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All Things Imaging in Multiple Sclerosis

Sahra Omar, RT(R)(MR) and Ellen Condon, RT(R)(MR)

   *Research MRI Technologist Functional MRI Facility, National Institute of Mental Health/National Institutes of Health, Bethesda, Maryland.
   †Research MRI Technologist Functional MRI Facility, National Institute of Mental Health/National Institutes of Health, Bethesda, Maryland.
   Address correspondence to: Sahra Omar, RT(R)(MR), Research MRI Technologist Functional MRI Facility, National Institute of Mental Health/National Institutes of Health, 10 Center Drive, Building 10, Bethesda, MD 20892-1148. E-mail: omars@mail.nih.gov.

Disclosure Statement: Ms Omar reports having no significant financial or advisory relationships with corporate organizations related to this activity. Ms Condon reports having no significant financial or advisory relationships with corporate organizations related to this activity.

ABSTRACT

Multiple sclerosis (MS) is a condition marked by an extensive spectrum of neurologic signs and symptoms, and is believed to be caused by an autoimmune attack on the myelin and axons of the central nervous system. MS is the most common cause of nontraumatic disability in individuals of young and middle age. Although a careful neurologic history and physical examination are essential to making this sometimes elusive diagnosis, ever since magnetic resonance imaging (MRI) became more widely available in the 1980s, neuroimaging techniques have also played a prominent role in confirming the diagnosis, studying disease progression longitudinally, and assisting in the research and development of novel therapies. Today, sophisticated applications of magnetic resonance technology, such as magnetization transfer imaging, magnetic resonance spectroscopy, and diffusion tensor imaging, provide quantitative information about the extent of damage that occurs in MS (sometimes in normal-appearing white matter) that may or may not be visible in T1- and T2-weighted images. Likewise, lesions may be present in normal appearing gray matter and in the spinal cord, and may best be detected using fluid-attenuated inversion-recovery imaging. Functional MRI and positron emission tomography (the latter of which is an imaging technique separate from MRI) are mainly research tools that help scientists and clinicians to better understand the subtle (behavioral and cognitive) aspects of MS and to correlate the efficacy of new therapeutic interventions with evidence of MS progression that is not apparent using clinical or standard magnetic resonance information. This article will review the history, anatomy, physiology, and the pathophysiology of MS as background for an exploration of the imaging techniques key to the diagnosis and treatment of this sometimes devastating disease.

Introduction
Perhaps the first recorded case of multiple sclerosis (MS), a neurologic disease believed by many to have an autoimmune cause, may be attributed to Saint Lidwina of Schiedam. Saint Lidwina lived in Holland from 1380 to 1433, and at the age of 16, this young woman developed neurologic symptoms after suffering a fall while ice skating. Soon after, she developed walking difficulties and headaches. By the age of 19, Saint Lidwina was paralyzed from the waist down and had vision disturbances. For the rest of her life, Saint Lidwina experienced periods of exacerbations and remissions in her condition, which generally deteriorated until her death at the age of 53.

In retrospect, the description of her medical history is strongly suggestive of a clinical diagnosis of MS, as is the age of onset of her illness, her gender, and her northern European ancestry.1 Although it can affect all racial, gender, ethnic, and age groups, MS affects twice as many women as men, generally has an age of onset in the second or third decade of life, and is more common in geographically northern latitudes in the world.2 Today, worldwide, there are approximately 2.5 million individuals with MS, and 400 000 cases in the United States.3 It is the most common inflammatory demyelinating disease of the central nervous system (CNS), and the most common cause of nontraumatic neurologic disability among young and middle-aged individuals.4

The first known documented personal account of what we now believe to have been MS was recorded in the diary of Sir Augustus d'Esté, the illegitimate grandson of George III of England, who lived from 1794 to 1848. In his diary, not only does d'Esté note multiple neurologic signs and symptoms (such as paralysis and ataxia) consistent with this diagnosis (which would not be discovered until 20 years after his death), but there is also an obvious alteration in his penmanship—evidence of the decline d'Esté was experiencing in motor function (Figure 1).1

Figure 1 

Multiple sclerosis was recognized and described by a series of eminent anatomists and pathologists beginning in the 18th century culminating with its detailed description in 1868 by the noted French neurologist, Jean-Martin Charcot. Charcot is credited with making the connection between the symptomatology of MS and the pathologic changes found on postmortem examinations.1 He correctly described it as a disease that causes lesions in the white matter of the CNS. However, since that time scientists have discovered that there is much more to MS than a condition that causes white matter lesions.

