Multiple Sclerosis

1 Multiple Sclerosis: Pathophysiology, Clinical Features, Diagnosis, and Management

Amir-Hadi Maghzi1,2,3, Aimee Borazanci4, Jeanie McGee4, J. Steven Alexander5, Eduardo Gonzalez-Toledo4,6, Alireza Minagar 4 1 

Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan, Iran Isfahan Neuroscience Research Center, Isfahan University of Medical Sciences, Isfahan, Iran 3  Neuroimmunology Unit, Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK 4  Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA 5  Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA 6  Department of Radiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA 2 

Introduction Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS), which largely affects young adults with certain genetic backgrounds, often following exposure to several as yet unidentified environmental antigen(s) [1,2]. It is believed that the interactions between environmental and genetic influences are required to trigger the massive immune response against putative CNS antigens (e.g., myelin proteins that surround axons). This progressive inflammatory process affects both gray and white matters of the brain and spinal cord and ultimately causes neurodegeneration and axonal loss, with resultant permanent disability. Inflammatory demyelination in MS slows impulse conduction or leads to complete cessation of nerve impulse transmission. Axonal loss and neurodegeneration are the fundamental mechanisms underlying brain atrophy and permanent loss of motor function. The lesions of MS can affect any region of the neuroaxis; therefore, the anatomic location of MS lesions plays a significant role in determining clinical symptoms. Based on the clinical disease pattern, four types of MS are recognized: relapsing– remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive Neuroinflammation. DOI: 10.1016/B978-0-12-384913-7.00001-0 © 2011 Elsevier Inc. All rights reserved.

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Neuroinflammation

MS (PPMS), and progressive relapsing MS (PRMS) [3]. Interestingly, it appears that these four different forms of MS have dissimilar underlying neuropathologies, which in turn indicates that MS may represent a heterogeneous group of related diseases. The clinical course of RRMS is characterized by clear disease relapses with development of new neurologic deficits or worsening of older symptoms that last more than 24 h; each relapse is typically separated from the last attack by at least 1 month of stability. Patients with relapse of MS, either with treatment with corticosteroids or spontaneously, may return to their baseline neurologic status or may recover partially, with residual neurologic deficits. Usually, during the interval between relapses there is no clinical disease progression. Clinically, RRMS is the most common form of MS; more than 85% of patients initially present with this form. SPMS is recognized by an initial RRMS that progresses to SPMS within 10–15 years. During this phase of MS, the underlying inflammatory cascade and clinical relapses decrease in severity, while the neurodegenerative process builds to become the dominant pathology. In certain ways, SPMS may be regarded as a long-term product of RRMS. Up to 15% of MS patients initially present with PPMS, which is characterized by a relentless progression with no obvious relapses; patients occasionally exhibit transient minor improvement. PRMS is characterized by progressive and devastating attacks of the disease from the beginning with acute relapses, with or without recovery. Importantly, the intervals between relapses are marked by continuous disease progression. This form of MS is the least common clinical form. The most common form of MS, RRMS, begins with a single unifocal or multifocal demyelinating attack (known as clinically isolated syndrome [CIS]), with a complete or partial resolution of the attack. This form of MS with its dominant neuroinflammatory sequelae is clinically recognized by relapses and development of new lesions on magnetic resonance imaging (MRI) studied by CNS neuroimaging. Of course, during this process, the neurodegenerative arm of MS continuously proceeds with progressive axonal and neuronal loss to the point that the patient’s capacity to sustain any new attacks without suffering additional disability decreases. Within a few years of the onset of RRMS, the underlying neuropathology of MS involves more neurodegeneration with fewer clinical relapses, more clinical deterioration, and accumulating disability. Patients with PPMS have a progressive course from the beginning without significant evidence of inflammatory lesions on CNS neuroimaging and with no proven therapeutic response to immunomodulatory medications as compared to RRMS.

Epidemiology The diverse worldwide epidemiology of MS provides clues to the genetic and environmental risk factors for MS. The observations from migrant studies showing that migration from high- to low-risk areas before puberty provides some protection against developing MS, and vice versa, highlight the importance of environmental factors in MS [4]. The highest incidence and prevalence of MS are more likely to be observed at the highest latitudes in both the northern and southern hemispheres.

