Decreased exercise-induced natural killer cell redistribution in multiple sclerosis.

BACKGROUND: Exercise may have beneficial effects in MS, remaining controversial its possible disease-modifying effects and which mechanisms might be involved. We evaluated whether exercise-induced lymphocyte redistribution differ in MS patients as compared to controls. METHODS: Exercise was assessed in 12 relapsing-remitting MS patients and 11 controls in a cycle ergometer, obtaining blood samples before exercise, at maximal exercise capacity (T1), and after resting (T2). Peripheral lymphocytes were evaluated by flow cytometry, assessing chemokine receptor expression to study cell trafficking properties. RESULTS: Lymphocyte subsets in all cases increased after exercise and decreased at resting. However, total natural killer (NK) cells in patients as compared to controls had a lower exercise-induced redeployment at T1 (696 ± 581 cells/µL vs.1502 ± 641 cells/µL, p < 0.01). Evaluating NK cell subsets, CD56bright NK cells numbers decreased in peripheral blood in MS patients after resting (T2), contrasting with values remaining above baseline in healthy controls. NK cells mobilized after exercise at T1 in controls, as compared to patients, had a higher CX3CR1 expression (1402 ± 564/µL vs. 615 ± 548 cell//µL, p < 0.01). CONCLUSION: Exercise-induced redeployment of NK cells may be reduced in MS patients, as well as their migration capabilities, pointing to potential immunological mechanisms to be enhanced by exercise training programs.

Delayed B cell repopulation after rituximab treatment in multiple sclerosis patients with expanded adaptive natural killer cells.

BACKGROUND AND PURPOSE: The aim was to evaluate whether adaptive NKG2C+ natural killer (NK) cells, characterized by enhanced antibody-dependent cell cytotoxicity (ADCC), may influence time to B cell repopulation after rituximab treatment in multiple sclerosis (MS) patients. METHODS: This was a prospective observational study of MS patients treated with rituximab monitoring peripheral B cells for repeated doses. B cell repopulation was defined as CD19+ cells above 2% of total lymphocytes, classifying cases according to the median time of B cell repopulation as early or late (≤9 months, >9 months, respectively). Basal NK cell immunophenotype and in vitro ADCC responses induced by rituximab were assessed by flow cytometry. RESULTS: B cell repopulation in 38 patients (24 relapsing-remitting MS [RRMS]; 14 progressive MS) was classified as early (≤9 months, n = 19) or late (>9 months, n = 19). RRMS patients with late B cell repopulation had higher proportions of NKG2C+ NK cells compared to those with early repopulation (24.7% ± 16.2% vs. 11.3% ± 10.4%, p < 0.05), and a direct correlation between time to B cell repopulation and percentage of NKG2C+ NK cells (R 0.45, p < 0.05) was observed. RRMS cases with late repopulation compared with early repopulation had a higher secretion of tumor necrosis factor α and interferon γ by NK cells after rituximab-dependent NK cell activation. The NK cell immunophenotype appeared unrelated to B cell repopulation in progressive MS patients. CONCLUSIONS: Adaptive NKG2C+ NK cells in RRMS may be associated with delayed B cell repopulation after rituximab, a finding probably related to enhanced depletion of B cells exerted by NK-cell-mediated ADCC, pointing to the use of personalized regimens with anti-CD20 monoclonal antibody therapy in some patients.

Dynamics and Predictors of Cognitive Impairment along the Disease Course in Multiple Sclerosis.

(1) Background: The evolution and predictors of cognitive impairment (CI) in multiple sclerosis (MS) are poorly understood. We aimed to define the temporal dynamics of cognition throughout the disease course and identify clinical and neuroimaging measures that predict CI. (2) Methods: This paper features a longitudinal study with 212 patients who underwent several cognitive examinations at different time points. Dynamics of cognition were assessed using mixed-effects linear spline models. Machine learning techniques were used to identify which baseline demographic, clinical, and neuroimaging measures best predicted CI. (3) Results: In the first 5 years of MS, we detected an increase in the z-scores of global cognition, verbal memory, and information processing speed, which was followed by a decline in global cognition and memory (p < 0.05) between years 5 and 15. From 15 to 30 years of disease onset, cognitive decline continued, affecting global cognition and verbal memory. The baseline measures that best predicted CI were education, disease severity, lesion burden, and hippocampus and anterior cingulate cortex volume. (4) Conclusions: In MS, cognition deteriorates 5 years after disease onset, declining steadily over the next 25 years and more markedly affecting verbal memory. Education, disease severity, lesion burden, and volume of limbic structures predict future CI and may be helpful when identifying at-risk patients.

