Update on clinically isolated syndrome.

To cite this article: Thouvenot É. Update on clinically isolated syndrome. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.03.002 Presse Med. 2015; //: ///

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Quarterly Medical Review

Update on clinically isolated syndrome Éric Thouvenot 1,2

Available online:

1. Hôpital Carémeau, service de neurologie, 30029 Nîmes cedex 9, France 2. Université de Montpellier, institut de génomique fonctionnelle, équipe « neuroprotéomique et signalisation des maladies neurologiques et psychiatriques », UMR 5203, 34094 Montpellier cedex, France

Correspondence: Éric Thouvenot, hôpital Carémeau, service de neurologie, place du Dr-Debré, 30029 Nîmes cedex 9, France. [email protected]

Multiple sclerosis: from new concepts to updates on management David-Axel Laplaud, Nantes, France The autoimmune concept of multiple sclerosis Bryan Nicol et al., Nantes, France Environmental factors in multiple sclerosis Vasiliki Pantazou et al., Lausanne, Switzerland Update on clinically isolated syndrome Eric Thouvenot, Nimes, France Update on treatments in multiple sclerosis Laure Michel et al., Montréal, Canada Treatment of multiple sclerosis in children and its challenges Sona Narula et al., Philadelphia, United States Advanced imaging tools to investigate multiple sclerosis pathology Benedetta Bodini et al., Paris, France

Summary Optic neuritis, myelitis and brainstem syndrome accompanied by a symptomatic MRI T2 or FLAIR hyperintensity and T1 hypointensity are highly suggestive of multiple sclerosis (MS) in young adults. They are called "clinically isolated syndrome'' (CIS) and correspond to the typical first multiple sclerosis (MS) episode, especially when associated with other asymptomatic demyelinating lesions, without clinical, radiological and immunological sign of differential diagnosis. After a CIS, the delay of apparition of a relapse, which corresponds to the conversion to clinically definite MS (CDMS), varies from several months to more than 10 years (10–15% of cases, generally called benign RRMS). This delay is generally associated with the number and location of demyelinating lesions of the brain and spinal cord and the results of CSF analysis. Several studies comparing different MRI criteria for dissemination in space and dissemination in time of demyelinating lesions, two hallmarks of MS, provided enough substantial data to update diagnostic criteria for MS after a CIS. In the last revision of the McDonald's criteria in 2010, diagnostic criteria were simplified and now the diagnosis can be made by a single initial scan that proves the presence of active asymptomatic lesions (with gadolinium enhancement) and of unenhanced lesions. However, time to conversion remains highly unpredictable for a given patient and CIS can remain isolated, especially for idiopathic unilateral optic neuritis or myelitis. Univariate analyses of clinical, radiological, biological or electrophysiological characteristics of CIS patients in small series identified numerous risk factors of rapid conversion to MS. However, large series of CIS patients analyzing several characteristics of CIS patients and the influence of disease modifying therapies brought important information about the risk of CDMS or RRMS over up to 20 years of follow-up. They confirmed the importance of the initial MRI pattern of demyelinating lesions and of CSF oligoclonal bands. Available treatments of MS (immunomodulators or immunosuppressants) have also shown unequivocal efficacy to slow the conversion to RRMS after a CIS, but they could be unnecessary for patients with benign RRMS. Beyond diagnostic criteria, knowledge of established and potential risk factors of conversion to MS and of disability progression is essential for CIS patients' follow-up and initiation of disease modifying therapies.

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In this issue

tome xx > n8x > xx 2015 http://dx.doi.org/10.1016/j.lpm.2015.03.002 © 2015 Published by Elsevier Masson SAS.

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To cite this article: Thouvenot É. Update on clinically isolated syndrome. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.03.002

É Thouvenot

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ultiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) affecting over 2.5 million people worldwide and generating high economic burdens. The most common form ( 85% of patients) is relapsingremitting multiple sclerosis (RRMS), characterized by remission and relapse periods occurring at irregular intervals after an initial demyelinating event (clinically isolated syndrome, CIS) [1]. CIS is typically the first MS episode and generally consists in optic neuritis, myelitis or brainstem syndrome. It corresponds to the presence of a demyelinating lesion in the CNS, usually consisting in a symptomatic T2 or FLAIR hyperintensity and T1 hypointensity, sometimes enhanced after gadolinium injection, and generally accompanied by other asymptomatic preexisting lesions (figure 1). However, CIS can remain isolated in the long-term, especially for idiopathic optic neuritis or myelitis, in about one third of the cases [2]. Specific forms of MS and differential diagnoses must be discussed according to the clinical, radiological and immunological context. After a CIS, the delay of apparition of a relapse, which corresponds to the clinically definite MS (CDMS), varies from several months to more than 10 years (10–15% of cases, generally called benign RRMS), and is clearly associated with the number and location of demyelinating lesions of the brain and spinal cord. In the last 15 years, the diagnosis of MS after a CIS has evolved from CDMS [3] to the detection of new lesions on follow-up scans [4,5]. More recently, diagnostic criteria were simplified and the diagnosis can be made a by a single initial scan proving the presence of active asymptomatic lesions (with gadolinium enhancement) and of unenhanced lesions [6]. These criteria allow clinicians to accelerate the diagnosis of MS and constitute a useful tool for clinicians, but the time to CDMS remains highly unpredictable for a given patient.

Glossary

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CDMS CIS CNS CSF DIS DIT DMT EP HR MS NMO OCB OCT OR RNFLT RRMS SPMS

clinically definite multiple sclerosis clinically isolated syndrome central nervous system cerebrospinal fluid dissemination in space dissemination in time disease modifying therapy evoked potentials hazard ratio multiple sclerosis neuromyelitis optica oligoclonal bands optic coherence tomography odd ratio retinal nerve fiber layer thickness relapsing-remitting multiple sclerosis secondary progressive multiple sclerosis

Available treatments of MS (immunomodulators or immunosuppressants) have shown unequivocal efficiency to prevent relapses. In particular, most of them can slow the conversion to RRMS after a CIS, but could be unnecessary for patients with benign RRMS. However, numerous other demographical, clinical and immunological factors can help to predict the time to conversion and their consideration could help to refine individual prognosis. Here, we summarize the recent advances in CIS diagnosis and prognosis, and address future challenges about the management of CIS patients in the light of emerging diagnostic tools.

Definition of CIS A CIS is defined as an acute or subacute episode of neurological symptoms due to inflammatory demyelinating lesion in the CNS, which lasts more than 24 hours and occurs in the absence of fever, infection or encephalopathy [7]. The clinical characteristics of a CIS are typical of MS relapses and generally consist in optic neuritis, myelitis or brainstem syndrome. CIS is generally monofocal, but can be plurisymptomatic in 10–15% of cases [8], associating for instance optic neuritis with ataxia or pyramidal symptoms, and corresponding to multiple active lesions disseminated in space. Symptoms generally recover within days or weeks after onset, with or without treatment, either completely or sometimes with definitive neurological disability or minimal signs (e.g. pyramidal syndrome, hypopallesthesia, or relative afferent pupillary defect [RAPD]). The demographic characteristics of CIS patients are similar to those of MS, with a median age of 30 years and a female predominance [1,8].

