Diagnostic Testing In MS

Objective
To describe the current understanding of the diagnosis and treatment of Multiple Sclerosis (MS) and to explore the use of Magnetic Resonance Imaging (MRI) assessment as a prognostic tool and an indicator in the diagnosis of MS.

Summary
MS is a chronic, progressive, DeMyelinating Disease of the Central Nervous System that is associated with a significant economic burden.

At this time, ImmunoModulatory agents (Interferon-beta-1a (IFN-ß-1a) [Avonex], IFN-ß-1a [Rebif], IFN-ß-1b [Betaseron], and Glatiramer Acetate [Copaxone]) are first-line agents, which are reported to reduce relapse rates.

The diagnostic criteria for MS have evolved over time to include MRI findings as an integral part of the diagnosis.

However, the most recent criteria (McDonald) are focused on the diagnosis of definite MS and do not address the status of patients with a first DeMyelinating event (Clinically Isolated Syndrome [CIS]).

This is an important issue because a CIS is highly predictive of developing further inflammation and definite MS when the episode occurs in conjunction with lesions on the initial MRI.

Many times, MRI findings do not correlate with clinical symptoms, and clinically silent lesions are identified. Therefore, the use of MRI is salient to the early diagnosis of high-risk patients.

The evolution of thought concerning early treatment in MS is based on an increased understanding of the pathology of the disease. Axonal Loss occurs early in the disease process, and both White Matter and Gray Matter are affected.

Studies that have analyzed early treatment in patients highly likely to have MS (Clinically Isolated Events with evidence of lesions on MRI) report significant benefits in delaying further changes on MRI and further attacks.

Patients who begin treatment later do not reap the same benefits as those who begin treatment earlier during the disease course.

Conclusion
Patients with Clinically Isolated Events should be referred promptly to a Neurologist for assessment, including MRI scans.

An early recognition of the inflammatory process enables patients to begin treatment with an ImmunoModulatory agent even before the technical diagnosis of Definite MS so that the degenerative progression of MS can be retarded.

Objective
To evaluate the relative sensitivity of MR scanning for Multiple Sclerosis (MS) at 1.5 Tesla (T) and 3.0 T using identical acquisition conditions, as is typical of multicenter clinical trials.

Methods
Twenty-five subjects with MS were scanned at 1.5 T and 3.0 T using Fast Spin-Echo, and T₁-weighted SPGR with and without Gadolinium contrast injections.

Image data, blinded to field strength, were analyzed using automated segmentation and lesion counting.

Results
Relative to scanning at 1.5 T, the 3.0 T scans showed:
1. A 21% increase in the number of detected Contrast Enhancing Lesions
2. A 30% increase in Enhancing Lesion Volume
3. A 10% increase in Total Lesion Volume

Discussion
The improved detection ability using high-field MR imaging is prominent even when sequence parameters are optimized around the midfield units.

Multicenter trials using both 1.5 T and 3.0 T instruments may be affected by these sensitivity differences.

Magnetic Resonance Imaging (MRI) is very useful as a method form confirming the lesion distribution of Multiple Sclerosis (MS).

Although MS should be diagnosed primarily on clinical grounds, MRI aids the diagnosis by providing paraclinical evidence for the dissemination in both Time and Space.

Recently, a new guideline for MS diagnosis was proposed by International Panel. This guideline set out to integrate MRI into the overall diagnostic scheme because of its unique sensitivity to pathological changes.

In Japanese, however, the so-called Optic-Spinal form of MS, which is characterized by the selective involvement of the Optic Nerves and the Spinal Cord, is relatively common.

Moreover, most of Japanese MS patients without OligoClonal Bands show atypical Brain lesions which do not fulfill the MRI criteria for Brain abnormality.

Multiple Sclerosis (MS) is the most common DeMyelinating Inflammatory Disease of the Central Nervous System (CNS), presenting with multifocal, disseminated inflammatory lesions referred to as Plaques.

Magnetic Resonance Imaging (MRI) typically depicts multiple, round to oval, circumscript lesions predominantly involving PeriVentricular and SubCortical White Matter, BrainStem and Cerebellum.

More recent investigations have demonstrated that the macroscopically visible plaques only present the tip of the iceberg:

Already early in its course, MS causes NeuroAxonal damage and diffusely involves the entire Brain Parenchyma including Normal-Appearing White Matter.

