The McDonald committee sought to devise criteria that

1. could be used by practicing physicians,

2. could be adapted for clinical trials,

3. would integrate MRI into the diagnostic scheme,

4. would include a scheme for the diagnosis of primary progressive MS, (a category that was not recognized at the time the Poser committee met),

5. would clarify certain definitions,

6. would simplify diagnostic classifications and descriptions, and

7. would retain as many as possible useful features of the existing criteria.

The committee emphasized several general conclusions:

1. Definitive diagnosis requires objective evidence of dissemination in time and space, as well as the exclusion of other, better explanations for the clinical picture.

2. Definitive diagnosis requires that clinical evidence depend primarily on objectively determined clinical signs. Historical accounts of symptoms are alone insufficient for diagnosis of MS.

3. Radiologic and laboratory investigations may add to a clinical diagnosis and may be essential in making a diagnosis when clinical presentation alone does not allow diagnosis.

4. Following diagnostic evaluation, an individual is usually classified as either having MS or not having MS.

These first two principles re-emphasized those established previously. However, the McDonald criteria eliminated the Poser category of "probable MS.'' In the new diagnostic scheme, all patients who neither meet criteria for "definite" MS nor have a specific alternative diagnosis established are regarded to have "possible" MS.

The committee also clarified several critical definitions to facilitate diagnosis:

1. "An 'attack' refers to an episode of neurological disturbance of the kind seen in MS, when clinicopathological studies have established that the causative lesions are inflammatory and demyelinating in nature.''

A. An attack, defined either by subjective report or by objective observation, should last for at least 24 hours.

B. "Whereas suspicion of an attack may be provided by subjective historical reports from the patient, objective clinical findings of a lesion are required to make a diagnosis of MS.''

C. "Single paroxysmal episodes (e.g., a tonic spasm) do not constitute a relapse, but multiple episodes occurring over not less than 24 hours do.''

2. A new attack is defined as symptoms beginning 30 days after the onset of the previous attack.

3. ''Abnormality'' on MRI required the more stringent criteria of Barkhof et al. (16) and Tintore et al. (17), rather than the more sensitive but less specific criteria of other authors, including Paty et al. (18) and Offenbacher et al. (19). The more stringent criteria require three out of four of the following:

A. One gadolinium-enhancing lesion or nine or more lesions on T2-weighted images.

B. One or more infratentorial lesion.

C. One or more juxtacortical (involving subcortical U fibers) lesion.

D. Three or more periventricular lesions.

Only lesions that are at least 3 mm in cross-section are counted. The panel also allowed the substitution of a spinal cord lesion for a brain lesion.

The committee further commented, ''Whereas it is possible that, in the absence of brain lesions, two or more spinal cord lesions clearly separated in time and/or space could satisfy criteria, prospective data in this regard are still awaited.''

4. "Abnormality on CSF analysis can provide supportive evidence of the immune and inflammatory nature of lesion(s), which may be helpful when imaging criteria fall short, when they lack specificity (as in the older patient), or when the clinical presentation is atypical.'' CSF determinants are:

A. Presence of oligoclonal bands different from those in serum and preferentially obtained by isoelectric focusing.

B. Presence of increased IgG index.

C. Lymphocytic pleocytosis should not exceed 50 cells.

5. Abnormal visual-evoked potential should be typical of MS, i.e., delayed but with a well-preserved waveform.

6. MRI criteria for dissemination of lesions in time:

A. If the first scan was obtained three or more months after the onset of symptoms:

a. A gadolinium-enhanchig lesion satisfies dissemination in time.

b. If no gadolinium-enhancing (Gad+) lesion, a follow-up scan (three months recommended) with either a new T2 or Gad+ lesion satisfies dissemination in time.

B. If the first scan was obtained less than three months after the onset of the clinical event, a second scan should be obtained three or more months after the onset.

a. A new Gad+ lesion equals dissemination in time.

b. If no Gad+ lesion, do another scan, "not less than three months after the first scan,'' either a new T2 or Gad+ lesion equals dissemination in time.

Using the above definitions, the diagnostic scheme for determination of clinically definite multiple sclerosis (CDMS), i.e., the satisfaction of the criteria of dissemination in time and space, is shown in Table 2.

The criteria for the diagnosis of primary progressive multiple sclerosis (PPMS), which are derived from a proposal by Thompson et al. (20), have not been established on the basis of the type of prospective MRI analysis used for the criteria of dissemination in space recommended for relapsing MS. The necessity of a positive CSF for establishing the diagnosis is also uncertain. The importance of this information may become clearer after further analysis of the patients included in a recently concluded trial of glatiramer acetate versus placebo in PPMS, which included patients both with and without positive CSF.

The diagnostic criteria established by the McDonald committee are clearly an important advance, especially by incorporating MRI evidence. Nonetheless, they

Table 2 New Multiple Sclerosis Diagnostic Criteria

Clinical (attacks) Objective lesions Additional requirements to make diagnosis

2 or more 2 or more None: clinical evidence will suffice (additional evidence desirable but must be consistent with MS) 2 or more 1 Dissemination in space by MRI or positive CSF

and 2or more MRI lesions consistent with MS or further clinical attack involving different site 1 2 or more Dissemination in time by MRI or second clinical attack

Dissemination in space by MRI or positive CSF

and 2 or more MRI lesions consistent with MS Dissemination in time by MRI or second clinical attack Positive CSF

Dissemination in space by MRI evidence of 9 or more T2 brain lesions 2 or more cord lesions or 4-8 brain and 1 cord lesion

Positive VEP with 4-8 MRI lesions Positive VEP with less than 4 brain lesions plus 1 cord lesion

Dissemination in time by MRI or continued progression for 1 yr

Abbreviations: MS, multiple sclerosis; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid.

1 mono-symptomatic 1

0 (progression from 1


leave a number of ambiguities and have been criticized by some for the stringency of the MRI criteria (21). Undoubtedly, further revisions and refinements of the diagnostic process will be forthcoming.

Nonetheless, the use of McDonald criteria has allowed earlier diagnosis of MS than the Poser scheme did. In one study, using the McDonald criteria allowed 38/79 (48%) patients to be classified as "definite" MS compared to 16/79 patients by (20%) applying the Poser criteria, after one year of follow-up (22). In another similar study, 5l/l39 (37%) met McDonald criteria for "definite" MS, whereas only 15/139 (11%) did so using the Poser requirements (23).

Physicians should recognize the difference between making a definitive diagnosis of MS and making a decision to initiate therapy. Treatment decisions should be based on the clinician's risk-potential benefit analysis (and sometimes cost-potential benefit analysis) and discussion with the patient about the pros and cons of initiating therapy. Therapy might be recommended, even in the absence of a definitive diagnosis, if the physician judges that the risk-potential benefit ratio of starting treatment exceeds that of deferring treatment.

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