A Brief Review of the Nervous System Anatomy and Physiology
In order to fully comprehend the pathophysiology of MS and how imaging techniques may be used to diagnose and track treatment responses, a brief review of the structure of the nerve cell may be helpful. MS is a disease of the CNS, which is comprised of the brain and spinal cord. Within the CNS, individual nerve cells (neurons) are composed of a soma, or cell body, dendrites (branch-like extensions from the cell body), and an axon (Figure 2).5 Impulses generally flow unidirectionally from one neuron to another after they cross a synapse, or gap, between neurons. This may be facilitated by the use of various chemicals called neurotransmitters. Neurons receive impulses at the cell body and dendritic tree, then transmit the output via the axon. Each signal travels along the neuron's axon to the terminal bouton, where it is then transmitted to the next neuron. The axon is covered in a myelin sheath (Figure 3),6 which is a lipid-protein bilayer (80% lipid; 20% protein) that insulates the nerve to help transmit the electrical signal along the length of the axon. Forty percent of the weight of myelin is water, which fills the intracellular and extracellular spaces between the bilayers, and its presence plays an important role in the use of imaging techniques in MS. The axon has periodic foci along its length called nodes of Ranvier that are unmyelinated regions that divide myelinated portions into so-called internodes. Because of the saltatory nature of the transmission as it leaps from internode to internode along the axon, myelin increases the speed of nerve impulse transmission by 10 to 100 times, compared to the continuous conduction of an impulse afforded by sodium channels along an unmyelinated nerve cell.6 In the CNS, myelin is primarily found in white matter (deep structures of the brain and superficial portions of the spinal cord) and gives it the color for which it is named. However, myelin is also present in small amounts in gray matter. White matter (myelinated axons) connects various gray matter areas (the locations of nerve cell bodies) of the brain to each other and, as has already been noted, carries nerve impulses between neurons. Myelin is produced by specialized cells called oligodendrocytes, the cell membranes that wrap around the axon in concentric rings (Figure 3).6

Figure 2

Figure 3

Pathophysiology of MS: What Goes Wrong?
Although the exact cause of MS remains unknown, the most commonly accepted theory is that MS is an autoimmune disease whereby the body establishes an inflammatory response against its myelin, resulting in destruction of regions of myelin along the white (and sometimes gray) matter of the brain and spinal cord. These demyelinated regions are replaced by sclerotic plaques. Depending on the location of the damage (eg, spinal cord or optic nerve), the patient will experience a variety of neurologic signs and symptoms (transverse myelitis and optic neuritis, respectively).7 In addition to loss of myelin and oligodendrocytes, the axon itself may be damaged, as can astrocytes. An astrocyte is another type of nerve cell that provides structural and metabolic support to the brain. Specifically, astrocytes provide nutrients, regulate ion concentration and synaptic transmission, and most importantly in MS, promote the myelinating activity of oligodendrocytes. MS is characterized by multifocal regions of demyelination, loss of oligodendrocytes, and scarring of astrocytes. There may also be cerebral atrophy.