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In addition, the prevalence and incidence of MS are shown to be associated with the distance from the equator [5]. This has been mostly linked to the effects of sunlight exposure and vitamin D, leading to the formulation of a hypothesis that vitamin D deficiency may enhance the risk of MS; this hypothesis was later strengthened by further immunologic studies [6]. In addition, similarities between the epidemiology of MS and primary Epstein–Barr virus (EBV) infection (infectious mononucleosis [IM]) have been well documented, and several studies have shown that the risk of MS is elevated after IM, which has led to a growing body of evidence linking EBV to MS [7]. MS is also observed more commonly among smokers, those of higher socioeconomic class, and those with low dietary vitamin D intake [8–10]. The epidemiology of MS has been changing during recent decades. Generally, there has been an increase in the prevalence and incidence of MS worldwide, especially in previously low-risk regions such as the Middle East [5,11]. This has been partly attributed to the better diagnosis of MS secondary to enhanced diagnostic criteria, an increase in the number of neurologists, more availability of disease-modifying drugs, enhanced awareness, and more widespread use of MRI. However, these factors cannot fully explain the increase in the prevalence of MS. It is plausible that changes in lifestyle and environmental exposures have also contributed to the increase in the prevalence and incidence of MS. More evidence comes from studies that have documented an increase in the sex ratio of MS during recent decades in different parts of the world [5,12,13]. Since all these changes have occurred during a short period, they are more likely due to environmental changes rather than genetic ones. For instance, in Western countries, where smoking has been recognized as a risk factor for MS, the increase in the sex ratio of MS has been attributed to the growing number of female smokers, while in an Iranian study this was linked to an increase in the vitamin D deficiency among the young female population [12,14]. Epidemiologic investigations have shown that individuals of Western European ancestry have a higher susceptibility to MS. On the contrary, there are ethnic populations such as Hutterites and the Natives of western Canada who appear to be resistant to the disease despite living in relatively high-risk regions for MS. First-degree relatives of MS patients have a 20 times higher incidence of MS than the general population. Studies on monozygotic twins show that the concordance rate is 30% compared with rates of less than 5% in dizygotic twins [15]. Genetically unrelated family members living in the same environment have a risk of MS that is no higher than the background population. All these observations point toward a genetic component for MS. To date the most significant genetic component discovered remains the HLA-DRB1*15 [15].

Pathophysiology The exact cause of MS remains unknown, but evidence indicates that its pathophysiology includes two key and interconnected components: neuroinflammation and neurodegeneration [1,16]. The inflammatory component of the pathophysiology of MS includes abnormally excessive activation of the immune system against

Neuroinflammation

Th2 cytokines (IL-4, 5, –6, –13) FOXP3 CD4+/ CD25+ T-regs Tr1/IL-10 TGF-β/Th3

EBV

APC (DC) Putative Ag

HSV-6

Inflammation

Antiinflammatory

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Environment trauma

T-cells

Adherens tight junctions

Th1 cytokines (TNF-a, IFN-g, IL–12, –15, –17) HLA-DR CD71 CD80/B7-1 CCR-5/CXCR3

BBB disturbances

T-cells (CD4+, CD8+) B-cells, monocytes

VE-cadherin Occludin claudins

Adhesion

ICAM-1, VCAM-1/α4β1 MAdCAM-1/α4β7

Transmigration MS injury

Demyelination

(loss of oligodendrocytes)

(B-cells)

IgG/Oligoclonal bands

Myelin Ags MBP MOG

Neurodegeneration

Figure 1.1  Proposed MS pathogenesis. After exposure to environmental antigen(s) (e.g., EBV or HSV-6), myelin-sensitized autoreactive leukocytes are activated via binding of the T-cell receptor to the putative antigen(s), which is conveyed to them by antigen-presenting cells (such as dendritic cells) (trimolecular complexes). The activated leukocytes (T cells, B cells, and macrophages) cross the BBB (transmigration) through the disrupted cerebral endothelial tight and adherens junctions (by disintegrating junctional complexes containing VE-cadherin, occludin, claudin, and junctional adhesion molecules). The activated leukocytes also secrete a number of pro- and anti-inflammatory cytokines that play regulatory roles in polarization of the peripheral environment toward inflammatory or anti-inflammatory mechanisms. Once these cells gain access to the CNS environment, they identify more autoantigens and generate and release more cytokines and autoantibodies, causing loss of myelin/oligodendrocyte complex as well as neurodegeneration.

CNS antigen(s), which leads to interactions between autoreactive leukocytes and the inflamed cerebral endothelium, disintegration of the blood–brain barrier (BBB), and penetration of these activated leukocytes into the CNS parenchyma [1,17–19] (Figure 1.1). The early events that trigger these exuberant immune responses and activation of leukocytes against self-antigens remain hard to pin down, but viral and bacterial antigens are relevant and probable stimuli triggering the original MS pathophysiology [7,20]. Exposure to or infection with a number of viruses, such as hepatitis B and EBV, has been proposed as the activating factor for the T lymphocytes that are sensitized against viral proteins that share similar structural motifs with CNS proteins such as myelin basic protein (MBP); this is the so-called “molecular mimicry hypothesis.”

