[Comorbidities in multiple sclerosis and their influence on the choice of treatment]. / Comorbilidades en la esclerosis múltiple y su influencia en la elección del tratamiento.

Clinical trials of disease-modifying therapies (DMTs) for people with multiple sclerosis (pMS) are conducted in selected populations, excluding patients with comorbidities or concomitant medications. However, a large percentage of pMS have some additional disease, which could affect the response and choice of the DMT. The objective of this review is to assess how concurrent pathologies can impact the choice of DMTs. Relevant articles were selected through a systematic search in PubMed. Comorbidities were grouped for better classification into autoimmune, chronic infections, cardiovascular and metabolic, oncological and neuropsychiatric. In autoimmune pathologies, it is key to take into account the effects of TME on them and the possibility of interaction with their specific treatments. Immunomodulatory therapies are safe for people with chronic infections. Immunosuppressive treatments are generally contraindicated in people with active infections. In cardiovascular and metabolic comorbidities, infusion reactions associated with monoclonal antibodies, and the phenomena of starting treatment with S1P modulators, must be taken into account. DMTs with an immunosuppressive effect are contraindicated in people with active malignancies. Although psychiatric pathology per se does not preclude the use of DMTs, caution should be exercised when new psychiatric symptoms appear. For these reasons, among the multiple factors that must be considered when starting or changing a DMT in pMS, comorbidities constitute a decisive element.

TITLE: Comorbilidades en la esclerosis múltiple y su influencia en la elección del tratamiento.Los estudios clínicos de tratamientos para personas con esclerosis múltiple (pEM) se realizan en poblaciones seleccionadas, que excluyen a pacientes que presenten comorbilidades o medicaciones concomitantes. Sin embargo, un gran porcentaje de las pEM tiene alguna enfermedad adicional, que podría afectar a la respuesta y la elección del tratamiento. El objetivo de esta revisión es valorar cómo pueden las diferentes patologías concurrentes impactar en la elección de las terapias modificadoras de la enfermedad (TME) en las pEM. Se seleccionaron artículos relevantes mediante búsqueda en PubMed. Las comorbilidades se agruparon, a los fines de mejor ordenamiento de los artículos encontrados, en patologías diversas: autoinmunes, infecciones crónicas, cardiovasculares, respiratorias, metabólicas, oncológicas, neuropsiquiátricas y epilepsia. En cuanto a las patologías autoinmunes, es clave tener en cuenta los efectos de las TME sobre ellas y la posibilidad de interacción con sus tratamientos específicos. Las terapias inmunomoduladoras son seguras para personas con infecciones crónicas. Los tratamientos inmunosupresores, en general, están contraindicados en personas con infecciones activas. En las comorbilidades cardiovasculares y metabólicas deben tenerse en cuenta las potenciales reacciones de infusión asociadas a anticuerpos monoclonales, y los fenómenos asociados al inicio de tratamiento con moduladores del receptor de la esfingosina-1-fosfato. Las TME con efecto inmunosupresor están contraindicadas en personas con malignidades activas. Aunque la patología psiquiátrica de por sí no impide el uso de TME, debería tenerse precaución cuando aparecen nuevos síntomas psiquiátricos, y siempre tenerse en cuenta su monitorización y tratamiento. Por este motivo, entre los múltiples factores que deben considerarse a la hora de iniciar o cambiar una TME en pEM, las comorbilidades constituyen un elemento muchas veces decisivo.

[Argentinean consensus guidelines on the identification and clinical care of secondary progressive multiple sclerosis]. / Consenso sobre la identificación y seguimiento de la esclerosis múltiple secundaria progresiva en Argentina.

INTRODUCTION: The identification, diagnosis, follow-up, and treatment of patients with secondary progressive multiple sclerosis (SPMS) show significant differences between health care professionals in Argentina. AIM: To provide consensus recommendations on the management of patients with SPMS in Argentina to optimize patient care. DEVELOPMENT: A panel of expert neurologists from Argentina dedicated to the diagnosis and care of multiple sclerosis patients gathered during 2019 and 2020 to carry out a consensus recommendation on the diagnosis and treatment of SPMS patients in Argentina. To achieve consensus, the methodology of 'formal consensus-RAND/UCLA method' was used. Recommendations were established based on published evidence and the expert opinion. Recommendations focused on how to define SPMS and how to follow SPMS patients. CONCLUSION: The recommendations of this consensus guidelines attempt to optimize the care of SPMS patients in Argentina.