Some research indicates that axonal damage and cerebral atrophy may not be related to immune/inflammatory mechanisms, suggesting that MS is a complex disease with other possible underlying pathologic pathways. The trigger for MS may be environmental, such as from being exposed to a virus (eg, the Epstein Barr virus), receiving a vaccine (there is little support for this hypothesis), or inhabiting a certain geographic region. However, alternate theories regarding possible underlying causes of MS also include genetic, rather than environmental, origins.8

Clinical Course, Signs, and Symptoms of MS
Although there are no signs or symptoms that are unique to MS, certain clinical features are highly suggestive of this disorder; for example, a clinical course that is comprised of relapses and remissions, with an onset between age 15 and 50 years. Vision changes, such as blurred vision, double vision, red-green color distortion, or blindness may occur with MS. Two ophthalmologic conditions that are often present in MS include optic neuritis and internuclear ophthalmoplegia; optic neuritis is associated with eye pain and vision loss whereas the latter causes abnormal eye movements. Early on, sensory symptoms are also common in MS. These may include paresthesias or numbness, with decreased perception of pain and light touch. Conversely, patients with MS may experience electric shock-like sensations and a heightened sense of pain. Motor symptoms may include muscle weakness of the extremities, fatigue, spasticity, tremors, and some difficulties with coordination and balance. Some MS patients also experience bladder and bowel control issues or sexual dysfunction. The disease may cause hearing and speech impairments. Small increases in body temperature may trigger an exacerbation (Uhthoff's phenomenon). Last but not least, MS patients also may experience some degree of depression and/or cognitive decline.8

Although mortality is low and generally attributed to a secondary complication, such as pneumonia, MS is associated with significant morbidity. There are several variants of the disease with differing courses and degrees of severity. The majority of patients (85%) initially present with relapsing-remitting MS (RRMS), but this may ultimately convert to the second most common form of MS, secondary progressive MS. The remainder of patients have the primary progressive (PPMS) or progressive relapsing types. In patients with RRMS, deficits in sensory, motor, cerebellar, and/or autonomic functions are generally transient, with full recovery after a few weeks. Fifteen percent of these patients will remain clinically stable for 20 to 25 years and are considered to have a benign form of MS.4 Disease progression is most accurately monitored with magnetic resonance imaging (MRI) studies and clinical disability, frequently assessed using the Kurtzke Expanded Disability Status Scale (EDSS).

Diagnostic Criteria for MS
Because there is no definitive diagnostic test for MS, clinicians must rely on a thorough history and physical examination coupled with a battery of laboratory and imaging investigations to support the diagnosis and rule out others that might present with similar signs and symptoms. These may include analysis of the cerebrospinal fluid (CSF) for oligoclonal bands that represent antibodies commonly found in patients with clinically definite MS (CDMS), evoked potentials (CNS electrical events representing abnormal sensory organ function), and examination of the blood for antimyelin antibodies and/or for evidence suggesting other conditions. However, perhaps the most important contributing investigations for MS are conventional MRI and advanced applications of this technique. This article will discuss these neuroimaging techniques, and how they may make an important contribution to the initial diagnosis and to monitoring the natural history of MS both for individual patients and in the ongoing research quest for a cure.

Poser and McDonald Criteria
Beginning in the 1980s, diagnostic criteria based on clinical data (clinical lesions found on history and physical examination) and laboratory analysis (CSF, evoked potential, MRI, or urodynamic studies) were developed. The Poser criteria categorized individuals as having clinically definite MS, laboratory-supported definite MS, clinically probable MS, or laboratory-supported probable MS.9 In 2001 and 2005, the International Panel on MS Diagnosis developed updated guidelines and categorized individuals as having MS if the diagnostic criteria were fulfilled, having "possible MS" if the criteria (now called the McDonald criteria) were not completely fulfilled, and "not MS" if the criteria were fully evaluated but not met.10,11 The McDonald criteria, which are still in use today, also emphasized the distinction of symptoms as being either monofocal (stemming from a single lesion) or multifocal (consistent with >1 lesion). Most important to the diagnosis of MS based on these new criteria is evidence that the CNS lesions are "disseminated in space and time." This is defined as more than 1 area of involvement of the CNS ([brain, spinal cord, and/or optic nerves] representing space) and more than 1 clinical episode (representing time; Table 1).4,11-13 Because of the new emphasis on lesions, MRI imaging took on a new role, critical to the diagnosis and staging of MS.

