimed to assess the prognostic role of visual evoked potentials (VEPs) of the non-neuritic eye at the diagnosis of multiple sclerosis (MS). Patients and methods: We enrolled 181 MS patients (62% females, mean age at diagnosis: 38 years, standard deviation: 12) at the time of the first diagnostic work-up, including VEPs. We collected P100 latency and N75-P100 amplitude of non-neuritic eyes at diagnosis, and then we calculated the mean values in 127 patients with no history of optic neuritis (ON) or considered the unaffected eye in the remaining. At last follow-up (minimum: one year), disability was evaluated according to MS Severity Score or MSSS (median: 2.44, range: 0.18-9.63). Statistical analysis included Mann-Whitney descriptive analysis, Spearman correlation for independent samples, and linear regression for significant predictors of MSSS. Results: 38/181 patients had P100 latency >115 ms, and 63/181 showed N75-P100 amplitude < 5 microV in the unaffected eyes at MS diagnosis. At last follow-up, MSSS correlated with P100 latency (rho = 0.21, p = 0.004) and N75-P100 amplitude (rho = 0.19, p = 0.009) collected at diagnosis. P100 latency (not N75-P100 amplitude) resulted in a predictor for disability over time (MSSS) in the regression model (along with age at onset, MS course, and disease-modifying treatments). Conclusions: Our study showed a prognostic value of VEPs in clinically unaffected eyes at MS diagnosis to predict future disability, independently from a history of ON.

Susac Syndrome: an uncommon cause of impaired vision.

A 35-year-old Caucasian woman presented an abrupt onset of bilateral impaired vision, and arrived to our attention two weeks later. She had a previous episode of mild dizziness. She underwent a fluorescein angiography showing branch retinal artery occlusions and a brain magnetic resonance imaging (MRI) revealing several supraand infratentorial FLAIR-hyperintense white matter lesions, two with contrast enhancement. Thrombophilic, autoimmune and infective (including Human Immunodeficiency Virus, Borrelia burgdorferi, Hepatitis B Virus, Hepatitis C Virus, Herpes Simplex Virus 1-2, Varicella Zoster Virus) screening was negative. Cerebrospinal fluid analysis showed intrathecal IgG synthesis. We suspected a Primary Central Nervous System Vasculitis, and intravenous steroids were started. Three months later a second brain MRI showed seven new lesions without contrast enhancement, and she revealed a cognitive impairment and bilateral hearing loss. Reviewing the clinical history and MRI, she fulfilled diagnostic criteria for Susac syndrome. She had two cycles of cyclophosphamide, and recovered in 6 months and then remained stable with metotrexate.

Serum Vitamin D as a Marker of Impaired Information Processing Speed and Early Disability in Multiple Sclerosis Patients.

Slowed information processing speed (IPS) is the hallmark and first cognitive domain to be altered in multiple sclerosis (MS) patients. Insufficient serum vitamin D was previously associated with disease development, relapses, and progression, but little is reported on cognition. However, vitamin D and cognitive impairment (CI) in other neurodegenerative diseases have already been linked. We explored the possible correlation between vitamin D and IPS at diagnosis and early disability at last follow-up in 81 MS patients. At diagnosis, we collected vitamin D levels and performed a Symbol Digit Modalities Test (SDMT). Raw scores were adjusted for age, gender, and educational level. Early disability was evaluated with MS severity score (MSSS) and age-related MSSS (ARMSS). A total of 71 patients (86.58%) showed hypovitaminosis D (19.71 ± 8.76 ng/mL) and 18 patients (21.95%) had CI. Patients with CI showed severe hypovitaminosis D (p = 0.004). No patients with sufficient vitamin D levels had CI. We found a positive correlation between vitamin D levels at diagnosis and (1) SDMT raw and z-score that persisted after correction for sunlight exposure and MRI baseline characteristics, and (2) EDSS, MSSS, and ARMSS after a mean 2 year follow-up. Low vitamin D levels may affect both cognition and early disability in newly diagnosed MS patients.