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Pathophysiology of MS involves both the innate and acquired immune systems. One hypothesis about the pathophysiology of MS is that the initial event begins in the peripheral circulation with activation of immune cells outside the CNS such as dendritic cells [18,19]. Numerous scientific studies on experimental MS in mice (experimental autoimmune encephalomyelitis [EAE], the closest animal model of MS) have revealed that autoreactive CNS-antigen(s)-directed T lymphocytes (CD4, CD8) play significant roles in the development of CNS demyelinating lesions. At some point in the early stages of the MS development, T lymphocytes become sensitized against several suspected CNS antigens, including MBP, proteolipid protein, and myelin oligodendrocyte glycoprotein [21], and activate a massive immune response that leads to their migration across the BBB, leading to its dysregulation. Autoreactive T lymphocytes and monocytes interact with inflamed cerebral endothelial cells through rolling and firm binding in the cerebrovascular space. This binding process is the most significant component of the leukocyte–endothelial interaction and commits the leukocytes to migrate across postcapillary venules into the CNS environment [17]. Loss of the BBB endothelial integrity layer is associated with disassembly and destruction of endothelial tight junctions and junctional proteins such as occludin and VE-cadherin [22] as well as claudins, which facilitate movement of the leukocytes. Once autoreactive T lymphocytes and monocytes breach the CNS at the perivenular areas, the immune cascade escalates and more varied CNS antigens become identified as potential immune targets for T cells, a diversification of antigenic specificity over the course of the disease (the episode spreading concept) [23]. The pro-inflammatory Th1 lymphocytes express high levels of activation markers (HLA-DR and CD71), co-stimulatory molecules (CD80/ B7-1), and Th1-cell chemokine receptors (CCR5 and CXCR3). These cells produce high levels of pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-12, IL-15, and IL-17. The Th2 lymphocytes, which switch the environment toward anti-inflammatory or protective mode, secrete cytokines such as IL-4, IL5, IL-6, and IL-13 [24]. Other cells involved in reducing the inflammatory response include various kinds of CD4 regulatory cells such as FOXP3 CD4CD25 Tregs, the IL-10–generating Tr1 cells, and the transforming growth factor β–generating Th3 cells. However, regardless of their Th polarization, the movement of immune cells into the CNS parenchyma can disturb BBB integrity. During the past decade, neuroimmunologists have focused on the role of emerging cytokines such as IL-12, IL-27, and IL-23 in the pathogenesis of MS. Members of the IL-12 family proteins are involved in regulation of T-lymphocyte responses and may be important in the pathophysiology of MS [25]. IL-17, a potent inflammatory cytokine, promotes CNS inflammation by disrupting the BBB, allowing greater permeation of autoreactive peripheral CD4 T cells into the CNS [26]. Recently, Alexander et al. [27] published the results of a 1-year prospective study of serum levels of IL-12p40, IL-17, and IL-23 prior to and at 3-month intervals after treatment with IFN-β1b. The investigators reported that continuous treatment with IFN-β1b reduced serum levels of IL-12p40 and IL-23 and showed a trend for decreasing IL-17. The investigators concluded that early treatment of MS with IFN-β1b may stabilize the clinical course of MS by decreasing levels of these inflammatory cytokines.

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Neuroinflammation

The humoral arm of the immune system also is significantly involved in the pathophysiology of MS. Under normal circumstances, B lymphocytes do not cross the BBB. However, during the course of MS and along the massive immune cascade, B lymphocytes become activated, produce antibodies, and cross the BBB. In 1942, Kabat et al. [28] reported the presence of the oligoclonal bands (evidence of intrathecal antibody production) that were not present in the concurrent serum. While it is known that oligoclonal bands are present in the cerebrospinal fluid (CSF) of patients with other inflammatory and infectious etiologies, their presence in the appropriate setting strongly supports a diagnosis of MS. Increased intrathecal synthesis of immunoglobulins is reflected by evidence of several factors and events in the CSF of MS patients, including the presence of oligoclonal bands, an elevated IgG index, B-cell clonal expansion somatic hypermutation [29,30], and B-cell receptor revision (editing) in clonally expanded B cells [31]. These all provide strong support for roles of activated B cells in the massive immune response that occurs during the pathogenesis of MS. Neuropathologic studies of CNS tissues from MS patients show an underlying “pathologic heterogeneity.” A milestone Mayo Clinic neuropathologic study of a large group of active MS white matter lesions suggested four patterns of MS neuropathologies based on the location of the plaques, the extent and pattern of damage and loss of oligodendrocytes, the pattern of myelin protein loss, and evidence of complement activation along with deposition of immunoglobulins [32]. Pattern I lesions reveal strong involvement of T lymphocytes and macrophages with sharp lesion edges and survival of oligodendrocytes and remyelination. In these lesions the expression of all myelin proteins, such as MBP, PLP, myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (MOG), is decreased. Pattern II lesions demonstrate antibody complement–associated demyelination with plaques showing sharply defined borders. These lesions also show the presence of macrophages and T lymphocytes as well as surviving oligodendrocytes and remyelination. Pattern III plaques demonstrate hypoxiainduced distal oligodendrogliopathy with fuzzy borders and apoptosis of oligodendrocytes. There is no evidence of activity of humoral immune response in these lesions. Pattern IV lesions reveal sharply bordered plaques that also contain macrophages and T lymphocytes with no evidence of immunoglobulin or activated complement deposits within them. The proposed mechanism for the formation of these lesions is a primary oligodendrogliopathy (primary oligodendrocyte degeneration). This form of neuropathology is uncommon among MS patients and is limited to patients with PPMS.