TITLE: Consenso sobre la identificación y seguimiento de la esclerosis múltiple secundaria progresiva en Argentina.Introducción. Existen diferencias significativas en el diagnóstico, la identificación y el seguimiento de pacientes con esclerosis múltiple secundaria progresiva (EMSP) entre los profesionales de la salud a cargo de su tratamiento. Objetivo. Proveer recomendaciones sobre el tratamiento de los pacientes con EMSP en Argentina con el fin de optimizar su cuidado. Desarrollo. Un grupo de neurólogos expertos en esclerosis múltiple de Argentina elaboró un consenso para el tratamiento de pacientes con EMSP en la región mediante metodología de ronda de encuestas a distancia y reuniones presenciales. Se establecieron 33 recomendaciones basadas en la evidencia publicada y en el criterio de los expertos que participaron. Las recomendaciones se enfocaron en el diagnóstico y el seguimiento de los pacientes con EMSP. Conclusión. Las recomendaciones establecidas en el presente consenso permitirían optimizar el cuidado y el seguimiento de los pacientes con EMSP en Argentina.

Gender ratio trends over time in multiple sclerosis patients from Argentina.

Several studies in multiple sclerosis (MS) suggest a trend of increasing disease frequency in women during the last decades. A direct comparison of gender ratio trends among MS populations from Argentina remains to be carried out. The objective of the study was to compare gender ratio trends, over a 50-year span in MS populations from Argentina. METHODS: multicenter study that included patients from 14 MS Centers of Argentina. Patients with definite MS with birth years ranging from 1940 to 1989 were included. Gender ratios were calculated by five decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the Argentinean national registry of births. The F/M ratios were calculated using a multivariate logistic regression per five decades by the year of birth approach. Analyses were performed using Stata 10.1. RESULTS: 1069 patients were included. Gender ratios showed a significant increase from the first to the last decade in the whole MS sample (from 1.8 to 2.7; p value for trend=0.023). The Gender ratio did not show differences considering MS subtype. CONCLUSION: our study showed a modest increase of the F/M ratio (from 1.8 to 2.7) over time among patients affected by MS in Argentina.

Disease onset in familial and sporadic multiple sclerosis in Argentina.

UNLABELLED: The present study was carried out to assess if there is an anticipation of age at onset in younger generations of familial multiple sclerosis (FMS) vs. sporadic MS (SMS) in Argentina. METHODS: multicenter study that included patients from 14 MS Centers of Argentina. Patients were considered as FMS if they had in their family at least one relative of first or second degree diagnosed with MS; otherwise, patients were considered to have SMS. We compared the age at onset between familial and sporadic cases as well as the age at onset between relatives from different generations in FMS vs. SMS. RESULTS: 1333 patients were included, 97 of them were FMS (7.3%). A lower age at onset in the younger generations of FMS cases was found compared with older generations of FMS as well as. SMS cases (24.1±3.7 years vs. 30.3±5.7 years, and 32.4±9.4 respectively; p<0.001). No differences were observed between older generations of FMS vs. SMS cases (p=0.12). CONCLUSION: we observed an anticipation of age at onset of MS in younger generations of patients with FMS vs. older generations of FMS and SMS.

Utility of the INECO frontal screening (IFS) in the detection of executive dysfunction in patients with relapsing-remitting multiple sclerosis (RRMS).

Several studies have reported that about 65 % of patients with relapsing-remitting multiple sclerosis (RRMS) suffer from cognitive impairment, with executive dysfunction being the most frequently described. Even if several executive screening tests have been designed to specifically detect executive deficits, few studies have investigated their ability to tackle such dysfunction particularly in multiple sclerosis (MS). The aim of the present study was to evaluate the sensitivity and specificity of the INECO frontal screening (IFS) in the detection of executive dysfunction in patients with relapsing-remitting MS (RRMS). 54 patients with RRMS were included in the study. 34 presented executive dysfunction while 20 did not. 32 control subjects matched for age, sex, and educational level were also included. All were evaluated with the IFS and with a battery of classical executive tests. A patient was considered to have executive dysfunction if he/she scored a one and a half standard deviation below the control mean in at least one of the classical executive tests. Sensitivity and specificity of the IFS in its ability to detect executive dysfunction in MS was analyzed. Using a cut-off of 25.5 points, sensitivity of the IFS was 73.53 %, and specificity 78.13 % in differentiating controls from MS patients with executive dysfunction. The IFS showed excellent concurrent validity with executive tasks. The IFS can be considered a brief, easy-to-administer, cost-less tool for the detection of executive dysfunction in patients with RRMS.