Efficacy of Cannabinoids on Spasticity and Chronic Pain in a Patient with Co-occurrence of Multiple Sclerosis and Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease involving the skin and central nervous system (CNS), and also characterized by skeletal and spinal schwannomas that may cause chronic neurogenic pain. Furthermore, pain in NF1 is underestimated, even though it has an impact on quality of life. Multiple sclerosis (MS) is the most common acquired demyelinating disease that may in later stages present with refractory spasticity, particularly in the lower limbs. Oromucosal cannabinoid sprays are currently available for spasticity treatment in MS, with encouraging results on MS pain, but few data have been reported regarding the use of cannabinoids in NF1. We report the successful treatment of chronic neurogenic pain and spasticity in a patient with co-occurrence of NF1 and MS after a poor response to standard approaches. LEARNING POINTS: Chronic pain is a possible complication of several neurological conditions and may show a poor response to standard drugs, thus affecting quality of life.Oromucosal cannabinoid sprays are routinely used in multiple sclerosis spasticity.Cannabinoids may be also effective against neurogenic pain in neurofibromatosis type 1.

Paraneoplastic neuromyelitis optica spectrum disorders: a case series.

Aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSD) are rare idiopathic autoimmune diseases, presenting with optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), and brainstem syndromes and a prevalence range between 0.5 and 4/100,000. Only 3% to 25% of NMOSD have been described as a paraneoplastic (PN) syndrome (PNNMOSD). Both idiopathic NMOSD (INMOSD) and PNNMOSD cases mostly affect females, but PNNMOSD usually presents with a spinal cord or brainstem involvement in elderly patients. Few cases of both malignancies (for the majority breast or lung cancer) and benign tumors (monoclonal gammopathy) were previously reported. Currently, there is no consensus on treatment approach for PNNMOSD (only surgical removal or surgery combined with chronic immunosuppression). Here, we present a series of three newly diagnosed PNNMOSD cases, who differ from each other for demographic and clinical features, tumor association, long-term treatment, and outcome. We propose that a PN etiology should be considered always whenever a new diagnosis of NMOSD is made, not only in patients over 50 years old or in spinal cord/brainstem lesions presentations. Our findings add to existing evidence and raise awareness on PNNMOSD. We enhance the importance for the clinicians of recognizing tumor symptoms and signs whenever a NMOSD is newly diagnosed.

Cannabinoids in multiple sclerosis: A neurophysiological analysis.

OBJECTIVES: To investigate the action of cannabinoids on spasticity and pain in secondary progressive multiple sclerosis, by means of neurophysiological indexes. MATERIAL AND METHODS: We assessed 15 patients with progressive MS (11 females) using clinical scales for spasticity and pain, as well as neurophysiological variables (H/M ratio, cutaneous silent period or CSP). Testing occurred before (T0) and during (T1) a standard treatment with an oral spray containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Neurophysiological measures at T0 were compared with those of 14 healthy controls of similar age and sex (HC). We then compared the patient results at the two time points (T1 vs T0). RESULTS: At T0, neurophysiological variables did not differ significantly between patients and controls. At T1, spasticity and pain scores improved, as detected by the Modified Ashworth Scale or MAS (P = .001), 9-Hole Peg Test or 9HPT (P = .018), numeric rating scale for spasticity or NRS (P = .001), and visual analogue scale for pain or VAS (P = .005). At the same time, the CSP was significantly prolonged (P = .001). CONCLUSIONS: The THC-CBD spray improved spasticity and pain in secondary progressive MS patients. The spray prolonged CSP duration, which appears a promising tool for assessing and monitoring the analgesic effects of THC-CBD in MS.

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Multiple Sclerosis Severity.