Clinical Manifestations Lesions of MS affect many areas of the brain and spinal cord and may damage many aspects of the CNS functions. Clinically, MS may vary from benign MS to more aggressive and progressive forms of MS such as SPMS and PRMS. Fatigue is the most common complaint among MS patients. Fatigue, either mental or physical, affects all aspects of the MS patient’s life profoundly and results in reduced mental or physical activities. In many cases the fatigue compounds the coexisting depression and intensifies the symptoms.

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Clinical manifestations of MS stem from disturbances of the sensorimotor, bowel and bladder, sexual, brain stem and optic nerve, and neuropsychiatric functions. MS lesions demonstrate a predilection for certain areas of the neuroaxis, such as brain stem, periventricular area, cerebellum, optic nerve, and spinal cord, which in turn leads to the development of neuroanatomic-based symptoms. For example, involvement of the medial longitudinal fasciculus at the peri-aqueductal location causes internuclear ophthalmoplegia, which manifests with impairment of the conjugate lateral gaze with limitation of the adduction of the affected eye, along with compensatory nystagmus of the abducted eye. Patients with internuclear ophthalmoplegia complain of double vision, while convergence remains intact. Other abnormalities of the brain stem in the context of MS include impairments of extraocular motility, which manifest with horizontal or vertical gaze paresis, one-and-a-half syndrome, weakness of the extraocular muscles (cranial nerves 3, 4, or 6), or skew deviation. Facial paresis of the central or peripheral type manifests in MS and originates from demyelination of the facial nerve within the brain stem. Facial myokymia is an undulating, wavelike twitching that starts in the orbicularis oculi and occasionally presents in MS. Patients with MS frequently manifest dysarthria and dysphagia [33]. One particular form of speech impairment, scanning speech, is typical for MS patients. Hearing loss is uncommon in MS, but many MS patients frequently complain of vertigo. Many MS patients develop optic neuritis, either as the initial manifestation or as a part of their disease process. Optic neuritis usually begins with subacute visual loss in one or both eyes. As the disease progresses the scotoma becomes larger and the patient develops disturbances of color perception and contrast sensitivity. Patients with optic neuritis often complain of retro-orbital pain that is deteriorated with eye movement. Neuro-ophthalmologic evaluation may reveal a normal optic disc (if the neuritis is retrobulbar) or papillitis as well as the presence of relative afferent pupillary defect. Visual acuity is decreased and the patient suffers from visuospatial deficits. Motor symptoms in MS mainly originate from involvement of the corticospinal tract, which clinically translates into heaviness, stiffness, weakness, pain, or paralysis that can cause hemiparesis or paraparesis or paraplegia. In the course of MS, the lower extremities are more commonly affected than the upper extremities. Other manifestations of corticospinal tract involvement include the presence of hyperactive deep tendon reflexes, spasticity of the affected extremities, and the presence of the Babinski response. Corticospinal tract demyelination and neurodegeneration result from lesions within deep hemispheric white matter, basis pontis, cerebral peduncles, medullary pyramids, internal capsule, or spinal cord. Sensory symptoms of MS include tingling, burning, a pins-and-needles sensation, or complete loss of sensation. Frequently, MS patients complain of abnormal feeling occurring in a band-like distribution around the chest or abdomen. The sensory complaints in MS may stem from demyelination of the posterior columns (gracilis and cuneatus fascicule) or spinothalamic tracts. Lhermitte’s sign consists of a sudden electric-like sensation traveling down the spine or the extremities for a brief period. Apart from these sensory complaints, MS is potentially a painful disease and patients may develop trigeminal or glossopharyngeal neuralgia. Patients who suffer from

