Atención primaria de salud y prevención de lesiones de tráfico : estudio de una cohorte de personas conductoras /

Les col·lisions de trànsit són un problema de Salut Pública que es pot mesurar i prevenir. Hi ha problemes de salut de risc per a la conducció que van ser categoritzats pel projecte EU-I05ORTAL. També hi ha fàrmacs de risc per a la conducció que van ser categoritzats pel projecte DRUID. L'augment de l'esperança de vida i la desacceleració del creixement de la població està provocant un augment progressiu, d'una banda, de la gent major de 64 anys i, de l'altra, de la gent que pateix problemes de salut crònics. La llei espanyola de trànsit i seguretat vial exigeix una autorització administrativa que implica un reconeixement mèdic que garanteixi les capacitats de la persona per a conduir amb seguretat. No existeix, tanmateix, un protocol que indiqui què cal fer en cas de pèrdua d'aquestes capacitats en els terminis entre reconeixements quan ho detecta la pròpia persona conductora ni tampoc en cas de ser detectades per un professional sanitari en una visita ordinària. Tampoc es coneix la relació entre la percepció del risc de patir una col·lisió per la persona conductora i el seu estat de salut ni existeixen programes de suport i assessorament per la presa de decisions sobre el cessament de la conducció. La feina de l'Atenció Primària de Salut consisteix a fer prevenció, promoure la salut, atendre els malalts i fer recerca per a aconseguir la millora de la salut de la població atesa. Hi ha una població de persones conductores susceptibles de rebre accions de prevenció i promoció de la salut en l'àmbit de la seguretat vial duta a terme per l'Atenció Primària de Salut. L'objectiu general d'aquesta tesi és conèixer les característiques de les persones conductores ateses a 25 Centres d'Atenció Primària de Catalunya. També per una banda, es vol estudiar la percepció del risc de col·lisió i els seus factors associats i per altra, estimar la incidència de col·lisió a la població d'estudi i el seus factors associats. Amb aquesta finalitat, es va dur a terme un estudi observacional, multicèntric, amb dues fases: la primera va ser una fase transversal (2009) i la segona, una fase de seguiment prospectiu de dos anys (2010-2020). A la primera es van realitzar enquestes presencials a un total de 1.949 persones (56,5% homes i 43,5% dones); i a la segona, enquestes telefòniques que van permetre contactar amb el 95% de la població inicial. Aquesta tesi aporta dades sobre les diferències per sexe i edat en les característiques de la població de persones conductores. Ha permès apropar-se a la valoració de la percepció del risc de patir una col·lisió de trànsit i els seus factors associats. Alhora ha permès estimar el càlcul de la incidència de col·lisió de trànsit de la població de persones conductores estudiades durant el període de seguiment. També estat possible estimar aquesta incidència tenint en compte si: hi va caldre atenció mèdica o no; si hi va haver problemes de salut de risc o no i si van consumir fàrmacs de risc per la conducció. En aquest cas, també es van estudiar els factors associats. Finalment, ha posat de manifest que és possible la recerca sobre Seguretat Vial des de l'Atenció Primària de Salut.Las colisiones de tráfico suponen un problema de Salud Pública medible y evitable. Por un lado, existen problemas de salud y fármacos que suponen un riesgo para la conducción, los primeros han sido categorizados por el proyecto EU-IMMORTAL y los segundos por el proyecto DRUID. La desaceleración del crecimiento de la población y el aumento de la esperanza de vida han provocado un aumento progresivo tanto del porcentaje de población mayor de 64 años como el de la población que padece problemas crónicos de salud y consume fármacos de forma crónica. Por otro lado, la Ley de Tráfico y Seguridad Vial española exige una autorización administrativa que implica un reconocimiento médico que garantice las capacidades de la persona para conducir de forma segura. Pero no está bien protocolizado qué hacer en caso de perder esas capacidades en los periodos inter-reconocimientos percibidos por la propia persona conductora ni tampoco en caso de ser detectados por un profesional sanitario en una visita ordinaria. Tampoco se conoce la percepción del riesgo de colisión en función del estado de salud de la persona conductora ni existen programas de apoyo y asesoramiento en la toma de decisiones sobre el cese de la conducción. Las labores de la Atención Primaria de Salud (APS) abarcan la prevención y promoción de la salud, la asistencia de las personas y la investigación encaminada a mejorar la salud de la población que atiende. La población de personas conductoras es susceptibles de recibir acciones de prevención y de promoción de la salud en el campo de la seguridad vial desde la APS. El objetivo general de esta tesis consiste en conocer las características de las personas conductoras, atendidas en 25 Centros de Atención Primaria de Cataluña, además de conocer la percepción del riesgo de colisión y sus factores asociados, así como también calcular la incidencia de colisión en esta población y sus factores asociados. Para ello, se llevó a cabo un estudio observacional, multicéntrico, con dos fases: una primera transversal (2009), basada en entrevistas personales a una población de 1.949 personas conductoras (56,5% hombres y 43,5% mujeres), y una segunda de seguimiento prospectiva de 2 años de duración (2010-2012), basada en entrevistas telefónicas consiguiéndose contactar con el 95% de la población inicial. Esta tesis proporciona datos sobre las diferencias por sexo y edad en las características de la población de personas conductoras atendidas en la APS. Ha permitido realizar una aproximación a la valoración de la percepción del riesgo de sufrir una colisión de tráfico por dichas personas, encontrándose factores asociados. Al mismo tiempo, ha permitido estimar la incidencia total de colisión de tráfico de la población estudiada durante el periodo de seguimiento, y también teniendo en cuenta: si precisaron atención médica o no; si existían problemas crónicos de salud de riesgo para la conducción o no; y si existía consumo crónico de fármacos de riesgo para la conducción o no. También en este caso, se estudiaron los factores asociados. Finalmente, este trabajo ha puesto de manifiesto que la investigación en Seguridad Vial desde la Atención Primaria de Salud es posible.Motor vehicle collisions (MVC) are a measurable preventable Public Health concern. EU-project IMMORTAL categorised medical conditions associated with an increased risk of being involved in a motor vehicle crash. DRUID classification system established criteria to categorise commonly used medicines based on their influence on fitness to drive. Against a backdrop of lower population growth and longer life expectancy, people aging 64 or more and people with chronic diseases are making up an increasing share of the total population. According to the Spanish Road Safety and Traffic Law , driving license applicants must complete their medical examination with authorised physicians before receiving their official permit. There is currently no proper protocol to follow in case of loss of fitness to drive detected either by the driver or by physicians before the following mandatory medical examination. The connection between motor vehicle collision risk perception and driver's health condition is unknown to date . There are no available programs to help drivers with decision-making about giving up driving. Primary Care Health Physicians carry out preventive medicine, health promotion and patient assistance activities, as well as, research to improve patients' condition. Primary Health Care can carry out Road Traffic Injury Preventive and Promotion efforts on its driving population too. This thesis' overall aim is to determine the characteristics of drivers treated by 25 Catalonian Primary Health Centres. As well as to study the connection between MVC risk perception and its related factors and to estimates MVC incidence rate and its related factors. To that end, a two-stage multi-centre observation-based study was designed. The first stage was a cross-sectional study based on face-to-face interviews conducted in 2009 on 1.949 people (56,5% men and 43,5% women). The second stage was a two-year-prospective-follow-up study based on phone interviews conducted between 2010 and 2012. It was possible to contact with the 95% of the initial studied population. This thesis provides data about drivers' characteristics disaggregated by sex and age. It approaches MVC risk perception assessment and its related factors. At the same time, it has also estimated MVC incidence rate (MVCIR) along the follow-up period and its related factors. In order to estimates MVCIR following circumstances were also taken into consideration: whether medical attention was required or not; whether drivers suffered from chronic medical conditions that increased risk of being involved in a MVC or not; and whether drivers took medicines that impaired fitness to drive or not. MVCIR related factors were also studied. Lastly, it has demonstrated the feasibility of road safety research by Primary Health Care