Background: The association between lifestyle factors and Multiple Sclerosis (MS) disease severity and progression has been investigated to a lesser extent compared with susceptibility to the disease. Objective: We aimed to assess the impact of lifetime alcohol and cigarette smoking load on MS severity. Methods: Design: a cross-sectional study. Three hundred fifty-one patients consecutively admitted to the Department of Neurology were asked to complete the "Questionnaire of Lifestyle" (part of the European Prospective Investigation into Cancer and Nutrition project). An estimation of the cumulative lifetime cigarette smoking and alcohol load was calculated as the weighted sum of the mean number of cigarettes smoked and standard alcoholic drinks consumed per day at different ages. The measure of exposure was expressed in terms of pack-year and drink-year. Disease severity was estimated by the Multiple Sclerosis Severity Score (MSSS). Logistic regression analyses were performed using MSSS (first tertile vs. third tertile) as the outcome. Results: The median MSSS was higher (3.2 vs. 2.3, p = 0.002) in ever- vs. never-smokers, but we did not find a difference between ever- and never-drinkers (2.7 vs. 2.8, p = ns). Ever-smokers were almost twice as likely to fall in the upper MSSS tertile than never-smokers. Ever-drinkers did not show a statistically significant association between alcohol intake and MS severity. The risk of falling in the worst MSSS tertile for smokers was 10.81 (2.0-58.48; p < 0.01) if they were never-drinkers, whereas it was only 1.65 (0.89-3.03, p = 0.11) if they were also drinkers. On the other side, the risk of falling in the worst MSSS tertile for drinkers did not change as much, whether they also were smokers (0.46; 0.13-1.65; p = 0.23) or not (1.49; 0.55-4.04, p = 0.43). Conclusions: Cigarette smoking, unlike alcohol consumption, is associated with MS severity. Alcohol consumption may attenuate the effect of smoking on disease severity, acting as an effect modifier. The biological background of this effect is unknown. The limitations of our study are mostly due to its cross-sectional design.

Post-lumbar puncture headache: an adverse effect in multiple sclerosis work-up.

BACKGROUND: Lumbar puncture (LP) is a safe procedure commonly performed in the diagnostic work-up of multiple sclerosis (MS), and its main adverse event is post-LP headache (PLPH). Predictors for PLPH in MS are not established. AIMS: To describe the occurrence of, and, factors related to PLPH in patients with suspected MS, studied on a daily-basis admission. PATIENTS AND METHODS: One hundred patients (70 females) were admitted for a diagnostic LP (standardized with a traumatic 19-G needle), observed for 6 h, and evaluated for adverse events 2 and 7 days later. Descriptive statistics and a multivariate analysis (for PLPH) were performed. RESULTS: Fifty-seven (57%) patients had PLPH at 48 h, which persisted 1 week in 31, and only two presented beyond the first 2 days. Other adverse events were tinnitus and neck stiffness. None required investigations or was hospitalized. Age was the only predictor for PLPH at day 2, whereas the onset of headache within 48 h and female gender were predictors for PLPH at day 7. CONCLUSION: PLPH is a frequent complication of LP performed on daily-basis admission in MS work-up. The maximum onset is within the first 48 h. Age and gender seem the only predictors for the appearance and persistence of PLPH.

Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?

BACKGROUND: Despite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation. OBJECTIVE: To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. METHODS: Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail. RESULTS: The three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration. CONCLUSION: In these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use.

Combined use of Kappa Free Light Chain Index and Isoelectrofocusing of Cerebro-Spinal Fluid in Diagnosing Multiple Sclerosis: Performances and Costs.