Table 1 

Table 1

Conventional (Structural) MRI
As has been previously discussed, inflammation is a primary cause of pathology in MS. Inflammatory cells may breach the blood-brain barrier (BBB) causing demyelination by macrophages and producing inflammatory substances, such as nitrous oxide, that further damage nerve conduction. This damage may leave behind lesions or markers that could be identified with various imaging techniques. Demyelinated plaques are associated with inflammation, loss of myelin, axons, and gliosis, the latter of which is the production of astrocytes that occurs in response to damage to neurons.7

When clinical signs and symptoms are compared to MRI findings, it has been found that MRI is extremely sensitive in detecting plaques, indicating clinically silent episodes of CNS inflammation 10 times more frequently than patient reports of relapses. This makes MRI an important diagnostic tool, not only in the initial diagnosis of MS, but also as a biomarker for monitoring relapses, response to therapies, and in clinical trials of new treatments.14,15 Ninety-five percent of patients with CDMS have multifocal cerebral white matter lesions and 75% to 85% have focal spinal cord lesions. Lesions are also found in a majority of patients with the clinically isolated syndrome (CIS), suggesting that these findings point toward the likelihood of individuals who have had an episode of demyelination progressing to a diagnosis of CDMS.7

How Does MRI Detect Lesions?
Magnetic resonance imaging works based on the nuclear magnetic resonance phenomenon.16 When placed in a strong external magnetic field, the magnetic moment of hydrogen nuclei (spins) tends to align itself parallel or antiparallel to the magnetic field. The macroscopic quantity magnetization, defined as the amount of spins per unit volume by applying energy to the body by means of radio frequency pulses, can be disturbed or rotated from equilibrium state, resulting in precession that can be measured by MRI.17 During the magnetization precession or return to equilibrium, to distinguish spatial locations within the body, magnetic field gradients also are being used to encode the spatial information.17 The return magnetization to equilibrium is characterized by 2 relaxation times: spin-lattice or longitudinal (T1) and spin-spin or transverse (T2). Those relaxation times, besides concentration of the hydrogen atoms, are main factors in determining the MRI contrast. Several variables may affect the quality of the MRI. These include the strength of the magnet, the orientation, and the slice thickness. The magnet strength is an important variable: the higher the magnetic strength, the higher the signal-to-noise ratio and the better the image quality. Thinner slices increase lesion volume coverage by 20% when slices are less than 5 mm (3-mm slices are used to minimize partial volume effects whereas 4- to 5-mm slices are used to increase the signal-to-noise ratio). Furthermore, image resolution is improved as scanner hardware and software improve, therefore making it possible to use 3-dimensional techniques, contiguous slices, and straight transverse planes versus oblique transverse planes.16,17

Spin-Echo Noncontrast T1-Weighted and T2-Weighted MRI Techniques
The conventional MRI used for research and clinical imaging relies on 2 different relaxation signals or time frames: T1-weighted and T2-weighted. The T1-weighted images (longitudinal relaxation time) have a short relaxation time, meaning that the time in between the pulsed radio waves is short. This type of imaging provides excellent anatomical detail, although MS lesions are not generally visible on a T1-weighted MRI scans. This is because most MS lesions have the same signal as normal brain tissue, and thus these lesions are referred to as "isointense" lesions. However, some MS lesions are visible on T1-weighted images. These lesions are known as "black holes"; they are less intense (hypointense) and are gray or black in appearance (Figure 4).18 Approximately 50% of T1-weighted images disappear within a few months of their initial appearance and may be caused by reversible edema or partial demyelination from transient inflammation. Black holes that persist are probably the result of repeated or chronic inflammation of an area in which there has been loss of myelin and axons, and are often associated with severe and permanent disability for the patient.18-22