Evolution of the diagnostic criteria for MS after a CIS Brain or spinal cord magnetic resonance imaging (MRI) must confirm the presence of a demyelinating lesion, either isolated or in association with typical demyelinating lesions as those seen in MS (preferentially located around ventricles, in the corpus callosum, in the juxtacortical or in the posterior fossa), which explains the neurological symptoms. Rarely, MRI shows a single or multiple atypical demyelinating lesions evocative of non-MS isolated inflammatory demyelinating diseases [9]. Tumefactive brain lesions (> 20 mm) can also be observed alone or in association with typical MS lesions [10]. The presence of typical MS lesions on first brain MRI strongly increases the probability of CDMS during follow-up, with 72% conversion at 15 years for optic neuritis patients with one or more lesions on baseline brain MRI, and 82% conversion at 20 years in CIS patients with abnormal baseline MRI [2,11]. The risk of conversion also depends on the location of demyelinating lesions observed on the initial brain MRI. Different lesion patterns have been evaluated for their sensitivity and specificity to predict CDMS during follow-up. Barkhof criteria better classified

tome xx > n8x > xx 2015

To cite this article: Thouvenot É. Update on clinically isolated syndrome. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.03.002 Update on clinically isolated syndrome

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Figure 1 Typical brain and spinal cord MRI lesions of multiple sclerosis (MS) in a patient with isolated optic neuritis T1 before (A) and after (B) gadolinium injection, echo-T2 (C) and FLAIR (D) sequences show multiple periventricular, juxtacortical and infratentorial lesions typical of MS. Two supratentorial lesions are enhanced after gadolinium injection, one in a punctiform shape (B, arrow) and the other with a ring shape (B, arrowhead). Spinal sagittal T2 sequence of the spinal cord (E) shows a partial posterior myelitis at the T8–T9 level. Dissemination in space (DIS) and dissemination in time (DIT) are established in this patient on a single MRI according to the 2010 McDonald criteria.

Typical and atypical CIS presentations

evolution of the disease [8,15]. The typical characteristics of optic neuritis are unilateral blurred vision worsening over hours or days and orbital pain, especially on eye movement. The visual acuity is generally reduced, color vision is impaired and a relative afferent papillary defect and a central scotoma are usually observed [15]. Optic disc swelling is observed in one third of the cases of optic neuritis and corresponds to the "retrobulbar neuritis''. MRI of the optic nerve typically shows a T2 hyperintensity with gadolinium enhancement in T1. Beside this typical optic neuritis generally observed in MS associated CIS, several atypical signs may be observed including severe visual impairment, worsening after steroid pulses, absence of pain, and bilateral involvement, suggest differential diagnoses such as ischemic optic neuropathy, Leber's hereditary optic neuropathy, neuromyelitis optica (NMO) or neurosarcoidosis (table I) [7,16].

Optic neuritis

Myelitis

Optic neuritis is the first manifestation of MS in 15–30% of cases and half of patients with MS report optic neuritis during the

The most common CIS presentation is a partial spinal cord syndrome secondary to a partial acute transverse myelitis [8].


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patients compared to the previous Paty and Fazekas criteria, as confirmed by Tintore et al. [12,13]. Barkhof criteria have been used to assess dissemination in space (DIS) of the demyelinating lesions for the diagnosis of MS in the McDonald criteria [4,5] (figure 2). MS can be confirmed either by a relapse at least 30 days after the first episode (CDMS) or by the presence of new lesions on later scans, corresponding to dissemination in time (DIT). Newer and simplified criteria were proposed for DIS and DIT by Swanton et al. with a better accuracy than Barkhof–Tintore criteria [14], and were used in the last revision of the McDonald criteria [6]. These last criteria also introduced the possibility to achieve DIT by the simultaneous presence of gadoliniumenhancing and non-enhancing lesions that do not cause neurological symptoms, i.e. asymptomatic lesions (figure 2) [6].


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Figure 2 Evolution of McDonald diagnostic criteria for multiple sclerosis

The association of sensory and motor symptoms depends on the location of inflammation and is generally associated with a sensory level after ascending from the legs or spreading to the other side. Mild sphincter dysfunction and proprioceptive ataxia with Romberg sign are typical. Lhermitte's sign may be as well observed in patients with cervical cord involvement. MRI of the spinal cord typically shows a partial, rather posterior, T2 hyperintensity extended over less than two vertebral bodies in height. Longitudinally-extensive transverse myelitis over more than three vertebral segments or acute transverse myelitis are atypical and rather suggest NMO or myelitis associated with different systemic inflammatory diseases like lupus, sarcoidosis or Sjögren syndrome, medullar infarcts and infectious or parainfectious causes [17,18].

Brainstem syndromes

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Brainstem syndromes are described in around 25% of CIS cases [7]. They manifest with a large variety of oculomotor symptoms (double vision due to internuclear ophthalmoplegia or a sixth nerve palsy), ataxia (cerebellar, vestibular), sensory disturbance or motor weakness of the face [7]. Brainstem MRI generally

shows lesions of the dorsal surface of the pons and middle cerebellar peduncle in MS cases. Cortical cerebellar grey matter involvement rather suggests a vascular process.

Atypical presentations of CIS MRI of the brain, spinal cord or optic nerves is essential to confirm the presence of typical demyelinating lesions of the CNS and to exclude differential diagnosis like optic nerve or medullar compression, brain tumor or abscess. Less frequently, CIS correspond to large or strategic supratentorial demyelinating brain lesions, accompanied with hemiparesis, homonymous hemianopia, aphasia or apraxia. Large demyelinating lesions may suggest an acute disseminated encephalomyelitis (ADEM) or correspond to tumefactive MS lesions, defined by a diameter > 20 mm and often associated with an open ring-enhancing MRI appearance [10]. Other symptoms rarely observed in MS and rather suggestive of ADEM can also be observed in CIS, such as cognitive impairment, headache, seizures, fever or even diabetes insipidus [19]. Atypical forms of demyelination include ADEM, acute hemorrhagic leukoencephalitis (AHL), acute hemorrhagic leukoencephalomyelitis



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TABLE I Typical and atypical symptoms of multiple sclerosis Localisation

Typical features

Atypical features

Optic nerve

Unilateral optic neuritis

Bilateral optic neuritis

Mild pain on eye movement

Painless or very severe pain

Reduced visual acuity, scotoma

No perception of light

Normal disc or mild disc swelling

Severe haemorrhages and exudates

Relative afferent pupil defect (RAPD)

Vitritis and neuroretinitis

Dyschromatopsy

Photophobia

Bilateral internuclear ophthalmoplegia

Complete external ophthalmoplegia

Ataxia and gaze-evoked nystagmus

Vascular territory signs

Sixth nerve palsy

Isolated trigeminal neuralgia

Unilateral cerebellar syndrome

Progressive trigeminal sensory neuropathy

Multifocal signs

Movement disorders

Incomplete transverse myelitis

Complete transverse myelitis

Lhermitte's syndrome

Complete Brown-Séquard syndrome

Sphincter symptoms

Pure motor syndrome

Brainstem or cerebellum

Spinal cord

Asymmetric limb weakness

Areflexia

Deafferented hand

Localised or radicular spinal pain Sharp level to all sensory modalities

Cerebral hemispheres

Hemiparesis

Encephalopathy

Hemisensory disturbance

Epileptic seizures

Quadrantanopia

Cortical blindness Fever

Modified from Miller et al. [34].

