Confirming the MS Diagnosis

Confirming the MS Diagnosis

A Garca-Merino, MR Blasco
Neuroimmunology Unit, Department of Neurology, Hospital Puerta de Hierro, Universidad Autnoma de Madrid, Madrid, Spain

Summary
Progress in understanding the pathophysiology of MS has shown that irreversible damage to the central nervous system may occur early in the disease course. Evidence from clinical trials suggests that part of this damage might be prevented by the early use of disease-modifying drugs; this therefore increases the importance of an early MS diagnosis. All diagnostic criteria for MS have KEY WORDS: MULTIPLE
SCLEROSIS;

incorporated definitions for dissemination in space and in time, along with the exclusion of alternative diagnoses. The McDonald criteria include magnetic resonance imaging definitions for such concepts, which enable MS to be diagnosed much sooner, in many cases. This paper reviews the steps to be taken in the diagnostic evaluation of patients with suspected MS.

MCDONALD

CRITERIA;

EARLY

THERAPY;

MAGNETIC

RESONANCE IMAGING;

DIFFERENTIAL

DIAGNOSIS;

PAEDIATRIC MS; CLINICAL

EVALUATION

Introduction
As our knowledge of MS pathophysiology increases, growing evidence is emerging that nerve-tissue damage including white and grey matter damage may occur, even in early stages of the disease.1 Magnetic resonance imaging (MRI) studies show that irreversible tissue damage can be detected in clinically isolated syndromes.2 Part of this damage can be prevented by initiating beta interferon therapy in patients after the first demyelinating event:3 Phase III clinical trials have shown the beneficial effect of such interventions in delaying the appearance of a second episode, i.e. clinical MS.46 As each patient with symptoms suggestive of MS may initially have a unique disease course, controversy surrounds those who should be treated (and when they should receive treatment).7,8 However, most clinicians now agree that patients with active disease should be treated as quickly as possible. This and the availability of approved medications, suitable for treating patients as early as the first demyelinating episode have increased the importance of confirming the MS diagnosis, when facing a clinical condition consistent with this disease. Current criteria permit such an early diagnosis. 58 Since the publication of Schumachers criteria over 40 years ago,9 the core of all MS diagnostic requirements has been the demonstration of dissemination in space and time, reflecting the tendency of MS to involve numerous areas of the (predominantly) white matter of the central nervous system (CNS) over time.1012 As no clinical or paraclinical finding is pathognomonic of MS, a further requirement has always been the exclusion of an alternative explanation. The Poser criteria,11 which have been widely used by the scientific community for almost 20 years, include several categories of diagnostic certainty: clinically definite MS, laboratory-supported MS, clinically probable MS and laboratory-supported probable MS. With the incorporation of MRI for the definition of dissemination in space and in time, the McDonald criteria, published in 2001,12 permitted an accurate diagnosis of MS before the appearance of a second clinical attack; they also included only two diagnostic categories: MS and possible MS. It is generally accepted that an earlier diagnosis is possible when the McDonald criteria are used. In fact, in a series of patients followed for 1 year The International MS Journal 2007; 14: 5863

Confirming the MS Diagnosis

after the first attack, these criteria identified more than three times as many patients with clinically definite MS, compared with the Poser criteria.13 A revision of McDonald criteria undertaken by an international panel of experts has now been published (Table 1).1417 In patients presenting with a past history of repeated attacks involving different areas of the CNS, the diagnosis of MS is clear; theoretically, no further tests are needed for confirmation. Nevertheless, even in these patients, it would be rather unusual not to undertake a confirmatory MRI study, unless this investigation is unavailable. It is Table 1: Revised McDonald diagnostic criteria.1417
Attacks 2 2 Objective lesions 2 1

possible to make an incorrect diagnosis, and several diseases that mimic MS will be mentioned below.

