The art of brain preservation in multiple sclerosis

What Are the Challenges in Diagnosing Multiple Sclerosis?

Challenges to Early Diagnosis

Multiple Sclerosis (MS) is a complex and unpredictable disease that can be difficult to diagnose.1-3

Despite a range of technological advances in recent years, there is still no single test that can be used to definitively confirm MS.1

In the absence of a clear biomarker,1,4 diagnosis may involve considering all of the following:

  • Clinical symptoms1,2
  • Laboratory evidence1,2
  • Imaging/radiologic evidence1,2
  • White Matter (WM) and Grey Matter (GM) pathology5

The most commonly used guidelines, the McDonald criteria, were first introduced in 2001 with 3 subsequent updates.1,6

In addition, while it is important to consider both WM and GM damage when looking at radiographic evidence,5 GM lesions can be difficult to detect, even when using the latest technology.5 While this may not prevent a definitive diagnosis, it can preclude a full understanding of the patient’s condition.

MRI images of Grey Matter and White Matter lesions obtained by using DIR technology

Papadopoulou A, Müller-Lenke N, Naegelin Y, et al. Multiple Sclerosis Journal. 19 (10). 1290-1296. © 2013. Reprinted by Permission of SAGE Publications, Ltd.

Images of WM and GM (cortical) lesions obtained by using double inversion recovery (DIR) technology. A) mostly WM lesions; B) both WM and cortical lesions (indicated by arrows); C) cortical lesions (arrows).7

The Importance of Early Diagnosis

Multiple Sclerosis (MS) is a complex and progressive neurological disorder that causes permanent damage to both White Matter (WM) and Grey Matter (GM) in the central nervous system (CNS). For most patients with MS, irreversible damage begins early in the course of disease.8-12

Evidence has shown that Early Damage can impact Neurological Reserve—the finite capacity of the brain to remodel itself after injury.2 As the Neurological Reserve is depleted, the debilitating damage of MS becomes more pronounced, manifesting as physical and cognitive impairment.8-12

As a result, it is important to diagnose MS as early as possible.

More information on Early Damage in MS

What Is the Prevalence of MS?

The understanding of the true prevalence of multiple sclerosis (MS) is evolving. A long established figure estimated that there were 300,000 to 400,000 people in the US with MS, while a more recent study by the US Multiple Sclerosis Prevalence Workgroup reported the figure to be potentially more than 900,000.13

Discover More About MS and Its Impact

The Most Common Early Symptoms of MS

While the type of symptoms that occur generally depends on where the lesions are located, there are several common symptoms that occur most frequently in patients first presenting with Multiple Sclerosis (MS). These early symptoms include9:

Early SymptomsDescriptionPatients, %
SensoryNumbness, tingling, burning pain40%
MotorWeakness, stiffness, impaired coordination, difficulty walking39%
VisualBlurry vision in one eye, eye pain/discomfort, double vision30%
FatigueLack of physical and/or mental energy30%

Cognitive impairment can also be found in patients with early MS, even in patients with little or no physical disability. In a clinical trial with 67 patients with probable MS, 54% exhibited signs of cognitive decline.14

More Information on Cognitive Impairment in MS

How Is MS Diagnosed?

Although Multiple Sclerosis (MS) can be difficult to diagnose, the process has been made easier and more accurate over time with the introduction of the McDonald criteria.1 This simple, focused approach has been widely embraced by the medical community and is commonly used in both clinical research and in day-to-day practice.