Intravenous Cyclophosphamide Pulse Therapy in the Treatment of Systemic Sclerosis-Related Interstitial Lung Disease: A Long Term Study

Interstitial lung disease (ILD) frequently complicates systemic sclerosis (SSc). Cyclophosphamide (CYC) is a promising immunosuppressive therapy for SSc-related ILD. Our objective was to investigate the effectiveness of an intravenous CYC (iv CYC) pulse regime in SSc-related ILD during treatment and thereafter. In a prospective observational study ten consecutive patients with SSc-related ILD were treated with iv CYC in a pulse regime lasting from 6 to 24 months. Clinical status, pulmonary functional testing (PFT) and high resolution computed tomography (HRCT) of the chest were evaluated at enrolment and 6, 12 and 24 months thereafter. After treatment withdrawal, patients were followed up every 6 months with PFT and chest HRCT to monitor lung disease. Clinical improvement was apparent in 8 out of 10 patients. The median values of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) as well as ground-glass pattern on HRCT did not change significantly after 6, 12 and 24 months of therapy. The follow-up continued in 8 out of 10 patients after treatment withdrawal for a median of 26.5 months (range: 12-48 months). The final median FVC was 54.5% of predicted value (interquartile range, IQR= 31.6%-94%). Only one patient suffered a FVC deterioration greater than 10%, even though less than 160 ml. The final median DLCO was 68% of predicted value (IQR=38.3-83.6%). Only 2 patients who developed pulmonary arterial hypertension deteriorated their DLCO values of more than 15%. An iv CYC pulse regimen over 24 months may stabilize pulmonary activity in patients with SSc-related ILD during the course of treatment and for a median of 26.5 months thereafter