Confirming Dissemination
Diagnostic difficulties commonly arise in patients presenting with a single attack. With a monofocal onset, evidence of dissemination both in space and time will be required. For dissemination in space, the presence of three of the four MRI diagnostic criteria developed by Barkhof et al.18 will suffice, since these criteria are considered to offer the best compromise between specificity (73%) and sensitivity (73%), as shown by Tintor et al.19 (Table 2). If these criteria are

Additional data needed for MS diagnosis None Dissemination in space by: positive MRI MRI (2 T2 lesions consistent with MS) plus positive CSF* 2nd attack involving a different CNS site Dissemination in time by: MRI 2nd attack Dissemination in space by: positive MRI MRI (2 T2 lesions consistent with MS) plus positive CSF1 and Dissemination in time by: MRI 2nd attack Sustained progression 1 year (retrospectively or prospectively determined) and two of the following: positive MRI or 4 T2 lesions plus positive VEP2** positive spinal cord MRI (2 T2 lesions) positive CSF1

2 (multifocal presentation)

1 (monofocal presentation; clinically isolated syndrome)

Insidious progression suggestive of MS

* Positive CSF: raised immunoglobulin (Ig)G index16 or IgG oligoclonal bands in CSF but not in serum.17 **Positive VEP: delay with a well-preserved wave form, as seen in MS.15 MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; CNS, central nervous system; VEP, visual evoked potentials.

Table 2: Magnetic resonance imaging criteria for dissemination in space*

Three of the following: 1 gadolinium-enhancing lesion(s) or 9 T2 hyperintense lesions 1 infratentorial lesion(s) 1 juxtacortical lesion(s) 3 periventricular lesions A spinal cord lesion is equivalent to a brain infratentorial lesion; an enhancing spinal cord lesion is equivalent to an enhancing brain lesion, and individual spinal cord lesions can contribute together with individual brain lesions to reach the required number of T2 lesions.
* Based on data by Barkhof et al.18 and Tintore et al.19

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Confirming the MS Diagnosis

not met, the presence of two or more T2 lesions and a positive cerebrospinal fluid (CSF) sample (with evidence of intrathecal immunoglobulin [Ig]G synthesis) are also sufficient. MRI can show dissemination in time before the appearance of a new attack, if an enhancing lesion is detected at least 3 months after attack onset, provided that it is located in a site different than that of the initial attack; alternatively, this can be shown by the detection of a new T2 lesion any time compared with a reference scan done at least 30 days after clinical onset

In clinical practice, however, it is fairly common to consider alternative diagnoses for patients in the upper or lower age range, for those with unusual clinical or laboratory findings or for those who have different ethnic backgrounds. The possibility of vascular disease in older people is a frequent source of diagnostic doubt that is not easily solved, since patients may seem to fulfil clinical and MRI criteria for dissemination: identifying a positive MRI of the spinal cord may help, because cord lesions are rare in cerebrovascular disease.21 If this examination is negative, however, the presence of delayed visual evoked potentials or intrathecal IgG synthesis may be useful to confirm any suspicion of MS. Paediatric MS is becoming increasingly recognized,22 although the spectrum of alternative diagnoses is wider in these patients. Therefore, in children, particular attention must be paid to metabolic disorders involving the white matter, to infectious diseases that are prevalent in childhood, or to collagen disorders. Acute disseminated encephalomyelitis (ADEM) is the most important diagnostic doubt in children, and although this condition is more likely to have multifocal involvement, pseudoencephalitic presentation or involvement of both optic nerves, it can rarely be distinguished from a first attack of MS. Another difficulty is that between 10 and 25% of ADEM patients may have relapses.23 It has been reported that children diagnosed with MS do not meet the MRI criteria established for adult patients.24 Individuals presenting with unusual manifestations for instance, acute hemispheric syndromes or symptoms suggesting cortical involvement, such as aphasia, dementia or epilepsy should be carefully evaluated. Atypical laboratory tests, including CSF pleocytosis (>50 cells/l) or persistently normal paraclinical tests (MRI scans, CSF analysis and evoked responses), will also require a special diagnostic workup. Both the clinical and MRI expression of MS may differ in patients from non-Caucasian ethnic backgrounds.25 In Asians, there is a frequent presentation of opticospinal forms of MS, many of which can be categorized as neuromyelitis optica by the presence of a serum Ig autoantibody that binds to The International MS Journal 2007; 14: 5863

