Diagnosis

The basis for the diagnosis of MS stems from the seminal clinicopathological observations of Charcot (3) and requires the demonstration of lesions disseminated over time and involving multiple, discrete anatomical loci in the white matter of the CNS. Schumacher et al. (4) proposed perhaps the first widely used scheme for the clinical diagnosis of MS in 1965, and all subsequent criteria have been based on these fundamental principles. Schumacher categorized patients as "clinically definite, probable, or possible'' MS, according to the number of the following criteria that were satisfied:

1. Age of onset between 10 and 50 years.

2. Objective neurological signs present on examination.

3. Neurological symptoms and signs indicative of CNS white matter disease.

4. Dissemination in time: (a) two or more attacks (lasting at least 24 hours) and separated by at least a month. (An attack is defined as the appearance of new symptoms, signs, or worsening of previous ones.) or (b) progression of symptoms and signs for at least six months.

5. Dissemination in space: two or more noncontiguous anatomical areas involved.

6. No alternative clinical explanation.

Patients were classified as "clinically definite MS'' if they met five or six criteria, always including the last criterion. Patients who satisfied fewer criteria were categorized as probable or possible MS.

The Schumacher criteria depended solely on clinical history and examination for diagnosis. However, in the 1970s and 1980s, technological advances permitted the demonstration of lesions that were clinically undetectable. Computer application allowed the development of evoked-response testing, a measure of electrophysiological dysfunction in the visual, brain stem auditory, or somatosensory pathways. In each of these domains, a repetitive stimulus is applied and computed elimination of random background activity allows the appearance of an identifiable waveform time-locked to the stimulus. Analysis of these responses permits identification of lesions that are not apparent clinically.

Beginning with computed tomography (CT) in the early 1970s, revolutionary advances in neuroimaging have occurred. Magnetic resonance imaging (MRI) is a much more sensitive technique for the detection of MS lesions and is usually the imaging procedure of choice. These new imaging modalities have provided a means of demonstrating anatomical lesions that are not clinically evident (see Chapter 7). Indeed, cranial MRI demonstrates activity, as much as five to ten times, more frequently than clinical relapse is apparent (5). Still newer MR techniques, such as measurements of brain atrophy, MR spectroscopy (MRS), magnetization transfer, and diffusion tensor imaging promise further progress in our assessment and understanding of MS through neuroimaging.

In addition, increasingly sensitive methods for the study of cerebrospinal fluid (CSF) led to the recognition that most MS patients have evidence of abnormal immunoreactivity that can be demonstrated by CSF analysis. Abnormalities include elevated immunoreactivity, elevated immunoglobulin IgG levels (6,7), increased IgG index (8), increased IgG synthesis rate (9), and oligoclonal bands (10-13).

The opportunities created by these new techniques led to the development of new criteria by a committee chaired by Poser (14). The Poser criteria (Table 1) modified Schumacher's by allowing the demonstration of "paraclinical" lesions (i.e., lesions detected by evoked-response testing or neuroimaging studies). In addition, the new criteria established an additional category of laboratory-supported MS based on the inclusion of CSF abnormalities.

The Poser criteria proved a useful tool for the diagnosis of MS for two decades, despite their having been developed primarily to classify the disease for research purposes. However, the Poser criteria were developed when the use of MRI was in its infancy. This imaging modality has clarified much about the biology of MS and a reassessment of the criteria used to diagnose the disease in the context of such knowledge was warranted. This had become critically important because of the availability of new drug therapies (see Chapters 14, 15). Because it appears beneficial to initiate treatment early, before permanent neurologic deficits develop, it is important to be able to diagnose the disease with reasonable certainty in the initial stages of the illness.

Because of the advances in understanding achieved through MRI and differences in the categorization of MS subtypes, an International Panel, under the chairmanship of W. I. McDonald gathered in 2000 and published its recommendations the following year (15).

Table 1 Poser Criteria for Multiple Sclerosis

Category

Clinical attacks

Paraclinical evidence

CSFa

Clinically definite CDMS A1 CDMS A2 Laboratory-supported definite

LSDMS B1 LSDMS B2 LSDMS B3 Clinically probable CPMS C1 CPMS C2 CPMS C3 Laboratory-supported probable LSPMS D1

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