How is multiple sclerosis diagnosed. What role does MRI play in MS diagnosis. Why is MS difficult to diagnose. What are the common symptoms of MS. How do doctors determine if a patient has MS.

The Complexity of Multiple Sclerosis Diagnosis

Multiple sclerosis (MS) presents a unique challenge in the medical field due to its complex nature and varied manifestations. Unlike many other conditions that can be diagnosed with a single test, MS requires a comprehensive approach involving multiple diagnostic tools and careful clinical evaluation.

Why is MS so difficult to diagnose? The answer lies in the diverse array of symptoms and the lack of a definitive test. Dr. Douglas C. Nathanson, a neurologist at Geisinger Wyoming Valley Medical Center, explains, “Symptoms of multiple sclerosis vary widely among patients, and even within the same patient over time. Even when the symptoms follow a classic pattern, they must meet certain guidelines before the doctor or neurologist can be sure it’s MS.”

The Fundamental Challenge: No Single Diagnostic Test

The primary obstacle in MS diagnosis is the absence of a single, definitive test. This reality necessitates a multi-faceted approach to diagnosis, combining clinical observations, patient history, and various diagnostic tools, with MRI playing a central role.

The Pivotal Role of MRI in MS Diagnosis

Magnetic Resonance Imaging (MRI) has revolutionized the diagnosis of multiple sclerosis, becoming an indispensable tool in the diagnostic process. While it’s important to note that MRI alone cannot diagnose MS, it provides crucial evidence that, when combined with clinical findings, significantly aids in reaching a diagnosis.

MRI’s Contribution to MS Diagnosis

• Revealing asymptomatic lesions
• Demonstrating dissemination in space and time
• Ruling out alternative diagnoses
• Monitoring disease progression

How does MRI aid in MS diagnosis? MRI is the most sensitive method for revealing asymptomatic dissemination of lesions in space and time, two critical factors in MS diagnosis. The pattern and evolution of MRI lesions, when considered alongside clinical symptoms, have made MRI abnormalities invaluable criteria for the early diagnosis of MS.

Understanding Multiple Sclerosis: A Disease of the Nervous System

Multiple sclerosis is a complex condition affecting the nervous system, impacting approximately 2.3 million people worldwide. But what exactly happens in MS?

MS is classified as an “inflammatory demyelinating condition.” This means that the disease causes inflammation that damages myelin, the fatty material insulating nerves. Dr. Nathanson provides an apt analogy: “Think of myelin as the protective cover that wraps around an electrical wire. When that covering is damaged, the electrical impulse traveling through that wire can’t reach its destination smoothly or efficiently. This is similar to what happens to nerves with MS.”

When myelin is damaged or stripped away, impulses traveling to and from the brain and the rest of the body are disrupted. These damaged areas, known as lesions, are responsible for the diverse symptoms experienced by people with MS.

The Diagnostic Criteria: Dissemination in Space and Time

The principles of MS diagnosis are rooted in demonstrating the dissemination of white matter lesions in space and time. But what do these terms mean in the context of MS diagnosis?

Dissemination in Space (DIS)

Dissemination in space refers to the presence of MS lesions in different areas of the central nervous system. MRI plays a crucial role in identifying these lesions, even when they are asymptomatic.

Dissemination in Time (DIT)

Dissemination in time involves the development of new lesions over time, indicating disease activity. MRI can provide evidence of DIT by showing new or enlarging lesions on follow-up scans.

How effective are these criteria? The sensitivity of diagnosing MS within the first year after a single attack is 94%, with a specificity of 83%. This high sensitivity allows for early diagnosis and timely treatment initiation.

Characteristic MRI Findings in Multiple Sclerosis

While MRI findings in MS are not pathologically specific, certain characteristics are more commonly associated with the disease. What are the typical MRI features of MS?

• Dawson’s Fingers: Lesions perpendicular to the lateral ventricles
• Ovoid lesions
• Corpus callosum lesions
• Asymptomatic spinal cord lesions

It’s important to note that while these features are characteristic of MS, they are not exclusive to the disease. Other white matter diseases can present similar appearances on MRI, underscoring the importance of clinical correlation.

The Role of Gadolinium Enhancement

Gadolinium-enhanced MRI provides valuable information about new lesion activity and helps rule out alternative diagnoses. How does gadolinium enhancement contribute to MS diagnosis? A single gadolinium-enhanced MRI can potentially provide evidence for both dissemination in space and time, aiding in early diagnosis.

Common Symptoms of Multiple Sclerosis

The symptoms of MS can vary widely, depending on the location of lesions in the brain and central nervous system. What are the most common symptoms experienced by MS patients?

1. Fatigue
2. Numbness and tingling
3. Weakness throughout the body
4. Dizziness
5. Sexual problems
6. Walking difficulties
7. Muscle spasms
8. Vision problems
9. Cognitive changes
10. Bladder and bowel dysfunction

The variability of these symptoms contributes to the diagnostic challenge, as they can mimic other neurological conditions. This is why a comprehensive approach, including MRI and other diagnostic tools, is crucial for accurate diagnosis.

The Importance of Differential Diagnosis in MS

Given the non-specific nature of MS symptoms and MRI findings, differential diagnosis plays a critical role in the diagnostic process. How do doctors rule out other conditions that may mimic MS?

MRI is instrumental in this process, helping to exclude alternative diagnoses such as:

• Spinal stenosis
• Brain tumors
• Vascular malformations
• Leptomeningeal disease

Certain MRI findings can suggest diagnoses other than MS. These include:

• Persistent gadolinium enhancement lasting more than three months
• Lesions with significant mass effect
• Meningeal enhancement

The presence of these features should prompt further investigation into alternative diagnoses.

The Limitations of MRI in MS Diagnosis

While MRI is a powerful tool in MS diagnosis, it’s crucial to understand its limitations. Can MRI definitively diagnose MS? The answer is no. MRI evidence plays a supportive role in what is ultimately a clinical diagnosis of MS, always in the appropriate clinical context and after excluding alternative diagnoses.

A negative MRI at the time of a clinically isolated syndrome (CIS) does not rule out MS. Conversely, the presence of MRI lesions alone is not sufficient for an MS diagnosis without corresponding clinical symptoms.

The Future of MS Diagnosis: Emerging Technologies and Approaches

As our understanding of MS grows and technology advances, new diagnostic approaches are emerging. What innovations are on the horizon for MS diagnosis?

Advanced MRI Techniques

Researchers are exploring advanced MRI techniques that may provide more specific information about MS pathology. These include:

• Magnetization transfer imaging
• Diffusion tensor imaging
• Functional MRI

These techniques aim to provide more detailed information about myelin damage and repair, as well as functional changes in the brain associated with MS.

Biomarkers

The search for reliable biomarkers for MS is an active area of research. Potential biomarkers include:

• Neurofilament light chain (NfL) in cerebrospinal fluid and blood
• MicroRNAs
• Specific antibodies

These biomarkers could potentially aid in earlier diagnosis, predict disease progression, and monitor treatment response.

Artificial Intelligence and Machine Learning

The application of artificial intelligence and machine learning to MS diagnosis is a promising field. How might AI contribute to MS diagnosis? AI algorithms could potentially:

• Improve the detection and characterization of MS lesions on MRI
• Predict disease progression based on imaging and clinical data
• Aid in differential diagnosis by identifying subtle patterns

While these technologies are still in development, they hold the potential to enhance the accuracy and efficiency of MS diagnosis in the future.

In conclusion, the diagnosis of multiple sclerosis remains a complex process, requiring a multifaceted approach. MRI plays a crucial role, providing valuable evidence of disease activity and helping to rule out alternative diagnoses. However, it’s essential to remember that MS diagnosis is ultimately a clinical one, based on a combination of symptoms, physical examination findings, and supportive test results. As research progresses and new technologies emerge, we can hope for even more accurate and timely diagnoses in the future, leading to better outcomes for patients with MS.

The role of MRI in the diagnosis of multiple sclerosis

There is no single test that is diagnostic of MS, including MRI. The lesions detected with MRI are pathologically nonspecific. The principles of MS diagnosis are based on showing dissemination of white matter lesions in space and time. MRI is the most sensitive method for revealing asymptomatic dissemination of lesions in space and time. The pattern and evolution of MRI lesions, in the appropriate clinical setting, has made MRI abnormalities invaluable criteria for the early diagnosis of MS. The first important role for MRI in the diagnosis of MS allows for an early diagnosis of MS for CIS patients using the IP diagnostic criteria, including MRI for dissemination in space (DIS) and time (DIT). The sensitivity of diagnosing MS within the first year after a single attack is 94%, with a specificity of 83%. The MRI evidence required to support the diagnosis varies, depending on the strength of the clinical findings. Allowing a new MRI lesion to substitute for a clinical attack doubles the number of CIS patients who can be diagnosed as having MS within 1 year of symptom onset. Increasing the sensitivity of the test with more lenient criteria, as recommended by the AAN subcommittee, can result in decreased specificity. The second important role for MRI in the diagnostic work-up of suspected MS patients is to rule out alternative diagnoses obvious on MRI, such as spinal stenosis and most brain tumors. Characteristic lesions that favor MS include Dawson Fingers, ovoid lesions, corpus callosum lesions, and asymptomatic spinal cord lesions. However, other white matter diseases can have similar appearances on MRI. Persistent gadolinium enhancement greater than three months, lesions with mass effect, and meningeal enhancement suggest other disorders. A standardized MRI protocol for brain and spinal cord is crucial for comparing across studies or between centers. T2W MRI cannot distinguish between acute and chronic lesions. Gadolinium provides useful information about new lesion activity and is helpful in ruling out alternative diagnoses such as neoplasm, vascular malformations, and leptomeningeal disease. A single gadolinium-enhanced MRI can potentially provide evidence for dissemination in space and time. Spinal cord imaging is equally valuable to rule out spinal stenosis or tumor, and for detecting asymptomatic lesions when brain imaging is nondiagnostic in patients suspected of having MS. Precise criteria may be too suggestive that MS can be diagnosed by MRI and a negative MRI at the time of CIS does not rule out MS. MRI evidence plays a supportive role in what is ultimately a clinical diagnosis of MS, in the appropriate clinical situation, and always at the exclusion of alternative diagnoses.

Why multiple sclerosis is difficult to diagnose

Some diseases and medical conditions are relatively easy to diagnose. Your doctor can do a rapid test to determine if you have strep throat, and see your broken arm using an X-ray. Unfortunately, multiple sclerosis (MS) is much more complex and can take months, or even longer, to accurately diagnosis. There is no single test that will tell you if you have MS. Doctors arrive at a diagnosis based on a combination of your symptoms and the results of several different tests.

“Symptoms of multiple sclerosis vary widely among patients, and even within the same patient over time,” said Douglas C. Nathanson, M.D., a neurologist at Geisinger Wyoming Valley Medical Center in Wilkes-Barre. “Even when the symptoms follow a classic pattern, they must meet certain guidelines before the doctor or neurologist can be sure its MS.”

Understanding MS

Multiple sclerosis is a common disease of the nervous system that affects 2.3 million people worldwide. It’s known as an “inflammatory demyelinating condition,” which means that the disease causes inflammation that damages myelin, the fatty material that insulates nerves.

“Think of myelin as the protective cover that wraps around an electrical wire,” said Dr. Nathanson. “When that covering is damaged, the electrical impulse traveling through that wire can’t reach its destination smoothly or efficiently. This is similar to what happens to nerves with MS.”

When myelin is damaged or stripped away, impulses traveling to and from the brain and the rest of the body are disrupted. These damaged areas are called lesions, and they cause the symptoms that people experience with MS.

The challenge of the diagnosis

While MS has some common symptoms, they often vary depending on where in the brain or central nervous system the lesions occur. These symptoms may include:

• Fatigue
• Numbness and tingling
• Weakness throughout the body
• Dizziness
• Sexual problems
• Walking problems
• Muscle spasms
• Vision problems
• Bladder and bowel problems
• Cognitive changes
• Emotional changes and depression

“No two people with MS will have exactly the same symptoms, and many of these symptoms may have other causes,” said Dr. Nathanson. “A big part of the MS diagnosis is ruling out other diseases and conditions that may cause the same symptoms.”

The other diseases and conditions that need to be ruled out are numerous, including Lyme disease, migraine headaches, lupus, stroke, fibromyalgia, several inflammatory autoimmune diseases, and even vitamin B12 deficiencies.

The three tests to diagnose MS

“Based on your history and neurological exam, there may be enough evidence to warrant more testing for MS,” said Dr. Nathanson. “There are three tests that can help confirm the diagnosis.”
These three tests include:

• Magnetic Resonance Imaging (MRI): The MRI is a test that creates a picture of your brain using a magnetic field and pulses of radio wave energy. The doctor uses this test to find the hallmark lesions or plaques created by MS.
• Lumbar puncture: This test is also called a spinal tap and it’s used to examine cerebrospinal fluid – the fluid the surrounds the brain and spinal cord – to look for proteins and antibodies characteristic of MS.
• Evoked potential test: This test measures how long it takes nerves in different areas of the body to respond to a stimulus by measuring your brain waves. Common areas for testing are vision, hearing, and feeling in your arms and legs.

“A combination of the results from these tests, your symptoms and medical history will help with your ultimate diagnosis,” said Dr. Nathanson. “As hard as it will be, stay patient and maintain hope, since a proper diagnosis will be the first step in managing your disease.”

Douglas C. Nathanson, M.D., specializes in the care of patients with multiple sclerosis. To schedule an appointment, please call 1-800-275-6401 or visit Geisinger.org. 

How multiple sclerosis is diagnosed

Multiple sclerosis (MS) is a complex and unpredictable disease. There is no single blood test, symptom, or physical finding which can definitely diagnose a person with the disease. Some early signs or symptoms of multiple sclerosis can also be caused by other diseases.

A diagnosis must be made by going through a careful process, making sure the findings are consistent with multiple sclerosis and ruling out other causes.

What should I do if I think I have multiple sclerosis?

If you’re concerned you have multiple sclerosis symptoms please see your GP in the first instance. They may refer you to a Neurologist if they believe further tests are necessary. Remember, you can seek support from health professionals before, during and after a diagnosis.

Criteria for a MS diagnosis

There can be many reasons your body is showing the first signs associated with MS. However, there are ways to confirm if those signs actually lead to a diagnosis.

While there is no exact formula, the basic “rule” for a diagnosis has two criteria:

1. There must have been two attacks at least one month apart. An attack, also known as an exacerbation, flare, or relapse, is a sudden appearance or worsening of one or more multiple sclerosis symptoms, lasting at least 24 hours.
2. There must be more than one area of damage to the sheath that protects your nerves, called myelin. These are the scars or ‘sclerosis’ caused by the disease. The damage to myelin must have occurred at more than one point in time.  It’s also important to ensure the damage hasn’t been caused by another disease.

MRI (magnetic resonance imaging)

MRI is the preferred method used to detect lesions (also known as scarring or damage) caused by multiple sclerosis in the central nervous system (made up of the brain, the optic nerves and the spinal cord).

A multiple sclerosis diagnosis may not always be made solely on the basis of MRI.