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Neuroinflammation

these neuralgias report frequent, severe, short-lasting lancinating pain that affects their face or head and neck area. In addition, patients with MS have more generalized headaches and migraines than healthy individuals. Cerebellar involvement in MS stems from both vermian and hemispheric lesions and clinically manifests with gait ataxia, dysmetria upon performance of the finger-to-nose and heel-to-shin test, and inability to do tandem gait. Limb ataxia and intention tremor may be present in up to 50% of MS patients. Up to 65% of MS patients suffer from neuropsychiatric abnormalities. A decline in language skills, memory, and intellectual function is commonly observed in MS patients. Neuropsychological assessment of MS patients reveals mild to moderate slowing of thinking process, poor recent memory, word-finding difficulties, slow information processing, and difficulty with concentration [34–37]. The pattern of cognitive impairment in MS is similar to the pattern of other neurologic disorders that involve subcortical structures, such as HIV-related encephalopathy and Parkinson’s disease. Therefore, the presence of aphasia and neglect in MS patients is unusual. Mood disorders, particularly depression and bipolar mood disorder, are common among MS patients. These patients also frequently demonstrate euphoria, which indicates their inability to inhibit emotional expression. A number of abnormal involuntary movements may present in the context of MS. Some patients may develop rubral tremor, chorea, segmental myoclonus, and dystonia. Autonomic disturbances, including impairment of bowel and bladder dysfunction, and abnormal sweating, with unusual coldness or discoloration of the legs or feet, may be present in MS. Any cognitive or physical deficits in MS can be stereotypically and reversibly enhanced with exposure to heat, prolonged exercise, or infection (Uthoff’s phenomenon).

Neuroimaging: A Concise Review The use of various neuroimaging procedures, particularly different MR techniques, for the diagnosis, management, and follow-up of MS patients has fundamentally changed our view and understanding about the nature and pathophysiology of MS. The role of MRI in the world of MS is so significant that without an abnormal brain MRI, a diagnosis of MS must be reconsidered. MRI of the brain and spinal cord is the only objective tool that provides clinicians with a solid view about the natural history, disease activity, disease burden, severity of brain and spinal cord atrophy, and any therapeutic response to the administration of disease-modifying agents and immunosuppressants. Application of MRI has even changed the diagnostic criteria for MS and allows for the development of new T2-weighted lesions 1 month or more after the last MRI to fulfill the criteria for dissemination in time (Table 1.1) as well as development of one or more than one lesions in each of more than two characteristic sites for MS lesions to meet the criteria for dissemination in space [38]. As we learn more about MS, we also learn more about other diseases that imitate MS clinically. Therefore, MRI serves as an accurate diagnostic procedure to exclude MS imitators.

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Table 1.1  MRI Criteria for Dissemination in Space and Dissemination in Time for Patients with MS

Dissemination in Space McDonald [46]

Three or more of the following: Nine T2-weighted or one Gd-enhancing lesions; three or more periventricular lesions; one juxtacortical lesion; one or more posterior fossa lesions (*One spinal cord lesion can replace brain lesion.)

McDonald [47]

Three or more of the following: Nine T2-weighted lesions or one Gd-enhancing lesions; three or more periventricular lesions; one or more juxtacortical lesions; one or more posterior fossa lesions or spinal cord lesions (*A spinal cord lesion can replace an infratentorial lesion. **Any number of spinal cord lesions can be included in the total lesion count.)

New criteria

>1 lesion in each of >2 characteristic locations; periventricular, juxtacortical, posterior fossa, and spinal cord

Dissemination in Time McDonald [46]

Detection of Gd enhancement 3 or more months after CIS; a new T2-weighted lesion with reference to a previous scan 3 or more months after onset of CIS

McDonald [47]

A Gd-enhancing lesion 3 or more months after CIS; a new T2-weighted lesion with reference to a baseline scan obtained 30 days or more after onset of CIS

New criteria

A new T2-weighted lesion on follow-up MRI irrespective of timing of baseline scan

Gd, gadolinium; CIS, clinically isolated syndrome. Source: Adapted with permission from Lancet Neurology.

The other role of MRI is in follow-up and assessing a patient’s response to therapy. Currently, the treatments for MS approved by the US Food and Drug Administration (FDA) are expensive, and it is necessary to objectively document a patient’s favorable response or lack of response to treatment. Serial MRI of the patient’s brain and spinal cord, before and after treatment with disease-modifying agents, enables clinicians to assess and measure the quantity and the volume of MS lesions on various MR sequences; this in turn translates into a deeper understanding of the extent and severity of the underlying disease process. In addition, since MS is a “whole brain disease,” MRI shows us the extent of involvement of both white and gray matters and particularly demonstrates the severity of brain atrophy, which is a long-term indicator of disability in MS. At present, performing sophisticated MR techniques is the principal component of clinical trials for MS. The standard protocol for neuroimaging of MS patients proposed by the Consortium of MS Centers is presented in Table 1.2 [39]. The most informative MR sequences for neuroimaging of MS on routine MR