Isolated CIS At the opposite, some patients present with no other lesion than the symptomatic demyelination, generally in the optic


nerve or in the spinal cord. In these cases, CIS can remain isolated on the long-term in a greater proportion of patients who never convert to MS. In the largest series of optic neuritis (389 subjects of the optic neuritis treatment trial [ONTT]), patients converted to MS in 50% of cases within 15 years (95% confidence interval, 44%–56%) [11]. Seventy-five percent of patients with no lesions on baseline brain MRI remained CIS at 15 years. In the absence of MRI-detected lesions, male sex, optic disc swelling and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS [11]. However, differential diagnoses of MS are not discussed in this series of patients, while NMO is initially misdiagnosed as optic neuritis in MS or other conditions such as anterior ischemic optic neuropathy (AION) and Leber's disease. In these cases, differences are generally seen in the clinical presentation of optic neuritis (table I).

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(AHEM), and Hurst acute necrotizing hemorrhagic leukoencephalitis [9]. Tumefactive MS can also be represented by Balo concentric sclerosis, Marburg type demyelination or Schilder's disease [9]. Severe isolated optic neuropathy or longitudinal extensive transverse myelitis is more suggestive of NMO. The main characteristics of these syndromes are summarized in table II. Finally, CIS can also correspond to other inflammatory or noninflammatory diseases of the CNS, generally accompanied by atypical clinical or MRI MS characteristics (table II). Miller et al. described the list of red flags suggestive of differential diagnoses and proposed a strategy for exclusion of potential MS mimics and classification of CIS [7].


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TABLE II Atypical forms of demyelination Clinical syndrome

Definition

CIS ADEM Tumefactive MS Marburg type Balo concentric sclerosis

Schilder disease

Hurst acute necrotizing hemorrhagic leukoencephalitis NMO spectrum disorders (NMOSD)

Isolated optic neuritis Chronic relapsing isolated optic neuropathy (CRION) Idiopatic transverse myelitis

First clinical CNS demyelinating event > 24 h and consistent with MS Acute or subacute demyelinating event affecting multiple areas of the CNS with encephalopathy At least one large (> 2 cm) acute demyelinating enhancement with headache, confusion, aphasia, apraxia, and seizures Tumefactive MS with numerous large multifocal demyelinating lesions in deep white matter Tumefactive MS with concentric layers of partial demyelination alternating with bands of demyelination. Alternating isointense and hypointense concentric rings on T1-weighted images in MRI, partial enhancement limited to T1-hypointense areas Myelinoclastic diffuse sclerosis, usually characterized by a single or 2 symmetrically arranged lesions measuring at least 2 3 cm with involvement of the centrum semiovale in setting of symptoms unusual for MS Rare, severe, rapidly progressive inflammatory and hemorrhagic demyelinating disorders of the CNS, considered as variants of ADEM 1. Optic neuritis 2. Acute myelitis 3. At least two of the following three supportive criteria: i. Contiguous spinal cord MRI lesion extending over at least 3 vertebral segments ii. Onset brain MRI not meeting the diagnostic criteria for MS iii. NMO-IgG seropositivity status Optic Neuritis, generally more severe than in MS, with normal brain and spinal cord MRI, normal CSF tests Recurrent or chronic unilateral or bilateral inflammatory optic neuropathy, distinct from MS Inflammation and demyelination across both sides of one level, or segment, of the spinal cord resulting in symptoms of neurological disconnection and dysfunction below the level of the demyelinating area

Adapted from Karussis [9]. ADEM: acute disseminated encephalomyelitis; CSF: cerebrospinal fluid; CIS: clinically isolated syndrome; CNS: central nervous system; MS: multiple sclerosis; NMO: neuromyelitis optica.

In a series of 107 patients comprising 51% cases of optic neuritis, 23% of brainstem syndromes and 26% of myelitis, 79% patients with normal baseline MRI remained CIS at 20 years [2]. In another series of 114 patients followed 4 years after a partial acute transverse myelitis, the classical medullar syndrome of MS, 36 patients did not convert to MS [20]. Finally, in a series of 61 acute transverse myelitis patients, 41% of them with partial acute transverse myelitis and normal brain MRI converted to CDMS after a mean follow-up of 25 months, while no patients with complete acute transverse myelitis and normal brain MRI did [21].

Predictive factors of conversion to MS

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When differential diagnoses and atypical forms of CIS are excluded, the hypothesis of MS remains, especially when MRI shows demyelinating lesions. Several factors can influence the time to conversion to CDMS after a CIS. Large cohorts of CIS patients have been studied to describe the probability of

conversion to CDMS over the long-term, according to epidemiological, clinical, MRI or biological factors. For example, some patients from the ONTT trial were followed for up to 15 years, and the presence of at least one brain demyelinating lesion resulted the most predictive factor of CDMS [11].

Epidemiological, genetic and environmental risk factors MS is characterized by a number of epidemiological risk factors including gender, age, ethnicity, country of birth, Epstein–Barr virus (EBV) immunization, vitamin D level, obesity and smoking. Among these, gender, age and ethnicity were found to be predictive of CDMS after a CIS. In a meta-analysis of 33 studies with 4732 subjects reported by Dobson et al., women had an increased relative risk of CIS (RR 2.12) and of developing MS following CIS (RR 1.20), compared with men, implying that the gender bias seen in MS is caused by factors acting early in the disease process [22]. In the same



Symptoms After a CIS, the risk of conversion to MS either by a new relapse or by the presence of new brain lesions on follow-up scans varies according to the type of CIS. In a series of 320 patients with a CIS classified into CIS of the optic nerve (n = 123), brainstem (n = 78), spinal cord (n = 89), hemispheric (n = 6), polyregional (n = 12) or undetermined (n = 12) topographies, Pelayo et al. reported that the conversion rates for optic neuritis were lower (28%) than for the other CIS types (myelitis 36%, brainstem 42%, hemispheric 50%, polyregional 50%) [27]. Although polyregional CIS involve different functional systems [28] it is not correlated to a higher risk of conversion. This was also observed in the study by d'Alessandro et al., which included 168 CIS patients followed 2–4 years, and showed a higher conversion to CDMS in patients with only one altered functional system (44%) as compared to patients with 2 or more functional systems involved (65%) [29]. In this study, the global neurological disability measured by EDSS at baseline was also associated with the risk of conversion to MS (37% conversion for EDSS 0–1 and 44% conversion to CDMS for EDSS > 1). In another study of


