The radiologically isolated syndrome

Abstract

Even prior to the introduction of criteria defining the radiologically isolated syndrome (RIS), longitudinal clinical data from individuals with incidentally identified T2 lesions suggestive of multiple sclerosis (MS) were described. Healthy individuals who do not exhibit signs of neurological dysfunction may have a brain MRI performed for a reason other than suspicion of MS that reveals unexpected anomalies highly suggestive of demyelinating plaques given their size, location, and morphology. These healthy subjects lack a history or symptomatology suggestive of MS and fulfill formal criteria for RIS, a recently described MS subtype that shares the phenotype of at-risk individuals for future demyelinating events. A formal description of RIS was first introduced in 2009 by Okuda et al., and defines a cohort of individuals who are at risk for future demyelinating events. European or North American observational studies have found that up to 30–45% of patients presenting with RIS will present with neurological symptoms, either acute or progressive. The median time to clinical conversion differs between studies. It was 2.3 years for a series of French patients and 5.4 years for an American cohort. Most patients who developed clinical symptoms had prior radiological progression. The presence of asymptomatic lesions in the cervical cord indicated an increased risk of progression, either to relapsing or to progressive MS. The consortium studying the epidemiology of RIS worldwide (RISC) presented their first retrospective cohort last year. Data were available for 451 RIS subjects (F: 354 [78.5%]). The mean age at RIS diagnosis was 37.2 years with a mean clinical follow-up time of 4.4 years. The observed 5-year conversion rate to the first clinical event was 34%. Of the converters within this time period, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age, sex (male), and lesions within the cervical or thoracic spinal cord were identified as significant predictors for the development of a first clinical event. Cognitive impairment is observed in RIS patients, and two studies demonstrated a significant proportion of patients with cognitive decline compared with healthy controls. Despite progress into the characterization of RIS subjects and into our understanding of risk factors for initial symptom development, the natural course of such cases and risk-profiles for a seminal neurological event, from prospectively acquired data, remain unclear. A prospective study is mandatory to increase our knowledge about these asymptomatic patients and individual therapeutic initiatives cannot be undertaken until a prospective clinical study demonstrates the benefit of introducing a disease modifying treatment for this very early stage of a chronic demyelinating disease.

Résumé

Bien avant la parution des critères diagnostiques du syndrome radiologique isolé (RIS), plusieurs observations cliniques rapportaient des cas de patients qui présentaient sur l’IRM cérébrale des anomalies de signal T2 découvertes fortuites, évocatrices de sclérose en plaques, mais sans histoire de symptômes neurologiques et un examen clinique strictement normal. Ces patients avaient réalisé une IRM pour une raison tout autre qu’une suspicion de maladie démyélinisante, mais les hyperintensités révélées par leur IRM correspondaient exactement en localisation, taille, aspect à celles qui sont comptabilisées actuellement dans les critères de dissémination spatiale pour les syndromes cliniques isolés. Les critères diagnostiques de RIS ont été publiés en 2009 par Okuda et al., et identifient des patients à risque de développer un premier évènement clinique démyélinisant. Les cohortes observationnelles françaises et nord américaines ont rapporté que 30–45 % des patients avec un RIS présenteront dans les années qui suivent la réalisation de leur première IRM, une première poussée clinique, aiguë ou progressive. Le temps médian de survenue de ce premier évènement clinique varie selon les études : 2,3 ans pour la cohorte française du CFSEP et 5,4 ans pour la cohorte nord américaine. La majorité des patients ayant présenté un évènement clinique pendant le suivi avait, sur les IRM de suivi, des critères de dissémination temporelle avec, soit de nouvelles lésions T2, soit des prises de contraste. La présence de lésions sur l’IRM médullaire était un facteur de risque indépendant pour la conversion clinique. Le consortium international d’étude des RIS (RISC) a publié sa première étude épidémiologique l’année dernière. La cohorte regroupait 451 patients RIS (F : 354 [78,5 %]). L’âge moyen au diagnostic de RIS était de 37,2 ans avec un suivi moyen de 4,4 ans. Le taux de conversion clinique à 5 ans était de 34 % dont 9,6 % sur un mode progressif. En analyse multivariée, le jeune âge, le sexe (male), et la présence de lésions sur l’IRM médullaire étaient des marqueurs pronostiques péjoratifs pour le risque d’évènement clinique. Des signes d’atteinte cognitive similaires aux patients CIS, une fatigue significative et une altération de la qualité de vie ont été rapportés. Une étude internationale prospective est en cours afin de mieux déterminer l’histoire naturelle de cette maladie infraclinique et d’identifier des marqueurs clinique et biologique prédictifs du risque de conversion clinique. Il n’est pas recommandé, en dehors d’une étude clinique contre placebo qui en démontrerait l’efficacité, de traiter individuellement ces patients qui ne rentrent pas dans l’indication des molécules prescrites pour les patients ayant une SEP. Cette étude clinique de phase III, qui débutera en 2015, nous permettra de répondre à la question de l’intérêt d’un traitement préventif.

Introduction

Multiple sclerosis (MS) is a common cause of neurological disability in young adults and results from an autoimmune disease within the central nervous system (CNS). The diagnosis is made by fulfilling both spatial criteria, by meeting the requisite number of lesions within the brain or spinal cord, along with criteria for time, by demonstrating a history of at least a second clinical attack or the development of a new MS lesion on magnetic resonance imaging (MRI) after the seminal neurological event [1], [2], [3]. As for many other chronic diseases, before the clinical event that leads to a formal diagnosis, signs of impending disease may be observed in the months to years preceding the documented clinically isolated syndrome (CIS) [4].

With the widespread use of MRI, it is not uncommon that healthy individuals who do not exhibit signs of neurological dysfunction have a brain MRI, which is performed for a reason other than suspicion of MS, that reveals unexpected white matter T2 lesions [5]. Nevertheless, only a few patients presenting with T2 abnormalities that are highly suggestive of demyelinating plaques given their size, location, and morphology fulfill dissemination in space criteria [6]. These healthy subjects lack a history or symptomatology suggestive of MS and, while fulfilling MRI criteria for MS, are now diagnosed with radiologically isolated syndrome (RIS) [7]. In 2007, a Task Force consisting in 18 international experts worked on differential diagnosis in MS to develop a perspective that clinicians may use to address the principle of no better explanation for a suspected MS clinical presentation [8]. In their recommendations and consensus perspectives, they listed MRI red flags but recognized an exceptional scenario in which a patient has no clinical presentation suggestive of a demyelinating disease, but a MRI suggestive of subclinical MS. After the publication of 3 retrospective cohorts, this situation was described as a MS subtype that expands beyond the phenotype of at-risk individuals for future demyelinating events [7]. In the 2013 revision of defining MS subtypes, it was declared that until more information is available from prospective RIS cohorts, RIS should not be considered as a distinct MS phenotype [9]. From a practical point of view, to account for these intracranial abnormalities of potential clinical significance, RIS now sits at the far left of the MS diagnostic spectrum and is defined as presenting with MRI findings highly suggestive of MS based on location and morphology within the central nervous system but in the absence of overt clinical symptoms (Fig. 1).