There are other diseases that cause lesions in the central nervous system that look like those caused by multiple sclerosis. There are also lesions found in healthy people, particularly in older people, that are not related to any ongoing disease.

A normal MRI doesn’t absolutely rule out multiple sclerosis either. Sometimes your medical history and the results of other clinical testing can indicate multiple sclerosis. There are many factors that create a clear diagnosis.

Clinical examination

Other symptoms of multiple sclerosis are evaluated during a clinical exam from a physician. This covers an extensive review of mental, emotional and language functions, movement and coordination, vision, balance and the functions of the five senses. The person’s history is also taken into consideration.

Sometimes other tests are needed

It’s not usually necessary to do all diagnostic tests for every person. Sometimes if a clear-cut diagnosis can’t be made based on MRI and clinical exams, additional tests may be ordered. These include:

• electrical diagnostic studies which can show if there is a slowing of messages in the various parts of the brain
• cerebrospinal fluid studies which test for the presence of oligoclonal bands, indicating an abnormal autoimmune response (these are present in other diseases as well so they can’t be used as positive proof of multiple sclerosis)
• blood tests which may rule out other causes for various neurological symptoms.

If you think you’re showing first or early signs of MS, take the first step and see your GP today. We have many resources and support systems in place to help you through the entire process. Feel free to call our friendly team on 1800 042 138 for advice.

Frontiers | LesionQuant for Assessment of MRI in Multiple Sclerosis—A Promising Supplement to the Visual Scan Inspection

Introduction

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disorder of the central nervous system. Most frequently MS is characterized by a relapsing remitting disease course (RRMS) that over the years often converts to a secondary progressive disease course (SPMS). MS leads to variable degrees of physical and cognitive impairment. About 10 percent of the patients experience a progressive disease course from disease onset [primary progressive MS (PPMS)] (1, 2). A key challenge in MS care is to identify and develop prognostic biomarkers for the disease course (3). Magnetic resonance imaging (MRI) is still the most important tool for the diagnosis and monitoring of MS (4–6). MRI has a high sensitivity for the evaluation of inflammatory and neurodegenerative processes in the brain and spinal cord and it is the most commonly used method in the follow-up of MS patients (7).

Visual inspection of the MRI scans of people with MS is time consuming for the neuro-radiologist. Subjective measurements based on a radiologist’s visual inspection may result in low reproducibility (8). In addition, the degrees of brain atrophy and MS-related pathology in the gray and white matter may be difficult to estimate, especially in early adulthood (9, 10).

Advanced tools have been shown necessary to detect early brain atrophy in MS (11). New MRI post-processing tools that automatically analyse complex brain volumetric information and lesion load have recently become commercially available. A study comparing two different software types for assessment of longitudinal whole brain atrophy in MS patients found a strong level of statistical agreement and consistency between the two programs in a real-world MS population (12). The authors conclude that automated measurements of atrophy show promise as biomarkers of neuro-degeneration in clinical practice and will enable more rapid clinical translation. If these types of programmes are to be introduced, in addition to showing their performance compared to competing programs or established research tools, we need to evaluate their use compared to clinical practice today. Do they perform as well, or better than current practice, and in what way can they be useful and valuable?

Although a neuro-radiological evaluation of structural brain MRI in MS patients can easily estimate the pathologic burden of abnormalities such as T2 hyperintense lesions, limited correlation exists between these measures and the clinical phenotype (13). This has been termed the “clinico-radiological paradox” and is well-described for both physical and cognitive impairments. Some explanations to this paradox have been suggested, including inappropriate clinical rating, and underestimation of damage to the normal appearing brain tissue (14). In a large meta-analysis including 2,891 patients, Mollison et al. found a modest correlation (r = –0.30) between MRI measures of total brain white matter lesions and cognitive function in people with MS (13).

LesionQuant(LQ) by CorTechs Labs is a software that automatically segments and measures volumes of brain structures and compares these volumes to norms based on the more established NeuroQuant(NQ) software (15). LQ was specifically designed for the evaluation of lesions and atrophy in MS patients. LQ also provides volumes and counts of new and enlarging brain lesions, and it automatically labels, visualizes and obtains the volumetric quantification of lesions based on brain MRI. LQ can therefore be used in the longitudinal follow-up of patients with MS. A recent study compared NQ to another software tool, Functional Magnetic Resonance Imaging of the Brain’s (FMRIB’s) Integrated Registration Segmentation Tool (FIRST), for estimating overall and regional brain volume in patients with clinically isolated syndrome (16). To our knowledge, no data is published that compares the LQ software in MS with visual evaluations performed by neuro-radiologists.

By using data from our prospective longitudinal study of newly diagnosed MS patients, results from longitudinal LQ analyses were compared to visual evaluations performed by neuro-radiologists in our hospital. We hypothesize that quantitative measurements of brain lesions and atrophy, using an unbiased automatic tool, may improve the correlation between clinical phenotype and MRI results.

Our aims were to evaluate (a) The performance of LQ at detecting brain lesions compared to a neuro-radiologist, and (b) brain atrophy as measured by LQ in comparison to the visual inspection by the neuro-radiologist. (c) The correlations of results from both visual assessment and LQ with clinically relevant variables and (d) the correlation between the segmented brain volumes and lesion volumes acquired from LQ and volumes from the two brain segmentation tools, FreeSurfer and Cascade.

Materials and Methods

Participants

All analyses were based upon carefully phenotyped MS patients in an ongoing prospective longitudinal MS study in Oslo (17, 18). A total of 56 MS patients were included in this study, which had been examined on average 1 year after diagnosis. The inclusion criteria were a diagnosis of RRMS in the period 2009–2012 and age 18–50 years. The exclusion criteria were a history of psychiatric or other neurological diseases than MS, drug abuse, previous adverse Gadolinium reaction, pregnancy or breast-feeding at inclusion, or non-fluency in Norwegian. Data from two time-points after diagnosis of MS were included in this study; data from time-point 1 (TP1) was collected 13 months after diagnosis (±9, n = 56) and data from time-point 2 (TP2) after 66 months (±12, n = 56). At both time-points an expanded disability status scale (EDSS) score was calculated based on a standard neurological examination by trained clinicians (19, 20). For assessment of walking ability and upper extremity function we also performed timed 25-foot walk test (T25FT) and 9-Hole Peg Test (9HPT). A brain MRI scan for clinical and research setting, was performed at both time-points.

We classified the disease modifying treatments (DMTs) as follows; group 0: no treatment, group 1: Glatiramer Acetate, Interferons, Teriflunomide or Dimetylfumarate, group 2: Fingolimod, Natalizumab or Alemtuzumab.

MRI Acquisition

MS patients were scanned at both time-points with the same MRI scanning protocol in the same 1,5 T scanner (Avanto, Siemens Medical Solutions; Erlangen, Germany). The following two MRI sequences were required for the LQ analyses in this study;

(a) A Sagittal 3D T1 MPRAGE (FOV: 240 × 240 mm; slice thickness: 1.2 mm; voxel size: 1.3 × 1.3 × 1.2 mm; TR: 2,400 ms; TE: 3.61 ms; TI: 1,000 ms; flip angle: 8 deg.

(b) Pre-contrast sagittal 3D FLAIR (FOV: 260 × 260 mm; slice thickness: 1 mm; voxel size: 1 × 1 × 1 mm; TR: 6,000 ms; TE: 333 ms; TI: 2,200 ms.

The neuro-radiologist could in addition use all available other sequences in the study protocol, as mentioned in previous publications (17, 21).

LesionQuant Analyses of Lesion Count, Brain Volume, and Lesion Volume

The MRI data from the 56 patients were analyzed using the LQ tool (version 2.3.0), comparing data at TP1 and TP2. For each patient, T1-weighted and FLAIR sequences were uploaded to the LQ server from the PACS system in the hospital, without the need for pre-processing. Finalized LQ-reports were received after ~10 min. The reports provided volumes and counts of all lesions, including new and enlarging lesions at TP2. A lesion was defined by LQ as being ≥ 4 mm³. Volumes of brain structures in the MS patients were compared with age and sex matched healthy controls from the LQ reference database. To establish the normative LQ database, CorTechs Labs combined data from several thousand scans including publicly available studies, studies by collaboration partners, and other proprietary data sources (age range 3–100 years, acquired using Siemens, GE and Philips MRI scanners with both 1. 5T and 3T field strength).

The LQ-reports provided information about volumes of different brain structures, including whole brain, thalamus, cerebral white matter, volume of white matter lesions and cortical gray matter. The results for each patient are illustrated both using percentiles and absolute values (Figure 1). A cut off for atrophy was defined as a 10 percentile drop in brain volume for LQ between TP1 and TP2 (= 5-year interval).

Figure 1. LesionQuant report. Example of a LesionQuant report from one MS subject comparing two MRI scans with a 5-month time interval between the two time-points.

MRI Evaluation of Lesion Count and Brain Volume Presented by the Neuro-Radiologist

The brain MRIs from the included MS patients were systematically evaluated by a neuro-radiologist who carefully counted all lesions on the MRI scans of the patients at TP1 and TP2. A lesion was defined as having a high T2/FLAIR signal ≥ 3 millimeters in diameter. To evaluate the intrareader variability the neuro-radiologist read the data twice in 10 of the patients. A second neuro-radiologist also calculated the number of lesions in the same 10 patients to give information about the interrater variability. In addition to this, another method for evaluating the number of lesions was added. Two neuro-radiologists estimated a lesion number score at TP1. If the number of lesions were between 0 and 9 the lesion number score given was 1, if the number of lesions were between 10 and 19 the lesion number score given was 2, if the number of lesions were more than 20 the lesion number score given was 3.

A neuro-radiologist also assessed whether increased whole brain atrophy was visually evident between the two time-points or not (Figure 2). Visual evaluation of atrophy was done using the 3D T1 series, where increased CSF in the sulci or on the surface of the brain or volume loss of the gyri between TP1 and TP2, was regarded as atrophy.

Figure 2. An example of the visual assessment by the neuro-radiologist. In (A) we see an axial T1 MRI at time-point 1, while in (B) we see the MRI at time-point 2, highlighting a circle with an example of a new lesion evolving during the follow-up period. The oval circle is an example of an area showing increased CSF in the sulcus, which was evaluated as representing atrophy between the two time-points.

The exact lesion number, lesion number score, and the evaluation of atrophy were then compared to the output from LQ. The assessment by the neuro-radiologist was used as the gold standard to compare the LQ data with.

MRI Evaluation of Brain Volume and Lesion Volume Using Freesurfer and Cascade

To compare LQ with other research methods for brain segmentation we compared LQ with the softwares FreeSurfer and Cascade (22). To compare brain volume between the different softwares we used the measure for whole brain volume from both LQ (including brain stem) and FreeSurfer (excluding brain stem) (23). To compare the lesion volume between the different softwares we used the measure for total lesion volume from both LQ and Cascade.

Statistical Analysis

We used R (R Core Team, Vienna, 2018, version 3.6.1) for statistical analyses. To assess reliability of the whole brain volumes from LQ and FreeSurfer we computed the intraclass correlation coefficient (ICC) using the R package “irr” (24). Figures were made using “ggplot2” (25) and “cowplot” (26) in R.

To evaluate the associations between the assessment provided by LQ, the neuro-radiologist, analysis using the FreeSurfer and Cascade softwares and the clinical data, we used the “stats” package in R and calculated the Pearson’s correlation coefficient and applied the student’s t-test (27).

To adjust for multiple comparisons, we calculated the degree of independence between the four clinical variables available, making a 4 × 4 correlation matrix based on the Pearson’s correlation between all pair-wise combinations of clinical data. Utilizing the ratio of observed eigenvalue variance to its theoretical maximum, the estimated equivalent number of independent traits in our analyses was 3.0 (28). To control for multiple testing, our significance threshold was therefore adjusted accordingly from 0.05 to 0.017 (28).

Results

Participant Demographics and Characteristics

At TP1 mean age of the study participants was 36 years (range 21–49 years), 70% were females and 96% were classified as having RRMS. EDSS was stable between TP1 and TP2 with median EDSS 2.0 (range 0–6). Time since MS diagnosis was on average 12.9 months (SD = 9.3) at TP1 and 66.0 months (SD = 11.7) at TP2. At TP1, 25% did not receive any DMT for MS, 63% received a group 1 DMT (moderately effective treatment) and 12% a group 2 DMT (highly effective treatment). At TP2, 34% did not receive any DMT, 36% received a group 1 DMT and 30% a group 2 DMT (Table 1).

Table 1. Demographic and clinical characteristics of the multiple sclerosis patients.

Cross-Sectional Comparison of Lesion Count Between the LesionQuant Reports and the Neuro-Radiological Evaluations

The lesion count assessments by LQ and the neuro-radiologist were significantly correlated at TP1 (cor = 0.92, p = 2.2 × 10⁻¹⁶) and TP2 (cor = 0.84, p = 2.7 × 10⁻¹⁶) (Supplementary Figure 2). The lesion counts were identical in only two and three patients at TP1 and TP2, respectively. While lesion counts were higher by the neuro-radiologist in 39 and 40 patients at TP1 and TP2, respectively. Lesion counts were lower by LQ in 15 and 13 patients at TP1 and TP2, respectively. In general, the differences in number of lesions evaluated by LQ and the neuro-radiologist increased with age. For patients with higher number of lesions the neuro-radiologist tended to count more lesions than LQ, and the opposite with lower number of lesions, see Supplementary Figure 1. To evaluate the intra and interrater variability the neuro-radiologist recounted the lesions in 10 of the patients, and a second neuro-radiologist counted lesions in the same 10 patients. Both the intra- and the inter-rater variability were significantly correlated (cor = 0.96, p < 0.001, cor = 0.97, p < 0.001). This was also the case for the lesion number scores estimated between LQ, and two different neuro-radiologists.

The lesion volume assessments by LQ and the Cascade software were significantly correlated (cor = 0.7, p < 0.001).

Longitudinal Evaluations of Atrophy and Lesions

We also compared the LQ software with the assessment by the neuro-radiologist in identifying whole brain atrophy at TP2. The neuro-radiologist classified 12 subjects to have brain atrophy. These 12 subjects also had significantly lower scores on whole brain atrophy by LQ (mean brain volume percentile 37.0, range 10–80), compared to the subjects that were not classified as having brain atrophy (mean brain volume percentile 48.7, range 2–99).

At TP2, LQ and the neuro-radiologist agreed in classifying 33% of the subjects with atrophy (four out of 12 subjects). In addition, the neuro-radiologist identified eight more subjects with brain atrophy (mean LQ whole brain percentile 31.3).

LQ detected a reduction in whole brain percentile >10 in 10 patients between TP1 and TP2, while the neuro-radiological evaluation identified six of these. The evaluation by the neuro-radiologist identified an additional six patients with increased atrophy between TP1 and TP2, all of whom displayed low whole brain percentiles at TP2 (median 11, range 8–28) and decreasing percentile between the time-points.