Table 3: Magnetic resonance imaging criteria for dissemination in time

1. Detection of gadolinium enhancement 3 months after the onset of the initial clinical event if not at the site of the initial event OR 2. Detection of a new T2 lesion if it appears any time compared with a reference scan done at least 30 days after the onset of the initial clinical event

(Table 3). This approach has simplified the MRI requirements of the original McDonald criteria. For those with multifocal presentation in whom the clinical examination objectively shows the involvement of more than one area of the CNS, the only requirement for confirming the diagnosis is dissemination in time. For the diagnosis of progressive MS, the revised McDonald criteria require at least 1 years sustained disease progression and two of the following: positive brain MRI (nine or more T2 lesions, or at least four T2 lesions, plus delayed visual evoked potentials), positive spinal cord MRI (two or more focal T2 lesions), positive CSF.

Excluding Alternative Diagnoses

The McDonald criteria offer a good mix of specificity, sensitivity, and accuracy (83% for each of these three parameters after 1 year, as reported20) for the adult population of Caucasian origin with classical MS in particular, when applied in individuals between 10 and 59 years of age with well-performed paraclinical tests. 60

Confirming the MS Diagnosis

the aquaporin-4 water channel (NMO-IgG)26; these antibodies are also detectable in some patients with conventional MS.27 Spinal cord lesions tend to extend beyond two vertebral bodies; this would be an unexpected finding in Caucasian patients.28 Opticospinal MS forms may also be more frequently found among African-Americans.29 There is no agreement on which blood tests should be performed in patients who are suspected of having MS. In the initial evaluation, in addition to standard blood-cell counts and routine biochemical and urine analyses, many clinicians also test for syphilis, antinuclear antibodies, IgG, IgM, antibodies against Borrelia burgdorferi, anti-phospholipid antibodies and vitamin B12 levels.

Key Points Most clinicians agree that patients with active disease should be diagnosed and treated as quickly as possible Thorough clinical evaluation is the first, and most important, element of diagnosing or refuting a case of suspected MS Several criteria are available to aid diagnosis. The recently updated McDonald criteria offer a good mix of specificity, sensitivity, and accuracy Both the clinical and magnetic resonance imaging expression of MS may differ in patients from non-Caucasian ethnic backgrounds

Disorders that Mimic MS

A long list of disorders mimic relapsing MS or clinically isolated syndromes, including inflammatory, infectious, vascular, metabolic, genetic or structural conditions. Obviously, if collagen disorders, paraneoplastic syndromes, tropical spastic paraparesis or human immunodeficiency virus infection are suspected, the proper evaluation of specific antibodies is required. Several metabolic and degenerative disorders can also be ruled out, using biochemical and genetic tests. The possibility of sarcoidosis requires angiotensin-converting enzyme levels to be assessed, in addition to other tests. As mentioned, NMO-IgG measurement enables a positive diagnosis of neuromyelitis optica to be made, in opticospinal cases. Patients with suspected optic neuritis should always undergo an ophthalmological evaluation to exclude conditions that cannot be distinguished from optic neuritis. The differential diagnosis of MS may be a considerable clinical challenge, but its description is beyond the scope of this article; the interested reader is referred to a detailed review.30

the absence of an adequate clinical evaluation.12 Clinical examination is an essential first step to assess the degree of neurological involvement and to judge to what extent the symptoms and signs are typical of MS or whether other diagnostic possibilities should be considered. Besides, a well-taken clinical history may reveal past symptoms highly suggestive of MS (e.g. Lhermittes sign, transient diplopia, or monocular blurring of vision). Strictly applied, the McDonald criteria do not take into account past attacks in the absence of objective evidence of CNS involvement. That said, historical information may be highly useful for clinicians, providing orientation towards the cause of the current neurological complaints. An MRI of the brain is the next usual step. This investigation should be performed for all patients presenting with a single attack and symptoms and signs of presumed demyelinating origin (usually optic neuritis, a brainstem syndrome or spinal cord involvement), either alone or in combination. In patients with an incomplete myelitis, it is necessary to obtain another brain MRI in addition to spinal cord imaging. The ideal study should also include a T1 series, after gadolinium infusion. To avoid interference with the detection of enhancing lesions, the first MRI scan should be performed before any intravenous steroid therapy is initiated. As mentioned earlier, a patient with a past history of repeated attacks and evidence of one lesion may receive a definite diagnosis of MS if the MRI 61