Today, patients with MS are being diagnosed

10x faster than 40 years ago9

Overall, the McDonald criteria have helped to bring some consistency to the diagnostic process and has significantly reduced the time it takes to confirm MS in patients presenting with symptoms.9 In the United States neurologists are diagnosing MS 10x faster than in the 1980s, which means that more patients are being treated in the early stages of disease.9

Mean Time to Diagnosis From Symptom Onset9

1980s

7.2 years

Today

0.6 years

The McDonald criteria focus on 3 types of evidence: Clinical Symptoms, Imaging Evidence, and Laboratory Evidence.9,15-18

  • Clinical Symptoms may include disruption of speech, gait, gestures, body movements, and vision9,15
  • Imaging Evidence should be taken directly from scans of the brain generated using magnetic resonance imaging (MRI) McDonald criteria. In some cases, scans of the spinal cord may also be required16
  • Laboratory Evidence generally focuses on an examination of the patient’s cerebrospinal fluid (CSF), with clinicians looking for oligoclonal banding, an elevated immunoglobulin (IgG) index, or a high level of myelin protein17,18

Two important ideas in the McDonald criteria are Dissemination in Space and Dissemination in Time.16

Dissemination in Space

Evidence of disease activity in more than one location in the CNS

Dissemination in Time

Evidence of disease activity over time—months or years

The McDonald Criteria for Diagnosing MS1

Clinical PresentationAdditional Evidence Needed for Diagnosis of MS
≥2 Relapses (symptoms/attacks)
≥2 Lesions (imaging evidence)

No Additional Data Needed

  • Positive Diagnosis

≥2 Relapses
1 Lesion

Either of the Following:

  • New Relapse—with symptoms that suggest a new lesion at another site in the CNS
  • Direct MRI Evidence of a New Lesion—seen in a different location in the CNS
1 Relapse
≥2 Lesions

Either of the Following:

  • New Relapse or New Lesion—showing additional evidence over time
  • Oligoclonal Banding—laboratory evidence of disease activity from CSF
1 Relapse
1 Lesion

One of the Following:

  • New Relapse or New Lesion—indicating a new lesion at different location in the CNS
  • New Relapse or New Lesion—indicating new disease activity over time
  • Oligoclonal Banding—laboratory evidence from CSF

≥2 Relapses, ≥2 Lesions

No Additional Data Needed

  • Positive Diagnosis

≥2 Relapses, 1 Lesion

Additional Evidence Needed

Either of the Following:

  • New Relapse—with symptoms that suggest a new lesion at another site in the CNS
  • Direct MRI Evidence of a New Lesion—seen in a different location in the CNS

1 Relapse, ≥2 Lesions

Additional Evidence Needed

Either of the Following:

  • New Relapse or New Lesion—showing additional evidence over time
  • Oligoclonal Banding—laboratory evidence of disease activity from CSF

1 Relapse, 1 Lesion

Additional Evidence Needed

One of the Following:

  • New Relapse or New Lesion—indicating a new lesion at different location in the CNS
  • New Relapse or New Lesion—indicating new disease activity over time
  • Oligoclonal Banding—laboratory evidence from CSF

 

In the end, diagnosing MS quickly and accurately is vitally important because the long-term consequences of early damage can be devastating for patients. With each new iteration of the McDonald criteria, it becomes increasingly more valuable as a diagnostic tool.

More Information on the Long-term Consequences of Early Damage

The Role of Imaging in MS Diagnosis

The development of magnetic resonance imaging (MRI) revolutionized the process of diagnosing Multiple Sclerosis (MS). Using MRI technology, clinicians have been able to clearly visualize lesion activity in the White Matter (WM) of the brain and spinal cord. As a result, MRI evidence has quickly become the gold standard for diagnosing patients with MS.19 While Grey Matter (GM) lesions have historically been difficult to visualize, recent advances in MRI technology have improved our ability to detect them.5

MRI Images of WM Lesions in a Patient With MS20

MRI images of White Matter lesions in Patients with MS
Acer N, Turgut AT, Özsunar Y, Turgut M. Neurodegenerative Diseases. Processes, Prevention, Protection and Monitoring. InTechOpen. © 2011 Neurodegenerative Diseases. Processes, Prevention, Protection and Monitoring published by InTechOpen, Ltd. Licensed through Creative Commons, Attribution 3.0 Unported (CC by 3.0). Adaptation: Labels added to graphic. Available under Public License at: https://www.intechopen.com/books/neurodegenerative-diseases-processes-prevention-protection-and-monitoring/quantification-of-volumetric-changes-of-brain-in-neurodegenerative-diseases-using-magnetic-resonance.