At TP2 we found that LQ showed reduced whole brain volume in 51 patients compared to TP1 with a mean reduction in volume of 20.5 ml/1.59% (range 0.4–109.4 ml/0.03–8.08%) of the whole brain volume. In the remaining five patients we found an increased volume with a mean increase in volume of 6.8 ml/ 0.56% (range 0.2–17.4 ml/0.02–1.44%).

To evaluate the sensitivity of LQ in detecting new lesions, compared to the neuro-radiologist, the difference in number of lesions assessed at the two time-points was analyzed in a 2 × 2 table (Table 2). The sensitivity of the LQ-analysis to correctly classify the patients according to the gold standard neuro-radiological evaluation was 53% (17/32 patients). The specificity of the LQ-analysis to correctly evaluate the MRI follow-up as stable according to the neuro-radiological evaluation was 75% (18/24). In total, 43 % of the patients were evaluated with no new lesions on MRI at TP2 by the neuro-radiologist. Also, 57% (32 patients) had new lesions according to the neuro-radiologist, and only 17 of these had new lesions according to the LQ-reports (Table 2 and Figure 3).

Table 2. A 2 × 2 table based on the ability to capture MRI activity based on the presence of new lesions in our longitudinal MS sample.

Figure 3. An overview of the evaluations of change in lesions between the two time-points. The LesionQuant assessments are depicted with a circle, while the neuro-radiological evaluations are depicted using a triangle. Each subject is visualized with both assessments and with a unique color. The green circles show examples of assessments with good agreement between LQ and neuro-radiologist, while the red circles show assessments where the two methods differ a lot in the same patient.

Correlations Between MRI Features and Clinical Variables

We found significant positive correlations between T25FT and the lesion volume as measured by LQ at both TP1 (t = 3.08, p = 3.2 × 10⁻³) and TP2 (t = 3.72, p = 4.8 × 10⁻⁴) (Table 3). These results also indicate slower test performance by T25FT in patients with a higher burden of lesion volume. In addition, we found a significant positive correlation between the 9HPT using the left hand and lesion volume at TP2 (t = 5.34, p = 2.09 × 10⁻⁶), indicating slower test performance with increased lesion volume. We also found a significant negative correlation with EDSS and whole brain volume at TP1 (t = −2.68, p = 9.8 × 10⁻³), indicating higher EDSS scores with lower brain volumes. We found no significant correlations between the number of lesions reported by the neuro-radiologist and the clinical variables. All significant correlations reported were adjusted for multiple testing.

Table 3. Associations between LQ-variables and clinical variables.

Reliability of LesionQuant Volumes

To validate the LQ data with the established FreeSurfer output for brain segmentation we compared the measure for whole brain volume from both LQ (including brainstem) and FreeSurfer (excluding brain stem), (Supplementary Figure 2). At both TP1 (t = 51.6, cor = 0.99) and TP2 (t = 45.2, cor = 0.99), Pearson’s correlations were highly significant. We also validated regional volumes for thalamus using both raw FreeSurfer data and data processed through the longitudinal stream compared to the LQ data, yielding less significant correlations (t = 2.4–2.8 and, cor = 0.32–0.35, p = 0.02–0.008).

LesionQuant Reports and Neuro-Radiological Evaluation

All longitudinal LQ-data yielded excellent concurrence. To evaluate the consistency and agreement of the longitudinal LQ-reports, we measured the Intraclass correlation coefficients (ICC) between TP1 and TP2 for brain volume (ICC = 0.97, p = 2 × 10⁻³⁵), lesion count (ICC = 0.91, p = 1.4 × 10⁻²³), lesion volume (ICC = 0.88, p = 5.2 × 10⁻²⁰) and thalamus volume (ICC = 0.91, p = 3.0 × 10⁻²³) (Supplementary Table 1). We found significant correlations between lesion volume and the number of lesions at both TP1 (t = 6.32, p = 5.05 × 10⁻⁸) and TP2 (t = 4.21, p = 9.77 × 10⁻⁵). We found no significant changes in the parameters between TP1 and TP2 (Supplementary Table 1). As a sanity check, the ICC for lesion counts reported by the neuro-radiologist was very high (ICC = 0.99, p = 2.6 × 10⁻⁵⁰), as expected.

Discussion

Magnetic resonance imaging is an important para-clinical tool for the diagnosis and monitoring of MS. Quantitative measurements of lesion volume and distribution of lesions have a significant value for evaluating disease progression in a clinical setting and brain atrophy is a possible new measurement to be used in future evaluation in MS patients. In this study we explored the use of the LQ software for evaluating cerebral MS lesions as well as brain atrophy in a clinical setting, and investigated if an automatic analysis of MRI scans using such software shows promise for use in the clinical follow-up of MS-patients.

We found a high correlation between lesions counted by the neuro-radiologist at TP1 and TP2 and the lesion count output from LQ. In evaluation of atrophy between TP1 and TP2 there was only agreement between the neuro-radiologist and LQ in 50% of the patients (6 out twelve). Differences in whole brain percentiles between TP1 to TP2 were detected with LQ in the majority of patients, ranging between 0.03 and 8.08%. Lesion volume from LQ analysis correlated with outcome of clinical tests of walking speed and upper extremity function. Significant positive correlation was identified between lesion volume measured by LQ and test performance on the T25FT both at 1–5 years after diagnosis. There was a significant correlation between the results of LQ and the segmented volumes by FreeSurfer, showing high reliability of LQ output for whole brain volume. The correlation between lesion volume estimated by LQ and by the Cascade software were also highly significant.

In order to evaluate treatment-effect, it is of importance to see if new or enlarging lesions appear on a follow-up MRI scan. The lesion counts of the LQ software and the neuro-radiologist were highly correlated at both timepoints. However, visual assessment revealed somewhat higher lesion counts than the LQ assessment, more so in patients with a high number of lesions. The explanation of this difference in lesion number could be explained in differences in the definition of a lesion. As mentioned in the materials and method chapter a lesion was defined as having a T2/FLAIR signal ≥ 3 millimeters in diameter when analyzed by visual evaluation, but the lesion size set by LQ was ≥ 4 mm³. With the high correlation of lesion count overall, the LQ tool should be valuable for detecting lesions in routine follow-up MRI in MS. The resulting LQ report could then be controlled by a neuro-radiologist.

Regarding the detection of lesions, we used the assessment by the neuro-radiologist as the “gold standard.” However, it is well-established that the detection of cortical lesions may be challenging using conventional brain MRI and these may be missed by radiologists (29). This is shown in a study comparing the number of MS lesions counted by radiologists and as analyzed by MSmetrix (today known as IcoBrain MS), a software comparable to LQ (30). This study showed a higher recount-difference when recounting was performed by radiologists than in MSmetrix (31). Therefore, the gold standard as we defined it in this paper, may be more variable than the automated software tool.

Reliable evaluation of atrophy is difficult with only visual inspection, although it is not a very time-consuming task. Results from studies comparing visual ratings of atrophy using GCA have shown Inter-rater reliability of > 0.6 and Intra-rater reliability of >0.7, which is considered moderate agreement (32). When the neuro-radiologist evaluated the MRI, images from TP2 was compared with the MRI scan at TP1 for each patient. In a clinical routine setting, the neuro-radiologists often compare to the previous MRI, which may be taken months or up to a year before. The changes in atrophy are rather small from year to year −0.2 to −0.3% per year in our patients’ age range) (33) and it is not possible to detect such small changes in reduction of brain volume for the neuro-radiologist. A better approach may be to always compare the last scan to the first MRI in order to increase sensitivity of visual atrophy assessment. But even if there are several years between the MRI scans it could be difficult to estimate reduction in brain volume if the patients evaluated are young and stable. The discrepancy between the 12 patients found to have atrophy from visual inspection, to the 51 patients showing reduced brain volumes in the 5-year follow-up may indicate that LQ would be helpful in clinical practice. Never the less we should have in mind the risk of detecting reductions in whole brain volume with LQ which is not clinically relevant. Our MS population is young (mean age 36 years) and relatively stable (median EDSS 2,0). Finding small reductions in brain volume in such a population would not necessarily improve their general health condition. But overall, our results indicate that the automated method LQ performs better than the visual evaluation method in terms of atrophy evaluations, as discussed above.

Most of the MS patients were treated with moderately or highly efficacious disease modifying therapies at TP1 and TP2. In total, 10 MS patients changed to a more efficient MS treatment during the follow-up. We found no significant differences in brain volumes or change in brain volumes between the patients who increased treatment efficiency during the follow-up and those who either used the same treatment or reduced the efficacy of their MS treatment during the follow-up period. As a confounding factor we have to consider that switching to more efficacious treatments would impact the brain volumes by possible pseudoatrophy during the first 6 months (34). Although, during our observational period we did not find any significant differences. Other short term confounding factors affecting brain volume measurements are known, such as fluid restriction, the time of the day for MRI measurements, corticosteroids, antipsychotic treatment and short-term effects of pathological processes that decrease global brain volume (35).

LQ compared differences in brain volume during approximately a 5-year period (2012/2013 and 2016/2017). During this period the patients were scanned on several occasions, which were not part of the study. One of the main benefits of using automated methods for image analysis in MS patients, is the possibility to perform more reliable and quick evaluation of brain atrophy. As shown by Pareto et al. when comparing two different tools for automated volume analysis of different brain regions, the size of the brain region of interest seems to be important (16). We found an excellent correlation between the FreeSurfer and LQ software’s in the assessment of whole brain atrophy (cor = 0.99). However, for thalamus we only found modest correlations between both the raw and processed volumes estimated by LQ and FreeSurfer (cor = 0.32–0.35, p = 0.02–0.008, respectively), confirming the results of Pareto et al. In a recent paper, Storelli et al. also studied reproducibility and repeatability using different software’s for atrophy measurements (10). They concluded that an improved reproducibility between scanners is required for clinical application.

In our study the LQ software estimated an unexpected increased whole brain volume in six patients between TP1 and TP2. This could be due to variability in the MRI scanner or other technical reasons. Alternatively, changes in lesion load in the patient over time may affect the atrophy measurements (10).

We hypothesized that improved measurements of brain lesions and atrophy, using an unbiased automatic tool, may improve the correlation between clinical phenotype and MRI results. We found that only the automated LQ software was able to show significant correlation with the standard clinical tests (T25FT, 9HPT, and EDSS). We consider this to be a robust and expected finding as only LQ and not the neuro-radiologist could provide volumetric information. In line with this, the 9HPT was positively correlated with lesion volume at time-point two; although only significant for the left hand, the same trend was seen for the right hand. The EDSS scale, which is the most widely used method to grade disability in MS, was only associated with whole brain volume at TP1 (t = −2.68, p = 9.8 × 10⁻³). There were no correlations between lesion count, either from LQ or the neuro-radiologist and the EDSS, T25FT or 9HPT, also showing the value of having volumes of the lesions and whole brain available.

In general, we found very high levels of intraclass correlation coefficients (0.88–0.97), showing consistency and agreement among the longitudinal LQ-reports. A strength of this paper is the longitudinal design where the MS patients were examined clinically and with brain MRI both one and 5 years after diagnosis. The patient cohort is well-characterized by trained clinicians, performing the clinical and MRI assessments. The same MRI scanner and protocol was used for all patients at the two time-points of evaluation, and all patients were scanned in the afternoon/early evening. The neuro-radiological evaluation of the 56 patients at TP1 and TP2 was performed by the same neuro-radiologist, and in addition both inter and intrarater evaluations were performed. Thus, the quality of the data included in this study is suitable for addressing the research question. A weakness of the study is that we did not perform visual assessment by two independent raters for the visual evaluation of atrophy. Also, there was no control group.

The structured LQ report is acquired using fully automated MRI post-processing software, which requires only minimal effort and reduces bias of different raters, which is present when using visual inspection of images. Another advantage is the very short processing time of LQ compared to similar software used for research, with only about 10 min from the uploading of images to the final report is received. In comparison, software like FreeSurfer needs hours to process the data, cannot be interpreted for individual patients and is not feasible for clinical practice.

Conclusion

In conclusion, automatic analyses of MRI scans of MS patients may provide faster assessments than the traditional evaluation performed by the neuro-radiologist. LQ seems like a promising supplement to the evaluation by the neuro-radiologist, providing an automated tool for assessment of MS lesions and brain volume in MS patients.

Data Availability Statement

The current dataset cannot be made publicly available for ethical reasons, and public availability would compromise patient confidentiality and participant privacy. The study was conducted in humans and the dataset includes sensitive and personal information on individuals. A portion of data can be made available upon request to interested, qualified researchers provided that an agreement is made up. The minimal data set will enable replication of the reported study findings. Requests to access the datasets should be directed to Hanne F. Harbo, [email protected].

Ethics Statement

The studies involving human participants were reviewed and approved by The South Eastern Regional Committee for Medical and Health Research Ethics. The patients/participants provided their written informed consent to participate in this study.

Author Contributions

SB, EH, PB-H, HH, and MB contributed to the conception, design of the study, and drafted the text and figures. SB, EH, VC, GN, PB-H, HH, PS, and MB contributed to the acquisition and analysis of data. During review and editing of this manuscript, all authors contributed.

Funding

This project was supported by grants from The Research Council of Norway (NFR, grant numbers 240102 and 223273) and the South-Eastern Health Authorities of Norway (Grant Nos. 257955 and 2019111).

Conflict of Interest

SB has received honoraria for lecturing from Biogen and Novartis. EH has received honoraria for lecturing from Biogen, Merck and Sanofi-Genzyme. PB-H has received advisory board and/or speaker honoraria from Biogen, Novartis, Merck, UCB, and Teva. PS has received honoraria for lecturing and travel support from Merck. HH has received travel support, honoraria for advice or lecturing from Biogen Idec, Sanofi-Genzyme, Merck, Novartis, Roche, and Teva and an unrestricted research grant from Novartis and Biogen. MB has received honoraria for lecturing from Novartis and Biogen Idec, Merck AB, Roche Norge, and Sanofi Genzyme.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank all the patients who participated in our study. We acknowledge the collaboration with members of the Multiple Sclerosis Research Group at the University of Oslo and Oslo University hospital, especially Professor Elisabeth G. Celius. We acknowledge the collaboration with the Regional Core Facility in Translational MRI with leader Frode A. Tuvnes, Lisa Kjønigsen and research assistant Eva B. Aamodt.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2020.546744/full#supplementary-material

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MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—clinical implementation in the diagnostic process

Multiple Sclerosis MRI – How is MS Diagnosed?

Multiple sclerosis (MS) is a chronic condition that affects the central nervous system.

But accurately diagnosing the disease is extremely tricky. Both the symptoms and appearances on MRI results can mimic other conditions, such as migraines, stroke, and vitamin B-12 deficiency.

In a recent study, researchers found that nearly 1 in 5 people diagnosed with MS do not actually have the disease.

So what’s being done to prevent misdiagnosis? While there is no single test that can be used to confirm multiple sclerosis, MRI plays an important role in diagnosing and managing the disease.

From the benefits and limitations of a multiple sclerosis MRI to specific markers that help guide image interpretation – we spoke with expert neuroradiologist, Dr. Michael Rozenfeld, to find out what patients can do to ensure an accurate multiple sclerosis diagnosis.

