Diagnosing Multiple Sclerosis

In 26 patients with Multiple Sclerosis 100% responded abnormally to Magnetic Resonance Imaging of the Brain.

Lesions in the Posterior Fossa were observed in 18 patients. The BrainStem Auditory Evoked Response was abnormal in 15 patients, and 22 had abnormal ImmunoGlobulins in the CerebroSpinal Fluid.

The correlation between abnormalities of the Auditory BrainStem Response and the Magnetic Resonance Images was greatest in a subgroup where the two investigations were performed within a ten day interval.

Results from Magnetic Resonance Imaging, Evoked Potentials and CerebroSpinal Fluid investigations were used to reclassify 13 of 15 patients with Clinically "Possible" or "Probable" Multiple Sclerosis to a higher level using Poser's Criteria.

Evoked Potentials (the Auditory BrainStem Response in particular) correlated best with clinical Multiple Sclerosis category.

We recommend that Magnetic Resonance Imaging is established as a first-hand investigation in evaluations of Multiple Sclerosis.

Evoked Potentials and CerebroSpinal Fluid investigations may prove to be more specific, however, and these investigations should also be performed as a routine.

Objective
To determine the value of diagnostic information to patients with suspected Multiple Sclerosis (MS).

Because treatment choices would be only minimally affected by earlier diagnosis for most patients with this clinical problem, this study assessed the "nondecisional" value of diagnosis.

Design
Prospective survey of patients before and after diagnostic workup, including imaging with Magnetic Resonance scanning.

We assessed the effect of diagnostic information on patients' sense of well-being, as well as direct measures of the utility of information (using time trade-off and willingness-to-pay techniques).

Setting
Patients referred from primary care practices for diagnostic workup for suspected MS to Neurology clinics and practices.

Patients
Sixty-eight individuals, mean age 37.5 years, 53 female and 15 male. Thirty-one patients were classified as having "probable MS," and 37 were classified as having "possible MS" by the examining Neurologist before workup.

Measurements
Present and future health perception, uncertainty about diagnosis-prognosis, and level of anxiety.

Willingness to pay for diagnostic information, quality of life as measured by the time trade-off technique, and psychological state of the patient before and after diagnosis.

Results
Diagnostic uncertainty fell significantly as a result of the diagnostic workup. Most patients (59/62) said that they were better off having received diagnostic information.

Although anxiety seemed to be reduced by testing, overall anxiety levels did not decrease as much as anticipated. Patients also became less optimistic about their future health after testing.

On average, patients were willing to forgo 4.5 quality-adjusted life days to receive an earlier diagnosis and their quality of life after diagnosis improved slightly. Subgroups of patients differed in their response to diagnostic information.

Those in whom no definitive diagnosis emerged tend to be more anxious rather than being reassured by the "negative" workup.

Individuals with "positive" workups became less anxious and expressed favorable feelings about the diagnostic workup even though they often faced a chronic disease.

Conclusions
Overall, the diagnostic workup seemed to benefit patients and improve their sense of well-being. However, whether the effects were beneficial or not depended on the results of the diagnostic workup itself.

In clinical practice the decision to undergo testing in situations in which definitive treatment is unavailable should be individualized. The potential for negative as well as positive consequences should be recognized.

Objective
Magnetic Resonance Imaging, Computed Tomography, CerebroSpinal Fluid analysis, and Evoked Potential Testing are used to assist in the diagnosis of patients suspected to have Multiple Sclerosis (MS).

The impact of these tests on a clinician's diagnosis of patients suspected to have MS has not been studied systematically.

Design
Clinicians made a diagnosis of each patient following clinical evaluation, again after reviewing the results of Magnetic Resonance Imaging, and finally after reviewing information from other laboratory testing.

These diagnoses were compared with the criterion standard of a masked "gold standard" panel reviewing all information after a mean follow-up of 0.9 year.

Setting
The General Neurology Clinic and Multiple Sclerosis Clinic of the Univ of Rochester (NY).

Patients
A consecutive sample of 62 patients diagnosed as having either possible or probable MS following clinical evaluation.

Main Outcome Measure
Changes in diagnostic certainty of clinicians following incremental presentation of new laboratory data and the accuracy of such diagnoses.

Results
Clinicians used Magnetic Resonance Imaging findings to diagnose definite MS or to eliminate MS from diagnostic consideration in 44% of cases.

In these cases, further laboratory testing did not alter clinicians' decisions.

In the remaining 56% of cases, in which Magnetic Resonance Imaging did not lead to a diagnosis of definite MS or eliminate MS from diagnostic consideration, further laboratory testing led to such diagnoses in an additional 13% of cases.

Gold standard diagnoses were in agreement with the clinician's assessments.

Conclusions
Magnetic Resonance Imaging aids in the evaluation of patients suspected to have MS; other subsequent studies (Computed Tomography, CerebroSpinal Fluid analysis, and Evoked Potential Testing) have less impact.