Figure 4 

T2-weighted images are basically achieved by a process that is the opposite of the one used to obtain T1-weighted images; therefore, the relaxation time (transverse relaxation time) is longer in between the pulsed radio waves, and the result is a bright (hyperintense) image of an MS lesion or plaque (Figure 5).18 This is because of the presence of increased water in the lesion. Although T2-weighted images are capable of differentiating normal from damaged tissues and reveal all MS lesions that have occurred during the course of the disease, the age of the lesions (acute vs chronic) cannot be determined from these images. This is because once they appear, they may get smaller, but rarely completely disappear.23 T2-weighted images are used to indicate total quantity of MS lesions in the brain, which helps in the process of analyzing "lesions burden of disease" (BOD). In addition, T2-weighted images are capable of revealing important details, such as presence and/or degree of inflammation, edema, demyelination, axonal loss, or damage.18 A ring-like pattern, as is evident in Figure 6, may indicate a more serious lesion.23

Figure 5

Figure 6

Although they can be found throughout the brain, MS plaques are most commonly found in the periventricular region, corpus callosum, centrum semiovale, optic nerves, and, more rarely, deep white matter structures and basal ganglia.15

Although MRI detects many more lesions than computed tomography scan and seems to identify lesions even in the absence of clinical symptoms, the downside to this is that, when correlated with histopathologic examination, it may be that the abnormal MRI signal is being generated from increased water content due to disruption of the BBB and may not always correlate with actual clinical or pathologic findings.8 The large-appearing plaques revealed by MRI may be much smaller when examined as pathologic specimens, or they may be secondary to other disorders (such as ischemia) that also result in bright white MRI images,6 especially in older patients. Furthermore, lesions may be detected that do not correspond well with actual disability as measured by scales, such as the EDSS (ie, they are "clinically silent", therefore their relevance to the actual patient is unclear). Individuals with a large number of lesions may not exhibit severe disability, whereas one small lesion in the spinal cord may cause significant symptoms for a patient.8 However, in general, the sensitivity and specificity of brain MRIs for diagnosing MS are approximately 90% and 70%, respectively, and the predictive value for conversion to CDMS from CIS ranges from 25% to 83%, depending on the study criteria.12,13,24,25 MRI techniques also may be used to evaluate lesions of the spinal cord, in addition to brain and spinal cord atrophy.18,26,27

Evaluation of Spinal Cord Lesions
In the case of spinal cord imaging, lesions may be difficult to detect because of the presence of CSF, which appears hyperintense on T2-weighted images. To overcome this difficulty, a special technique—proton density-weighted or fluid-attenuated inversion-recovery images—are obtained whereby the signal from the CSF is suppressed (Figure 5).18 Furthermore, to minimize artifact from movement, spin-echo or short tau inversion recovery or short T1 inversion recovery is preferred over gradient echo pulse sequences. Also, higher field strengths and closed-bore systems also yield better results.18

The presence of spinal cord lesions (Figure 7) helps to confirm the diagnosis of MS by contributing to the "dissemination in space" component of the McDonald criteria.18 Whereas control subjects have spinal cord lesions detected only 3% of the time, subjects with MS commonly have focal lesions located there—83% of the time in one study.28 This statistic is roughly equivalent to the frequency of brain lesions for the disease. However, to meet the McDonald criteria (Table 1), spinal cord lesions need to be focal rather than diffuse on T2-weighted images and have specific characteristics (little or no swelling, size >3 mm but <2 vertebrae in length, and with only partial cord involvement).11-13,28 Although spinal cord MRI findings from other conditions may mimic MS, conversely the presence of spinal cord lesions on occasion may help to clinch the diagnosis of MS in patients who have brain MRI findings that preclude excluding other diagnoses, such as age-related ischemic changes that are rarely found in the spine.

Figure 7 

Evaluation of Brain Atrophy (Volumetric MRI)
Aside from lesion load, brain atrophy also is considered to be an important indication of severity of MS. It is present in all types of brain pathology, including the various subtypes of MS (eg, RRMS and PPMS). Normally, as a result of aging, individuals experience brain atrophy at a rate of 0.1% to 0.3% annually. Patients with MS have a slightly higher rate of atrophy (0.6%-1%) annually.29,30 Volumetric MRI findings reflective of brain atrophy include enlarged ventricles and reduced corpus callosum (Figure 8).15,18 Some studies indicate that brain atrophy is a more accurate reflection of actual clinical disability and disease progression than lesion load, and that it also may serve as an important marker of the efficacy of various treatments in clinical trials.15