These changes are reflected by:
1. Strong T₁ HypoIntense lesions and Atrophy of early onset
2. Reduction of the Neuronal Marker N-AcetylAspartate (NAA) on Spectroscopy
3. Decrease of the Magnetization Transfer Ratio (MTR)
4. Increased in Diffusibility and decreased Anisotropy on Diffusion-Weighted Imaging (DWI)

MRI imaging is an important tool in the diagnosis of MS by revealing the characteristic spatial and temporal dissemination of the Cerebral and Spinal manifestations of this disease.

Diagnostic criteria increase the diagnostic specificity and allow better differentiation from other diseases with multifocal White Matter abnormalities.

We compared the sensitivity of T₂-weighted Spin-Echo (FSE) and fast Short-Tau Inversion-Recovery (fSTIR) sequences in detection of Multiple Sclerosis of the Spinal Cord:

In 100 consecutive patients with clinically confirmed Multiple Sclerosis (MS); 86 patients underwent also Brain MRI.

In all, 310 focal lesions were detected on fSTIR and 212 on T₂-weighted FSE, Spinal Cord lesions were seen better on fSTIR images, with a higher contrast between the lesion and the normal Spinal Cord.

In 24 patients in whom Cord plaques were shown with both sequences, the Cranial study was normal or inconclusive.

Assessment of Spinal plaques can be particularly important when MRI of the Brain is inconclusive, and in there situations fSTIR can be helpful.

To date, there is no biological test available with enough confidence to make alone a diagnosis of Multiple Sclerosis (MS).

MS diagnosis criteria are then an association of Clinical and ParaClinical criteria that allow an objective demonstration of dissemination of lesions in both Time and Space.

Adapted MRI criteria from Barkhof have a good sensitivity and the best specificity to evaluate MS; 3 of 4 criteria are necessary:

1. 1 Gadolinium enhancing lesion or 9 T₂ HyperIntense lesions
2. At least 1 InfraTentorial lesion
3. At least 1 JuxtaCortical lesion
4. At least four PeriVentricular lesions

NB: 1 Spinal Cord lesion can substitute for 1 Brain lesion.

New methods as Spectroscopy, Magnetization Transfer, Diffusion MRI and Functional MRI complete results of conventional MRI and give new information about PhysioPathology of MS DeMyelinating lesions.

Magnetic Resonance Imaging (MRI) is very sensitive in depicting Multiple Sclerosis (MS) lesions, but its specificity is poor.

New sequences such as Fast Spin-Echo and FLAIR (Fluid Attenuated Inversion Recovery) improve the detection of lesions.

The exploration of the whole Central Nervous System, Brain, Optic Nerves and Spinal Cord improves sensitivity and specificity.

The existence of lesions at different ages responds to temporal dissemination.

MRI has also allowed to better understand the natural history of MS, showing 5 to 10 times more radiological than clinical activity.

In case of Isolated DeMyelinating Syndrome, MRI is the best predictor of the occurrence of definite MS and of the severity of disability in the subsequent 10 years.

However, the diagnosis of MS remains clinical, and systematic control MRI are not useful in clinical practice.

Although sensitivity of MRI to MS is high, its specificity is limited and requires the use of criteria such as Paty's, Fazekas's and then Barkhof's, taking successively into account the technical progress and the use of contrast agents.

In the later the confidence level brought by contrast enhancement is equivalent to that of 9 HyperIntense lesions seen on T₂-weighted imaging.

Therefore MRI is now the first ParaClinical Test to perform for MS suspicion and is aimed at the diagnosis of MS from the first clinical event, without need to wait for the second relapse for temporal dissemination confirmation.

The goal is to be able to discuss early treatment if it becomes clear that it could prevent disease progression.

The early evidence of spatial and temporal dissemination of the disease takes equally into account the clinical and MRI information and eliminates the previous terminology of "Clinically Defined MS".

Presently the diagnosis is either confirmed or ruled out and in a limited number of cases or before the completion of the work up phase the category of "Possible MS" is used.

Although progress were also made in the field of prognosis evaluation of MS with MRI, it still brings less definitive information to predict individually the evolution of each form of the disease.

This opens a large place for new techniques such as Magnetization Transfer, Spectroscopy and Diffusion Imaging:

Which are already able to help PathoPhysiological understanding and which may play an increased role even at the individual level in the future.

In 85% of young adults with Multiple Sclerosis (MS), onset is a subacute Clinically Isolated Syndrome (CIS) of the Optic Nerves, BrainStem, or Spinal Cord.

Methods of assessing the prognosis for patients who present with a CIS have been sought, because only 30-70% of patients with a CIS develop MS.