Epidemiological characteristics of pregnancy, delivery, and birth outcome in women with multiple sclerosis in Argentina (EMEMAR study).

BACKGROUND: The influence of pregnancy on Multiple Sclerosis (MS) has been extensively studied but such influence on Latin American women with MS has not been characterized. Our objective was to describe the course of pregnancy and birth outcome in Argentinean MS patients and the evolution of MS during pregnancy and after delivery. METHOD: We used a retrospective design in eight MS centers in Argentina and administered a survey to women with definite MS (Mc Donald) with pregnancies during or after MS onset. We contacted 355 women of which 81 met inclusion criteria. We recorded 141 pregnancies. RESULTS: Involuntary abortion was observed in 16% of pregnancies (95% CI = 10-23). Thirty five women received immunomodulatory therapy (IMT) before 42 pregnancies. Twenty three (55%) out of 42 pregnancies were exposed to IMT. The mean time of IMT discontinuation before conception in 19 (45.2%) pregnancies without exposure, was 104 days (95% CI = 61.0-147.0). There were 103 deliveries: 79% full term. Birth defects were detected in 19% of pregnancies exposed to IMT (95% CI = 4-46) and in 2% of non-exposed (95% CI = 0.3-8.0). The mean relapse rate was: pre-pregnancy year: 0.22 (95% CI = 0.12-0.32); pregnancy: 0.31 in 1st (95% CI = 0.10-0.52), 0.19 (95% CI = 0.03-0.36) in 2nd, and 0.04 in 3rd trimester (95% CI = -0.04-0.12); 1st trimester post delivery: 0.82 (95% CI = 0.42-1.22). CONCLUSION: We observed a higher rate of birth defects among infants exposed to immunomodulators in utero than those not exposed. The reduction in MS relapses during 2nd and 3rd trimester of pregnancy and its increase during postpartum is consistent with previous reports.

Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina.

Switching treatment may be beneficial in patients with relapsing-remitting multiple sclerosis (RRMS) who respond inadequately to first-line immunomodulatory therapy. The objective of this study was to evaluate clinical outcomes after switching treatment in such patients. This prospective longitudinal observational study included 114 patients with RRMS who failed first-line monotherapy and were switched treatments after 3 years. Every 3 months, patients underwent a full neurological examination. Outcome was compared between the 3-year Before Switch and After Switch treatment periods. The primary outcome measure was the annualized relapse rate; secondary outcome measures were the proportion of relapse-free patients and the median change in Expanded Disability Status Scale (EDSS). Patients were switched either from low-dose to high-dose interferon-beta (IFNbeta; n = 31), from IFNbeta to glatiramer acetate (GA; n = 52) or mitoxantrone (n = 13), or from GA to IFNbeta (n = 16). In 3 years after switching, annualized relapse rates fell by 57-78% according to the group. The proportion of relapse-free patients varied from 56% to 81%. Least improved was observed in patients switching between INFbeta preparations. Median EDSS scores remained stable in all groups except the GA to IFNbeta switchers. In conclusion, patients who fail first-line immunomodulatory therapy generally benefit from switching to another class of immunomodulatory therapy.

A retrospective, observational study comparing the four available immunomodulatory treatments for relapsing-remitting multiple sclerosis.

