Clinically isolated syndromes

doi:10.1016/S1474-4422(11)70274-5

The Lancet Neurology

Volume 11, Issue 2, February 2012, Pages 157-169

https://doi.org/10.1016/S1474-4422(11)70274-5 Get rights and content

Summary

Clinically isolated syndrome (CIS) is a term that describes a first clinical episode with features suggestive of multiple sclerosis (MS). It usually occurs in young adults and affects optic nerves, the brainstem, or the spinal cord. Although patients usually recover from their presenting episode, CIS is often the first manifestation of MS. The most notable risk factors for MS are clinically silent MRI lesions and CSF oligoclonal bands; weak or uncertain risk factors include vitamin D deficiency, Epstein-Barr virus infection, smoking, HLA genes, and miscellaneous immunological abnormalities. Diagnostic investigations including MRI aim to exclude alternative causes and to define the risk for MS. MRI findings incorporated into diagnostic criteria in the past decade enable MS to be diagnosed at or soon after CIS presentation. The course of MS after CIS is variable: after 15–20 years, a third of patients have a benign course with minimal or no disability and a half will have developed secondary progressive MS with increasing disability. Prediction of the long-term course at disease onset is unreliable. Disease-modifying treatments delay the development from CIS to MS. Their use in CIS is limited by uncertain long-term clinical prognosis and treatment benefits and adverse effects, although they have the potential to prevent or delay future tissue damage, including demyelination and axonal loss. Targets for future therapeutic progress are to achieve safe and effective long-term immunomodulation with neuroprotection and repair.

Introduction

About 85% of people with multiple sclerosis (MS) have onset of MS with a relapse.1, 2 This relapse consists of an episode of neurological disturbance known as a clinically isolated syndrome (CIS). With improvement in diagnosis and the advent of disease-modifying treatment for MS, there has been much interest and research in patients with CIS. Studies have aimed to better understand disease cause and pathogenesis, to improve the accuracy of MS diagnostic criteria and differential diagnosis, and to assess disease-modifying treatments, both for the acute CIS and for modification of the subsequent course in individuals thought to be at high risk of developing MS and disability.

Since our previous reviews of CIS in 2005,3, 4 many studies have been done. This updated Review will consider the definition of CIS and its relation to MS (including diagnostic criteria), risk factors for MS and long-term disability, non-conventional MRI abnormalities, radiologically isolated syndromes, differential diagnosis, and treatment. We conclude with outstanding questions that warrant further research.

Section snippets

CIS and its relation to MS

CIS is a term widely used in contemporary neurological practice to describe a first clinical episode in which a patient has symptoms and signs suggestive of an inflammatory demyelinating disorder of the CNS.⁵ The term CIS is typically applied in a young adult (aged 20–45 years) with an episode of acute or sub-acute onset, which reaches a peak quite rapidly (within 2–3 weeks). To be termed CIS, the episode should last for at least 24 h and occur in the absence of fever or infection, with no

Risk factors for MS

Many risk factors for the development of CIS to MS have been investigated: MRI, CSF, clinical, genetic, environmental, and immunological. Of these, only MRI and CSF findings are routinely used in clinical practice to inform patients with CIS about the risk of conversion to MS.

Risk factors for long-term disability

Whereas robust risk factors are available to predict the evolution from a CIS to MS, prediction of the long-term course is weak. Clinical aspects of CIS that have been associated with future disability are pyramidal and cerebellar motor deficits and incomplete recovery. A short interval to the second relapse and a high relapse rate in the first 2 years¹ and involvement of multiple systems at onset⁶⁵ also indicate a poorer prognosis. Features that are associated with a better outlook are a

Non-conventional MRI abnormalities in CIS

Much evidence exists from non-conventional imaging studies that suggests a more disseminated CNS disorder in patients with CIS than is shown by MRI-visible lesions. Other non-conventional MRI abnormalities in CIS include regional atrophy in both cortical and deep grey matter,22, 66, 67 decreased magnetisation transfer ratio in white and grey matter,68, 69 decreased N-acetyl aspartate in whole brain⁷⁰ and normal-appearing white matter,71, 72 increased myoinositol in normal-appearing white matter,

Radiologically isolated syndromes

Brain MRI features typical of demyelination and fulfilling MRI criteria for MS are sometimes seen in healthy individuals or patients with non-specific symptoms (eg, headache, dizziness), and have been termed radiologically isolated syndromes. Follow-up studies done over 2–5 years have independently reported that about 30–40% of such people have one or more clinical events leading to a diagnosis of CIS or MS.83, 84, 85 This group can thus be thought to be at high risk for MS. The MRI criteria