Impact of cytomegalovirus infection on B cell differentiation and cytokine production in multiple sclerosis.

BACKGROUND: Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment. METHODS: HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry. RESULTS: HCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNß-treated RRMS patients but not in HCMV(-) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNß. Considering the B cell functional profile, HCMV(-) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001). CONCLUSIONS: Our study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS.

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Adaptive Features of Natural Killer Cells in Multiple Sclerosis.

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(-), and PLZF(-) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(-) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(-) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-ß therapy was associated with lower proportions of FcRγ(-) CD56dim NK cells in HCMV(+) and increased PLZF(-) CD56bright NK cells in HCMV(-) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(-) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS.

Antibody-Dependent NK Cell Activation Differentially Targets EBV-Infected Cells in Lytic Cycle and Bystander B Lymphocytes Bound to Viral Antigen-Containing Particles.

NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN-γ secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcγR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV+ individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-α and IFN-γ) against EBV-infected cells, enhancing NK cell activation. The effect was preferentially directed against cells in the lytic phase and was associated with surface expression of the gp350/220 envelope Ag. In contrast, binding of gp350+ particles, released by EBV-infected cells, to B cell lines or autologous primary B lymphocytes also promoted specific Ab-dependent NK cell degranulation and TNF-α production but induced minimal IFN-γ secretion. In that case, target cell damage appeared marginal compared with the effect of a control anti-CD20 Ab (rituximab) at concentrations that triggered similar NK cell activation, indicating that cell-associated gp350+ particles may divert the cytolytic machinery, impairing its direct action on the plasma membrane. These observations support that Ab-dependent NK cell activation plays an important role in the control of EBV, enhancing NK cell effector functions against infected B cells in the lytic cycle. In contrast, the data reveal that gp350+ particles bound to bystander B cells trigger Ab-dependent NK cell degranulation and TNF-α but not cytotoxicity or IFN-γ production, potentially favoring the progression of viral infection.

Development of the adaptive NK cell response to human cytomegalovirus in the context of aging.

Human cytomegalovirus (HCMV) establishes a highly prevalent life-long latent infection. Though generally subclinical, HCMV infection may have severe consequences during fetal development and in immunocompromised individuals. Based on epidemiological studies HCMV(+) serology has been associated with the development of atherosclerosis, immune senescence and an increase mortality rate in elderly people. Such long-term detrimental effects of the viral infection presumably result from an inefficient immune control of the pathogen, depending on the quality and evolution of the individual host-pathogen relationship. Together with antigen-specific T lymphocytes, NK cells play an important role in anti-viral immune defense. HCMV promotes in some individuals the differentiation and persistent steady state expansion of an NK cell subset bearing the CD94/NKG2C activating receptor. The relationship between this adaptive NK cell response to HCMV and aging is overviewed.

Adaptive natural killer cell response to cytomegalovirus and disability progression in multiple sclerosis.

BACKGROUND: Human cytomegalovirus (HCMV) causes a highly prevalent infection which may have a multifaceted impact on chronic inflammatory disorders. However, its potential influence in multiple sclerosis (MS) remains controversial. The HCMV-host interaction may induce an adaptive reconfiguration of the natural killer (NK) cell compartment, whose hallmark is a persistent expansion of peripheral NKG2C+ NK-cells. OBJECTIVE: The purpose of this study was to evaluate whether the HCMV-driven NKG2C+ NK-cell expansion is related to the MS clinical course. METHODS: Multicentre analysis of NKG2C expression and genotype according to HCMV serostatus and time of assignment of irreversible disability scores in 246 MS patients prospectively followed up in our institutions. RESULTS: NKG2C expression was unrelated to disease-modifying drugs, remained stable under steady-state conditions, and was higher in HCMV(+) NKG2C(+/+) homozygous individuals. NKG2C+ NK-cell expansion in HCMV(+) patients, as compared to HCMV(+) or HCMV(-) patients with lower NKG2C+ NK-cells proportions, conferred a lower risk of progression in Cox regression analysis (Expanded Disability Status Scale (EDSS)>3.0, hazard ratio (HR)=0.33, 95% confidence interval (CI) 0.15-0.71, p=0.005; EDSS>5.5, HR=0.23, 95% CI 0.07-0.74, p=0.014). Neither HCMV serostatus nor NKG2C genotype appeared to be related to disability progression. CONCLUSIONS: HCMV may exert a beneficial influence on MS, decreasing the risk of disability progression in those patients displaying a virus-driven NKG2C+ NK-cell expansion.