We performed an observational, retrospective analysis of outcome in a sequential cohort of patients with relapsing-remitting multiple sclerosis (RRMS) in Argentina. Patients treated for 16 months with interferon beta-1a (Avonex; 30 micrograms intramuscularly, once a week), interferon beta-1a (Rebif); 44 micrograms subcutaneously, thrice weekly), interferon beta-1b (Betaferon; 250 micrograms subcutaneously, every other day) or glatiramer acetate (Copaxone; 20 mg subcutaneously daily) were compared with a non-treated group of patients. The different treatment groups were similar in baseline demographic and clinical variables. A significant fall in the annual relapse rate was observed for all four treatments, with the largest effect observed with glatiramer acetate (81% reduction in relapse rate, compared with pre-treatment values). The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 37% in untreated patients to 83% in the glatiramer acetate treated group. No statistically significant changes in disability scores were observed over the treatment period. This first such comparative study in Latin America shows that treatment of multiple sclerosis patients with immunomodulatory therapies in the context of current standards of care in Argentina provides clinically important benefit, and suggest that some of these therapies may be better than others.

Subclinical sensory abnormalities in trigeminal neuralgia.

Trigeminal neuralgia is considered as a paroxysmal single nerve phenomenon. Abnormal sensory perception has been previously described in 15-25% of patients with clinical examination. Quantitative sensory testing (QST) was used to evaluate sensory perception in patients with idiopathic trigeminal neuralgia (ITN). Nine patients and 10 normal control subjects were evaluated in all six trigeminal branches. QST abnormalities were found in the symptomatic division and in the other two branches on the same side. Minor contralateral changes were also found. Differences consisted of cold and warm hypoaesthesia and higher cold and heat pain thresholds in patients. All differences proved statistically significant. Our findings suggest that trigeminal neuralgia is not only a paroxysmal single nerve disorder, but also that other higher structures may be involved.

Intracranial hypotension: the nonspecific nature of MRI findings.

We present three patients who complained of postural headache related to different types of intracranial hypotension: spontaneous or primary, and secondary, but presenting the same findings on brain magnetic resonance imaging. Diffuse pachymeningeal gadolinium enhancement supports the belief that the enhancement is a nonspecific meningeal reaction to low pressure.

Turning behavior induced by injections of glutamate receptor antagonists into the substantia nigra of the rat.

We have found recently that muscimol microinjections into the subthalamic nucleus produce contralateral turning activity [Murer and Pazo (1993) NeuroReport, 4:1219-1222]. To test the hypothesis that a reduced glutamate action on substantia nigra pars reticulata neurons mediates this turning response, we examined the effect of unilateral intranigral microinjections of the AMPA/kainate receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX) and the competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP-5). DNQX and AP-5 both produced a dose-dependent contralateral turning response, while vehicle administration did not induce turning activity. Application of glutamate receptor antagonists at adjacent regions of the mesencephalic tegmentum were also ineffective. Coadministration of NMDA or AMPA significantly reduced the turning response induced by AP-5 or DNQX, respectively. Lesions of the nigrostriatal pathway by 6-hydroxydopamine did not modify the response to DNQX or AP-5 administration into the nigra. However, their behavioral effects were significantly reduced by a lesion of the ipsilateral subthalamic nucleus. Our results show that the blockade of a tonic input acting on AMPA/kainate and NMDA receptors located at the substantia nigra produces contralateral turning behavior. The effect seems to involve pars reticulata cells since this area remains unchanged after destruction of dopaminergic neurons. The subthalamic nucleus seems to be the endogenous source of the agonist acting on the nigral glutamate receptors related to turning behavior.

Turning behavior in rats with unilateral lesions of the subthalamic nucleus: synergism between D1 and D2 receptors.

Rats with unilateral kainic acid lesion of the subthalamic nucleus showed a dose dependent rotational response to the lesioned side (ipsilateral) after systemic administration of the non-selective dopaminergic agonist apomorphine. Both D2 and D1 selective antagonists ((-)sulpiride and SCH23390) inhibited the response to apomorphine in these rats. Selective D2 and D1 agonists (quinpirole and SKF38393) were unable to induce turning behavior. However, an ipsilateral circling response was obtained after the simultaneous application of both agonists. The interaction mechanism between dopaminergic receptor subtypes seems to be similar to that of other normosensitive models of turning previously studied (Barone et al., 1986; Robertson and Robertson, 1986; Arnt and Perregard, 1987; Asim et al., 1990; Pazo et al., 1993). It is proposed that the ipsilateral turning response to dopaminergic agonists in rats with subthalamic nucleus lesion results from an impaired behavioral expression of the action of dopaminergic agonists on one side, leading the rats to turn away from the intact hemisphere.