DocPanel is committed to making sure every patient receives excellent care. If you would like an expert second opinion on your medical imaging scan from Dr. Rozenfeld or one of our other neuroradiology subspecialists, you can learn more here.

[DocPanel] What are the benefits of using MRI to diagnose multiple sclerosis rather than CT?

[Dr. Rozenfeld]

When diagnosing multiple sclerosis, we are using various tests and physical exam findings to look for demyelination (damage to the protective layer that surrounds the nerve fibers in your brain).

Currently, MRI is one of the main tools we use, and it is invaluable to detect, diagnose, and monitor the progression of multiple sclerosis.

CT can play an important role in emergency settings. Because it is much quicker to perform than MRI – CT is useful in ruling out intracranial hemorrhage (bleeding that occurs inside the skull). But a dedicated multiple sclerosis protocol MRI is required to further investigate and make a diagnosis.

[DocPanel] What symptoms indicate the need for a multiple sclerosis MRI?

[Dr. Rozenfeld]

Multiple sclerosis can affect vision, cognition, and coordination, as well as cause pain, numbness, and paresthesias, among other symptoms. But it varies greatly from person to person, making the diagnosis difficult. Also, symptoms in the early stages of MS can be quite subtle.

Since there is no definitive test for MS, a diagnosis takes time. It is a process that involves ruling out all other possible causes. If you are worried that you have symptoms of MS, it’s important to seek medical help right away.

[DocPanel] Are there any limitations in using MRI to diagnose MS? Should any other imaging tests be used in conjunction with MRI to diagnose the disease?

[Dr. Rozenfeld]

MRI has greater than 90% sensitivity in the diagnosis of MS; however, other white matter diseases can sometimes have a similar appearance on medical imaging. In older patients, age-related white matter changes and small vessel ischemia can also share similar features.

Because of this, multiple sclerosis MRI scans must always be looked at in conjunction with a patient’s history, physical exam performed by a neurologist, and any other diagnostic tests such as lumbar puncture and visual evoked potentials.

[DocPanel] What white matter patterns are indicative of MS?

[Dr. Rozenfeld]

The McDonald criteria is a tool utilized when interpreting suspected multiple sclerosis MRI scans. To be applied, it requires lesions in at least 3/4 of the following locations: periventricular, juxtacortical, infratentorial, and spinal cord.

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[DocPanel] Do all MS patients have brain lesions?

[Dr. Rozenfeld]

About 5% of patients with MS do not have brain lesions detected with current multiple sclerosis MRI techniques.

[DocPanel] What other specific markers help guide a multiple sclerosis MRI interpretation?

[Dr. Rozenfeld]

The role of imaging in the diagnosis of multiple sclerosis is to establish dissemination in space (lesions in different typical locations) and dissemination in time (lesions of different ages). Dissemination in space can be established with one MRI but dissemination in time requires an MRI with and without contrast and often a follow-up MRI.

[DocPanel] How can a patient ensure they are not misdiagnosed?

[Dr. Rozenfeld]

Any patient concerned about multiple sclerosis should seek the opinion of an experienced neurologist. Some neurologists sub-specialize in MS – which would be the best option.

A multiple sclerosis MRI is difficult to read. Imaging exams should be interpreted by a board-certified radiologist with a certificate of added qualification (CAQ) in neuroradiology. Keep in mind that scans are often initially interpreted by general radiologists, especially when performed in the emergency setting. A second opinion on medical imaging from an experienced neuroradiologist can add immense value.

[DocPanel] What role does MRI play in the treatment and management of MS?

[Dr. Rozenfeld]

A multiple sclerosis MRI is utilized to follow up on the efficacy of treatment as well as to exclude other diseases when new symptoms present. Just as with making a diagnosis, managing a disease also requires the expertise of an experienced physician.

[DocPanel] What advice do you have for patients who are navigating a potential MS diagnosis?

[Dr. Rozenfeld]

I would suggest finding an experienced neurologist whom you trust and enjoy working with because you will be seeing them for the rest of your life. Don’t be afraid to seek a second or third opinion until you feel that you have found the right doctor for you. Consider joining an MS support group, online or in person. And finally, don’t delay diagnosis and treatment.

[DocPanel] Is AI making an impact on the diagnosis of MS? If so, how?

[Dr. Rozenfeld]

In the future, artificial intelligence will have a large impact on all types of medicine, including the diagnosis, treatment, and follow up of diseases like multiple sclerosis. This may even include the interpretation of MRIs. This technology is, however, currently in the early research phase and will take many many years before it can be utilized clinically.

Multiple Sclerosis is a complex disease with varied presentations that are often misdiagnosed. It is important to seek a second, and sometimes third, opinion from a specialist if you are experiencing unexplained symptoms or are concerned that your diagnosis is incorrect.

Multiple Sclerosis: The Role of MR Imaging

Abstract

Summary: MR offers by far the most sensitive technique for detecting multiple sclerosis (MS) lesions and has proved to be an important paraclinical tool for diagnosing MS and monitoring therapeutic trials. Technologic advances of MR in recent years have dramatically improved our understanding of MS disease. This review will focus on the contribution of MR imaging in MS and provide a discussion of conventional and advanced nonconventional MR techniques with regard to current findings, clinical correlations, and future directions.

Multiple sclerosis (MS) is considered an inflammatory autoimmune neurologic disease that is characterized by pathologic changes, including demyelination and axonal injury. The first MR images of MS were produced in the early 1980s, when MR was introduced into hospitals. The high conspicuity abnormal signal intensities of MS lesions seen on MR imaging provided the best view yet of tissue injury, lesion activity, and disease accumulation compared with all other imaging modalities, including CT. Since then, MR imaging has become a routine clinical examination in MS and is used to help the diagnosis and track the natural course of the disease. With the advent of newer quantitative MR techniques—including volumetric MR imaging, magnetization transfer imaging (MTI), diffusion tensor imaging (DTI), and proton MR (¹H-MR) spectroscopy—our ability to detect and characterize the disease burden, including occult microscopic disease invisible when using conventional MR techniques, has largely improved. Today, MR imaging is the most important paraclinical tool for MS, and MR imaging–derived measures have been established as standard outcome markers to monitor the treatment response in various MS clinical trials.

Conventional MR Imaging

Conventional MR scanning offers the most sensitive way to detect MS lesions and their changes and plays a dominant role in ruling in or ruling out a diagnosis of MS. Although MS lesion plaques can be found throughout the brain, they have a predilection for periventricular white matter and tend to have an ovoid configuration with the major axes perpendicular to the ventricular surface.¹ At the initial stage, the lesions are typically thin and appear to be linear (Dawson’s fingers), which is probably associated with the inflammatory changes around the long axis of the medullary vein that create the dilated perivenular space² (Fig 1). Histopathologically, such perivascular inflammation has been thought to play a primary role in the disruption of the blood-brain barrier (BBB), in myelin breakdown, and in the formation of new lesions.³ In addition to the periventricular region, the corpus callosum, subcortical region, brain stem, U-fibers, optic nerves, and visual pathway are also regions where lesions are frequently located. The focal demyelinating lesions located along the lateral borders of the corpus callosum are best depicted by sagittal fluid-attenuated inversion recovery (FLAIR) imaging (Figs 2 and 3). The abnormalities of the corpus callosum, U-fibers, and optic nerves, however, may allow for the differentiation of MS from cerebrovascular disease. Although MS is a disease that predominantly affects white matter, lesions can and do occur in gray matter and are better detected on FLAIR imaging.⁴ In gray matter, MS lesions are usually small with an intermediate high signal intensity and a less severe degree of inflammation, which may cause the obscure appearance of gray matter lesions on MR imaging compared with that of white matter lesions.⁵ Optic neuritis, which appears early and may be the only presentation in the initial stage of MS, can be detected by using a fat-suppression technique combined with contrast-enhanced imaging or by using long-echo short-tau inversion recovery (STIR) imaging.^6,7

Fig 1.

Axial T2-weighted images of a 43-year-old RRMS patient show prominent perivascular spaces (short arrows), which project radially and are aligned with lesions, following the course and configuration of deep venular structures. This may be associated with perivascular inflammation, which initiates the development of new lesions (long arrow). These prominent perivascular spaces might have implications for differentiating primary from secondary demyelinating lesions.

Fig 2.

A 30-year-old female RRMS patient shown on T2WI (A), FLAIR (B), and contrast-enhanced T1WI. The lesions on FLAIR are usually prominent and several small lesions are depicted only on FLAIR (arrows). The lesion enhancement can be nodule (as shown in this case) or ringlike on T1-weighted imaging.

Fig 3.

MS lesion (arrow) in corpus callosum on FLAIR imaging is failed to be picked up on T2-weighted imaging.

On T1-weighted imaging (T1WI), the acute MS lesions are often isointense to the normal white matter but can be hypointense if chronic tissue injury or severe inflammatory edema occurs. The accumulation of hypointense lesions (so-called black holes) may correlate with disease progression and disability.⁸ In the acute inflammatory phase, the lesion may disrupt the BBB, leading to gadolinium enhancement (Fig 2) that is believed to be the first detectable event on conventional MR imaging,^9,10 and may last from days to weeks.^11,12 Enhancing lesions, which may vary in shape and size; usually start as homogeneous enhancing nodules and subsequently progress to ringlike enhancements. Contrast-enhanced T1WI is now routinely used in the study of MS and provides one in vivo measure of inflammatory activity. It is able to detect disease activity 5–10 times more frequently than the clinical evaluation of relapses,¹³ which suggests that most of the enhancing lesions are clinically silent. In the chronic stage, lesions often appear as isointense or hypointense on T1WI and usually persist for many years on T2WI. Some patients may experience the expansion of a pre-existing lesion with or without enhancement.

In recent years, MR imaging findings including the lesion number and location are included in the diagnostic criteria of MS.¹⁴ To address the role of conventional MR imaging in MS, however, several issues must be noted. First, the ability to detect lesions depends on not only the pulse sequence and imaging parameters, but also the field strength. Keiper et al found a mean of 88 more lesions on images obtained at 4T compared with images obtained at 1.5T in 15 patients with MS.¹⁵ Second, the number of enhancing lesions, which is suggestive of new lesions and inflammatory MR imaging activity, can be influenced by the dosage of the contrast agent. Studies have shown that a triple dose or 3 subsequent single doses can result in an increased number and size of enhancing lesions.^16,17 Third, numerous cortical lesions have been observed on histopathologic examination,¹⁸ but they are not commonly seen on conventional MR imaging. Further work must be done to develop a better sequence that would provide optimal higher spatial resolution and contrast for these lesions.

Volumetric MR Imaging: Lesion Quantification and Brain Atrophy

Lesion Load

In the past 2 decades, MR imaging has been frequently used to assess the disease burden, which is often based on the quantification of the T2 lesion load (ie, the total lesion volume and/or number) on MR imaging. A number of computer-assisted techniques for measuring MS lesion load have been developed to provide a fast, objective, and precise quantitative means for determining the extent of disease abnormality. The accuracy and reproducibility of these techniques depend on the imaging sequence, the section thickness, the degree of automaticity, and the technique itself.¹⁹ By applying the measures of lesion load on T2WI and total lesion activity on enhanced T1WI to clinical trial studies, objective screening of new putative therapies has been achieved to determine whether the drug favorably modifies the total pathologic evolution.^20–22 The T2 lesion volume increases approximately 10% each year in early relapsing-remitting (RRMS) despite month-to-month fluctuations,²³ which indicates that most RRMS will eventually develop into secondary progressive MS (SPMS). Overall, T2 lesion load is significantly higher and enhancing T1 lesion load is lower in SPMS than in RRMS.^24,25

The T1 lesion load including enhancing lesions or black holes correlated more closely than T2 lesion load with clinical outcome²⁶ as measured by Kurtzke’s Expanded Disability Status Scale.²⁷ MS lesions on T2WI, however, are spatially and pathologically nonspecific and T2 lesion load does not include the pathology underlying so-called normal-appearing white matter (NAWM), which is now clearly known to be abnormal. Therefore, although lesion load measures may not appear to adequately account for the patient’s functional state, they provide important information in monitoring the natural history and treatment effects of the disease.²⁸

Brain Atrophy

In addition to lesions, another imaging hallmark of MS is brain atrophy, which is considered to be a net accumulative disease burden as the ultimate consequence of all types of pathologic processes found in the brain.²⁹ Brain atrophy in MS usually appears as enlarged ventricles and the reduced size of the corpus callosum.³⁰ Recently, numerous quantitative methods have been developed for the precise measurement of global and regional brain tissue loss.²⁹ Atrophy is seen in all stages in a progressive manner, including patients with early MS,³¹ emphasizing the need for the earlier involvement of neuroprotective intervention. The rate of brain atrophy is higher in MS (0.6–1.0% annually) than in the normal aging process (0.1–0.3% annually).^32–36 Although the exact mechanism of atrophy in MS is not completely clear, it may result largely from myelin and axonal loss. A study found significant loss of white matter rather than gray matter in the early stage of MS,³⁷ which might indicate a different mechanism of atrophy in MS versus other neurodegenerative diseases such as Alzheimer disease.³⁷ Wallerian degeneration, particularly in the neuronal pathways, may also contribute to tissue loss in MS.³⁸ It has been suggested that the rate of brain atrophy is independent of the disease subtype^33,35 despite the significantly higher inflammatory activity often observed in RRMS versus SPMS.²⁵ The short-term fluctuation of brain volume (including a small increase) is more likely to be observed in RRMS.³⁹ Steroid treatment can reduce inflammation and may also cause short-term brain volume changes.⁴⁰ Global atrophy has been found in other forms of MS, including primary progressive MS and MS with monosymptomatic disease,^41,42 which indicates that atrophy is a significant and universal feature of MS. With this in mind, the quantitative measure of atrophy has been studied and included as an outcome measure in clinical trials of new disease-modifying agents. Several studies have already shown some therapeutic effects on atrophy on the basis of such atrophy measures.^20,43,44 Importantly, the correlation between brain atrophy and clinical disability is stronger than the correlation between lesion load and clinical disability.⁴⁵

In sum, volumetric MR imaging provides an objective account of the natural history of disease progression, activity, and tissue loss in MS and provides clinicians with a valuable tool for quantifying the disease. Currently, however, studies by using such automated segmentation techniques are mainly based on programs that were developed “in-house.” A reliable, quick, and clinician-friendly technique that can be used in the routine clinical setting remains in strong demand.