Influence of the LILRA3 Deletion on Multiple Sclerosis Risk: Original Data and Meta-Analysis.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. OBJECTIVES: In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. RESULTS AND CONCLUSION: Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15:01 risk allele.

Cannabis use in Spanish patients with multiple sclerosis: fulfilment of patients' expectations?

OBJECTIVE: Medicinal use of cannabis in chronic neurological diseases is a controversial topic of medical research and the subject of intense public debate. The aim of the study was to evaluate the prevalence of cannabis use, related factors, and degree of satisfaction in Spanish patients with multiple sclerosis (MS) prior to the establishment of medically supervised use. METHODS: Cross-sectional, questionnaire-based survey provided during routine medical visits to consecutive patients in two university-based neurology clinics. RESULTS: The questionnaire was returned by 175 MS patients (94.1% response rate). The prevalence of ever-use and medicinal cannabis use were 43% and 17.1%, respectively. At the time of the survey, cannabis was being used by 12.5% (5/45) of recreational and 56.7% (17/30) of medical users (p<0.001). First cannabis consumption was after MS onset in 15 (50%) medicinal users. Clinical improvement was reported by 14 (46.7%) medicinal users. Smoking use, awareness of cannabis potential benefits, pain, higher disability, and lower age were independently associated with the medicinal use of cannabis. Most patients would support a future legalisation of cannabis for the control of their symptoms and were willing to receive cannabis under medical control once legalised (83.4% of never-users, 94.5% of ever-users, p<0.05). CONCLUSION: Almost half of our MS patients had tried cannabis at some time. However, medicinal use was low and clinical improvement after cannabis use was only reported by a subset of patients. Overall, MS patients were highly motivated for a future medically controlled use.

Steno-occlusive arterial disease and early neurological deterioration in acute ischemic stroke.

AIM: To evaluate the influence that steno-occlusive arterial disease may have on the development of early neurological deterioration (END) in a large series of patients with acute ischemic stroke. METHODS: We studied a prospective cohort of 1,093 patients admitted to a single tertiary hospital with presence of neurological symptoms in the first 24 h after stroke onset. END was defined as any increase in the National Institutes of Health Stroke Scale score >or=4 points in the first 72 h. The arterial study assessed the presence of arterial occlusion or significative stenosis in the symptomatic territory. Additionally, age, initial stroke severity, blood pressure, glucose levels, vascular risk factors, lacunar stroke and prior use of antithrombotic treatment were also analyzed in a multivariable analysis. RESULTS: END was detected in 179 patients (16.3%). Steno-occlusive disease (adjusted OR 3.60), initial blood pressure and abdominal obesity were independently associated with END. Both arterial stenosis (adjusted OR 2.33) or occlusions (adjusted OR 3.65) were associated with END. The higher adjusted OR (5.49) was obtained for steno-occlusive arterial disease in the vertebrobasilar system. CONCLUSIONS: An early arterial study may provide key data for the selection of patients with higher risk of END after acute ischemic stroke.