163 patients followed for 7 years, where the main clinical factors of conversion to CDMS were the involvement of the motor system and a polysymptomatic presentation, the cutoff was between EDSS 2 and EDSS 2.5, [30]. However, Mowry et al. reported a higher risk of second relapse within 1 year in patients with a lower number of functional systems affected (HR for every one less FS involved: 1.31) [23]. Authors suggest these patients could have a more efficient temporary suppression of immunological activity after a more destructive demyelination, or alternatively an initial pronounced disability could mask further evolution. Moreover, D'Alessandro et al. showed an increased risk of CDMS in patients with more altered cognitive functions estimated using paced auditory serial addition task (PASAT), one item of the multiple sclerosis functional composite (MSFC) [29]. More detailed cognitive evaluation using Rao's battery and the Stroop test was performed in a series of 56 CIS patients [31]. The failure of at least three tests was found to be predictive of conversion to multiple sclerosis after a CIS (HR 3.3). In these subjects, cognitive impairment has a prognostic value in predicting conversion to CDMS and may therefore play a role in therapeutic decisionmaking. Already at the stage of CIS, fatigue is a very common symptom, with a severity similar to fatigue in MS patients [32]. A Fatigue Severity Scale (FSS) score 5.0 was associated with a diagnosis of CDMS in univariate analysis (HR 2.6) of 127 patients and in a multivariate analysis correcting for sex, age, neuroanatomical localization of CIS, vitamin D, anxiety, depression, Swanton criteria for DIS and gadolinium enhancement (HR 4.5). Fatigue seems to be an independent predictor of a subsequent MS diagnosis. Finally, in some optic neuritis and myelitis, specific symptoms have been associated with a higher risk of conversion to CDMS. In the ONTT study, the risk of CDMS conversion is associated with a normal optic disc appearance (no disc edema) and to the presence of pain in the affected eye [11]. In the study reported by Ruet et al. including 114 patients with a clinically isolated spinal cord syndrome and 86% of conversion after 4 years of follow-up, bladder involvement as well as age, spinal and brain MRI characteristics ( 2 cord lesions on MRI, 9 brain lesions, 3 periventricular lesions) and intrathecal IgG synthesis predicted conversion to CDMS [20]. However, severe loss of visual acuity and complete transverse spinal cord syndrome are suggestive of isolated optic neuritis and complete transverse myelitis, which are often associated with differential diagnoses of MS.

MRI MRI is the most powerful and discriminating tool for predicting conversion to CDMS after a CIS [9,33,34]. The brain MRI protocol should include at least an axial or 3D FLAIR, an axial fast spin echo proton density/T2 and a 3D contrast-enhanced T1 [35,36]

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manner, the risk of CDMS was increased of 1.46 for each 10-year decrease and of 2.06 for non-whites compared to whites in a North-American study [23]. Immune responses to Epstein–Barr virus (EBV), human herpes virus 6, cytomegalovirus, and measles were tested in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls. Increased EBVencoded nuclear antigen-1 (EBNA1)-specific IgG levels was the only factor to predict conversion to MS based on the 2005 McDonald criteria in a univariate analysis [24]. It was also associated with the number of T2 lesions, the number of Barkhof criteria at baseline, and the presence of new T2 lesions and Expanded Disability Status Scale (EDSS) score during follow-up. In a retrospective study of 100 CIS patients including 52% with vitamin D deficiency (25(OH)D < 50 nmol/L) followed more than 7 years, 55 patients developed CDMS. Patients with very low (< 10th percentile) and low (< 25th percentile) 25(OH)D levels were particularly at risk of CDMS [25]. This association was even stronger after adjustment for additional risk factors for CDMS (age, gender and time of follow-up on disease modifying therapy one the one hand), and type of onset (monofocal, multifocal), type of recovery from the first neurological episode (partial, complete), cerebrospinal fluid (CSF) oligoclonal bands (OCB), T2 and gadolinium-enhancing lesions at baseline brain MRI. In a study of 129 patients followed 36 months after a CIS with disseminated white matter lesions on brain magnetic resonance imaging and positive OCB in the CSF, smokers had a higher risk for progression to CDMS (hazard ratio [HR] 1.8) and a significantly shorter time interval to their first relapse than nonsmokers [26].

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(figure 1). A 3D unenhanced T1, axial DWI with ADC map and a 2D gradient echo-T2 could also be useful for differential diagnosis. The spinal cord MRI should include a sagittal T2 and a sagittal T1 with gadolinium injection and additional axial sequences (axial T2 gradient echo and axial T1 with gadolinium injection) in case of lesion. Sagittal STIR appears more sensitive than sagittal T2 but shows more often artifacts. MRI is also very sensitive to detect new asymptomatic lesions of the brain and spinal cord, which represent about 70% of brain and 30% of spinal cord lesions [37]. New silent lesions can appear up to 10 times more frequently than clinically expressing lesions and show the activity of the inflammatory process [9]. Around 60% of patients with a CIS show one or more symptomatic demyelinating lesions on baseline brain MRI that determines the risk of conversion to MS in the following years. However, hyperintense T2/FLAIR lesions in the white matter can be detected in numerous differential diagnoses of CNS inflammatory diseases or even in patients with vascular risk factors or migraine, and are not always specific of MS. Typical CNS lesions suggestive of MS include T2/FLAIR hyperintense periventricular, juxtacortical and brainstem lesions (Barkhof criteria), lesions of the corpus callosum and of the posterolateral compartment of the spinal cord (figure 1) [9,12,13]. In a collaborative study reported by Korteweg, 532 patients were followed 85 months after a CIS; 45% of them with 3 or 4 Barkhof criteria converted to CDMS compared to about 10% of those with no asymptomatic lesions at baseline [38]. For patients with a follow-up of at least 2 years, the fulfillment of the MRI criteria showed an accuracy of 68% (sensitivity 49%, specificity 79%) for predicting conversion and an increased risk of nearly four times for conversion compared with those not fulfilling the criteria (OR 3.7). The 2001 and 2005 McDonald criteria rely on the evidence for DIS according to the Barkhof criteria and CSF data can be used when too few lesions are present [4,5]. In 2006, new criteria were proposed in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal cord) and DIT requires at least a new T2/FLAIR lesion on a followup scan (figure 1) [39]. These criteria are simpler, more sensitive and specific than previous ones to predict conversion to MS. The presence of a gadolinium-enhanced T1 asymptomatic brain lesion on a single MRI study obtained within the first 3 months after symptom onset is also at risk of rapid conversion to CDMS after a CIS. In a cohort of 220 patients with a CIS suggestive of MS, DIT, defined by the simultaneous presence of gadoliniumenhancing and non-enhancing lesions on a single MRI, showed similar sensitivity and specificity between early and delayed MRI. In addition, the use of less stringent criteria for DIS yielded better sensitivity and similar specificity, particularly when assessed in the first weeks after CIS onset. A single brain MRI study, which demonstrates DIS and shows both gadolinium-enhancing and