T1-weighted19,21

  • WM is light
  • GM is grey
  • Fat is bright
  • CSF is dark

Best for detecting:

  • T1 hypointense lesions (“black holes”) in WM
MRI Brain Image T1-weighted
Reproduced from Trip SA, Miller DH. Imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(suppl III):iii11-iii18, with permission from BMJ Publishing Group Ltd.

T2-weighted19,21

  • WM is dark grey
  • GM is light grey
  • Fat is dark
  • CSF is bright

Best for detecting:

  • T2 hyperintense lesions in WM
MRI Brain Image T2-weighted
Reproduced from Trip SA, Miller DH. Imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(suppl III):iii11-iii18, with permission from BMJ Publishing Group Ltd.

Fluid-attenuated Inversion Recovery (FLAIR)22

  • WM is dark grey
  • GM is light grey
  • Fat is light
  • CSF is dark

Best for detecting:

  • T2 hyperintense lesions in in periventricular and juxtacortical WM
  • GM lesions in the cortex
MRI Brain Image using Fluid-attenuated Inversion Recovery (FLAIR)
Reproduced from Trip SA, Miller DH. Imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(suppl III):iii11-iii18, with permission from BMJ Publishing Group Ltd.

Double Inversion Recovery23

  • WM is dark
  • GM is light grey
  • CSF is dark

Best for detecting:

  • GM lesions in the cortex
MRI Brain Image using Double Inversion Recovery
Reproduced with permission of Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA, from Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging, Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA. AJNR Am J Neuroradiol. 2007;28(9):1645-1649; permission conveyed through Copyright Clearance Center, Inc.

Imaging Grey Matter Lesions

While magnetic resonance imaging (MRI) has been a powerful tool for visualizing White Matter (WM) pathology, it has not been as effective in visualizing Grey Matter (GM) pathology, which is essential to understanding MS. GM lesions can be difficult to image because they tend to be smaller, with a less severe degree of inflammation.24

However, recent technological advances have significantly improved our ability to visualize GM damage. Cortical GM lesions in the brain are best detected using double inversion recovery (DIR), phase sensitive inversion recovery (PSIR), or fluid-attenuated inversion recovery (FLAIR) imaging.24,25

Cortical Lesions Visualized Using Different MRI Sequencing25

3 MRI images of cortical lesions using DIR, PSIR, and FLAIR
Reproduced with permission of Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA, from Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging, Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA. AJNR Am J Neuroradiol. 2007;28(9):1645-1649; permission conveyed through Copyright Clearance Center, Inc.

As evidence continues to accumulate about the importance of GM pathology in MS, the need to accurately image GM lesions is greater than ever. For instance, research has found that intracortical lesions discovered using DIR and PSIR are correlated with cognitive impairment in patients with MS.26

 

More Information on Grey Matter Lesions in MS

Using Laboratory Tests for Diagnosis

While clinical symptoms and CNS imaging are the most important factors in diagnosing Multiple Sclerosis (MS), laboratory tests can also play a role. Some tests commonly used to help confirm a diagnosis of MS include1,2,16,27,28:

  • Cerebrospinal fluid (CSF) tests
  • Evoked potential assessments
  • Optical coherence tomography (OCT) imaging

Cerebrospinal Fluid

The most commonly used laboratory tests to help diagnose MS involve the use of CSF, which is obtained from the patient through a lumbar puncture. The CSF is then processed and analyzed for signs of elevated gamma globulin proteins or oligoclonal banding. The presence of oligoclonal banding in CSF is considered a hallmark sign of MS, with 90% of patients with MS testing positive for this disease marker.18,27

Graphic showing MS Test - Oligoclonal Banding in CSF

Oligoclonal banding is found in
90% of patients with MS29

Reproduced from Multiple Sclerosis Trust. Lumbar puncture. https://www.mstrust.org.uk/a-z/lumbar-puncture. Updated March 2018. Accessed June 10, 2019.