Steps Towards MS Confirmation

Clinical Assessment Despite impressive advances in MRI, the diagnosis of MS is still based on clinical parameters, namely a detailed history and a careful examination, both undertaken by a competent neurologist. Even the most recent diagnostic criteria cannot be applied in The International MS Journal 2007; 14: 5863

Confirming the MS Diagnosis

obtained at this point fulfils the MRI criteria for dissemination in space; with two or more T2 lesions, a diagnosis of MS is made if there is also a positive CSF sample (Table 2). In cases where there has been only one attack and there is evidence of two or more lesions, the examination may serve to confirm dissemination in time on subsequent scans (Table 3); if the presentation was monofocal, the MRI may disclose dissemination in space, as well as in time, on follow-up scans. MRI has a strong supportive value in MS diagnosis and also plays a key role in ruling out other conditions. It is important to stress that the MRI criteria derive from studies that investigated conversion from clinically isolated syndromes to clinically definite MS; their specificity with regard to other diseases that may have clinical or radiological similarities is not known.31 A systematic review of the accuracy of different MRI criteria for early MS diagnosis in patients suspected of having the disease indicates the limitations of this tool, both in ruling in and ruling out MS in patients after long follow-up periods.32 In fact, an abnormal MRI in a person who has experienced a single demyelinating episode is not always followed by conversion to clinically definite MS: this was observed in only 88% of patients after 14 years, in one series,33 and in only 58% of patients with optic neuritis at 10-year followup.34 Conversely, however, a negative MRI scan does not exclude a diagnosis of MS. Evoked potentials have the highest diagnostic usefulness when they reveal the involvement of a clinically unaffected sensory system, therefore contributing to the concept of dissemination in space.15 The typical finding is the slowing of the conduction velocity in optic, auditory or somatosensory tracts, with preservation of the waveforms. Since the publication of the McDonald criteria, only the visual evoked potentials are taken into account because of the lesser diagnostic value of other evoked potentials.35 Cerebrospinal fluid analysis reveals the most frequent immunological abnormality of MS intrathecal synthesis of IgG. Several formulae and techniques are available to assess this abnormality: the IgG index (equal to CSF/serum IgG:CSF/serum and the determination of oligoclonal bands of IgG, present in CSF but not in serum, are most frequently used. 62 albumin)16

Isoelectric focusing with IgG staining is the preferred method for oligoclonal band detection, as these bands appear in > 95% of patients, whereas the IgG index is elevated in about 70% of MS patients.17,36 For diagnostic purposes, both the IgG index and the presence of IgG oligoclonal bands are considered as positive findings. CSF examination is particularly useful in those who do not fulfil the criteria for dissemination on clinical or MRI grounds, in older patients in whom the MRI images may be less specific, in progressive syndromes and whenever other diagnostic possibilities are seriously considered. The detection of oligoclonal bands in clinically isolated syndromes may have a high predictive value of conversion into MS, with a sensitivity of 91.4% and a specificity of 94.1%, compared with a sensitivity of 74.23% and a specificity of 88.2% of the current MRI criteria in the same series.37

Conclusions
The availability of medications that may favourably modify the course of relapsing MS, and the concept that the highest benefit may be obtained when they are applied early in the disease course, have increased the importance of confirming the MS diagnosis. Progress in MRI techniques, as incorporated in the current diagnostic criteria, allows for diagnoses to be made much earlier in the disease process. However, a diagnosis of MS should never be made on MRI grounds alone. Careful clinical evaluation is the first step necessary to assess symptoms and signs that the patient may present with, and to interpret correctly the results provided by the diagnostic tools used.

Conflicts of Interest
No conflicts of interest were declared in relation to this paper.

Address for Correspondence

Dr A Garca-Merino, Neuroimmunology Unit, Servicio de Neurologa, Hospital Puerta de Hierro, Universidad Autnoma de Madrid, San Martn de Porres, 4, 28035 Madrid, Spain E-mail: gmerino@meditex.es
Received: 23 June 2006 Accepted: 24 July 2006

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Confirming the MS Diagnosis

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