Figure 8 

Post-contrast Gadolinium T1-Weighted Images
As has been previously discussed, simple T1- and T2-weighted images fail to distinguish definitively between an active and chronic demyelinated lesion. In general, acute lesions tend to be larger with less defined margins; as edema and inflammation resolve, plaques may become smaller, leaving only residual areas of demyelination, gliosis, and enlarged extracellular space with remission.31 Gadolinium (Gd)-DTPA is a paramagnetic contrast agent that may be administered intravenously; obtaining T1-weighted MRI images before and after injection is important. Gd shortens the T1 of neighboring water molecules and increases signal intensity.23

Because Gd can only cross a disrupted BBB, and inflammation with its associated pathology is linked to acute MS activity and disruption of the BBB, Gd enhancement can be used as a measure of acute activity for MS, because there appears to be restoration of the BBB with remission.18 The interruption of the BBB as the Gd penetrates the extracellular space of the abnormal brain is the result of shortened T1- and T2-relaxation time. This creates atypically bright lesions or hyperintensified areas on T1-weighted images (Figure 9).18

Figure 9 

Gd enhancement is a very important MRI technique for tracking the natural history of MS, because it is frequently the first abnormality noted on neuroimaging, indicating early and acute disease activity—often before clinical signs and symptoms appear. In other words, the accumulation of Gd in plaques is associated with new or newly active plaques and with pathologically confirmed acute inflammation in MS. However, it is a transient finding lasting only a few weeks (4-6 weeks) for most patients.23,31 Therefore, continuous Gd enhancement noted on longitudinal studies using serial MRI scans might indicate continuous inflammatory disease activity in an individual.32,33 Furthermore, some studies have demonstrated that the number of Gd-positive lesions may predict the risk for relapse for the patient.33 Thus, Gd enhancement is probably best used in the early stages of RRMS. From a technical perspective, Gd enhancement may be further improved through use of higher doses of the contrast agent, obtaining thinner slices, or delayed imaging.31

Magnetization transfer imaging (MTI) is an advanced magnetic resonance technique that uses Gd and can further elucidate the diagnosis and course of MS. In the sections that follow, we discuss more sophisticated techniques, such as MTI, MR spectroscopy (MRS), diffusion tensor imaging (DTI), functional MRI (fMRI), and positron emission tomography (PET).

Advanced Imaging Techniques
Magnetization Transfer Imaging
Because MS pathology does not only restrict itself to plaques, there may be other evidence of inflammation, gliosis, and axonal damage to be found in so-called normal-appearing white matter (NAWM) or normal-appearing gray matter (NAGM). This may be revealed as generalized brain atrophy as previously discussed. In addition, MTI can detect decreases in magnetization transfer ratios (MTRs) that are expressed as histogram values to reveal loss of complex tissues, such as myelin, throughout what appears as NAWM and NAGM on conventional MRI scans (Figure 10).34 MTR technique correlates well with T2-weighted MS lesion load,7 and the MTR abnormality is increased with the severity of the T2-weighted lesions. MTI is based on an application of off-resonance radio-frequency pulses and observing their effects on MRIs, in addition to measuring the signal intensity with and without application of the pulses (ie, MTR). This method draws on the relaxation properties of water protons. Because MTI can enhance image contrast and tissue specificity, use of MTRs may allow clinicians and researchers to divide MS lesions into various subtypes, such as those with very low MTR (demyelinated lesions) and slightly decreased MTR (edematous lesions). MTI also may be able to detect damage to axons (Wallerian degeneration).34 Tissue damage is reflected by a decrease in the exchange of mobile and bound protons resulting in a reduction in MTR. MTR declines before the appearance of Gd-enhancing lesions and continues to decline even after lesions are apparent. How dramatically the MTR declines may predict how severe the lesion will be and whether it will be permanent.23