Magnetization Transfer Imaging

Unlike conventional MR imaging, MTI offers greater pathologic specificity for macromolecules such as myelin, and its signal intensity is inherently independent.⁴⁶ Dousset et al⁴⁷ and Grossman et al⁴⁸ quantified the MT effects by calculating the magnetization transfer ratio (MTR), which provides a unique imaging marker of myelin disorder. Normally, white matter has higher MTR than gray matter⁴⁹ probably because of the larger amount of myelin. Because MTR is proportional to the concentration of macromolecules (eg, myelin attenuation), the reduced MTR indicates the presence of pathologic and/or structural tissue injury. To assess the pathologic specificity of MTR in MS, studies by using MTI on experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune demyelination, have shown that the MTR correlates well with the level of demyelination.⁵⁰ In addition, the greater pathologic specificity of the MTR has also been demonstrated in several brain development studies,^51,52 in which the MTR has been shown to increase gradually with age during normal brain maturation in children. For example, a study by Engelbrecht et al⁵¹ showed a significant increase in MT contrast ranging from 13%–19% to 34%–37% in white matter in children aged 1–80 months. This is largely attributed to the progress of myelination, as the concentration of cholesterol and galactocerebroside in the myelin sheath increase.⁵³

Regional Differences: Region of Interest Analysis in MS

By using the region of interest analysis, studies found that hypointense lesions had a lower MTR than isointense lesions,⁵⁴ the central portion of ring-enhancing lesions had a lower MTR than homogeneously enhancing lesions,⁵⁵ and demyelinating lesions had a lower MTR than inflammatory lesions (edema).⁴⁷ In addition, the perilesional MTR is lower than that of the remote region.⁵⁶ The MTR in dirty-appearing white matter is lower than that of NAWM but higher than that of lesions.⁵⁷ Finally, the MS lesions usually have a more reduced MTR as compared with ischemic lesions in small vessel diseases.^58,59 These results suggest that MTI may increase the specificity of MR imaging in assessing the extent of demyelination or residual myelination of MS lesions.

Subtle pathologic changes are known to occur in the NAWM in patients with MS, which are not visible on conventional MR imaging but may represent a significant component of disease burden. MTI is sensitive in detecting not only the MS plaques, but also NAWM abnormalities.⁶⁰ The mean MTR was found to be significantly lower in many NAWM regions for MS patients than for normal controls.^61,62 Such MR imaging occult lesions in NAWM may involve low-grade burned demyelination, perivascular infiltration, axonal loss, and oligodendrocyte loss.⁶³ More interesting, several longitudinal studies^64–66 of lesion evolution have shown that the areas of NAWM that have a progressive, marked decline of the MTR will eventually develop into the new lesions on conventional MR imaging. The significant decline of the MTR at the onset of lesion development, however, can have a temporary profile of recovery after the new lesion is formed⁶⁷ and then subsequently experience a progressive decline as the lesion ages.⁶⁵ This temporary increase of the MTR is possibly associated with the dynamic inflammatory changes (eg, edema). Further, MTR might be a potential biologic marker for remyelination, an important repair process involving newly formed thin myelin that is now known to frequently occur in MS. A postmortem study has shown that the MTR in remyelinated lesions differs from the MTR in both NAWM and demyelinated lesions.⁶⁸

Global Assessment: MTR Histogram Analysis

MTI can also play an important role in assessing the disease burden by applying an MTR histogram based on whole brain tissue (so-called volumetric histogram analysis) as introduced by van Buchem et al.⁶⁹ The global MTR histogram allows for the evaluation of data from all pixels of the brain tissue (ie, parenchyma, gray matter, white matter), and therefore provides a more complete picture of disease burden, including the substantial occult pathology in NAWM. This is achieved by the registration and transformation of an MTR parameter map onto a segmented tissue map. The global analysis is particularly useful in assessing diseases with a diffuse nature such as MS, because such quantitative analysis can also be performed longitudinally to monitor disease progression or treatment efficacy. MTR histogram-derived measures including mean, peak position, and peak height appeared significantly different in MS patients as compared with normal controls.^69–71 The characteristics of the MTR histogram also differ between the various clinical forms of MS.^71,72 Several studies have found a correlation between global MTR histogram metrics and neurocognitive impairment,^70,71,73 which indicates that global MTR histogram analysis is sensitive to clinical changes in neurocognitive functions.

Classically, MS is defined as a white matter disease; however, evidence from both imaging and histopathologic studies increasingly shows that gray matter is not spared from the disease.^74–76 Because gray matter and white matter differ both anatomically and functionally, lesions in these 2 tissues are also different regarding their imaging and histopathologic features.^5,75 When measured globally, there are significant differences in the MTR histogram metrics for both normal-appearing gray matter (NAGM) and NAWM between patients and normal controls (Fig 4).^24,76 The cerebral T2 lesion load tended to have a negative correlation with the MTR histogram measures for global NAGM only,²⁴ which indicates the effects of retrograde neurodegeneration from distal white matter lesions on cortical gray matter. The MTR abnormalities in NAWM, however, may arise from a primary demyelinating process that is independent of the lesions. In addition, the changes of the MTR in normal-appearing brain tissues also differ between MS phenotypes (Fig 4)²⁴ and show different rates of progression.⁷³ The separate analysis of gray and white matter may allow for the improved detection of underlying subtle tissue abnormalities as well as a better understanding of the natural history of MS disease.

Fig 4.

Averaged magnetization transfer ratio histograms from 3 groups (healthy control, RRMS, and SPMS) for global NAGM (A) and NAWM (B) tissues. Lower normalized peak height in SPMS population indicates relatively less residual normal brain tissue compared with that in RRMS patients.

Compared with conventional MR imaging, MTI has shown increased pathologic specificity and high sensitivity to NAWM abnormalities. Therefore, MTI offers a unique, noninvasive tool for imaging myelin disorder, remyelination process, and occult pathology in MS.

Diffusion Tensor Imaging

Water molecule self-diffusion, referring to the microscopic random motion in biologic tissues, provides the basis of the modern picture of diffusion-weighted imaging (DWI). When water diffusion is measured for a complex medium, the diffusion coefficient of biologic tissue is lower than that in free liquid, and hence an “apparent diffusion coefficient” (ADC) is actually measured. In tissues, such as white matter, molecular movement is not the same in all directions (so-called anisotropy) due to the structural barrier within the fiber tracts, leading to an orientation-dependent diffusion property. DTI is acquired with diffusion weighting gradients in at least 6 noncolliner directions that allows for the construction of a tensor.⁷⁷ The tensor can be used to produce images of both mean diffusivity (MD) and fractional anisotropy (FA), which demonstrate voxel-by-voxel differences in the magnitude and directionality of water diffusion, respectively. Therefore, DTI may provide information about tissue microstructure and architecture including size, shape, and organization⁷⁸ and in turn constitutes a proved and effective quantitative method for evaluating tissue integrity at a microscopic molecular level. In addition, the information provided by FA can also serve as the basis for fiber tractography,⁷⁹ a method to determine the pathways of anatomic white matter connectivity.

Regional Differences: Region of Interest Analysis in MS

MS lesions are pathologically heterogeneous⁸⁰ and also show highly variable values of diffusion indices. In general, lesions have an increased MD or ADC and decreased FA when compared with the contralateral NAWM or normal white matter (Fig 5),⁸¹ which indicates the disruption of myelin and axonal structures that leads to disorganization and increased extracellular space. The increased values of the MD in MS lesions have been confirmed in studies of EAE.^82,83 The highest diffusion values (MD), however, appear to be found in hypointense lesions as compared with enhancing lesions and isointense lesions,^84–86 representing the long-standing destructive damage in the hypointense lesions⁸⁷ where water diffusion is most mobile or least restricted; however, the findings of whether enhancing lesions differ from nonenhancing lesions in terms of their ADC are inconsistent,^84–86,88 though FA is always lower in enhancing than in nonenhancing lesions.^89–91 This may suggest that the inflammatory effects (eg, edema) have a more variable impact on the ADC or MD than on FA, and that the BBB breakdown may also vary during this temporarily active period. In addition, FA is found to be markedly reduced in ring-enhancing lesions compared with homogenous enhancing lesions.⁸⁸ Because lesions in SPMS are often old and exhibit extensive tissue destruction, studies also reported a larger degree of changes in the MD and FA of such lesions as compared with those found in RRMS.⁸⁷

Fig 5.

DTI (left, b = 0), FA (middle), and MD (right) maps of a 31-year-old female patient with RRMS. The decreased value of FA and increased value of MD for the lesions (arrows) are shown in their maps. Note that the decreased FA (arrowhead) in some white matter areas is probably due to fiber crossing.

Studies of DTI in NAWM have also revealed a decreased FA and an increased MD in different regions,⁸¹ which is in agreement with findings from MTR studies and suggests the presence of subtle microstructural changes (eg, the loss of barriers) in the NAWM that are beyond the resolution of conventional MR imaging. DTI abnormalities in NAWM tend to be more severe in the periplaque regions.⁹² Several studies, however, did not show abnormalities of DTI indices in NAWM in early MS.^93,94 One study of DTI⁹⁵ showed significant water diffusion changes in the normal-appearing corpus callosum (NACC) in a group of patients with early MS; however, such significant abnormalities were not observed in other NAWM regions, which suggests a preferential occult injury of the corpus callosum in MS. The diffusion abnormalities of the corpus callosum also correlated with the cerebral lesion load,⁹⁵ which is probably due to the accumulative bridging effects of the corpus callosum that result in the wallerian degenerative changes from the connecting distal white matter plaques.⁹⁶ This is in agreement with a recent quantitative postmortem study⁹⁷ which showed a significant reduction in axonal attenuation or the total number of axons passing through the areas of corpus callosum that grossly appeared normal in MS.

In certain regions of NAWM, however, FA can be very low in the areas of fiber crossing, therefore, may not be a reliable marker for the diffusional abnormalities. By calculating the eigenvalues in different directions or by quantifying the radial diffusivity in a fiber tract region with known orientation, Song et al showed in an animal model the potential of DTI in differentiating myelin loss and axonal injury,⁹⁸ which should be validated with human data, given that such detailed and accurate information of axonal preservation in demyelinating lesions is clinically relevant in understanding disease severity and guiding treatment.

Global Analysis of the DTI Histogram

In MS, methods for quantifying the disease burden are always desirable to monitor disease progression and assess the efficacy of new drugs.⁹⁹ As with MTI,⁶⁹ DTI can also be assessed globally by using a histogram analysis, which also showed a significant difference between patients and controls.¹⁰⁰ Substantial clinical correlations between DTI findings and clinical disability were found in recent studies by using a histogram analysis of global or large amounts of tissue^101,102 but were not found in earlier studies based on region of interest analyses.^84,85 The involvement of gray matter is also indicated by DTI studies, and the abnormalities are shown to be greater in the progressive form of MS.^103,104 A moderate correlation between cognitive impairment and gray matter MD was observed in patients with RRMS, which suggests that DTI may reflect the severity of the linguistic, attention, and memory deficits due to the disruption of cortical function in these patients.¹⁰⁴

Fiber Tractography in MS

Recently, there has been interest in using fiber tractography obtained from DTI datasets to characterize white matter tract directionality and integrity in central nervous system (CNS) diseases. Recent experimental work¹⁰⁵ has demonstrated that the fiber tract disruption caused by the transection of lesions can be directly visualized on fiber tractography (Fig 6). Compared with NAWM, these lesions were associated with significantly fewer fiber tracts and lower FA.¹⁰⁶ Because MS lesions often occur in the white matter pathway, by using DTI tractography we have observed fewer fibers generated in the corticospinal tract at the brain stem level in patients with a higher cerebral lesion load than in patients with a lower lesion load.¹⁰⁵ The observation that fiber tract loss in the corticospinal tract is associated with distal upstream lesions supports the concept of wallerian degeneration and axonal transection in MS disease.¹⁰⁷ It should be noted, however, that, though the number of fibers can be quantified via tractography, this depends on the FA threshold and the degree of the trajectory angle provided. With continued advances and additional clinical applications, fiber tractography should play a vital role in not only the identification of tracts of interest, but also the quantification of the degree of axonal loss and demyelination within a specific white matter tract. This would improve the specificity of MR in monitoring the disease progression of motor and cognitive deficits in MS.

Fig 6.

Fiber tractography in a patient with MS (A) and a healthy volunteer (B). All the MS plaques (arrows) were marked and constructed in 3D. Note the reduced number of fibers when they traverse white matter lesions in the patient.

Perfusion Imaging

Because it has long been noted that vascular inflammation in the brain is the critical event in the pathogenesis of MS, there has been an increasing interest in studying the microvascular abnormalities in MS by using advanced MR imaging. The assessment of brain hemodynamics, including cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) is now possible by applying dynamic susceptibility contrast MR imaging (DSC-MR imaging), a technique that is being used more widely in clinical practice for measuring blood perfusion. Studies by using DSC-MR imaging demonstrate a significantly decreased CBF and prolonged MTT in periventricular regions of NAWM in patients with MS compared with controls.¹⁰⁸ The diminished perfusion in NAWM is supported by the histopathologic evidence and may indicate that MS has a primary vascular pathogenesis. The frequent edematous onion-skin changes on the vein wall and vascular occlusion have been documented in the early pathologic studies.^109,110 Recent work based on modern histopathologic techniques also demonstrates the hypoxia-like tissue injury¹¹¹ or thrombosis of small veins.¹¹²

Studies of MS lesions by using perfusion MR imaging have also shown evidence of hemodynamic abnormalities^113–115 including the increased CBV in acute lesions, which suggests that microcirculation may be modulated by inflammation or acute hypoxia. In a study by Wuerfel et al,¹¹⁴ the altered local perfusion changes can be detected before the disruption of the BBB and new lesion formation. By detecting various lesion types, Ge et al¹¹⁵ found not only enhancing lesions, but also some chronic nonenhancing lesions showing increased perfusion, which may indicate lesion reactivity or renewed inflammatory changes, which are also before BBB breakdown and not visible on conventional MR imaging. These findings are important in that hemodynamic abnormality is a significant component in the pathophysiology of MS lesions. Perfusion imaging may have a predictive role of lesion reactivity and/or new lesion formation and, therefore, has the potential to predict disease activity, and monitor disease progression or the effects of therapy.

¹H-MR Spectroscopy

The recent development of ¹H-MR spectroscopy has enabled the in vivo study of certain chemical compounds or metabolites in a variety of pathologic processes that affect the CNS. As a noninvasive adjunct to MR imaging, ¹H-MR spectroscopy offers potentially unique insights into the histopathology of MS.

Localized

¹H-MR Spectroscopy

In MS lesions, the most common and remarkable finding is the reduction of the N-acetylaspartate (NAA) peak (Fig 7) compared with other metabolites. In acute active lesions, the initial reduction of NAA at the onset of lesion development can be partially restored after the acute phase on serial MR spectroscopy studies,^116,117 which suggests that the decrease in the values of NAA does not necessarily imply permanent neuronal and axonal loss. The recovery of NAA may be related to the resolution of edema or neuronal dysfunction recovery. Choline (Cho) is found to be increased in the acute pathologic phase,¹¹⁸ which may be associated with the release of membrane compounds during active myelin breakdown, resulting in an increase of phosphocholine and glycerol-phosphocholine. In addition, a higher concentration of lactate may also be observed in the acute phase and is possibly related to the inflammatory or ischemic condition.^119,120 After careful exclusion of the spectral of lipid contamination, prominent resonances presumably originating in lipids or fatty acids may also be observed in the earlier stage of the disease,^121,122 indicating the breakdown of myelin and phospholipids due to active inflammation. Elevated concentrations of myo-inositol in MS plaques but not in other age-related white matter lesions may be observed and are thought to be of special interest for their differentiation.¹²³ The regional changes in all of these metabolite levels, however, have been observed to be dynamic and variable over time in MS,¹²⁴ and, as result, careful interpretation of the MR spectroscopy data is needed, depending on technical and physiologic conditions.