High sensitivity and negative predictive value of the DETECT algorithm for an early diagnosis of pulmonary arterial hypertension in systemic sclerosis : application in a single center

Pulmonary arterial hypertension (PAH) is one of the most relevant causes of death in systemic sclerosis. The aims of this study were to analyse the recently published DETECT algorithm comparing it with European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines: as screening of PAH; (2) identifying median pulmonary arterial pressure (mPAP) ≥21 mmHg; and (3) determining any group of pulmonary hypertension (PH). Eighty-three patients fulfilling LeRoy's systemic sclerosis diagnostic criteria with at least right heart catheterization were studied retrospectively. Clinical data, serological biomarkers, echocardiographic and hemodynamic features were collected. SPSS 20.0 was used for statistical analysis. According to right heart catheterization findings, 35 patients with PAH and 28 with no PH met the standards for DETECT algorithm analysis: 27.0% of patients presented with functional class III/IV. Applying DETECT, the sensitivity was 100%, specificity 42.9%, the positive predictive value 68.6% and the negative predictive value 100%, whereas employing the ESC/ERS guidelines these were 91.4%, 85.7%, 88.9% and 89.3%, respectively. There were no missed diagnoses of PAH using DETECT compared with three patients missed (8.5%) using ESC/ERS guidelines. The DETECT algorithm also showed greater sensitivity and negative predictive value to identify patients with mPAP ≥21 mmHg or with any type of PH. The DETECT algorithm is confirmed as an excellent screening method due to its high sensitivity and negative predictive value, minimizing missed diagnosis of PAH. DETECT would be accurate either for early diagnosis of borderline mPAP or any group of PH

Early- versus late-onset systemic sclerosis. Differences in clinical presentation and outcome in 1037 patients

Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤ 30 years (early onset), age between 31 and 59 years (standard onset), and age ≥ 60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P &lt; 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P &lt; 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P &lt; 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P &lt; 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE)

Aim: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. Material and methods: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. Results: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77-2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10-1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52-2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01-1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18-4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24-2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45-0.97; P = 0.036). Conclusions: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Registry of the Spanish network for systemic sclerosis: survival, prognostic factors, and causes of death

Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan-Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors

Enteropatia sensible al gluten en pacients amb malalties autoimmunes sistèmiques: Aspectes fisiopatològics i rellevància clínica