BACKGROUND: Isoelectrofocusing (IEF) to detect oligoclonal bands (OBCs) in cerebrospinal fluid (CSF) is the gold standard approach for evaluating intrathecal immunoglobulin synthesis in multiple sclerosis (MS) but the kappa free light chain index (KFLCi) is emerging as an alternative marker, and the combined/sequential uses of IEF and KFLCi have never been challenged. METHODS: CSF and serum albumin, IgG, kFLC and lFLC were measured by nephelometry; albumin, IgG and kFLC quotients as well as Link and kFLC indexes were calculated; OCBs were evaluated by immunofixation. A total of 150 consecutive patients: 48 with MS, 32 with other neurological inflammatory diseases (NID), 62 with neurological non-inflammatory diseases (NNID), and 8 without any detectable neurological disease (NND) were investigated. RESULTS: Both IEF and KFLCi showed a similar accuracy as diagnostic tests for multiple sclerosis. The high sensitivity and specificity associated with the lower cost of KFLCi suggested to use this test first, followed by IEF as a confirmative procedure. The sequential use of IEF and KFLCi showed high diagnostic efficiency with cost reduction of 43 and 21%, if compared to the contemporary use of both tests, or the unique use of IEF in all patients. CONCLUSIONS: The "sequential testing" using KFLCi followed by IEF in MS represents an optimal procedure with accurate performance and lower costs.

Multiple sclerosis progression is not associated with birth timing in Italy.

BACKGROUND: Month of birth has been associated in some studies with the susceptibility to develop Multiple Sclerosis (MS). However, only few studies have evaluated whether birth timing also affects disease progression. OBJECTIVES: To assess whether season and month of birth are associated with disease progression in a large cohort of Italian patients. METHODS: Quantile regression was used to analyze the impact of each month and season of birth with all the others combined on the median Multiple Sclerosis Severity Score of 1866 MS patients. RESULTS: No significant temporal trend was found after adjustment for multiple comparisons. CONCLUSIONS: Birth timing showed no association with MS progression in Italian patients.

Chronic cerebrospinal venous insufficiency is not associated with multiple sclerosis and its severity: a blind-verified study.

BACKGROUND: Chronic Cerebrospinal Venous Insufficiency (CCSVI) has been associated with multiple sclerosis (MS) with a risk ranging from as high as two-hundred-fold to a protective effect. However, not all studies were blinded, and the efficacy of blinding was never assessed. OBJECTIVE: To evaluate the association of CCSVI with MS in a cross-sectional blinded study and look for any association of CCSVI with the severity of MS. METHODOLOGY/PRINCIPAL FINDINGS: The Echo-color Doppler examination was carried out in accordance with Zamboni's five criteria in 68 consecutive MS patients and 68 healthy controls, matched by gender and age (±5 years). Four experienced neurosonologists, blinded to the status of cases and controls, performed the study and were then asked to guess the status (case or control) of each participant. The number of positive CCSVI criteria was similar in the two groups. CCSVI, defined as the presence of two or more criteria, was detected in 21 cases (30.9%) and 23 controls (33.8%), with an OR of 0.9 (95%CL = 0.4-1.8, p = 0.71). The prevalence of CCSVI was related to age in cases (OR increasing from 0.2 to 1.4), but not in controls. CCSVI positive (N = 21) and negative (N = 47) MS patients were similar in clinical type, age at disease onset, disability, and fatigue. Disease duration was longer (16.5±9.8 years) in CCSVI positive than negative patients (11.5±7.4; p = 0.04). The operators correctly guessed 34/68 cases (50%) and 45/68 controls (66%) (p = 0.06), indicating a different success of blinding. CONCLUSIONS/SIGNIFICANCE: CCSVI was not associated with MS itself, nor its severity. We cannot rule out the possibility that CCSVI is a consequence of MS or of aging. Blinding of sonographers is a key point in studying CCSVI and its verification should be a requisite of future studies.

Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects.

BACKGROUND: The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the protective effect of HLA A*02. OBJECTIVES AND METHODS: Since A*02-Cw*05 is carried by two HLA extended haplotypes characterised by the B*4402 and B*1801 alleles, respectively, the association analysis was extended to HLA B*44 and B*18 in an Italian sample (1445 MS cases and 973 controls) and these associations were verified in a UK cohort (721 MS cases, 408 controls and 480 family trios). RESULTS: A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR 0.27, p=3.3×10(-5)) was seen in the Italian samples and confirmed in UK family trios (OR 0.33, p=5.5×10(-4)) and in a combined cohort of UK families and case-controls (OR 0.53, p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR 0.38, p=6.5×10(-7); UK: OR 0.60, p=0.0029), indicating that it was not secondary to linkage disequilibrium with B*44. Different from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44) protection when adjusted for the remaining markers. CONCLUSIONS: This study identified at least two independent protective effects which are tagged by A*02-Cw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalysed factor characterising the HLA extended haplotype(s) carrying A*02 and Cw*05 or to a direct interaction between these alleles.