Fig 7.

Axial T2-weighed (TE/TR = 90/2500 msec) image of a 26-year-old woman MS patient superimposed with the MR spectroscopy volume of interest. Spectra from 2 lesions (2 and 4) and 2 contralateral NAWM regions (1 and 3) are shown on common intensity and chemical shift (ppm) scales.

¹H-MR spectroscopy can detect the biochemical alteration of metabolites in NAWM adjacent to or distant from lesions in MS. The extent of NAA decrease and Cho increase in NAWM may progress over time into new lesion^125,126 or lead to wallerian degeneration in certain white matter tracts.¹²⁷ In a study of clinical trials, patients with treatment showed a large increase of NAA/creatine (Cr) (71%) in NAWM during the 2 years of treatment, whereas NAA/Cr decreased (8.9%) in patients without treatment.¹²⁸ Taken together, NAA appears to be a sensitive marker for detecting axonal dysfunction in NAWM and is valuable in monitoring the therapeutic effects.

Global

¹H-MR Spectroscopy

Despite the potential benefits of localized ¹H-MR spectroscopy, its current form has certain limitations, including the diversity of neuroanatomic locations, the normal variation of chosen tissues, partial coverage, and serial data misalignment. To solve these problems, a nonlocalized ¹H-MR spectroscopy sequence has been developed for quantifying whole-brain NAA (WBNAA) concentrations,¹²⁹ which may be more likely to reflect the total axonal/neuronal dysfunction. A comparison study showed significantly lower WBNAA in patients with RRMS compared with age-matched controls,¹²⁹ and such a decline may vary in patients according to their particular NAA concentration dynamics,¹³⁰ which suggests that WBNAA might allow for the prediction of disease course, as well as reflect disease severity and improve clinical trial efficiency by enabling the selection of candidates on the basis of WBNAA dynamics in addition to clinical status. Measures of WBNAA were also compared with whole brain atrophy in a group of patients with RRMS to explore the relationship between WBNAA loss and brain atrophy. Patients exhibited a 3.6-fold faster rate of loss of WBNAA than the rate of loss of brain tissue as measured by fractional parenchyma volume, which suggests that neuronal/axonal dysfunction (NAA decline) may precede rather than follow parenchyma loss in MS.¹³¹

MR Imaging of Basal Ganglia Affected by MS

Gray matter, especially deep gray matter in the basal ganglia, is found to be associated with the presence and severity of various neurocognitive disabilities in MS.⁷⁴ Hyperintense lesions are not often seen in basal ganglia nuclei and the thalamus in MS. Conversely, abnormal hypointensities have indeed been observed on conventional T2 imaging.¹³² The reduced signal intensities may occur in all ferruginated neurons (Fig 8), which includes globus pallidus, putamen, caudate nucleus, substantial nigra, red nucleus, and thalamus. This is thought to be related to excessive iron deposition, which may cause injury because of oxidative stress. Using a newly developed method, magnetic field correlation (MFC), for iron quantification, one study found that MS patients had a significantly increased iron deposition in the basal ganglia, even in those cases with minimum signal intensity changes on conventional MR imaging,¹³³ which suggests that MFC imaging is sensitive in quantitatively detecting subtle iron accumulation. Such excessive iron can cause oxidative tissue injury through the formation of free radicals and the initiation of peroxidation with potential implications for clinically observed functional impairment. The exact mechanism for excessive iron deposition in the basal ganglia, particularly in iron-rich ferruginated neurons, remains unclear, though it may be associated with the interruption of the iron transport pathway or a hypoxia-induced iron increase.

Fig 8.

Axial gradient-echo imaging in a 29-year-old patient with MS (A) and a 34-year-old healthy volunteer (B). Greater hypointense signal intensities, which may be associated with excessive iron deposition, are seen in all ferruginated neurons in a patient compared with a healthy volunteer.

Spinal Cord Imaging in MS

The spinal cord is known to be frequently involved in MS or in combination with lesions in the brain. As many as 25% of cases have been found to involve only the spinal cord.^134,135 Most spinal cord lesions occur in the cervical cord. Cervical spinal MR imaging is particularly useful when the patient is suspected to have MS and brain lesions are absent. On T2WI spinal imaging, most plaques are peripherally located (commonly dorsolateral) and less than 2 vertebral body segments in length.¹³⁵ The lesions tend to be multifocal and present as well-circumscribed foci with an increased T2 signal intensity. With acute spinal cord lesions, enhancement is frequently seen. Spinal cord atrophy, which may reflect axonal loss, may also be observed and is believed to be an important element in disability.¹³⁶ Though rarely seen in other diseases, asymptomatic lesions of the spinal cord can be present in MS and may help lead to the correct diagnosis.¹³⁷

Relative to brain imaging, spinal imaging is more challenging because of the regional complex structures of the spine and intrinsic cord motion. Although fast spin-echo remains the preferred imaging technique, it may miss subtle lesions¹³⁸ and has been shown to be less sensitive than MT-prepared gradient echo and fast STIR sequences.¹³⁹ Unlike its applicability to the brain, FLAIR imaging appears unreliable in the detection of MS lesions in the spinal cord.¹⁴⁰ In recent postmortem MR imaging studies, cord abnormalities appeared more diffuse and marked despite their minute appearance on conventional MR imaging.¹⁴¹ During the past several years, quantitative MR imaging techniques have been applied to the spinal cord in an attempt to improve the detection of cord lesions and quantify the severity of tissue injury in lesions and a normal-appearing spinal cord. Several studies involving DTI have shown a significantly increased MD and decreased FA in a cross-sectional area of the cervical spinal cord in patients relative to controls.^142,143 DTI abnormalities in normal-appearing spinal cords are found to be more prominent in the lateral and posterior regions of the cord.¹⁴³ In addition, with advanced MTI and optimized sequences, subtle cord abnormalities were also detected in established MS¹⁴⁴; this is not the case for patients with clinical isolated syndrome by using regular MTI.¹⁴⁵ As faster and more advanced alternative techniques emerge in the clinical setting, spinal cord imaging will become more widely used in both the diagnosis and follow-up of MS and help monitor the disease progression and therapeutic effects.

High-Field MR Imaging and MS

High-field (≥3T) MR systems have been increasingly installed worldwide in recent years. It is important to note that continued advances in higher field strength with the leading edge technology may be applicable to both the clinical practice and the basic science research of CNS diseases including MS. One of the most obvious advantages of high-field imaging is the high signal intensity–to-noise ratio (SNR) that can be achieved. A higher SNR allows for thinner sections and higher-resolution matrices, which can improve the detection of lesions.¹⁵ The lesion counts can be 45% higher on a 4T system with better appreciation of tissue heterogeneity within lesions as compared with a 1.5T system. With higher resolution and increased contrast, high field also has the potential to detect cortical lesions, which are often obscure at conventional field strength. All of these improvements may allow for the earlier diagnosis of MS, especially in those patients who clinically are suspected to have the disease.

Another notable benefit of using high-field strength is that the susceptibility (T2*) effects are boosted, which improves the examination of microscopic venous structures, brain iron, and microbleeds in the CNS diseases. The enhanced visualization of microvascularity in brain tumors has been shown at higher strength.¹⁴⁶ In MS, the distribution of lesions usually follows a perivenous origin²; therefore, the relationship between microvascular abnormalities and lesions¹⁴⁷ will be more appreciated at higher field. The enhanced T2* effects are also beneficial for dynamic contrast-enhanced perfusion MR imaging and functional MR imaging due to the increased resolution and conspicuity of paramagnetic contrast agents and deoxyhemoglobin. However, the susceptibility-induced signal intensity loss and distortion near the skull base and air sinuses are also prominent at higher field strengths and should be carefully considered in clinical applications. In addition, with the improved sequence and design of the RF coil, the advantages of performing MR spectroscopy at higher field strengths should also achieve increased SNR for more detailed compounds that are obscured at 1.5T.¹⁴⁸ Thus, with the appropriate optimizations, high-field MR imaging will further strengthen the role of MR imaging in the study of MS.

Conclusions

In the past 2 decades, MR imaging has brought about dramatic changes in the clinical evaluation of a host of neurologic disorders. The application of MR imaging to MS is a well-recognized example with regard to the impact of MR imaging on MS, including diagnosis, natural history, and therapeutic monitoring. Several new imaging terms/concepts that have been developed through the study of MS—including “lesion load,” “NAWM,” “MTR,” and “WBNAA”—are now widely used in the evaluation of many other CNS diseases. MS is a challenging disease in all aspects ranging from etiology to diagnosis and treatment. It is also a disease that has greater heterogeneity in terms of clinical forms, imaging appearance, and treatment response. With the ever-advancing technology, MR imaging will certainly further improve our understanding of the MS disease and continue to play an extremely important role going forward. Table 1 lists characteristic imaging findings of MS. Table 2 summarizes the current and future role of MR imaging in MS.

Table 1:

MR imaging characteristics in multiple sclerosis

Table 2:

Summary of MR imaging in multiple sclerosis

Acknowledgments

This work was supported by grants R37 NS 29029-11 from the National Institutes of Health and NCRR M01 RR00096 (GCRC). Special thanks to Dr. Robert Grossman for the generous support of this work and the academic training over the years, and to Jennifer Mandell for manuscript preparation.

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• Copyright © American Society of Neuroradiology

Diagnosis of multiple sclerosis on MRI

Multiple sclerosis is a chronic progressive pathology of the nervous system that most often affects young people. This disease is very insidious, since its early signs are easily confused with symptoms of other diseases, which makes diagnosis very difficult. It is very important to make the correct diagnosis in a timely manner, this allows you to slow down the development of the disease, maintain working capacity for a long time and avoid dangerous complications.Today, the most informative method for diagnosing multiple sclerosis is magnetic resonance imaging.

Diagnostic benefits

The method of magnetic resonance imaging is very popular among doctors and patients. This is due to the following advantages:

• In just a couple of hours, the patient will be able to undergo a diagnosis, receive images along with a transcript, and go to the attending physician to make a diagnosis and prescribe treatment.
• The process of magnetic resonance imaging does not cause discomfort.
• Magnetic fields are harmless to the human body, unlike X-rays. Therefore, the number of MRI sessions is not limited.
• It is usually not necessary to specially prepare for the study, and the list of contraindications to it is small.

Indications for research

It is very important to detect multiple sclerosis in the early stages of the disease, therefore doctors conduct an MRI scan for potential patients.Diagnostics using magnetic resonance imaging can be prescribed in the following cases:

• Complaints of the patient about blurred vision, most often in one eye. Loss of vision, blurred vision, and a foreign body sensation in the eye may also occur.
• Periodic dizziness.
• Unsteadiness of gait and impaired coordination of movements.
• Impaired limb sensitivity: intermittent numbness, goose bumps, tingling sensations may occur.
• Muscle weakness.
• Possible disruption of the functioning of the pelvic organs. Most often this is manifested by sexual impotence (in men), as well as a violation of urination.
• Sleep disturbance.
• Feeling of anxiety, sudden fears.

Multiple sclerosis can present with other symptoms as well. The need for research is determined by the doctor.

Possible contraindications

Doctors may recommend a different type of diagnosis for multiple sclerosis if the patient has contraindications to MRI.

In what cases is research not allowed?

• If the body contains structures containing metal: pacemakers, wires, pins, implants, etc.
• If the patient has involuntary movements. For diagnosis, it is necessary to maintain a stationary state, otherwise the study may be insufficiently informative.
• With pronounced claustrophobia. Since the diagnosis of multiple sclerosis is carried out in a confined space, in the presence of claustrophobia, it is better to give preference to a different type of examination.

Contrast testing is prohibited for pregnant women (throughout pregnancy), during lactation, as well as with serious kidney disease. It is also required to conduct a test in advance in order to exclude an allergic reaction to the contrast agents used.

How to prepare for the procedure

Doctors say that urgently magnetic resonance imaging can be performed without prior preparation. If the MRI is scheduled for a specific day, try to follow a few guidelines:

• If an MRI scan with contrast is planned, you must come to the clinic on an empty stomach.The last meal should be no later than 5-6 hours before the MRI.
• Diagnostics can take up to 40 minutes, so it is better to go to the toilet in advance so as not to experience discomfort during the examination.
• If you are worried about the test, consult your doctor – he may prescribe you mild sedatives.
• It is forbidden to carry any metal objects into the tomograph capsule. Therefore, before the diagnosis, you need to take off all jewelry, hairpins, glasses and change into clothes without metal fittings.

How MRI is done in multiple sclerosis

For maximum information content and high quality of images, it is recommended to carry out diagnostics only in closed-type tomographs. Tell your doctor that an MRI is done to diagnose multiple sclerosis – this will help the doctor choose the right exam regimen. Before starting the diagnosis, you need to familiarize yourself with the simple rules:

• Do not be afraid of the noise that you hear when examining. If you are worried about loud noises, take earplugs with you.
• The patient must remain motionless during the MRI scan. Even small movements can lead to a decrease in the information content of pictures.
• Be sure to consult your doctor before making an MRI appointment. This type of research is absolutely safe only if there are no contraindications to the procedure.
• Despite the closed space, inside the device there are very comfortable conditions: ventilation, light, speakerphone, panic button (pressing it will stop the study).

The diagnostic procedure is as follows:

• The patient changes into a change of clothing that does not have metal inserts. You also need to take off your shoes.
• The examinee lies down on a pull-out table. To reduce the likelihood of accidental movements, the limbs and head can be fixed with soft straps.
• An injection with a contrast agent is injected into a vein if a study with contrast enhancement is prescribed (if necessary, this is done not before the study, but in the process, if the study without contrast enhancement revealed the presence of foci characteristic of the disease).
• The procedure takes about 40 minutes.

MRI with contrast

If an early stage multiple sclerosis is suspected, magnetic resonance imaging is most often performed with additional contrast enhancement. This makes it possible to recognize even the smallest pathological changes characteristic of this disease.

The contrast agent is injected intravenously a few minutes before the procedure and quickly spreads over the tissues and blood vessels, creating the effect of highlighting pathological foci in the images.

The advantage of contrast diagnostics also lies in the fact that it is completely harmless to the body. In just a day, the contrast is washed out of the body in a natural way, without accumulating in the tissues.

Interpretation of results

After the diagnosis is completed and the images are obtained, the doctor will have to decipher the images. This usually takes less than an hour.

How is disseminated syndrome recognized on images? With multiple sclerosis, the images show a typical distribution of foci in the white matter of the brain.In addition, this diagnosis is characterized by damage to the corpus callosum, arcuate fibers, temporal lobes, brain stem, cerebellum and spinal cord. Such a distribution of foci is not typical for other pathological processes, therefore, difficulties in making a diagnosis usually do not arise. In angiopathy, lesions of the brainstem are possible, but they are usually symmetrical and located centrally, while the lesions in multiple sclerosis are localized in the periphery.

Upon completion of the magnetic resonance imaging, the patient is given photographs and a transcript of the results in paper or digital form.Contact your doctor for diagnosis and treatment. Timely detection of multiple sclerosis prolongs the period of active life and performance.