Differential diagnosis

The differential diagnosis of CIS can be divided into three broad categories: idiopathic inflammatory demyelinating CNS diseases (IIDD; MS, acute disseminated encephalomyelitis, neuromyelitis optica, idiopathic transverse myelitis), inflammatory non-IIDD CNS diseases (eg, sarcoidosis, vasculitis, Behcet's disease, systemic lupus erythematosus), and non-inflammatory CNS diseases (eg, ischaemia or infarction, compression, haemorrhage, metabolic disorder). Panel 3 summarises the diagnostic

Treatment

Many CIS episodes are mild and resolve without therapeutic intervention. Clinical features that favour treatment include severe visual loss, pain in optic neuritis, or both, and pronounced motor dysfunction, ataxia, or vertigo in spinal cord and brainstem syndromes.

High-dose intravenous methylprednisolone in acute optic neuritis shortens the duration of visual deficit but not visual outcome after 1 year.⁹¹ It does not prevent optic nerve atrophy⁹² or visual evoked potential delay after optic

Future challenges

Grey matter lesions are often seen at post mortem in MS but rarely seen on conventional MRI. However, their detection is improved with the double inversion recovery sequences103, 104 and their detection at CIS onset was associated with increased conversion to clinically definite MS in one study.¹⁰⁵ Further work is needed to confirm this observation. The utility of detection of more white matter¹⁰⁶ and grey matter¹⁰⁷ lesions with a 3 T scanner in comparison with a 1·5 T scanner for MS diagnosis

Search strategy and selection criteria

We searched PubMed from Jan 1, 1997, through to Oct 31, 2011, with the search terms “clinically isolated syndrome” and “multiple sclerosis”. Only papers published in English were reviewed. The final list of publications was selected by the authors on the basis of relevance to the topic.

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ReviewClinically isolated syndromes

Summary

Introduction

Section snippets

CIS and its relation to MS

Risk factors for MS

Risk factors for long-term disability

Non-conventional MRI abnormalities in CIS

Radiologically isolated syndromes

Differential diagnosis

Treatment

Future challenges

Search strategy and selection criteria

Lancet Neurol

Lancet Neurol

Lancet Neurol

Neurobiol Dis

J Neuroimmunol

Lancet

Hum Immunol

Lancet Neurol

J Neuroimmunol

Lancet Neurol

Lancet Neurol

J Neurol Sci

Lancet Neurol

Lancet Neurol

Lancet

Lancet

The natural history of MS: a geographically based study 10: relapse and long-term disability

Brain

Natural history of MS: a unifying concept

Brain

Differential diagnosis of suspected multiple sclerosis: a consensus approach

Mult Scler

Consensus definitions proposed for pediatric multiple sclerosis and related disorders

Neurology

Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria

Ann Neurol

Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up

Arch Neurol

Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis

Brain

Brainstem lesions in clinically isolated syndromes

Neurology

Clinically isolated acute transverse myelitis: prognostic features and incidence

Mult Scler

Is the frequency of abnormalities on magnetic resonance imaging in isolated optic neuritis related to the prevalence of multiple sclerosis? A global comparison

J Neurol Neurosurg Psychiatry

Baseline MRI predicts future attacks and disability in clinically isolated syndromes

Neurology

Predictive factors for multiple sclerosis in patients with clinically isolated spinal cord syndrome

Mult Scler J

MRI characteristics are predictive for CDMS in monofocal, but not in multifocal patients with a clinically isolated syndrome

BMC Neurol

Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”

Ann Neurol

A single, early magnetic resonance imaging study in the diagnosis of multiple sclerosis

Arch Neurol

MRI criteria for MS in patients with clinically isolated syndromes

Neurology

Brain atrophy in clinically early relapsing-remitting multiple sclerosis

Brain

The predictive value of gray matter atrophy in clinically isolated syndromes

Neurology

Gray- and white-matter changes 1 year after first clinical episode of multiple sclerosis: MR imaging

Radiology

Early pericalcarine atrophy in acute optic neuritis is associated with conversion to multiple sclerosis

J Neurol Neurosurg Psychiatry

Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis?

Neurology

IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome

PLoS One

The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS)

PLoS One

Axonal damage markers in the cerebrospinal fluid of patients with clinically isolated syndrome improve predicting conversion to definite multiple sclerosis

Mult Scler

Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis

Brain

Clinical predictors of early second event in patients with clinically isolated syndrome

Review
Clinically isolated syndromes