non-enhancing lesions that suggest DIT, is highly specific for predicting the early development of CDMS, even when the MRI is performed within the first 3 months after the onset of a CIS (figure 1) [40]. In a multicenter study of 1165 patients with different types of CIS (spinal, hemispheric, multifocal, and brainstem/cerebellar), lesion probability map clusters were analyzed. The converting group showed less widespread lesion distribution and no significant lesion clusters were found in CIS patients with optic nerve and spinal cord onset. The involvement of specific white matter tracts, in particular those traversed by fibers involved in motor function and near the corpus callosum, seems to be associated with a higher risk of clinical conversion to MS in the short term [41]. Brain chronic black holes on T1-weighted MR images were recently described as predictive of conversion to CDMS [42]. In a series of 520 patients with a CIS, 87.7% patients had focal T2-hyperintense brain lesions and 41.4% of them presented at least one non-enhancing black hole, which were associated with a higher risk of conversion to CDMS. In the study by Ruet et al., the presence of two or more spinal cord lesions was predictive of CDMS [20]. In a study of 75 CIS patients followed about 6 years, 11 (14.6%) and 13 (17%) had one and two or more spinal cord lesions at the first scan. In multivariate analyses, the presence of one or of two or more focal spinal cord lesions were significantly associated with increased risk of conversion to RRMS (HR 3.5 and 5.9, respectively). CIS patients with an abnormal baseline spinal cord MRI have a higher risk for developing CDMS, independently of brain lesions as well as the presence of OCB [43]. In another series reported by Sombekke et al., 63 out of 121 patients had spinal cord syndromes and in only 36 cases brain MRI fulfilled Barkhof criteria [44]. By including spinal cord findings, 6 additional patients fulfilled these criteria. In non-spinal CIS patients that did not fulfill Barkhof criteria (n = 42), presence of a spinal cord lesion was associated with a higher risk of conversion to CDMS (OR 14.4) and shorter time to conversion to CDMS (HR 51.4). However, when two or more spinal cord lesions are present in patients with a spinal cord syndrome, it is difficult to determine which lesion is symptomatic. Accordingly, 2005 revision of McDonald criteria for DIS included MS-typical spinal cord lesions (little or no swelling of the cord; unequivocally hyperintense if detected with T2-weighted imaging; at least 3 mm in size, but less than 2 vertebral segments in length; and occupying only part of the cord cross section) as equivalent to a brain infratentorial lesion, but not for a periventricular or juxtacortical lesion [5]. Based on 2006 and 2007 Swanton studies, the 2010 revision of McDonald criteria incorporated the presence of a spinal cord lesion in the criteria for DIS (figure 1). However, when a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the criteria and do not contribute to lesion count [6].



Brain atrophy progression is one of the characteristic features of MS and is associated with MS relapses and EDSS progression. It was also shown by Di Filippo et al. to be an independent predictor of conversion to CDMS in patients with a CIS. Brain atrophy progression at 1 year compared to baseline was analyzed in 99 patients presenting with CIS using SIENA. Mean annual brain atrophy rates in patients who had developed MS at 6 years were doubled compared to those who had not ( 0.50% vs. 0.26%) [45]. Brain atrophy rate (P = 0.005) and baseline T2 lesion load (P < 0.001) were independent predictors of CDMS, suggesting that the initial modifications of brain volume are predictive of the clinical status 6 years after the initial demyelinating event. This was confirmed in a study reported by Uher et al. of 210 patients followed 4 years for whom the accumulation of new lesions, lateral ventricle volume enlargement and whole brain atrophy progression were predictive of conversion to CDMS [46]. Looking more precisely into the brain parenchymal (BPF), gray matter (GMF) and white matter (WMF) fractions in 176 CIS patients at baseline and 1 year after clinical onset, Perez-Miralles et al. showed a significant decrease in BPF and percentage of brain volume change (PBVC) in CDMS patients compared to the others and for GMF in all MS patients (second attack or MRIonly conversion) compared to CIS remaining patients [47]. However, WMF was unchanged in the different groups. Rate of global brain and grey matter loss within the first year after a CIS was predictive of conversion to MS. Similarly, in a study of 216 CIS patients with at least 2 lesions and positive OCB, thalamic volume and increase in lateral ventricle volume were associated with development of CDMS, [48]. Atrophy of superior frontal gyrus, thalamus, and cerebellum were also identified as independent predictors of conversion to MS in CIS patients [49].

Biomarkers Numerous CSF and serum biomarkers have been described in MS, but except intrathecal synthesis of IgGs, none of them is used in routine for the diagnosis of MS in CIS patients, [50]. Local B-cell response accompanying CNS inflammation can be established by the detection of an increased IgG index (CSF/serum IgG:CSF/serum albumin) or the presence of two or more IgG OCB in CSF compared to the corresponding serum [51]. Comparing Paty, Fazekas and Barkhof criteria for DIS with the presence/ absence of OCB in a series of 112 patients, Tintore et al. found the greatest accuracy when patients with positive OCB and three or four Barkhof's criteria were selected [52]. Despite the rarity of the IgG index increase in CSF OCB-negative MS patients, it can be used as additional criteria for intrathecal synthesis. In the 2001 McDonald criteria, the MAGNIMS panel proposed that positive CSF (presence of OCB or an elevated IgG index) associated with two or more MRI lesions could be used for determination of DIS [4].