What is multiple sclerosis, signs, stages, treatment

Multiple sclerosis is a chronic disease of the central nervous system. The pathology is based on autoimmune processes of damage to the myelin sheaths of axons. The conduction of nerve impulses is impaired, characteristic symptoms develop.A neurologist is involved in the treatment of the disease.

Etiology and causes

It is difficult to name the exact causes of multiple sclerosis – the mechanism of triggering autoimmune processes is unclear. It is only known that a viral infection can become a provoking factor. The microorganism in the human body produces proteins that trigger an abnormal immune response. In the lymph nodes, autoreactive B and T lymphocytes are activated.

People of all ages and both sexes are susceptible to the disease, but the diagnosis is more often made to young women of the Caucasian type living in countries of northern latitudes.

In the process of transmission of nerve impulses between cells, the myelin sheath of axons plays an important role. In multiple sclerosis, a person’s own immune system partially destroys this structure. Demyelination sites can be found in different parts of the body. In place of damaged cells, a sclerotic plaque of connective tissue forms, which completely blocks electrical signals. As a result, the main function of nerve fibers is inhibited.

One of the most common causes of multiple sclerosis is heredity.If there are people in the family with neurological diseases or autoimmune pathologies, the risks increase by about 30%. Another 70% are non-genetic factors of multiple sclerosis.

It is important to understand that it is not the disease itself that is inherited, but a predisposition to it. If one of the parents had multiple sclerosis, then in only 2% of cases, the child is diagnosed with the same. The rest of the babies have only an increased risk. That is, other things being equal, the risk of developing the disease in a child with a burdened heredity is higher than in children from healthy parents.

The provoking factors for multiple sclerosis are:

1. Age. Diagnosis is usually made between the ages of 20 and 40. But multiple sclerosis can develop in both children and the elderly. The later the debut, the more severe the disease progresses.

2. Infections. The risk of developing multiple sclerosis is increased by the presence of cytomegalovirus, polyoma and retroviruses, and the Epstein-Barr virus, which causes mononucleosis.

3. Dysbacteriosis. Oddly enough, the intestinal microflora directly affects the immune system. It is recognized that bacteria help active protective cells to recognize a threat and eliminate it in time. For unknown reasons, sometimes antigens of intestinal microorganisms provoke autoimmune processes and cause the progress of demyelination. Evidence for the theory comes from animal and human studies.

4. Smoking. Nicotine increases the risks and accelerates the destructive effects of the immune system.

5. Poor nutrition. Physicians around the world have suggested that excessive consumption of saturated animal fats may trigger the development of multiple sclerosis.

Symptoms of multiple sclerosis

The manifestations of the disease are individual. The nature of the symptoms depends on the location and degree of damage to the nerve fibers.

A sign of multiple sclerosis can be:

• numbness, weakness in the limbs;
• movement difficulties;
• reflex disorders;
• decrease in visual acuity for no apparent reason;
• unsteady gait;
• double vision, dizziness;
• increased muscle tone;
• change in the nature of speech: it may become delayed;
• increased fatigue and weakness;
• emotional instability;
• violation of urination, etc.d.

The first symptoms can appear at a young age, in 20-40 years. In the early stages of multiple sclerosis, patients rarely pay attention to alarming signs, continue to live and work in the same rhythm. Periods of exacerbations are followed by remissions, sometimes without taking medications. Several years can elapse between episodes of illness. The intervals are gradually reduced. When the disease progresses, a person himself notices changes in his condition and turns to a doctor.Severe symptoms of multiple sclerosis reduce quality of life.

In medical practice, there are cases of rapid progression. Early multiple sclerosis progresses to advanced stages in just a few years. Loss of physical activity progresses constantly and leads to disability, while other patients with the same debut continue to lead a full life in society.

Forms of multiple sclerosis

Allocate:

1. Clinically isolated syndrome (CIS). This is a harbinger of multiple sclerosis. A clinically isolated syndrome is a manifestation of one or more neurological symptoms for 24 hours or longer.

2. Remitting form of multiple sclerosis. The period between exacerbations lasts for years and even decades. At the same time, disability is growing steadily. The remitting form inevitably progresses. Sometimes it is short or absent altogether.

3. Secondary progressive form of multiple sclerosis. The disease develops within several years after the establishment of remitting pathology. In every second case, the secondary progressive form occurs 10 years after the onset of symptoms. 30 years after relapsing-remitting multiple sclerosis, 90% of patients are diagnosed with the transition to this stage. The disease is characterized by a severe course with a constant increase in symptoms.

4. Primary progressive form of multiple sclerosis. Pathology is difficult from the very beginning, without remission, leading to rapid disability.

Diagnostics

The disease has no specific symptoms. At an early stage of multiple sclerosis, examination of the patient does not reveal any pathologies. Inexperienced specialists often conclude that unusual symptoms are caused by overwork or emotional state of the patient. Retrospective assessments show that every second patient has been ill for at least 5 years by the time they see a doctor.

Any of the clear signs of multiple sclerosis can be observed in other pathologies of the nervous system. Therefore, it is important to carry out differential diagnosis with an experienced specialist.

The set of surveys includes:

1. MRI of the brain and spinal cord. The images show damaged areas of nerve fibers. For better detail, MRI with contrast is performed. If there are no plaques on the tomogram, but the patient is diagnosed with a clinically isolated syndrome, then the risk of developing multiple sclerosis is low.

2. Analysis of cerebrospinal fluid. A puncture is performed to collect cerebrospinal fluid. With multiple sclerosis, myelin breakdown products are found in the cerebrospinal fluid. The results of the analysis are not sufficient for an unambiguous diagnosis, but are necessary for a comprehensive assessment of the clinical picture.

3. Doppler ultrasonography of the vessels. Research is necessary to rule out other diseases with neurological symptoms.

4. Evoked potential analysis. A more precise diagnostic method based on measuring the electrical activity of neurons in response to stimulation of specific nerve pathways. The analysis allows you to establish a violation of the conduction of the impulse caused by changes in the sheaths of the axons.

5. Blood tests. Results are needed to rule out infectious diseases and autoimmune conditions that can affect the functioning of the nervous system.

To make an accurate diagnosis, the physician needs to detect signs of demyelination in two different zones of the central nervous system (dispersion), confirm the formation of plaques at different times, and exclude other possible neurological diseases.Therefore, according to the results of the first examination, the specialist writes assumptions. The final diagnosis is made after the discovery of new plaques on repeated images, which are taken at intervals of 6 months.

Treatment

Drug treatment

Multiple sclerosis therapy is aimed at reducing the activity of the immune system in terms of attacks on the sheaths of nerve fibers. The doctor prescribes medicines in the form of injections or tablets. Modern drugs help stop the processes of neurodegeneration and significantly increase the patient’s life expectancy.The earlier the treatment of multiple sclerosis is started, the more favorable the prognosis. In advanced cases, a persistent neurological deficit develops, which does not respond to therapy and leads to disability.

More than 10 drugs have been approved for the treatment of multiple sclerosis in the world, conditionally divided into 4 groups:

1. Immunomodulatory agents. Active substances suppress the activation of autoreactive lymphocytes.

2. Preparations with selective action. The drug binds to the receptors of the lymphocytes and prevents them from leaving the lymph nodes.

3. Humanized monoclonal antibodies. The drugs prevent the penetration of autoreactive lymphocytes to the site of inflammation.

4. Immunosuppressants. Suppress the activity of the immune system.

The effectiveness of drugs against remitting and secondary progressive forms of the disease has been proven. Research is currently underway on medications for the treatment of primary progressive multiple sclerosis. Some drugs are included in the list of vital drugs and are purchased with federal budget funds.

Multiple sclerosis with onset in middle age and without quality treatment for several years can be fatal. The cause of death is usually renal failure, which develops against the background of recurrent urinary tract infections.

Hemocorrection treatment

The goal of the doctor is to cleanse the blood from immune complexes and decay products of nerve cells.
There are several modern treatment methods:

1. Immunosorption. Selective method for removing immunoglobulins and low density lipoproteins from blood. The content of the remaining components remains unchanged.

2. Incubation of cell mass. The patient’s own blood structures are used – pharmacocytes. With the help of cells, drugs are delivered directly to the site of destruction. The method allows you to increase the effectiveness of drugs, reduce their dosage, and reduce the risk of side effects.

3. Plasma cascade filtration. Viruses, bacteria, toxic substances are selectively removed from the substance, all side elements are retained. Plasma passes through a special filter system.

4. Cryoapheresis. Semi-selective method based on the ability of large blood plasma molecules to form insoluble compounds and settle at low temperatures.

5. Lymphocytopheresis. Lymphocytes – cells of the immune system – are removed from the blood.The method allows you to suppress abnormal reactions without taking drugs and practically without side effects.

6. Photopheresis. Blood outside the patient’s body is exposed to ultraviolet radiation of a specific wavelength. Light causes the death of lymphocytes. After that, the blood is returned to the vessels.

Autologous stem cell transplantation

One of the new methods of treatment, which involves “rebooting” the immune system.Before transplantation, complete destruction of autoreactive lymphocytes is achieved. Then the patient is injected with his own hematopoietic stem cells, the immune system restores the protective structures, but already without abnormal reactions. The technique cannot influence the changes that have already taken place. But transplantation significantly slows down or completely stops further demyelination.

Treatment is complex, long, and requires constant medical supervision. The patient is in the hospital at this time.After transplantation, rehabilitation is required, which takes several months until the functions of the immune system are restored.

Over the past 20 years, doctors around the world have made great progress in the treatment of multiple sclerosis. Drugs are being developed that suppress autoimmune inflammation at various stages of development. Cellular technologies help to partially restore the lost functions of the nervous system, so far, of course, within the framework of clinical trials.

Diagnostics and treatment of multiple sclerosis in Moscow

Timely and high-quality medical care will help maintain the quality of life in multiple sclerosis for many years. Make an appointment with a neurologist at the MedEx clinic. In our center you will find a comprehensive examination and competent treatment. The doctors of the clinic are constantly improving their qualifications, studying new drugs and technologies, helping patients achieve the desired results. You can make an appointment through the feedback form or by phone.

Russian scientists proposed a method for detecting multiple sclerosis

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Russian scientists proposed a method for detecting multiple sclerosis

Russian scientists proposed a method for detecting multiple sclerosis – RIA Novosti, 04/10/2019

Russian scientists proposed a method for detecting multiple sclerosis

Siberian scientists proposed a quick and inexpensive method for detecting multiple sclerosis based on aptamers and bioluminescent proteins for analysis… RIA Novosti, 10.04.2019

2019-04-10T11: 43

2019-04-10T11: 43

2019-04-10T11: 43

science

Krasnoyarsk

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KRASNOYARSK, April 10 – RIA Novosti. Siberian scientists have proposed a quick and inexpensive method for detecting multiple sclerosis based on aptamers and bioluminescent proteins; it will be enough for the patient to donate blood for the analysis, the press service of the Federal Research Center “Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences” (FRC KSC SB RAS) reports.Multiple sclerosis is an autoimmune disease, a breakdown in the way the immune system protects the brain: it breaks down there and the immune system starts attacking the brain. The disease usually manifests itself in visual impairment, muscle weakness, impaired sensitivity and coordination of movements. In general, the clinical manifestations of multiple sclerosis are very diverse, which is why the diagnosis is often difficult. Experts note that early diagnosis and timely treatment can slow down the development of the disease and improve the patient’s life.At the moment, methods for determining multiple sclerosis are complex and not always available. Magnetic resonance imaging and analysis of cerebrospinal fluid are usually done to identify and confirm the diagnosis, which are expensive, complex and time-consuming. Scientists have proposed detecting disease using RNA aptamers and bioluminescent proteins. According to them, aptamers are DNA or RNA molecules synthesized in the laboratory that can recognize and bind to specific target molecules.This analysis targets pathogenic autoantibodies that attack their own body’s myelin. When an aptamer finds a target cell in the patient’s blood, it binds to it. The aggregate of the bound aptamer and the target itself does not manifest itself in any way. “To identify the obtained complexes, it was proposed to preliminarily” mark “the aptamer with a bioluminescent protein obelin, which is capable of glowing. If the target was not detected, the glow does not occur. 177 blood samples from healthy and sick people with a confirmed diagnosis.The fusion of the aptamer and the bioluminescent protein allows the molecules to be more sensitive to the target and detect it faster, “the report says. Studies have shown that the recognition of healthy patients with negative scores is 96%. The likelihood that patients with positive results actually have the disease is 52%. The test is not yet able to distinguish the stages of the disease. “We believe that in the future, after the refinement of our test system, it will be possible to recognize multiple sclerosis, monitor its course and evaluate the effectiveness of the therapy used.Nowadays, complex and expensive methods are used for this. Compared to this, blood diagnostics is easier, faster and more profitable “, – quotes the press service of a researcher at the Institute of Biophysics KSC SB RAS Vasilisa Krasavitskaya. According to her, the MRI study will remain the main method of making a diagnosis. The proposed analysis will be a convenient additional a tool suitable, including for a wide primary examination of patients.

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KRA April 10 – RIA Novosti. Siberian scientists have proposed a quick and inexpensive method for detecting multiple sclerosis based on aptamers and bioluminescent proteins; it will be enough for the patient to donate blood for the analysis, the press service of the Federal Research Center “Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences” (FRC KSC SB RAS) …

Multiple sclerosis is an autoimmune disease, a breakdown in the way the immune system protects the brain: a breakdown occurs there, and the immune system begins to attack the brain. The disease usually manifests itself in visual impairment, muscle weakness, impaired sensitivity and coordination of movements. In general, the clinical manifestations of multiple sclerosis are very diverse, which is why the diagnosis is often difficult.

5 December 2018, 11:22At the moment, methods for determining multiple sclerosis are complex and not always available. Magnetic resonance imaging and analysis of cerebrospinal fluid are usually done to identify and confirm the diagnosis, which are expensive, complex and time-consuming. Scientists have proposed detecting disease using RNA aptamers and bioluminescent proteins.

According to them, aptamers are DNA or RNA molecules synthesized in the laboratory that can recognize and bind to specific target molecules.This analysis targets pathogenic autoantibodies that attack their own body’s myelin. When an aptamer finds a target cell in the patient’s blood, it binds to it. By itself, the aggregate of the bound aptamer and the target does not manifest itself in any way.

3 January 2019, 19:00If the target was not detected, the glow does not appear. The study was conducted on 177 blood samples from healthy and sick people with a confirmed diagnosis. The fusion of the aptamer and the bioluminescent protein allows the molecules to be more sensitive to the target and to detect it faster, “the report says.

Studies have shown that the recognition of healthy patients with negative values ​​is 96%. The likelihood that patients with positive results do have the disease – 52%.The test is not yet able to distinguish the stages of the disease.

May 27, 2018, 08:00

“Half a body was numb.” How people with multiple sclerosis live

“We believe that in the future, with the refinement of our test system, it will be possible to recognize multiple sclerosis, monitor its course and evaluate the effectiveness of the therapy used. Nowadays, complex and expensive methods are used for this. this makes blood diagnostics easier, faster and more profitable “, – quotes the press service of a researcher at the Institute of Biophysics of the KSC SB RAS Vasilisa Krasavitskaya.