After all studies are performed, about half of such patients still have a tentative diagnosis.

The yield of paraclinical tests was evaluated in a prospective study of 189 consecutive patients referred for suspected Multiple Sclerosis (142 patients with Multiple Sclerosis, 47 Non-Multiple Sclerosis patients on discharge).

Patients were first classified according to the Poser's Criteria by the clinical findings.

Subsequently, the results of paraclinical tests (Cranial MRI, Visually Evoked Potentials (VEPs), SomatoSensory Evoked Potentials by Tibial Nerve Stimulation (SSEPs), Motor Evoked Potentials (MEPs), and analysis of CSF for OligoClonal Banding and IgG-index (CSF)) were taken into account.

The percentage of reclassified patients (reclassification sensitivity, RS) was always lower than the percentage of abnormal results (diagnostic sensitivity, DS), and the divergence of RS v DS differed between the tests (60% v 84% in MRI, 31% v 77% in CSF, 29% v 37% in VEPs, 20% v 68% in MEPs, and 12% v 46% in SSEPs respectively).

False reclassifications of Non-Multiple Sclerosis patients to Multiple Sclerosis would have occurred with all tests (MRI: six of 47 patients, (reclassification specificity 88%); CSF: one (98%); VEPs: two (96%); MEPs: two (96%); SSEPs: four (91%); P 0.05).

Although MRI had superior diagnostic capacity, 57 of the 142 patients with Multiple Sclerosis were not reclassified by the MRI result, 12 of whom were reclassified by CSF and 18 by one of the Evoked Potentials (EP) studies.

Of the 98 patients not reclassified by CSF, 53 were reclassified by MRI and 39 by EPs.

The results suggest that for the evaluation of paraclinical tests in suspected Multiple Sclerosis, comparison of diagnostic sensitivities is inappropriate.

We evaluated the usefulness of the MRI criteria for Multiple Sclerosis (MS) proposed by Paty et al and Fazekas et al in 36 Japanese MS patients, using HTLV-I-associated myelopathy (HAM)/Tropical Spastic Paraparesis (TSP) as the control.

Although 30 of 36 HAM/TSP patients had multiple White Matter lesions on T₂-weighted Cranial MRI, only two fulfilled the MRI criteria for MS.

At the same time, 31 of the 36 MS patients fulfilled the primary MRI criterion, yielding 93% specificity and 86% sensitivity for the criterion. MS has disease-specific MRI abnormalities.

As the function of the Autonomic Nervous System is often compromized in Multiple Sclerosis (MS), different standardized tests are used to detect disseminated abnormalities in CardioVascular Autonomic functions.

Sympathetic Skin Response (SSR), a slow wave generated in deep layers of the skin, is induced by reflex activation of Sudomotor Sympathetic efferent fibers.

SSR was studied in 70 patients classified into different categories according to the diagnostic criteria for MS.

We also obtained pattern reversal Visually Evoked Potentials and BrainStem Auditory Evoked Potentials as well as SomatoSensory Evoked Potentials (by median and posterior tibial nerve stimulation).

SSR was abnormal in 66 patients (94.2%), including abnormal foot latency with normal hand latency in 30 (42.8%), delayed foot and hand latencies in 30 (42.8%), and no response in 6 (8.6%).

The percentages of SSR abnormalities were similar in the different patient categories. Pathological SSR were more common than abnormal Evoked Potentials in suspected and Probable MS.

SSR appears to be a simple and effective means of assessing Sympathetic Sudomotor outflow disturbances in MS, providing a valuable addition to current ElectroPhysiological procedures for the detection of MS lesions.

To test the reliability of four previously proposed MRI criteria for the diagnosis of MS, we reviewed 1,500 consecutive Brain scans.

For the presence, number, size, and location of Areas of Increased Signal (AIS [Lesions]) on Proton-Density and T₂-weighted images.

Unaware of the patients' clinical presentations and ages. This series included 134 subjects with a Clinical Diagnosis of MS.

Relying exclusively on the presence of at least three or four AIS for a positive diagnosis of MS resulted in high sensitivity (90% for three AIS and 87% for four).

But inadequate specificity (71% for three AIS and 74% for four) and positive predictive value (23% for three AIS and 25% for four).

If one of these lesions was required to border the Lateral Ventricles, specificity was 92% and positive predictive value was 50% at a sensitivity of 87%.

Using the Fazekas Criteria, at least three AIS and two of the following features:
• Lesion abutting body of Lateral Ventricles,
• InfraTentorial Lesion location,
• Lesions larger than 5 mm

Led to a further highly significant improvement of specificity (96%; p = 0.0000).

And increase of the positive predictive value (65%) at the expense of a less significant decrease in sensitivity (81%; p < 0.01).