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In a large meta-analysis of CSF OCB in MS and CIS including 71 articles, Dobson et al. reported that 87.7% of 12.253 MS patients and 68.6% of 2685 CIS patients were OCB-positive [53]. OCB-positive CIS patients had an OR of 9.88 of conversion to MS. OCB have shown to be an independent predictor of conversion to CDMS in some studies, but not in others [54]. In particular, the last report from the 'Barcelona CIS inception cohort' by Tintore et al. at Copenhagen ECTRIMS (October 03, 2013) identified OCB as significantly predictive of conversion to CDMS in more than 1000 patients (adjusted HR 1.5) and of EDSS 3.0 (adjusted HR 2.2) independently of MRI and other confounding factors. However, given the very high sensitivity of MRI for the diagnosis of MS with only one lesion in at least 4 of the typical areas, the MAGNIMS panel believed that even further liberalizing MRI requirements in CSF positive patients was not appropriate [6]. Moreover, the CSF status was not evaluated in the studies on which the last revision of the McDonald criteria was based [14,55]. Prospective studies are needed to confirm the additional diagnostic value of CSF. Several other potential biomarkers of MS have been discovered, and some of them confirmed as predictive of conversion to CDMS, but they all need validation in large cohort studies to be used in routine [50]. Absolute CSF IgG kappa free light chains concentrations were shown to be highly sensitive – more than OCB testing – and specific for CIS, RRMS and primary progressive MS [56]. In parallel to IgG synthesis, IgM antibodies play a part in the inflammatory response in patients with MS and are associated with an aggressive disease course. In a series of 205 CIS patients who had performed a baseline lumbar puncture and MRI scan, presence of CSF IgM OCB were associated with an early conversion to CDMS [57]. Intrathecal synthesis of IgM measured after a first demyelinating event suggestive of MS was also associated with the number of gadolinium-enhancing lesions at baseline and with subsequent accrual of brain lesions, while the level of intrathecal IgG synthesis was not correlated with any MRI data [58]. Intrathecal B-cell response characterized by antibody production to neurotropic viruses (measles, rubella, and varicella zoster) has also been associated with an increased risk for conversion to MS [59]. CD5+ B-cells are involved in some autoimmune diseases and their proportion in healthy controls is below 3.5%. In CIS patients, a blood CD5+ B-cells percentage above this value was an independent predictor of earlier conversion to MS (HR 4.3) in CIS patients with OCB and Barkhof-Tintore criteria [60]. Autoantigens and inflammation associated proteins (cytokines, chemokines, etc.) were also described as biomarkers of MS. Among them, chitinase-3-like 1 protein (CHI3L1), a glycoside hydrolase that is secreted mainly by activated macrophages, was discovered in the CSF of MS and CIS patients using proteomic analyses in different studies [61,62]. CHI3L1 level is increased in the CSF from patients with a CIS who later convert to CDMS compared with patients who remain as CIS [61]. The same group

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of investigators validated this observation in an independent cohort of 813 CIS patients [63]. Another recent proteomic study identified CHI3L1 as a marker of MS and showed that, in CIS patients, CHI3L1 concentration in serum was also predictive of conversion to RRMS according to the 2005 McDonald criteria [64]. In their proteomics study, beside CHI3L1, Comabella et al. identified other putative biomarkers of conversion to CDMS after a CIS. Among them, Semaphorin 7A and Ala-beta-his-dipeptidase were further validated as biomarkers associated with the conversion from CIS to MS in a cohort of 56 CIS patients (29 patients converting to CDMS and 27 non-converters) and 26 controls with other neurological disorders [65]. CSF IL-8, CXCL13 and IL-12p40 levels are associated with MS [66]. CSF IL-8, a major proinflammatory cytokine, was associated with clinical progression in subjects with a radiologically isolated syndrome (RIS), and to the risk of conversion to MS in subjects with CIS [67]. Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the CSF during MS and are associated with markers of MS activity. CSF CXCL13 levels were increased in CIS converting to CDMS, and associated with relapse rate, EDSS and the number of lesions detected by MRI [68]. Interleukin12p40 (IL-12p40) in the CSF was also identified as a biomarker for CIS (n = 49) compared to other neurological diseases (n = 37) by means of ROC curves (AUC 0.87) and appears to be helpful in differentiating CIS from other neurological disease early in the process of clinical diagnostic assessment [69]. Markers of the neurodegenerative process are elevated in MS [70,71]. Elevated neurofilament light chain levels in CSF have also been identified as predictive of conversion to CDMS after a CIS [70].

Evoked potentials and optic coherence tomography

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Visual, somato-sensory and brainstem auditory evoked potentials (EP) are sensitive methods to detect demyelinating lesions in the CNS. Their diagnostic sensitivity is correlated with EDSS and raises up to 100% when they are combined in MS patients [72]. Furthermore, in the early stages of MS, multimodal EP may have a role in predicting the long-term clinical course [73]. In a study of clinically isolated optic neuritis, 27 patients were evaluated at first presentation by EP and MRI. Abnormal EP results were found in 6 out of 27 patients, four of whom presented CDMS and the two others MRI conversion. The majority, 19 out of 27 patients, had normal EP results, but converted to MS according to the McDonald criteria. Only 3 out of19 converted to clinically definitive MS, suggesting that abnormal EP examinations at the first episode of optic neuritis can be considered as a predictive factor only for the earlier clinical conversion to MS [74]. However, in a series of 245 consecutive CIS patients reported by Pelayo et al., multimodal (visual, somato-sensory and brainstem auditory evoked potentials) EP did not modify the risk of conversion individually, but identified CIS patients with a higher risk of developing disability assessed by an EDSS 3 (HR

7.0), independently of MRI findings. However, the utility of multimodal EP is limited by the low percentage of CIS patients having all three abnormal EP at baseline (8%) [75]. Visual pathway structure and function were analyzed by spectral-domain optical coherence tomography (OCT) and multifocal visual-evoked potentials in 29 patients with a CIS according to the McDonald criteria and no previous history of optic neuritis [76]. The visual pathway structure and function were. The OCT average retinal nerve fiber layer thickness (RNFLT) was significantly reduced in CIS patients compared with the control group, and OCT average RNFLT was found to be an independent predictor of clinically definitive MS diagnosis at 12 months. Retinal axonal loss measured by OCT is an important prognostic factor of conversion to MS in patients with CIS in absence of symptomatic optic neuritis. However, in another study of 56 consecutive patients with CIS (18 with optic neuritis and 38 without optic neuritis) and 32 control subjects, OCT did not reveal retinal axonal loss at the earliest clinical stage of MS and did not predict conversion to MS at 6 months [77].

Predictive factors of disability progression in CIS patients Although several factors associated with MS relapses help to predict the conversion and to establish its diagnosis, prognosis of MS appears extremely variable and unpredictable, with a great variability of baseline disability levels and evolution in different studies [78]. Several studies have analyzed the predictive factors of later neurological disability in CIS patients such as vitamin D levels, MRI lesions and atrophy, CSF OCB and evoked potentials. Lower vitamin D levels are known to be associated with disability in MS, even in fully ambulatory RRMS patients (EDSS < 4) [79]. Analyses using dichotomous 25(OH)D levels in the patients included in the BENEFIT study showed that values 50 nmol/L (20 ng/mL) at up to 12 months predicted lower disability ( 0.17 point of EDSS) during the subsequent 4 years [80]. Analysis of MRI parameters was reported in a cohort of 42 patients followed more than 8 years with conversion to CDMS in 26 (62%), of whom 14 (54%) progressed to an EDSS 3. Two or more infratentorial lesions best predicted long-term disability (HR 6.3), while gadolinium-enhancing and hypointense T1weighted lesions did not show prognostic value [81]. In a study including 157 patients, those with three to four Barkhof criteria on baseline MRI had an adjusted HR of 3.9 for reaching EDSS 3.0. At 10 years after a CIS [82]. Investigators also observed a significant relationship between the number of lesions at presentation and both EDSS (r = 0.45) and the type of disease at follow-up (secondary progressive multiple sclerosis [SPMS] vs. RRMS) [82]. In the paper by Fisniku et al., 67 out of 107 patients followed over 20 years developed CDMS [2]. Multiple sclerosis was still relapsing-remitting in 39 patients (58%) – including 26 (39%)