The expression pattern of inflammatory mediators in cerebrospinal fluid differentiates Guillain-Barré syndrome from chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) share histopathological features but display different disease courses; we measured the concentration of 50 inflammatory mediators in the cerebrospinal fluid (CSF) of patients with either of these diseases. PATIENTS AND METHODS: CSF samples were collected during a diagnostic lumbar puncture and stored at -30 degrees C. We analyzed the CSF of nine subjects with GBS; eight with CIDP; eight with diabetic polyneuropathy (DP) and seven with headache (controls). Fifty inflammatory mediators were simultaneously measured with a multiplex bead-based ELISA on a Suspension Array System. After Bonferroni's correction for repeated measures, non-parametric variance and post hoc test were calculated. RESULTS: Thirty-two inflammatory mediators were expressed. The median concentration of IL-6, IL-9, IL-15, IL-18, CCL4, CXCL1, LIF, MIF, PDGFbb, IFN-gamma2, IL-2ra, IL-12(p40), IL-16, SCGF-b, TRAIL, FGF, G-CSF, GM-CSF, and M-CSF was not different among groups (variance: n.s.). The median concentration of CCL2, CCL7, CCL27, CXCL9, CXCL10, CXCL12, ICAM-1, VCAM1 and VEGF was higher in CIDP and GBS compared with controls (p<0.002). The median concentration of IL-8 and IL-1ra was higher in GBS than CIDP or DP or controls, whereas stem cell factor (SCF) and hepatocyte growth factor (HGF) were higher in CIDP than GBS or DP or controls (p<0.002). DISCUSSION: Mediators of the recruitment and activation of lymphocytes and monocytes are expressed in the CSF of CIDP and GBS. IL-8 and IL-1ra are characteristic of GBS, whereas growth factors (SCF, HGF) of CIDP are possibly related to chronicity or to the survival/repair processes of neurons.

Elevation of Gas6 protein concentration in cerebrospinal fluid of patients with chronic inflammatory demyelinating polyneuropathy (CIDP).

INTRODUCTION: Gas6 enhances survival of Schwann cells and neurons in vitro and participates in autoimmunity in animal models. Since its concentration in human cerebrospinal fluid (CSF) is unknown, we measured it in samples from patients with non-inflammatory/non-autoimmune neurological diseases (NINAD) and autoimmune polyneuropathies. MATERIALS AND METHODS: Samples collected after informed consent during diagnostic lumbar puncture in the period 1999-2006 were stored at -30 degrees C. We considered subjects with NINAD (stroke, ALS, headache, psychiatric conditions simulating neurological diseases, otologic dizziness) or with Guillain-Barré syndrome (GBS) or CIDP. CSF and plasma total protein and age were obtained from clinical records. Gas6 was measured with an ELISA developed and validated in our laboratory (inter-, intra-assay CVs <10%, recovery 96%). Variance, Tukey's post-hoc test, regression were calculated with a statistical software (Statsoft). RESULTS: Mean Gas6 concentration in patients with NINAD was 6.5+/-2.4 ng/ml, 7.2+/-2.6 ng/ml in GBS and significantly higher (11.5+/-1.7 ng/ml) in CIDP than in the other conditions (post-hoc, p<0.005). It was not related to age, CSF total proteins or to CSF/plasma ratio of total proteins (regression, p>0.1). CONCLUSIONS: Gas6 is detectable in CSF and may be involved in chronic autoimmune demyelination or myelin repair.

Candidate gene analysis of SPARCL1 gene in patients with multiple sclerosis.