Evoked Potentials Test

Evoked potential tests measure how quickly electrical impulses travel through the CNS. These tests use sensory stimulation (lights, sounds, touch) to trigger a response in the patient showing any abnormalities in neurological conduction. With EP tests, the accuracy rate for diagnosing MS is between 67% and 85%.16,30,31

Optical Coherence Tomography

OCT is an imaging technique that uses near-infrared light to measure the thickness of retinal nerves and detect neurological damage at the back of the eye. This technique is accurate, fast, noninvasive, and relatively inexpensive.32

In patients with MS, research suggests that OCT imaging can be used to predict both visual function and broader disability progression.32

More information about Disability Progression in MS

The Problem of Misdiagnosis

While the process for diagnosing Multiple Sclerosis (MS) has improved significantly over the past 20 years, misdiagnosis continues to be a problem. An estimated 5% to 10% of patients diagnosed with MS are later found to have a different condition.33 Alternately, one study of 50 patients with MS found that 58% were previously misdiagnosed as having other conditions including psychiatric disorders, orthopedic problems, and viral infections.34

Among patients who are misdiagnosed, the disorders most commonly mistaken for MS include33,35:

  • Psychiatric disease
  • Migraine
  • Fibromyalgia
  • Other neurologic disorders
  • Psychogenic disorder
  • Acute disseminated encephalomyelitis (ADEM)
  • Neuromyelitis optica spectrum disorder (NMOSD)
  • Idiopathic transverse myelitis

 

In some cases, these patients may remain misdiagnosed for as long as 10 to 15 years. During this time, patients are often treated with medications that are inappropriate for their condition. In a 2015 study of 110 misdiagnosed patients, 33% remained diagnosed with the wrong condition for more than 10 years.35 For these misdiagnosed patients, there can be significant clinical, economic, emotional, and psychosocial consequences.2

 

In a study of 110 patients with MS who were misdiagnosed,

33% were misdiagnosed for
10 to 15 years35

How MS Misdiagnosis Occurs

Despite advances in technology and process, Multiple Sclerosis (MS) remains a difficult condition to diagnose. It is a complex and unpredictable autoimmune disease with high variability from patient to patient.1-3 Furthermore, there are other neurological diseases that mimic its pathology and symptomatology.1,2

The most common factors contributing to misdiagnosis of MS are2,35:

  • Misinterpretation of symptoms as relapses
  • Inability to establish dissemination in time
  • Inaccurate reading of magnetic resonance imaging (MRI) results
  • Misapplication of diagnostic criteria
  • Failure to consider, misapplication of laboratory test results

 

Examining Symptoms

If observed symptoms are believed to be caused by an indeterminate demyelinating event, clinicians should immediately begin classifying them as either typical or atypical for MS.3 Typical symptoms include visual disturbances, numbness or tingling, motor difficulties, and fatigue. If symptoms are not typical, it should raise suspicion.9

In a study of 110 patients with MS who were misdiagnosed,

65% presented with atypical symptoms35

MRI Evidence

Misinterpretation of MRI results can also play a role in misdiagnosis. MRI abnormalities that arise from other neurological conditions are often incorrectly attributed to MS. One study found that MRI abnormalities contributed to misdiagnosis in more than half of the patients in the study.35

In a study of 110 patients with MS who were misdiagnosed,

>50% of cases were attributed to MRI misinterpretation35

In patients with MS, MRI evidence typically includes well-circumscribed ovoid brain lesions that are periventricular, juxtacortical, or infratentorial. Spinal lesions are typically short (1 or fewer vertebrate segments) and tend to be located within the cervical or thoracic region of the spinal cord. Evidence of 2 or more of these lesions in different locations present clear evidence of dissemination in time, making it strongly suggestive of MS, rather than a different neurological disorder.26

More Information About MS Symptoms and Pathology

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