Figure 10 

MR Spectroscopy
As with MTI, MRS is not necessarily focusing on plaque, but rather focuses on the biochemical changes of lesions, NAWM, and NAGM of the brain of patients with MS. MRS uses MRI technology to generate spectra of hydrogen (proton)-containing metabolites (Figure 11).35,36 The technique can be used to look for markers of neuronal damage, such as N-acetylaspartate (NAA) levels that will be decreased when there is axonal loss. Specifically, MRS spectroscopy in MS suppresses signals emitted from water to be able to focus on those of protons associated with neurochemicals (such as NAA) that are important in MS pathology. Aside from NAA, the protons most easily visualized with MRS include creatine phosphate and phosphocreatine (Cr), choline, and lactate. Although its specific function within the brain is unknown, NAA is a metabolite of interest, because it is unique to neurons and its activity is a reflection of neuron function. Choline, on the other hand, is found in membranes, and levels increase in the presence of myelin breakdown. Lactate, a byproduct of anaerobic respiration, is not present in the normal brain but is evident in acute inflammatory MS lesions. Chronic MS is associated with a reduction in NAA as compared to Cr, and a reduced NAA/Cr ratio reflects loss of neurons and axons. Abnormalities on MRS may be detected several months before they appear as lesions on conventional MRI.17,23

Figure 11

Diffusion Tensor Imaging
Diffusion tensor imaging follows the movement of water molecules within the brain and indicates boundaries water molecules may encounter. Healthy white matter has a high degree of anisotropy, meaning that molecular movement is not the same in all directions. Specifically, water molecules prefer to diffuse in one direction, along the long axis of myelinated nerve fibers. DTI allows measurement of fractional anisotropy (FA), which reflects the degree to which the diffusion of water molecules follows one direction versus many directions. When there is damage to axons or their myelin sheaths, there may be increased diffusion of water across the white matter tract and a decreased FA.31 DTI can detect abnormalities in what would otherwise be NAWM or NAGM within and outside of T2-visible MS lesions (Figure 12).37,38 It can provide information at the microscopic molecular level about tissue microstructure and architecture, including size, shape, and organization, reflecting the disruption of myelin and/or axons.15

Figure 12 

Functional MRI and Positron Emission Tomography Scanning
Cognitive dysfunction is present in approximately 50% of all patients with MS.39 Both fMRI and PET scans offer a glimpse into the degree of functional disability for an individual affected by MS. Compared with traditional MRI scans that generally evaluate structural lesions and/or atrophy, fMRI evaluates blood flow to the brain (changes in the concentration of deoxygenated hemoglobin)40 within the context of the brain during its resting state versus during the performance of various cognitive or motor tasks. fMRI studies of patients with MS reveal that affected individuals use larger portions of the cortex than control subjects when attempting a simple task and that the abnormalities reflect T2-lesion load (BOD) and measurements of NAA.7

Positron emission tomography scans (Figure 13) assess cortical dysfunction by using various tracers, such as a tagged form of glucose called F-2-fluoro-2-deoxy-D-glucose, to trace glucose metabolism in the brain as a measure of cognitive and behavioral status and disease progression.39 PET scans, similar to fMRI, can evaluate blood flow, but also can look at energy metabolism because glucose is the main source of energy for the brain, and neuronal function in addition to inflammatory activity has been linked to glucose use.41 Other tracers, including a calcium analogue Co-55 and PK-11195, an isoquinoline, also can detect inflammatory activity.41 However, based on our unique research and clinical experience with MS, thus far PET scanning has been limited to the research arena in MS for a variety of reasons. Its cost is prohibitive compared to MRI techniques, it requires injections of radioactive isotopes and extended imaging times, and its resolution is not as sharp as fMRI. However, because of the potential to identify and quantify such "soft" clinical symptoms as fatigue and to follow disease progression from early to late in its clinical course, PET scanning may be a useful technique in the future for monitoring individual patients and assessing treatment efficacy.