with a 'benign' course (EDSS 3) – whilst 28 (42%) had developed secondary progression. T2 lesion volume at all time points correlated moderately with 20-year EDSS (r 0.48 to 0.67) and MSFC z-score (r 0.50 to 0.61). The estimated rate of lesion growth was 0.80 cm3/year in those who retained a relapsingremitting course and 2.89 cm3/year in those who developed SPMS. Lesion volume and its change at earlier time points were correlated with disability after 20 years. Lesion volume increased for at least 20 years in relapse onset multiple sclerosis and the rate of lesion growth was three times higher in those who develop SPMS than in those who remain RRMS [2]. In the voxel-based study by Dalton et al. including 74 patients followed for 20 years, patients with a CIS and EDSS > 3 were more likely to have optic radiation and left internal capsule T2 lesions, compared to those with EDSS 3 [83]. However, the lack of differences in lesion spatial distribution between RRMS and SPMS may suggest that focal pathology affects similar regions in both subgroups and does not identify clues to predict SPMS. In the study of Di Filippo et al. including 99 patients followed 6 years after a CIS, brain atrophy rate was a predictor of EDSS in a univariate analysis. One year T2 lesion load change and number of baseline gadolinium-enhancing lesion were independent predictors of EDSS score at the 6-year follow-up [45]. The combination of baseline MRI with its changes at 1 year was better predictor than baseline MRI alone. In a monthly MRI study after triple-dose gadolinium-DTPA during 6 months followed by subsequent MRI at 12 and 18 months; Paollilo et al. showed that the cumulative number and volume of new gadolinium-enhancing lesions developed during the initial 6 months of frequent MRI scanning were highly correlated with percentage of brain volume changes (PBVC) over the 18-month period [84]. However, atrophy appeared only after a delay of several months following acute inflammation. In several studies, gray matter (GM) atrophy was shown to be an independent predictor of neurological disability progression in patients with CIS [47–49]. In a prospective, observational, 48-month follow-up study reported by Uher et al. and including 210 CIS patients treated with 30 mg of intramuscular IFN b once a week, MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Increased lateral ventricle volume and decreased GM and cortical volumes were observed in patients with sustained disability progression compared to patients who remained stable or improved in disability [46]. In the meta-analysis of CSF OCB including 71 articles, Dobson et al. reported that OCB-positive MS patients had an OR of 1.96 of reaching disability outcomes, although a number of negative studies did not provide data [53]. In a cohort of 813 CIS patients, Canto et al. reported that CSF CHI3L1 was the only significant independent risk factor associated with the development of disability (HR = 3.8), compared to brain MRI and to CSF OCB [63]. Elevated neurofilament light chain levels in CSF and in


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serum have also been identified in several studies as predictive of disability progression after a CIS [71,85,86].

Therapeutic management of CIS patients After a CIS, given specific evolution of MS and treatments compared to other CNS inflammatory diseases, conversion by a new relapse (CDMS) or by the demonstration of DIT using MRI is necessary to establish the diagnosis of RRMS. Diagnostic criteria have been modified progressively to establish the diagnosis of MS earlier and to become more accurate (figure 1). Compared to later initiation of DMTs, onset of an immunomodulatory treatment within 1–3 months after a CIS demonstrated significant efficacy to prevent conversion to CDMS or DIT using MRI. Four studies have found that IFN-b significantly reduces the risk of a second event and therefore conversion to CDMS [87– 90]. Glatiramer acetate (GA) also showed significant efficacy in delaying conversion to CDMS in subjects presenting with a CIS [91]. Longer follow-up of patients enrolled in some of these studies revealed that early treatment with IFN-b or GA provided a lower risk of CDMS and better MRI outcomes compared to patients with treatment delayed at 3 and 5 years post-randomization [91–95]. The BENEFIT trial at 8 years showed persistence of significant differences in relapse rate and cognition using the paced auditory serial addition task (PASAT) between both groups, although disability outcomes remained similar across groups [96]. Later follow-up of the CHAMPS study at 10 years after randomization still showed a lower probability of conversion to CDMS in the early vs. delayed treatment [97]. The results of these trials in CIS patients show the same range of efficacy than in MS patients. Despite differences between early and delayed treatment onset, it is still difficult to know if the lower number of patients converting to CDMS during follow-up represents a cure for the disease or if this is just a transitory effect. Recently, teriflunomide daily doses of 7 mg and 14 mg were compared to placebo in a randomized controlled trial evaluating the efficacy at 2 years in CIS patients. Both regimens significantly reduced the risk of CDMS within the range reported for INF-b and GA (20–34% at 2 years) [98]. Other drugs have been tested in randomized controlled trials without success. Atorvastatin, treatment significantly decreased development of new brain MRI T2 lesion activity, but trial was discontinued due to slow inclusion rate, indeed only 81 of 152 planned subjects could be enrolled [99]. Vitamin D has also been proposed in CIS patients, as it is supposed to be safe even at high doses [100]. Although two randomized controlled trials are ongoing in CIS patients (D-lay MS, NCT01817166 in France and PrevANZ, ACTRN12612001160820 in Australia-New Zealand), there is no proof that vitamin D treatment can effectively reduce clinical activity of MS.

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Combination of multiple risk factors for conversion to CDMS and disability after a CIS