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Neuroinflammation

Table 1.2  The Consortium of MS Centers Standardized Brain and Spinal Cord MRI Protocol Brain MRI Sequence

Diagnostic Scan for CIS

New Baseline or Comment Follow-Up Scan in Definite MS

Three-plane scout

Recommended Recommended

Axial sections through the subcallosal line (joins the undersurface of the rostrum and splenium of the corpus callosum)

Sagittal FLAIR

Recommended Recommended

Useful for corpus callosum lesions

Axial fast spin– or turbo spin–echo PD/T2

Recommended Recommended

TE1 < 30 ms TE2 < 80 ms Useful for infratentorial lesions missed by FLAIR

Axial FLAIR

Recommended Recommended

Useful for most white matter lesions, including juxtacortical

Axial pre-contrast T1

Optional

Optional

Useful for T1 black hole assessment

Three-dimensional T1

Optional

Optional

Useful for brain volume measures

Axial post-contrast T1

Recommended Optional

Minimum of 5 min delay using a standard dose

Spinal cord MRI sequence

Spinal cord imaging following contrast-enhanced brain MRI (no further contrast is needed) sequence

Three-plane localizer pre-contrast sagittal T1

Three-plane localizer postcontrast sagittal T1

Sagittal fast spin–echo PD/T2

Sagittal fast spin–echo PD/T2

Axial fast spin–echo PD/ T2 through lesions

Post-contrast axial T1-weighted through lesions

Three-dimensional T1 (optional)

Axial fast spin–echo PD/T2 through lesions

Post-contrast sagittal T1

Three-dimensional T1 (optional)

Post-contrast axial T1 through lesions Slice thickness should be <3 mm with no interslice gap (contiguous) on a >1.0  T closed MRI scanner. FLAIR, fluidattenuated inversion recovery; MS, multiple sclerosis; PD, proton density. Source: Adapted with permission from Am J Neuroradiol [39].

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Figure 1.2  (A) MRI. Axial view, FLAIR sequence. Plaque in infratentorial location, right cerebellar. (B) MRI. Axial view, FLAIR sequence. Multiple demyelinating plaques in characteristic periventricular location following the periependymal veins (Dawson’s fingers). (C) MRI. Transverse slice, FLAIR sequence. (D) MRI. MT sequence, same level as (C). Compare the lesser number of plaques on the MT sequence. The lower magnetization value indicates lipoprotein loss. In this patient the volume for plaques was 23.5 cc on FLAIR and 4.2 cc on MT, indicating 18% of plaques have lipoprotein breakdown.

machines include sagittal fluid-attenuated inversion recovery (FLAIR), axial fast spin– or turbo spin–echo proton density (PD/T2-weighted), axial FLAIR, and axial pre- and post-contrast (gadolinium[Gd]) T1-weighted images. The FLAIR technique is a unique procedure currently used for the detection of white matter lesions, which appear as hyperintense signals on this sequence (Figure 1.2A–D). Typical MS lesions on FLAIR sequence are hyperintense periventricular lesions as well as corpus callosum lesions (Dawson’s fingers). Application of T2-weighted sequence is a classic approach to visualize MS disease burden and lesion formation over time [40]. However, the specificity of this MR technique is low since different pathophysiologic events such as edema, demyelination, remyelination, inflammation, Wallerian degeneration, and axonal loss all present as hyperintense lesions on this sequence. T2-weighted images can be obtained by applying a number of spin echo– or fast spin echo–based methods. T2-weighted

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Neuroinflammation

Figure 1.3  (A) MRI. T2-weighted axial view of brain showing MS plaques. T2 values were calculated: for a normal value of 95 ms in brain parenchyma, the plaques measure from 124 to 211 ms. (B) Post-contrast axial T1-weighted view showing enhancing plaque corresponding to one of the plaques appearing on the T2-weighted image.