In a prospective study, we evaluated the technique of Magnetically Evoked Motor Potentials (MEP) in the diagnosis of Multiple Sclerosis (MS).

We consecutively included 68 patients with symptoms or signs compatible with a DeMyelinative CNS affection.

We subjected all patients to CSF analysis, MRI studies of the Brain and BrainStem, Visual Evoked Potentials (VEP), BrainStem Auditory Evoked Response (BAEP), and SomatoSensory Evoked Potentials (SSEP).

We then used the results to categorize the patients according to the Poser's Criteria of Multiple Sclerosis.

Blinded from the results of the above investigations, one of the authors made MEP recordings from three muscles in the upper limbs and two in the lower limbs in all 68 patients.

Forty patients received an MS diagnosis, and in these, MRI was positive in 88%, MEP in 83%, VEP in 67%, SSEP in 63%, and BAEP in 42%.

As to the diagnosis of MS, the reliability of a prolonged Central Motor Conduction Time (CMCT) was 0.83 (0.73 to 0.93), while the reliability of a normal CMCT was 0.75 (0.61 to 0.98).

The information gained by MRI was best supplemented by VEP. Of the NeuroPhysiologic tests, the MEP was in closest agreement with the MRI with a concordance of 85%.

Over a hundred years ago, Charcot set down what he considered to be some of the clinical characteristics of Multiple Sclerosis (MS).

His Triad was not specific but it was the first attempt to separate this disease from the many others affecting the Nervous System.

The history of clinical diagnostic criteria demonstrates the evolution from rather tentative classifications of restricted value to the more elaborate 1983 scheme.

Which incorporates some laboratory procedures under the rubric paraclinical tests, considered to be extensions of the Neurological Examination, as well as a new category based on the presence of specific abnormalities of the CerebroSpinal Fluid (CSF).

It is curious that until then the term Definite MS had been avoided except for autopsy-proven cases, perhaps a wise move, since exact diagnosis may require long term observation.

All the proposed schemes have been based on the twin principles of dissemination in both Time and Space.

The diagnosis of MS must remain a clinical one, supported but not supplanted by the increasingly popular Magnetic Resonance Imaging.

Which is non-specific and is frequently overinterpreted by Radiologisits lacking appropriate clinical information.

Reliance on the MRI as the principal if not exclusive basis for the diagnosis leads to error in as many as one third of cases.

This assumes a great deal of importance considering that such non-MS patients may be counted in Epidemiological surveys.

And included in therapeutic trials for disease-modifying drugs, or eventually treated with these very expensive drugs with still controversial long term efficacy.

Not surprisingly, attempts to develop reliable criteria for the MRI diagnosis of MS have been unsuccessful in view of the lack of specificity of that procedure.

Great care should be taken to exclude the presence of extrinsic Cervical Spine lesions.

Which might impinge on the Cord, leading to the formation of Plaques, or mimic the course of MS.

An MRI of the Cervical Spine is recommended in all patients suspected of having MS who have symptoms suggestive of Spinal Cord involvement.

The diagnosis of MS is, and will remain, based on clinical criteria which codify the characteristic Dissemination in Time and Space of MS.

The International Panel on MS Diagnosis presents revised diagnostic criteria for Multiple Sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both Time and Space.

Magnetic Resonance Imaging is integrated with clinical and other paraclinical diagnostic methods.

The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations. Including:

1. "MonoSymptomatic" disease suggestive of MS
2. Disease with a typical Relapsing/Remitting course
3. Disease with insidious progression, without clear attacks and remissions

Previously used terms such as "Clinically Definite" and "Probable MS" are no longer recommended.

The outcome of a diagnostic evaluation is either MS, "Possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "Not MS."

Conventional Magnetic Resonance Imaging (MRI) has routinely been used to improve the accuracy of Multiple Sclerosis (MS) diagnosis and monitoring, detect the effects of disease-modifying therapy, and refine the utility of clinical assessments.

However, conventional MRI measures, such as the use of lesion volume and count of Gadolinium-enhancing and T₂ lesions, have insufficient sensitivity and specificity to reveal the true degree of pathological changes occurring in MS.

Newer metrics of MRI analysis, including T₁-weighted HypoIntense lesions (Black Holes) and Central Nervous System (CNS) Atrophy measures, are able to capture a more global picture of the range of tissue alterations caused by Inflammation, DeMyelination, Axonal Loss, and NeuroDegeneration.

There is mounting evidence that these MRI measures correlate well with existing and developing Neurological Impairment and disability.

In so doing, these MRI techniques can help elucidate the mechanisms underlying the pathophysiology and natural history of MS.

The current understanding is that T₁ Black Holes and CNS Atrophy more accurately reflect the NeuroDegenerative and destructive components of the MS disease process.

Therefore, the short and long-term studies that aim to measure the degree and severity of the NeuroDegenerative MS disease process should incorporate these MRI metrics as part of their standard routine MRI protocols.