Early arterial study in the prediction of mortality after acute ischemic stroke.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the value of the initial arterial study as a predictor of 90-day mortality in patients with acute ischemic stroke. METHODS: A total of 1220 unselected patients assessed during the first 24 hours after stroke onset were prospectively studied. Initial stroke severity was evaluated by the National Institutes of Health Stroke Scale and dichotomized in mild (National Institutes of Health Stroke Scale < or =7) and severe (National Institutes of Health Stroke Scale >7). Severe arterial stenosis (> or =70%) or arterial occlusion in the symptomatic territory was determined by a Doppler study and also by additional explorations (carotid duplex, MR or CT angiography) in the first 24 hours after admission. The following variables were also analyzed: age, gender, previous functional status, smoking, hypertension, hyperlipidemia, diabetes mellitus, peripheral arterial disease, ischemic heart disease, heart failure, atrial fibrillation, previous stroke, and prior use of antithrombotic or statins. Ninety-day mortality was the end point of the study. RESULTS: Ninety-day mortality was 15.7%. A total of 25.5% of all deaths were in patients with mild stroke. In addition to well-known factors related to mortality (age, stroke severity, ischemic heart disease, heart failure, and previous disability), severe arterial stenosis/occlusion was the factor with the highest relationship with 90-day mortality (adjusted OR: stenosis 2.13, occlusion 4.42, both 3.36). Arterial stenosis/occlusion was a higher predictor of 90-day mortality in patients with mild (adjusted OR: 5.38) than severe stroke (adjusted OR: 3.05). CONCLUSIONS: Severe arterial stenosis/occlusion in the early arterial study was highly related with 90-day mortality in an unselected series of patients with stroke. These data achieve special relevance in patients with initial mild stroke.

Atherosclerotic burden and early mortality in acute ischemic stroke.

BACKGROUND: The influence that previous clinical expressions of systemic atherosclerosis may have on evolution and early mortality in patients with acute ischemic stroke is not known. OBJECTIVE: To evaluate the influence that atherosclerotic burden (ATB), assessed by a simple clinical scale, has on the 30-day mortality in patients with first-ever ischemic stroke. DESIGN: Retrospective review of case series from a prospective stroke record. An ATB score ranging from 0 to 2 was created using the history of ischemic heart disease and peripheral arterial disease. The impact of this score on the 30-day mortality was analyzed by multivariate regression analysis. SETTING: Tertiary university hospital. Patients A total of 1527 patients with first-ever ischemic stroke. Main Outcome Measure Thirty-day mortality. RESULTS: The 30-day mortality rate was 13.8%. Multivariate regression analysis showed an association between the ATB score and the 30-day mortality (P<.001). Comparing patients having no previous ATB with those with an ATB score of 1 or 2, the odds ratio (OR) for 30-day mortality increased from 1.71 (95% confidence interval [CI], 1.06-2.75) for patients with an ATB score of 1 to 5.90 (95% CI, 2.48-14.04) for those with an ATB score of 2. Age (OR, 1.05; 95% CI, 1.03-1.08), National Institutes of Health Stroke Scale score at admission (OR, 1.22; 95% CI, 1.18-1.25), atrial fibrillation (OR, 1.61; 95% CI, 1.10-2.35), hyperlipidemia as protector (OR, 0.39; 95% CI, 0.25-0.60), and glycemia at admission (OR, 1.07; 95% CI, 1.02-1.12) were also predictors of 30-day mortality. CONCLUSION: Previous symptomatic atherosclerotic disease evaluated by a simple clinical score is an independent predictor of early mortality in patients with first-ever ischemic stroke.

[Comparative analysis of patients with narcolepsy-cataplexy, narcolepsy without cataplexy and idiopathic hypersomnia]. / Análisis comparativo de un grupo de pacientes con narcolepsia-cataplejía, narcolepsia sin cataplejía e hipersomnia idiopática.