La malaltia celíaca(MC) és una patologia inflamatòria de la mucosa del budell prim mediada pel gluten, que es resol amb la retirada d'aquest element de la dieta. La seva repercussió clínica i potencials complicacions fan important establir-ne el diagnòstic. El diagnòstic de la MC és complexe per les múltiples formes de presentació de la malaltia i per què prop del 50% dels pacients es mantenen asimptomàtics. Es fonamenta en la histologia, però actualment es disposa de marcadors serològics i genètics que permeten detectar individus amb risc. El cribatge de la malaltia s'aplica a individus amb sospita de MC i en poblacions establertes de risc, utilitzant tests serològics (anticossos antitransglutaminassa tisular -anti-tTG- i anticossos antiendomisi -EMA-). La sensibilitat i especificitat d'aquests tests, però, varia segons el grau de lesió de la mucosa; en aquest sentit, estudis recents demostren que, en una població de risc, complementar l'estratègia de cribatge habitual amb l'estudi genètic (HLA-DQ2 i HLA-DQ8), seguit de l'estudi histològic del budell prim, permet diagnosticar tres vegades més pacients amb MC que la serologia sola. La relació entre la MC i malalties autoimmunes organoespecífiques està ben establerta. Sembla també, que els pacients amb MC tenen un risc major de desenvolupar events autoimmunes al llarg de la seva vida, però, són escasses les evidències d'una prevalença major de MC entre els pacients amb malalties autoimmunes sistèmiques (MAS). A la present tesi doctoral s'aplica per primera vegada l'estratègia diagnòstica de MC descrita, avaluant el tipatge genètic (HLA-DQ2 i HLA-DQ8) afegit al cribatge serològic per tal conéixer la prevalença de MC en pacients amb MAS. Els objectius principals són: 1) conéixer si els pacients amb MAS constitueixen un grup de risc per desenvolupar MC i 2) avaluar l'etiologia i l'impacte clínic de l'enteropatia celíaca o no celíaca associada a MAS i la seva relació amb els diferents factors associats a les malalties o al seu tractament. Mètodes: Es van incloure 183 pacients amb MAS. Es va sotmetre a biòpsia duodenal a tots el pacients amb serologia i/o marcadors genètics de MC i/o símptomes de l'espectre de la MC. En el cas de trobar enteropatia, es van avaluar les posibles causes de la mateixa i quan no era cap evidenciable es proposava al pacient seguir una dieta sense gluten per avaluar la resposta clínica i histològica Resultats: Es va detectar una prevalença de MC amb atròfia de 0,55% (1/183 pacients). Trenta vuit dels 109 pacients que es van sotmetre a biòpsia duodenal presentaven enteropatia limfocítica (EL). La causa d'aquesta EL va ser en 8 casos infecciosa, en 5 per enteropatia sensible al gluten (ESG) i en 25 pacients no es va poder establir, 5 d'aquests presentaven predisposició genética de MC però no van acceptar seguir dieta sense gluten. L'estudi univariat es va dur a terme mitjançant test de Chi quadrat o F de Fisher. No es va trobar relació entre la EL i la situacio de la malaltia o l'ús de immunosupressors. L'HLA-DQ2 va ser més freqüent entre els pacients amb malalties del teixit connectiu (41,5%) comparat amb les vasculitis i malalties autoinflamatòries (17,9%) (p=0,02), en canvi, el percentatge de EL era menor en el primer grup (20,2% vs 41,6%). En els casos de EL d'etiologia no coneguda, la clínica era irrellevant. Conclusions: Es va detectar MC amb atròfia en un 0,55%, que és igual a l'esperable a la població general. Un terç dels pacients presentaven EL, en la majoria dels casos d'etiologia desconeguda, en pocs casos es va poder atribuir a ESG. En base als resultats del present estudi, els pacients amb MAS no constituirien una població de risc per desenvolupar MC

Estudio clínico y de resonancia magnética orientado al conocimiento del sustrato patológico de la discapacidad en la esclerosis múltiple primariamente progresiva