lesions of MS are observed in the periventricular white matter, corpus callosum, and juxtacortical and infratentorial areas, including brain stem, cerebellum, and spinal cord (Figure 1.3A). The T2-weighted lesions may be multifocal or as the underlying disease process advances they may become confluent. With time, the number and volume of T2-weighted lesions increase. However, with further disease progression with progression of central atrophy, the total brain volume as well as white matter volume is decreased, which translates into an overall decrease in the volume of T2-weighted lesions. Therefore, the T2-weighted lesion load may not demonstrate an accurate correlation with overall disability. Another MR technique to study MS is T1-weighted images obtained pre- and post-contrast infusion. Gd, the contrast material, is infused intravenously. The development of Gd-enhancing lesions on post-contrast T1-weighted images usually occurs at the early stages of lesion formation and may indicate BBB leakage (Figure 1.3B). The duration of the GD-enhancing T1-weighted lesions is short; they usually disappear within 2–6 weeks [41]. In addition, most of these lesions are clinically silent; therefore, MRI is 5–10 times more sensitive to MS disease activity than clinical observation alone [42]. Contrast-enhancing lesions may enhance homogeneously or present as ring-enhancing lesions. However, some of the contrast-enhancing T1-weighted lesions do not show a complete ring and manifest as “open ring”– enhancing lesions, in which case the opening of the ring points toward the cortex. The presence of open ring–enhancing lesions strongly supports a diagnosis of MS. In general, the ring-enhancing lesions are typically larger than nonring-enhancing lesions, show a shorter period of enhancement, and show a lower diffusion and magnetization transfer (MT) ratio. Therefore, these lesions may indicate the evolution of these lesions into T1-weighted black holes and may be associated with a

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Figure 1.4  (A) MR spectroscopy of the MS plaque. Echo time [TE]30 ms. Note the presence of lactate, indicating anaerobic metabolism, decrease in NAA (low neurons/axons), slight increase in choline (increased membrane metabolism, increased metabolic turnover), increased myoinositol (glial marker). (B) MR axial post-contrast T1-weighted enhancing hyperacute plaque over the left central region. (C) Axial apparent diffusion coefficient (ADC) map. (D) Axial diffusion-weighted image (DWI). Note hyperintensity on DWI and hypointensity on ADC, indicating restricted diffusion, seen in hyperacute plaques. With time the values increase and there will be no restriction.

stronger chance for brain atrophy. While the presence of contrast enhancement to a certain degree reflects inflammatory disease activity and disruption of the BBB, these lesions do not correlate potently with disability on longitudinal studies. The contrast-enhancing lesions are better indicators of active inflammatory stage, they point toward upcoming clinical relapses, and they are sensitive to treatment with corticosteroids and other immunomodulatory medications. A subgroup of T2-weighted lesions, which is also observable on T1-weighted images represents areas of hypointensity. Some of these areas may represent a temporary stage in the development of new MS lesions and may be associated with the inflammatory infiltrate in the newly developing lesions. However, a certain number of these lesions turn into persistent T1-weighted hypointensities also known as T1 black holes. T1 black holes are believed to show severe tissue loss with axonal loss, and the load of persistent T1-weighted black holes demonstrates a strong correlation with chronic disability [43]. T1-weighted black holes have been reported in both cerebral white matter and the spinal cord [44]. Another novel MRI technique is proton magnetic spectroscopy (1H-MRS), which allows determination of the chemical components and metabolite alterations within MS lesions as well as normal-appearing white matter (Figure 1.4). Assessment of MS

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Neuroinflammation

lesions using 1H-MRS allows insight into the biomolecules such as N-acetylaspartate (NAA), choline, creatine, myoinositol, glutamate, glutamine, lipids, and lactate. Each one of these metabolites appears at a unique site in the 1H-MRS spectrum (expressed at parts per million [ppm]). NAA is a specific marker of neuronal and axonal integrity and presents at 2.02 ppm. In active inflammatory lesions of MS there is a reduction of NAA peak along with increases in the choline, lactate, and lipid peaks. An increase in choline peak indicates increased cell membrane turnover marker, and its increase may be associated with infiltration of immune cells, demyelination, remyelination, and gliosis. Myoinositol is proposed to be a marker of glial proliferation.

Figure 1.5  (A) MRI. Axial diffusion-weighted image showing multiple hyperintense lesions, corresponding to MS plaques. Apparent diffusion coefficient (ADC) values (as n  10-3 mm2/s) were elevated compared to normal values (0.70  10-3 mm2/s). (B) MRI. Sagittal T1-weighted image with Gd contrast. MS plaques are perpendicular to ependyma (Dawson’s fingers).

Figure 1.6  (A) MRI. MT. MT ratio of a plaque is 33%, or 77% of normal. (B) Same patient 7 months after; plaque MT ratio is now 20%, or 44% of normal.

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Spinal cord lesions, which may be detected in up to 90% of patients with clinically definite MS, account for significant disability in these patients. The cervical cord is more frequently affected than the thoracic cord, and involvement of the spinal cord without cerebral involvement occurs in only 2% of MS patients. MS lesions affecting the spinal cord generally do not extend beyond two vertebral segments, and extensive longitudinal lesions, particularly when present acutely, should raise the diagnosis of neuromyelitis optica [45]. Many of the spinal cord lesions are clinically silent. Spinal cord lesions are better imaged on short tau inversion recovery (STIR) sequences. Other advanced MR procedures currently employed to better understand the pathogenesis of MS consist of diffusion-weighted MR (Figure 1.5), MT ratio (Figure 1.6), functional, perfusion MR imaging, and tractography.