BACKGROUND AND OBJECTIVE: To evaluate the distribution of clinical, electrophysiological and biological variables, and their relationship with the CSF hypocretin-1 levels, in patients with central hypersomnias diagnosed as narcolepsy-cataplexy (NC), narcolepsy without cataplexy (NnC) and idiopathic hypersomnia (IH) based on the ICSD-2 criteria. PATIENTS AND METHOD: We performed in all patients a clinical interview, a nocturnal polysomnogram and a multiple sleep latency test (MSLT), HLA analysis and measurement of CSF Hcrt-1 levels (low < or = 110 pg/mL). RESULTS: Out of 51 patients, 31 were classified as NC, 11 as NnC and 8 as IH. 34 patients (66.7%) had low CSF Hcrt-1 levels (29 NC, 3 NnC and 1 IH). In the NC group, 96.1% were HLA DQB1*0602 positive and 91% had low CSF Hcrt-1 levels. The most frequent variables found in NC patients and in those with a low CSF Hcrt-1 levels were cataplexy, fragmented nocturnal sleep, short refreshing naps, automatic behavior, HLA DQB1*0602, and, in the MSLT, a short mean sleep latency, a higher number of REM sleep episodes and a short mean latency of REM sleep episodes. A long nocturnal sleep time and morning sleep drunkenness, 2 variables used in the ICSD-2 for the diagnosis of IH, were not different among the three groups of hypersomnias. CONCLUSIONS: Central hypersomnias have a superposition of several clinical, electrophysiological and biological variables that makes sometimes difficult the differential diagnosis. The measurement of CSF Hcrt-1 levels may help in the diagnosis of those patients with unclear clinical or electrophysiological forms.

Análisis comparativo de un grupo de pacientes con narcolepsia-cataplejía, narcolepsia sin cataplejía e hipersomnia idiopática / Comparative analysis of patients with narcolepsy-cataplexy, narcolepsy without cataplexy and idiopathic hypersomnia

Fundamento y objetivo: Analizar la distribución de variables clínicas, electrofisiológicas y biológicas, así como su relación con los valores de hipocretina 1 (Hcrt-1) en el líquido cefalorraquídeo (LCR), en pacientes con hipersomnia central diagnosticados, según los criterios de la segunda revisión de la Internacional Classification of Sleep Disorders (ICSD-2), como narcolepsia-cataplejía (NC), narcolepsia sin cataplejía (NnC) e hipersomnia idiopática (HI). Pacientes y método: A todos los pacientes se les realizaron una entrevista clínica, un polisomnograma nocturno y un test de latencias múltiples de sueño, tipificación de antígenos de histocompatibilidad (HLA) y análisis de Hcrt-1 en el LCR (valores bajos ¾ 110 pg/ml). Resultados: De un total de 51 pacientes, se diagnosticó a 32 de NC, a 11 de NnC y a 8 de HI, y en 34 (66,7%) se encontraron valores bajos de Hcrt-1 (29 con NC, 3 con NnC y uno con HI). Entre los pacientes con NC, un 96,1% fueron positivos para HLA DQB1*0602 y el 91% presentó valores bajos de Hcrt-1. Las variables más frecuentemente encontradas en pacientes con NC y en aquéllos con valores bajos de Hcrt-1 fueron la cataplejía, el sueño nocturno fragmentado, siestas cortas reparadoras, conductas automáticas, el HLA DQB1*0602 y, en el test de latencias múltiples de sueño, una latencia media de sueño reducida, un número mayor de episodios de sueño REM y una latencia media reducida de éstos. El tiempo de sueño nocturno prolongado o las dificultades en el despertar, 2 variables incorporadas a la ICSD-2 en el diagnóstico de HI, no diferenciaron los distintos grupos. Conclusiones: Las hipersomnias centrales presentan una superposición de diversas características clínicas, electrofisiológicas y biológicas que dificultan su diagnóstico diferencial. La determinación de Hcrt-1 en LCR puede facilitar el diagnóstico en casos con escasa definición clínica y/o electrofisiológica

Backgrund and objective: To evaluate the distribution of clinical, electrophysiological and biological variables, and their relationship with the CSF hypocretin-1 levels, in patients with central hypersomnias diagnosed as narcolepsy-cataplexy (NC), narcolepsy without cataplexy (NnC) and idiopathic hypersomnia (IH) based on the ICSD-2 criteria. Patients and method: We performed in all patients a clinical interview, a nocturnal polysomnogram and a multiple sleep latency test (MSLT), HLA analysis and measurement of CSF Hcrt-1 levels (low ¾ 110 pg/mL). Results: Out of 51 patients, 31 were classified as NC, 11 as NnC and 8 as IH. 34 patients (66.7%) had low CSF Hcrt-1 levels (29 NC, 3 NnC and 1 IH). In the NC group, 96.1% were HLA DQB1*0602 positive and 91% had low CSF Hcrt-1 levels. The most frequent variables found in NC patients and in those with a low CSF Hcrt-1 levels were cataplexy, fragmented nocturnal sleep, short refreshing naps, automatic behavior, HLA DQB1*0602, and, in the MSLT, a short mean sleep latency, a higher number of REM sleep episodes and a short mean latency of REM sleep episodes. A long nocturnal sleep time and morning sleep drunkenness, 2 variables used in the ICSD-2 for the diagnosis of IH, were not different among the three groups of hypersomnias. Conclusions: Central hypersomnias have a superposition of several clinical, electrophysiological and biological variables that makes sometimes difficult the differential diagnosis. The measurement of CSF Hcrt-1 levels may help in the diagnosis of those patients with unclear clinical or electrophysiological forms