Recently, proteomic analysis in cerebrospinal fluid (CSF) from patients with MS identified four proteins which are present in MS but not in normal human CSF, including SPARCL1, an extracellular matrix-associated protein member of the SPARC family. One hundred eighty-six patients with MS and 185 age-matched controls were genotyped for A/G single nucleotide polymorphism (SNP) in exon 1 (rs1049539), C/G SNP in exon 4 (rs1049544), resulting in a substitution of an aspartate with an histidine, and A/G substitution in the exon 5 (rs1130643), leading to the substitution of alanine with threonine. No significant differences in either allelic or genotypic frequency of the three SNPs were found (P>0.05), even in stratifying MS patients according to the course of the disease. Stratifying according to gender, a trend towards a decreased frequency of the C/C genotype of the rs1049544 was observed in male patients as compared with male controls (30.2% versus 44.0%; P=0.217). Despite proteomic studies in CSF from MS patients suggested an important role for SPARCL1 in the development of the disease, SPARCL1 gene does not appear to act as susceptibility factor for MS in the population investigated here. However, the frequency of the C/C genotype of rs1049544 was decreased in male patients, possibly conferring a lower risk of developing MS in male population. Further studies are needed to clarify this issue.

Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis.

Cytokines and chemokines contribute to the pathogenesis of acute disseminated encephalomyelitis (ADEM). Using a multiplex immunochemiluminescence ELISA, we measured 8 Th1/Th2 cytokines and 18 chemokines in the cerebrospinal fluid (CSF) and serum of 17 ADEM patients, 14 multiple sclerosis (MS) patients, and 7 healthy controls (HCs). Relative to HCs, ADEM patients had significantly high mean CSF concentrations of chemokines with attractant/activating properties towards neutrophils (CXCL1 and CXCL7), monocytes/T cells (CCL3 and CCL5), Th1 cells (CXCL10), and Th2 cells (CCL1, CCL22, and CCL17). Mean CSF concentrations of CXCL7, CCL1, CCL22, and CCL17 were higher in ADEM than in MS, whereas those of CCL11 were lower in MS than in ADEM and HCs. CSF pleocytosis correlated with CSF concentrations of CXCL1, CXCL10, CCL1, CCL17, and CCL22. Most of the functionally homologous chemokines correlated with each other. CSF Th1/Th2 cytokines were not detectable in most samples. Their mean concentrations did not differ in the three groups, and the same held for serum cytokines and chemokines. Our data suggest that the upregulation of chemokines active on neutrophils and Th2 cells differentiates ADEM from MS inflammation, and that both Th1 and Th2 chemokines might be produced in ADEM. Chemokines upregulated in ADEM could become CSF biomarkers after a posteriori evaluations in unselected case series.

Cortico-motoneurone excitability in patients with obstructive sleep apnoea.

A disordered neuromotor control of pharynx muscles may play a role in the genesis of obstructive sleep apnoea syndrome (OSAS). This raises the possibility of a dysfunction of projections descending from the cortex to segmental nuclei. With single pulse transcranial magnetic stimulation (TMS) we studied the physiology of the corticospinal projection to hand muscles in seven OSAS patients. At first, we compared them with nine age- and sex-matched normal controls in the wake state. The only abnormality was a lengthening of the central silent period (P < 0.001). This supports a steady imbalance of motor cortical interneurone activities towards a state of enhanced inhibition. Then we looked at changes of the motor-evoked potential (MEP) size and latency, according to whether patients were awake, or in a non-rapid eye movement (REM) 2 sleep stage, or during a typical apnoea. During non-REM 2 sleep, the average MEP amplitude was significantly (P < 0.05) smaller than in the awake state. The MEP latency was, in turn, significantly longer (P < 0.05). During apnoeas, the MEP size decreased, and the latency increased further (P < 0.05), indicating an extra depression of the cortico-motoneuronal activity. All TMS changes were detected outside the pharyngeal district, suggesting a widespread dysfunction of the cortico-motoneuronal system in the OSAS, which is more evident during apnoeas.