When clinically silent Brain lesions are seen on MRI, the likelihood of developing MS is high. MS can be diagnosed within 3 months of CIS presentation with certain MRI and CSF criteria.

Disability from MS is less likely in patients with a CIS of Optic Neuritis or Sensory symptoms only, few or no MRI lesions, a long period to the first relapse, and no disability after the first 5 years.

Development of more reliable prognostic markers will enable new treatments to be targeted for those who are most likely to benefit.

We encourage continued clinical and laboratory assessment of patients with a CIS.

The onset of Multiple Sclerosis (MS) in 85% of young adults is with a subacute Clinically Isolated Syndrome (CIS) of the Optic Nerves, BrainStem, or Spinal Cord.

Whereas multifocal Brain lesions are present on MRI in many patients with a CIS, some patients have additional abnormalities on quantitative MRI in otherwise Normal-Appearing White and Gray Matter that suggest an extensive pathological process.

Functional outcome for patients with symptomatic CIS lesions is determined by the interplay of Inflammation, DeMyelination, Axonal Damage, ReMyelination, and Cortical Adaptation.

Recovery of function may be accelerated by high dose CorticoSteroids, and although Interferon-ß delays the development of a second relapse, its long-term effect is unknown.

A better understanding of pathological and pathogenetic processes in patients with a CIS will facilitate the development of disease-modifying treatments for patients with MS before they become disabled.

Continued clinical and laboratory investigation of patients with a CIS should be encouraged.

Demonstration of lesion Dissemination In Space (DIS) and time (DIT) is necessary for the diagnosis of Multiple Sclerosis (MS) in Clinically Isolated Syndromes (CIS).

The McDonald criteria accepted two methods to demonstrate DIS.

The fulfillment of at least three of four MRI Barkhof criteria (MRI-BC) or, alternatively, the finding of at least two MRI lesions on T₂-weighted images (T₂ lesions) plus the presence of OligoClonal IgG Bands (OCGB) in CerebroSpinal Fluid (CSF).

We aimed to evaluate the accuracy of both methods for DIS demonstration to predict conversion of CIS to MS using a new OCGB test.

We studied fifty-eight CIS patients with OCGB detection and Brain MRI, and followed them up during 6 years.

Twenty-eight patients fulfilled MRI-BC. Twenty-five of them converted to MS during follow-up (sensitivity 73.53%, specificity 87.50%, accuracy 79.31%).

Thirty-four patients had at least two T₂ lesions plus OligoClonal Bands. Thirty-three converted to MS during follow-up (sensitivity 94.29%, specificity 95.65%, accuracy 94.82%).

The presence of OligoClonal IgG Bands plus two T₂ lesions accurately predicts CIS conversion to MS.

MRI-BC criteria have a high specificity but less sensitivity and accuracy. These results reinforce the role of CSF study in MS diagnosis.

Background
The 2001 and 2005 McDonald criteria allow MRI evidence for Dissemination In Space (DIS) and Dissemination In Time (DIT) to be used to diagnose Multiple Sclerosis in patients who present with Clinically Isolated Syndromes (CIS).

In 2006, new criteria were proposed in which DIS requires at least one T₂ lesion in at least two of four locations (JuxtaCortical, PeriVentricular, InfraTentorial, and Spinal-Cord) and DIT requires a new T₂ lesion on a follow-up scan.

We applied all three criteria in a large cohort of CIS patients to assess their performance by use of conversion to Clinically Definite Multiple Sclerosis (CDMS) as the outcome.

Methods
Patients who had two MRI scans within 12 months of CIS onset were identified in four centres in the Magnims European research network.

The specificity and sensitivity of MRI criteria for CDMS after 3 years was assessed in 208 patients.

A Cox proportional hazards model was applied in a larger cohort of 282 patients that included all patients irrespective of length of follow-up.

Findings
The specificity of all criteria for CDMS was high (2001 McDonald, 91%; 2005 McDonald, 88%; new, 87%).

Sensitivity of the new (72%) and 2005 McDonald (60%) criteria were higher than the 2001 McDonald criteria (47%).

The Cox proportional hazards model showed a higher conversion risk for all three criteria in those with both DIS and DIT than those with either DIS or DIT alone.

When all three criteria were included in the model, only the new criteria had an independent significant effect on conversion risk.

Interpretation
The new criteria are simpler than the McDonald criteria without compromising specificity and accuracy.

The presence of both DIS and DIT from two MRI scans has a higher specificity and risk for CDMS than either DIS or DIT alone.