Evaluation of hypothalamic-specific autoimmunity in patients with narcolepsy.

An autoimmune-mediated mechanism is considered the most probable etiology for narcolepsy. However, this hypothesis remains unproven. Since narcolepsy is characterized by dysfunction of the hypothalamic hypocretinergic (orexinergic) system, we evaluated the presence of hypothalamic-specific antibodies in sera and CSF of 25 hypocretin-deficient and 6 non-deficient narcoleptic patients by immunohistochemistry and analyzing a screening of a rat cDNA expression hypothalamic library. There was no hypothalamic-specific reactivity in serum or CSF by inmmunohistochemistry. The screening of the hypothalmic library detected some reactive clones but not a common reactivity. Our study did not find any evidence of hypothalamic-specific autoimmunity in narcolepsy.

CSF markers in sleep neurobiology.

The cerebrospinal fluid has been used in the study of normal and pathological conditions of the central nervous system for more than a century. CSF analysis has also been applied to the study of sleep and its disorders but methodological aspects have often limited the results. The discovery of the hypocretin system (also known as orexin system) and its involvement in the pathophysiology of narcolepsy has opened a new field in the diagnosis of hypersomnia by CSF analysis and has revived the interest on this subject in sleep medicine. Older and new lines of research involving CSF measurement of hypocretin and other neurotransmitters in sleep and its disorders are reviewed.

Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness.

STUDY OBJECTIVE: Myotonic dystrophy type 1 is a multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment. This disorder is caused by a CTG triplet expansion in the 3' untranslated region of the DMPK gene on 19q13. Myotonic dystrophy type 1 is frequently associated with excessive daytime sleepiness, sharing with narcolepsy a short sleep latency and the presence of sleep-onset rapid eye movement periods during the Multiple Sleep Latency Test. Since narcolepsy is characterized by a dysfunction of the hypothalamic hypocretin system, we investigated whether patients with myotonic dystrophy type 1 with excessive daytime sleepiness have abnormalities in the hypocretin system. DESIGN/PARTICIPANTS: Six patients with myotonic dystrophy type 1 complaining of excessive daytime sleepiness and 13 healthy controls without a sleep disorder were included. The patients with myotonic dystrophy type 1 were evaluated using clinical interviews, nocturnal polysomnograms, and Multiple Sleep Latency Tests. All patients had a confirmed genetic diagnosis for DM1 and were HLA typed. Cerebrospinal fluid hypocretin-1 levels were measured using a direct radioimmunoassay in patients and controls. SETTING: University hospital sleep laboratory. INTERVENTIONS: N/A. MEASUREMENT AND RESULTS: The mean sleep latency on Multiple Sleep Latency Tests was abnormal in all patients (< 5 minutes in 2, < or = 8 in 4) and 2 sleep-onset rapid eye movement periods were observed in 2 subjects. All patients were HLA-DQB1*0602 negative. Hypocretin-1 levels were significantly lower in patients versus controls (p < 0.001); 1 case with 2 sleep-onset rapid eye movement periods had hypocretin-1 levels in the range generally observed in narcolepsy (< 110 pg/mL). Three cases had intermediate levels (110-200 pg/mL). Hypocretin-1 levels did not correlate clinically with disease severity or duration or with subjective or objective sleepiness reports. CONCLUSIONS: A dysfunction of the hypothalamic hypocretin system may mediate sleepiness and abnormal Multiple Sleep Latency Test results in patients with myotonic dystrophy type 1.