Con el objetivo de contribuir al estudio de los mecanismos que subyacen al aumento de la discapacidad en la esclerosis múltiple primariamente progresiva (EMPP), fijamos tres objetivos principales. Asimismo, nos propusimos hacer una revisión de la literatura sobre EMPP publicada hasta el momento actual, utilizando la web www.pubmed.com como herramienta de trabajo, que sirviera como introducción a los estudios de la tesis. El primer objetivo consistió en investigar el grado de correlación entre el daño en los diferentes tejidos cerebrales y diversos aspectos de la discapacidad, especialmente de la discapacidad cognitiva, en una cohorte de 27 pacientes con EMPP y 31 controles sanos, utilizando secuencias convencionales de resonancia magnética (RM) y parámetros relativos al ratio de transferencia de magnetización (MTR, del inglés Magnetization Transfer Ratio). Nuestros resultados mostraron que los parámetros que reflejaban daño en la sustancia gris (SG), parámetros de MTR de la SG, fueron los que mejor se correlacionaron con un peor índice global de rendimiento cognitivo, un mayor deterioro estimado del coeficiente intelectual verbal desde el inicio de la enfermedad y una mayor disfunción ejecutiva. No obstante, parámetros que reflejaban daño en la sustancia blanca (SB) también mostraron tener relevancia clínica. Por ello, sugerimos que los modelos de predicción del deterioro cognitivo en esta forma de la enfermedad deben incluir evaluaciones amplias de RM, en los que se explore tanto la SG como la SB. Nuestro segundo objetivo fue investigar qué parámetros de RM cerebral, medidos en fases muy tempranas de la enfermedad, eran capaces de predecir una peor evolución clínica, medida por el EDSS (Expanded Disability Status Scale) y por los subtest del MSFC (Multiple Sclerosis Functional Composite). Para este propósito estudiamos de forma prospectiva durante cinco años a 47 pacientes con EMPP temprana (menos de cinco años desde el inicio de los síntomas) y a 18 controles sanos. Así, vimos que parámetros lesionales y de MTR de la SG medidos a nivel basal fueron capaces de predecir de forma independiente el aumento de la discapacidad medida por el TWT (25-foot Timed Walk Test) a los cinco años, poniendo de manifiesto el papel complementario de estas medidas de RM en la predicción del aumento de la discapacidad. Además, un empeoramiento más pronunciado en la carga lesional y en los parámetros de MTR de la SG a lo largo de los cinco años del estudio se asoció a una mayor progresión clínica durante el mismo periodo. Finalmente, aprovechando que en nuestra unidad se llevó a cabo, entre 1998 y 2000, un ensayo clínico (EC) con interferón beta-1b (IFNb-1b) para formas primarias progresivas que mostró un discreto beneficio clínico (en cuanto al MSFC), nos propusimos, como tercer objetivo, investigar el impacto clínico-radiológico de la intervención con IFNb-1b en los pacientes con EMPP que participaron en el EC, cinco años después de haber finalizado el mismo. Se obtuvo información sobre el EDSS, el MSFC y parámetros neuropsicológicos en 63, 59 y 59 pacientes, respectivamente, de los 73 que participaron en el EC. En 50 de ellos se realizó una RM craneal. Después de cinco años sin tratamiento, los pacientes que habían recibido IFNb-1b durante el EC mostraron mejores puntuaciones en el NHPT (Nine-Hole Peg Test) y en un test relacionado con las funciones ejecutivas; además, presentaron una mayor indemnidad de los parámetros que reflejaban daño en el tejido de apariencia normal (MTR de la SB de apariencia normal y atrofia cerebral) que los pacientes del grupo placebo. Finalmente, considerando el grupo globalmente, un mayor aumento de lesiones durante el EC se correlacionó con un mayor empeoramiento en el EDSS durante los cinco años siguientes. Esta tesis pone de manifiesto que las dos grandes formas de afectación inmunopatológica en la EMPP, la afectación de la SB y la de la SG, son determinantes para la progresión de la discapacidad. Por ello, ambas deberían ser tenidas en cuenta a la hora de crear modelos de predicción de la discapacidad y de diseñar tratamientos que frenen la aparición de daño neurológico irreversible.In order to contribute to the study of mechanisms that underlie clinical progression in primary progressive multiple sclerosis (PPMS), three objectives were established. Besides, as an introduction to the main studies of the thesis, we also decided to review the literature about PPMS. Our first objective was to investigate the association between brain tissue damage and different aspects of disability, especially cognitive disability, in a cohort of 27 PPMS patients and 18 healthy controls, using conventional Magnetic Resonance Imaging (MRI) and Magnetization Transfer Ratio (MTR) parameters. We found that MRI parameters related to grey matter (GM) damage (GM MTR) were the main correlates of overall cognitive impairment, the estimated verbal intelligence quotient decline and executive dysfunction. Nonetheless, since MRI parameters related to white matter (WM) damage were also strongly associated with other aspects of cognitive impairment, we concluded that studies designed to evaluate cognitive dysfunction should include comprehensive MRI assessments. Our second objective was to evaluate the role of brain MRI parameters, when measured very early in the disease, in predicting progression of disability in PPMS, as measured by the EDSS (Expanded Disability Status Scale) and the subtests of the MSFC (Multiple Sclerosis Functional Composite). For this purpose, we prospectively studied 47 patients with early PPMS (with less than five years from symptom onset) and 18 healthy controls. Thus, we found that lesion load and GM MTR at baseline independently predicted the accrual of disability at five years of follow-up, as measured by the TWT (25-foot Timed Walk Test), highlighting the complementary roles of GM damage and lesions in predicting clinical disability. Furthermore, steeper increases in lesion load and more pronounced worsening in GM damage over five years were associated with faster clinical deterioration over the same period of time. Finally, since a clinical trial (CT) with interferon beta-1b (IFNb-1b) for patients with PPMS was carried out in our unit between 1998 and 2000, showing some positive effect on MSFC, our third objective was to investigate the impact of IFNb-1b treatment on clinical and MRI measures, five years after the termination of the CT. We obtained information about EDSS, MSFC and neuropsychological parameters in 63, 59 and 59 patients, respectively, out of the 73 that had participated in the CT. After five years without treatment, patients who had received IFNb-1b during the CT showed better scores on the NHPT (Nine-Hole Peg Test) and a test related to executive functions; moreover, they showed a greater indemnity of those MRI parameters associated with normal-appearing brain tissue damage (normal-appearing WM MTR and brain atrophy) than patients who had received placebo during the CT. Finally, considering the group as a whole, the in-trial increase of lesions correlated with the EDSS deterioration over the following five years. This thesis highlights that the two main forms of immunopathological damage in PPMS, the damage in the WM and that observed in the GM, are both crucial to the accrual of disability. Therefore, both types of damage should be taken into account for the creation of predictive models of clinical progression and the design of drugs that aim at slowing down the appearance of irreversible disability