Figure 13 

Standardized Protocol for Neuroimaging in MS
Because MRI has become an important contributor to the diagnosis, treatment, and tracking of disease progression in MS for individual patients and in research studies, guidelines have been developed recently for standardized MRI protocols.42 The highlights of these protocols may be found in Tables 2 and 3.42 In general, it is recommended that MRI be performed as part of the initial evaluation of an individual who has experienced a monosymptomatic attack (CIS) and who has a history that is suggestive of MS. Furthermore, a baseline MR evaluation should also be conducted for individuals already given a diagnosis of MS. This, along with a neurologic history and physical examination, will help to confirm the diagnosis and avoid misdiagnosis due to other entities with similar pathology. If necessary, when brain MR findings are equivocal, spinal cord MRI should be conducted. With respect to follow-up imaging, the guidelines do not recommend routine scans, but these should be performed if there is a change in the patient's status (worsening of his or her condition), if the clinician is considering another diagnosis, or on initiation of treatment. As far as specific techniques are concerned, the consensus panel recommends contrast-enhanced scans to be performed on at least a 1 Tesla magnet to optimize quality and tissue contrast.42

Table 2 

Table 3

Treatment Options
Although there is no known cure, early treatment has been shown to be the best option to slow disease progression. This is vital due to the fact that we know from neuroimaging and other testing that damage is occurring to the brain and spinal cord sometimes well in advance of any symptoms the patient may experience.43,44 Currently, there are injectable drug therapies available (no oral therapies exist at present); however, multiple drugs are seeking approval from the US Food and Drug Administration. Three of the many types of MS therapies that exist include immunomodulatory drugs, immunosuppressive drugs, and medications to manage the numerous and varied symptoms of MS. Immunomodulatory, or disease-modifying drugs, are all interferon-based; they are comprised of proteins or glycoproteins that can modulate immune responses from the body, and correct those that are faulty. By contrast, immunosuppressive medications attempt to prevent the body's leukocytes from attacking other leukocytes; in other words, they attempt to prevent the autoimmune inflammatory process. Additionally, nonpharmacologic, as well as many different complementary, holistic, or alternative therapies (such as therapeutic plasma exchange and exercise) have been used with success by patients and play an especially important role in enhancing patient comfort.45,46

Conclusions
We have seen that MRI, in addition to advanced approaches, including PET scanning, can detect a broad range of brain and spinal cord abnormalities from discreet lesions to subtle changes in NAWM and NAGM (Table 4).15 Although these techniques cannot stand alone in making the diagnosis of MS, they are key contributors to early detection and an understanding of the pathogenesis of the disease. Furthermore, it may be argued that neuroimaging plays the most important role in evaluating disease progression and the effects of various therapies by providing an ongoing measure of burden of disease (eg, number of lesions and degree of brain atrophy). Currently, conventional MRI, with and without Gd, is useful for the routine diagnosis and evaluation of MS. It is highly sensitive to inflammation, although its specificity has limitations. One goal for future applications of conventional MRI is an improved capability to detect lesions in gray matter. MTI and DTI reveal injury to NAWM. Continued perfection of these techniques as well as volumetric MRI may provide a practical means of monitoring the efficacy of various disease-modifying therapies for individual patients and in clinical trials. Finally, MRS and PET scanning, though dramatically different techniques, provide insights into the biochemistry of the nervous system and what goes wrong by tracking the behavior of various metabolites in the CNS. All in all, even though many of the tools discussed in this review are reserved primarily for research at this point, ultimately, they benefit all patients in assisting scientists to understand the pathogenesis and natural history of MS and in helping to identify new treatments.

Table 4

Acknowledgments 
The authors would like to thank Dr Peter Bandettini, Dr Jerzy Bodurka, Dr Nancy Richert, Joan Ohayon, and Judi Greif for their assistance with this article.

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All Things Imaging in Multiple Sclerosis

 
» Comment From: figgi » Posted on: 05/16/2008 12:58 PM
Very interesting and informative article
 
» Comment From: Deanna » Posted on: 05/16/2008 15:33 PM
for some reason the post test won't come up....am I doing something wrong.. or?
 
» Comment From: paul » Posted on: 05/25/2008 1:00 AM
it had alot of information.
 
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