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Large studies have tried to combine analysis of multiple factors predictive of CDMS in order to compare the power of these parameters, to identify associations between epidemiological, clinical, radiological and biological factors, and to evaluate the role of immunomodulatory treatments. In 2001, Tintore et al. combined the analysis of MRI with the results of CSF examination to compare different MS diagnostic criteria (Paty, Fazekas and Barkhof) to predict the conversion to CDMS [52]. They observed a high prevalence of OCB in CIS. OCB and MR imaging (Paty's and Fazekas' criteria) had a high sensitivity while Barkhof's criteria had a higher specificity. However, the greatest accuracy was achieved when patients with positive OCB and three or four Barkhof's criteria were selected. In 2008, the team from Barcelona studied whether OCB added information to MRI in first attacks of multiple sclerosis. They showed that the presence of OCB increased the risk of a second relapse (HR 1.7) independently of baseline MRI but did not modify the development of disability [54]. Rojas et al. analyzed the conversion time to MS after a CIS according to MRI and CSF analysis [101]. CIS patients with baseline positive OCB in CSF had a higher risk for developing CDMS. Moreover, when abnormal MRI was added to positive OCB, patients converted faster (mean time, 6 vs. 19 months). D'Alessandro et al. evaluated the risk of MS following CIS in 168 patients [29]. Multivariate analysis showed that lower age (< 32, OR 1.66), Barkhof criteria at first exam (positive, OR 2.17) increased the risk of CDMS while immunomodulatory therapy before conversion significantly reduced the risk of conversion (OR = 2.75). This information may be useful when considering treatment in CIS patients. In 2011 Schaffler et al. published a systematic review of MS diagnostic tests accuracy including studies of at least 40 patients followed up to 2 years based on McDonald 2001 and 2005 criteria [102]. Sensitivity of MRI criteria was between 35% and 100%, specificity was between 36% and 92%. OCB showed sensitivities between 69% and 91% with specificities between 59% and 94%. Combination studies of MRI and CSF indicated enhanced sensitivity (56–100%) and specificity (53–96%), while studies on EP did not confirm the value of electrophysiological explorations. The authors concluded that a combination of simplified MRI criteria with CSF might be the best approach for early MS diagnosis. In 2010, the last revision of McDonald criteria allowed diagnosing MS after a CIS with one single MRI scan proving DIS + DIT (figure 1). However, sensitivity of DIT + DIT is rather low (25–30%). In a study of 401 CIS patients followed more than 2 years, Ruet et al. confirmed the accuracy of new diagnostic criteria [103]. Moreover, in case of DIT without DIS and the presence of two or three predictive factors (age 40 years, positive OCB or 3 periventricular lesions) was highly

specific of developing CDMS or McDonald MS, especially in those with three periventricular lesions. More recently, two very large studies including more than 1000 CIS patients were reported. A large international collaborative study of 1047 CIS patients combining different risk factors for MS confirmed the higher risk of conversion to CDMS for patients with positive OCB (HR 2.18), number of T2 lesions at baseline MRI (2–9 lesions vs. 0/1 lesion, HR 1.97; > 9 lesions vs. 0/1 lesion HR 2.74) and lower age (HR 0.98 per year increase). Vitamin D deficiency was associated with CDMS in univariate analysis, but this was attenuated in the multivariate model. EBNA-1 IgG titers or cotinine (marker of smoking activity) were not significant in a multivariate model [85]. In parallel, the last report from the 'Barcelona CIS inception cohort' by Tintore et al. at Copenhagen ECTRIMS (October 03, 2013) identified OCB and EDSS 3 independently of MRI and other confounding factors as significantly predictive of conversion to CDMS in more than 1000 patients (adjusted HR 1.5 and HR 2.2, respectively). The team from Barcelona also reported the results of the analysis of 1015 CIS patients under 50-year-old followed more than 5 years (40% with 3–4 Barkhof criteria, 20% with 1–2 criteria and 40% with no criteria). Tintore et al. showed that the risk of progression to EDSS 3 was increased with positive OCB, 3–4 Barkhof criteria, male sex, no treatment and diminished in patients with optic neuritis in a multivariate analysis. Even though they were suppressed from 2010 McDonald criteria, OCB keep an interesting prognostic value.

Future challenges for CIS patients In the future, new tools should be developed to predict evolution of MRI and clinical activity as well as disability at the individual level, and to reach personalized medicine. The growing use of image analysis with software dedicated to volumetric analysis and the emergence of new MRI techniques not routinely used for MS diagnosis (diffusion tensor imaging, magnetization transfer imaging, proton MR spectroscopy, functional MRI, brain iron qualification, etc.) as well as of positron emission tomography (PET) could be exploited in the future to predict conversions to CDMS (see the article by Bodini et al. in this issue) [104]. In parallel, the emergence of '-omics' provides a new opportunity to identify new biomarkers of MS, or to test the power of some of them to predict CDMS after a CIS, alone or in combination with MRI data. Large collaborative works will be necessary to compare and validate the predictive value of different markers of MS activity and disability progression recently identified like atrophy, CSF CHI3L1 or vitamin D in combination with brain and spinal cord lesions, gender, age and the presence of OCB. In this context, machine-learning techniques represent an emerging tool that could be used to refine predictions of CDMS at the individual level. Indeed, in a series of 74 CIS patients, machine-learning-based classifications improved prediction of



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conversion to MS from subjects' baseline scans and clinical characteristics [105]. This approach could be potentially integrated into routine clinical practice in the future.

Conclusion Predictive markers of disease evolution after a CIS are dominated by MRI for predicting both conversion to CDMS and disability progression in the mid-term [106]. Parameters such as the increasing number of lesions and their location (brainstem or spinal cord) predict a higher risk of evolving to CDMS. Other useful markers include male sex, older age, the presence of OCB and an elevated CSF CHI3L1 level, although not included in the 2010 revisions to the McDonald criteria for RRMS. These factors, as well as incomplete recovery from the CIS, increase the risk of worse prognosis although disability milestones are

reached earlier in patients with an early disease onset. Beyond diagnostic criteria, these parameters have to be integrated to adapt treatment choice and its time of onset in individual CIS patients. In the future, new robust and routinely useful predictors should be added to the latter in order to refine individual prognosis of patients with a CIS, and help clinicians to determine the therapeutic strategy. Acknowledgements: Marielle Lomma for language editing. Disclosure of interest: the author declares that he has no conflicts of interest concerning this article. Fundings: none.

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Clinically isolated syndrome in pregnancy.

Diagnosis and trials of clinically isolated syndrome.

Parinaud's syndrome - A rare presentation of clinically isolated syndrome.

Muckle Wells syndrome associated with multifocal clinically isolated syndrome.

Predicting outcome in clinically isolated syndrome using machine learning.

Mood and coping in clinically isolated syndrome and multiple sclerosis.

Visual pathways involvement in clinically isolated syndrome in children.

Predictors of disability worsening in clinically isolated syndrome.

Antimyelin antibodies as predictors of disability after clinically isolated syndrome.

Impact of Helicobacter pylori on multiple sclerosis-related clinically isolated syndrome.

Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function.

Update on Lynch syndrome genomics.

Update on subclinical Cushing's syndrome.

Cushing syndrome: update on testing.

Hepatorenal syndrome: Update on diagnosis and treatment.

Update on pediatric opsoclonus myoclonus syndrome.

An update on early repolarization(ER) syndrome.

Nelson Syndrome: Update on Therapeutic Approaches.

Update on a new controversy in endocrinology: isolated maternal hypothyroxinemia.

Thalamic atrophy and cognitive impairment in clinically isolated syndrome and multiple sclerosis.

The incidence of clinically isolated syndrome in a multi-ethnic cohort.

Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome.

Hemodynamic evidence linking cognitive deficits in clinically isolated syndrome to regional brain inflammation.

Early MRI activity predicts treatment nonresponse with intramuscular interferon beta-1a in clinically isolated syndrome.