According to her, the study of MRI will remain the main method of making a diagnosis. The proposed analysis will be a convenient additional tool, suitable, among other things, for a wide primary examination of patients.

October 31, 2017, 12:15 PM

To begin with, it is worth noting that multiple sclerosis is a serious disease that requires constant attention and control, and not just distraction and forgetfulness, as many believe.In this disease, external symptoms are accompanied by damage to the myelin sheath, which covers the nerve fibers of the brain (brain, spinal). It is with the help of MRI that multiple sclerosis can be diagnosed in a timely manner and taken measures for treatment in time. The current possibilities of medicine can significantly reduce the severity of the disease and the number of exacerbations, but this requires high-quality diagnostics.

The inhabitants of our latitudes should be especially attentive to their health, since this disease and its prevalence, according to experts, largely depends on the place of residence of the person.The “higher” the degree of latitude, the greater the likelihood of multiple sclerosis. Most of all “chances” of getting this disease in people living on the 30th parallel and higher to the north. Thus, all citizens of Ukraine fall into the high-risk zone. And, by the way, residents of European countries suffer from multiple sclerosis more often than those living in various Asian countries. Residents of equatorial Africa, Malaysia, Ecuador and Colombia are practically not at risk of getting sick.

How to diagnose multiple sclerosis on MRI?

MRI in case of multiple sclerosis or suspicion of this disease is performed several times in order to make an accurate diagnosis, to reveal the extent of damage to nerve fibers, and also to monitor the effectiveness of the therapeutic measures taken.Such an examination usually involves a contrast agent containing gadolinium (gadodiamide, magnevist, gadovist, omniscan, etc.). In this case, the contrast is administered intravenously.

Let us clarify that MRI diagnostics establishes multiple sclerosis in the same way as other diagnoses: by interpreting the data obtained by exposure to a magnetic field on hydrogen atoms in the human body. Since the myelin layer is a fatty layer, it is water-repellent.Where this layer is damaged, no water-repellent effect is observed. As a result, the concentration of water in the damaged areas is higher than it should be normal.

How an MRI is done:

• Introduce contrast (special substance).
• The patient is placed in the tomograph.
• Position the body parts to be examined under the ring scanner.
• Take and visualize readings.

Therefore, when patients ask the question whether multiple sclerosis is visible on an MRI, a very specific answer can be given.The affected areas are displayed as a bright white spot or a darkened area. The imaging option depends on the type of MRI that will be selected for you individually.

Where to get an MRI scan for multiple sclerosis in Kiev?

If you or your relatives have multiple sclerosis, an MRI scan can be done in our Center “SDS” / “Successful Diagnostic Systems”. The research is carried out in any of the branches of Kiev or in Drohobych.

Treatment of multiple sclerosis in St. Petersburg (St. Petersburg) – clinic “Poem of Health”

This disease in recent years began to manifest itself in people of working age.In this regard, medical centers in St. Petersburg began to pay special attention to early detection and adaptive therapy.

Today in St. Petersburg multiple sclerosis can be cured in the multidisciplinary paid clinic Poem Health, where there is a neuralgia department and a diagnostic center equipped with modern equipment.

This allows you to undergo examination, therapy and rehabilitation in one medical institution.

Description of the disease

Multiple sclerosis, for the treatment of which only drugs registered and approved in the Russian Federation are used in St. Petersburg today, is a violation of the transmission of impulses along nerve fibers.This pathology has nothing to do with senile marasmus, which is popularly called sclerosis. Only in severe forms, patients can develop impaired mental activity and a decrease in intelligence. Meanwhile, the disease has a chronic course, due to the formation of defects in the sheath of nerve fibers.

Among the causes of multiple sclerosis, it should be noted hereditary predisposition, previous spinal cord and brain injuries, frequent infectious diseases, poisoning with poisonous substances and radiation exposure, as well as numerous and severe stresses.

The danger of MS lies in the fact that over time it leads to a decrease in mental abilities, the development of epilepsy and paralysis, prolonged depression, renal failure and other pathologies of the genitourinary system.

The risk group includes people from 20 to 40 years old, people with a hereditary predisposition, as well as those suffering from autoimmune diseases. According to the statistics, women more often than men suffer from multiple sclerosis, which does not respond to treatment; you can only provide assistance to reduce symptoms and improve the condition of patients.

In addition, it was noted that the pathology is dependent on race. Thus, representatives of European nations are more likely to suffer from multiple sclerosis. The disease is rare in Japanese, Koreans, Chinese.

Unfavorable environmental conditions, for example, increased radioactivity and air pollution with toxic substances, also affect the spread of the disease. Residents of metropolitan areas are more likely to suffer from multiple sclerosis.

Meanwhile, statistics indicate an increase in the number of patients in recent years.This is due to both a real increase in morbidity and an expansion of diagnostic capabilities, which make it possible to ascertain the presence of pathology.

Today, multiple sclerosis therapy consists of the appointment of potent hormonal drugs, correction of the immune system, psychotherapy and prevention.

Symptoms

The characteristic signs of multiple sclerosis are:

• Decreased physical activity and increased muscle tone.
• Numbness and tingling sensation in the limbs.
• Deterioration of tactile sensitivity.
• Impaired coordination (staggering when walking).
• Nystagmus and decreased visual acuity.
• Indistinctness and deceleration of speech function.
• Impaired concentration.
• Fading out of sexual activity.

In addition, patients with multiple sclerosis complain of general weakness, rapid fatigue, and irritability.

With the progression of the disease, affective disorders develop, which can manifest themselves as depressive states and outbreaks of euphoria.At the same time, prolonged depression of mood can be caused by the news of the diagnosis, against the background of domestic or work problems.

In euphoric states, there is a decrease in intelligence, there is no awareness of the seriousness of the disease. In the early stages of MS, 80% of patients experience mood swings.

The disease proceeds with alternating periods of exacerbations and remissions.

Diagnostic methods

Since the course and manifestation of MS depends on the area of ​​the brain and spinal cord lesions, it is necessary to conduct a thorough examination of patients in order to select an adequate therapy.

For this purpose, an MRI scan using a contrast agent is prescribed.

MS can develop due to a violation of the body’s immune response. Therefore, laboratory blood tests are carried out. In addition, differential diagnosis is carried out to exclude other neurological diseases.

Sometimes it is necessary to analyze the cerebrospinal fluid.

It should be noted that potent hormonal drugs are used in the treatment of MS, therefore, a digestive examination must be performed prior to prescribing them.That allows you to exclude possible contraindications. For this, an ultrasound diagnosis is prescribed.

All these and other necessary studies can be done at the Poem of Health clinic, since the center is equipped with advanced equipment and laboratory reagents to carry out high-quality analyzes.

In addition, comfortable conditions have been created for patients who can come to an appointment at a convenient time by appointment from the website or by phone.

Doctors of the Poem of Health believe that each person is individual, therefore, the choice of treatment tactics is always based on a thorough study of the patient’s body and its characteristics.

The advantage of the clinic is its reasonable pricing policy, which provides not only affordable cost of diagnostic and treatment procedures, but also discounts, promotions and comprehensive programs. This opens up the possibility of receiving highly qualified medical care for various segments of the population.

In addition to the main drug treatment of MS in the clinic, you can take a course of physiotherapy, as well as psychological assistance. Its purpose is to suppress stress in patients with multiple sclerosis.The fact is that the disease proceeds with periodic exacerbations. This leads to the fact that the person with MS is in constant expectation of a new manifestation of symptoms. Besides. psychotherapy is aimed at relieving prolonged depression, which has a positive effect on the results of drug treatment.

Patients with MS are advised to attend exercise therapy classes to improve their condition.

Neurologists, psychotherapists and physical therapy instructors at the Poem of Health clinic work in close contact.This allows in the treatment of multiple sclerosis to take an integrated approach, which opens up the possibility of achieving positive results of therapy.

Despite the fact that multiple sclerosis is an incurable disease, today it can be corrected, which significantly improves the quality of life of patients. It is necessary to include prevention in the complex of therapeutic measures, which consists in regular visits to the attending physician, conducting MRI and other apparatus studies during therapy to determine the dynamics, adherence to recommendations regarding nutrition and sleep and wakefulness, as well as cessation of smoking and alcohol.

In the early stages, multiple sclerosis occurs without pronounced symptoms, however, in some areas of the brain and spinal cord, lesions are already noted. Therefore, for the timely detection of the disease, persons at risk should undergo a preventive examination.

Prices for services

• Neurologist consultation

Pay attention! Prices are for adult patients. Please see the cost of a pediatric consultation with a neurologist in the Pediatrics section.

Our doctors

9000 9002 Neurologist, reflexologist Rasotherapist

, signs of sclerosis on MRI

Multiple sclerosis is accompanied by the appearance of lesions (demyelination – destruction of myelin) in the central nervous system.The disease is characterized by a variety of clinical manifestations. Magnetic resonance imaging is one of the most informative diagnostic methods. The study allows you to determine with the help of MRI signs of multiple sclerosis and choose the appropriate treatment.

The study is safe, can be repeated regularly without harm to the patient’s health. MRI is highly informative, it helps to identify the initial signs of damage to the white matter of the brain and other changes characteristic of multiple sclerosis.

What kind of MRI is done for multiple sclerosis?

In multiple sclerosis, the first step is to scan the brain. It is recommended to choose a tomograph with a high magnetic field strength (from 1.5 Tesla). In this case, it is possible to identify foci of multiple sclerosis on MRI, to confirm the diagnosis and select the appropriate medical tactics.

The detection of characteristic changes in the brain and the presence of a clinical picture is an indication for a neurologist to prescribe an MRI of the spinal cord in multiple sclerosis in order to assess the extent of the spread of pathology and damage to this organ of the central nervous system.Multiple sclerosis requires a differential diagnosis. It is necessary to conduct a comprehensive examination. Multiple sclerosis is differentiated from diseases that cause the appearance of multiple foci in the central nervous system (encephalitis, systemic vasculitis, collagenosis).

What does an MRI show in multiple sclerosis?

During the study, the diagnostician receives the finest sections of the structures of the spinal cord and brain. The specialist knows exactly what multiple sclerosis looks like on an MRI, but the final diagnosis can only be made after receiving the results of a comprehensive examination.

During tomography, not only new, but also old lesions of the central nervous system are visible. Additionally, specialists carry out contrast enhancement. The technique allows you to identify the smallest pathological changes, determining the stage of development of the disease. The applied contrast agent accumulates in the affected tissues, which is clearly visible in the images.

Signs of multiple sclerosis on MRI of the brain

Pathological foci of multiple sclerosis on MRI are located mainly in the white matter of the brain, along the edges of the corpus callosum, in the region of the cerebellum, trunk and legs.The most specific sign is the presence of juxtacortical localization, damage to the temporal lobe. In patients with multiple sclerosis, the lesions have an oblong shape, characteristic features (Dawson’s fingers), located perpendicular to the ventricles of the brain.

Figure. MRI for multiple sclerosis. In the substance of the brain, bright foci of demyelination are determined against the background of an unchanged signal from the substance of the brain. When performing mapping of MR spectroscopy data, an increase in the content of choline as a marker of destruction of cell membranes (red areas) is determined against the background of its normal content (green).

When using contrast, there is a clear increase in the MR signal from pathological foci that accumulate contrast agent and are located in the area of ​​arcuate fibers.

Conclusion MRI in multiple sclerosis

Conclusion MRI for multiple sclerosis is provided after the study and study of the obtained images. The specialist indicates the presence of characteristic MR signs of damage to the brain substance. In the white matter, zones with an altered signal and fuzzy contours are found.Multiple sclerosis lesions are predominantly oval in shape along the nerve fibers.

90,000 The aggressiveness of multiple sclerosis can be detected on MRI

Using a powerful magnetic resonance imaging scanner, a team of scientists from the National Institute of Neurological Disorders and Stroke NIH established that one of the regimens can be used to find out whether the disease will progress with current therapy, how quickly and how long term treatment prospects. The researchers concluded that it may be necessary to create new drugs, since not all of the existing ones have an adequate answer, as described in the journal JAMA Neurology.

In the modern world, there are about 2 million people with multiple sclerosis (MS), an autoimmune demyelinating disease in which the immune system attacks the myelin sheath of neuronal processes, which accelerates the conduction of electrical impulses. This disease, alas, is incurable, but there are drugs that allow you to control its course and “quench” the activity of the immune system in relation to myelin. However, in some patients, inflammatory “foci” in the brain continue to “smolder” (chronic active foci) and sometimes even grow despite taking medications, with aggravation and clinical symptoms.

The gold standard for the diagnosis of MS is a combination of a clinical examination by a neurologist and magnetic resonance imaging data. Moreover, changes should be observed on the part of the brain matter both in certain zones and after a certain time (dissemination in space and time). Nevertheless, routine scanning does not provide information right here and now about how aggressive the form of the disease in a given patient will be, and then, with repeated examinations, which foci have “died out” and which ones have a chronic inflammatory process.The patient is prescribed treatment and observation begins.

Researchers at the NIH National Institute of Neurological Disorders and Stroke, led by Senior Research Scientist Dr. Daniel S. Reich, have been working on progressive MS for over 10 years and have been using 7 Tesla MRI since 2013 (conventional “Clinical” power of tomographs, admissible in our country – a maximum of 3 Tesla). It turned out that with its help, in modes sensitive to the decay products of hemoglobin, iron, calcium (T2 * or SWI), a dark rim is formed around the chronically active foci, which is not around the “extinct” foci.

To find out, the team performed brain scans of 192 patients with multiple sclerosis who were being examined at the NIH Clinical Center. They found that, regardless of treatment, 56 percent of patients had at least one active focal lesion. Further analysis showed that only 44 percent of patients had lesions without a dark rim, 34 percent had one to three rimmed lesions, and 22 percent had four or more active inflammatory lesions.

These imaging data were combined with clinical data and found that people with four or more active lesions were 1.6 times more likely to be diagnosed with primary progressive multiple sclerosis. In addition, these patients developed motor and cognitive impairments earlier (at a younger age). Moreover, their white matter was more strongly destroyed in various parts of the brain.

What about long-term observations? The results of patients whose brains were scanned once a year for 10 years or longer showed that, as a rule, the lesions without a rim shrank, that is, they regressed, but the lesions with a rim either increased or did not change in size.As shown by histological examination during autopsy (some of the patients, unfortunately, died during the observation period), active inflammation remained there.

“We have found that you can use MRI to determine which patients are prone to more aggressive forms of multiple sclerosis. The more chronic active lesions a patient has, the more likely they are to develop this particular type of MS. We hope that our results will help to test the effectiveness of new methods of treating aggressive forms of the disease and reduce the suffering of patients, ”the authors of the work comment.

Text: Anna Khoruzhaya

Chronic active multiple sclerosis lesions are destructive on serial MRI and associated with in vivo disability by Absinta et al. in JAMA Neurology. Published 2019

DOI: 10.1001 / jamaneurol.2019.2399

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