Diagnosis The original diagnostic criteria proposed by Poser et al. (1983) [64] required clinical documentation of dissemination in time and space based on the physical examination. These criteria were modified to include MRI abnormalities [46,47]. The latest diagnostic criteria for MS are presented in Table 1.3.

Variants of MS Variants of MS include neuromyelitis optica (also known as Devic’s disease, which is discussed in a separate chapter), Marburg’s variant, Balo’s concentric sclerosis, and Schilder’s disease. Marburg’s variant of MS is a fulminant disorder with a rapidly progressive course, which is associated with severe axonal loss and causes the patient’s death. Balo’s concentric sclerosis is an uncommon form of MS that neuropathologically manifests with concentric rings of alternating demyelinated and undemyelinated areas. This form of MS, which is more common among Asians, presents as an acute condition and may result in severe disability or death. Unlike typical cases of MS, patients with Balo’s concentric sclerosis present with more cortical impairments such as seizures, aphasia, and cognitive decline. Schilder’s disease is a rare and progressive demyelinating disorder that affects children. Demyelinating lesions of Schilder’s disease are usually large, confluent, and extensive. Patients present with seizures, aphasia, weakness, speech impairment, personality changes, and poor concentration.

Differential Diagnosis A number of neurologic and nonneurologic diseases imitate MS and may present with nonspecific white matter lesions on brain or spinal cord MRI. In these cases, attention

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Table 1.3  Revised McDonald MS Diagnostic Criteria Clinical Presentation

Additional Requirements to Diagnose MS

2 or more attacksa

Noneb

2 or more objective clinical lesions 2 or more attacksa objective clinical evidence of 1 lesion

Dissemination in space, demonstrated by: MRIc or a positive CSFd and 2 or more MRI lesions consistent with MS or a further clinical attacka indicating a different location

1 attacka 2 or more objective clinical lesions

Dissemination in time, demonstrated by: MRIe or second clinical attacka

1 attacka objective clinical evidence of 1 lesion (monosymptomatic presentation; CIS)

Dissemination in space, demonstrated by: MRIc or positive CSFd and 2 or more MRI lesions consistent with MS and Dissemination in time, demonstrated by: MRIe or second clinical attacka

If criteria indicated are fulfilled, the diagnosis is multiple sclerosis (MS); if the criteria are not completely met, the diagnosis is “possible MS”; if the criteria are fully explored and not met, the diagnosis is “not MS.” a No additional tests are required; however, if tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF]) are undertaken and are negative, extreme caution should be taken before making a diagnosis of MS. Alternative diagnoses must be considered. There must be no better explanation for the clinical picture. b MRI demonstration of space dissemination. c Positive CSF determined by oligoclonal bands detected by established methods (preferably isoelectric focusing) different from any such bands in serum or by a raised IgG index. d MRI demonstration of time dissemination. e Abnormal visual evoked potential of the type seen in MS (delay with a well-preserved waveform). Source: From [47], Ann Neurology 2005. With permission from John Wiley and Sons, Inc.

to the details of the clinical history and neurologic examination as well as other laboratory tests usually assists the clinician to differentiate these diseases from MS. These imitators of MS include neurosarcoidosis, neurosyphilis, leukodystrophies, acute disseminated encephalomyelitis, ischemic demyelination, migraine, systemic lupus erythematosus, B12 deficiency, HIV encephalitis, HTLV-1–associated myelopathy, mitochondrial encephalopathy, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, ischemic stroke, fat embolism, and Behçet’s disease.

Management Currently, MS remains an incurable disease. Treatments for MS can be classified into three major categories: treatment for acute attacks, use of disease-modifying agents, and immunosuppressive agents.

Treatment of Acute Relapses Patients with MS frequently experience relapses; they may resolve completely or leave the patient with clinically detectable residual neurologic deficits. In addition,

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once the patient experiences a number of relapses, he or she accumulates significant functional disability. Multiple clinical observations have demonstrated that MS patients who are treated with corticosteroids or adrenocorticotropic hormone (ACTh) recover faster than untreated patients. Due to the powerful anti-inflammatory and immunosuppressive properties of corticosteroids and ACTh, neurologists commonly use these agents to treat acute relapses of MS. These medications decrease edema and inflammation as well as the number of contrast-enhancing lesions on T1-weighted brain MR images. Clinically, patients improve and usually recover more rapidly. One of these corticosteroid medications is methylprednisolone (Solu-Medrol), which is infused intravenously 1 g/day for 5 days, followed by abrupt withdrawal or a tapering regimen. ACTh is not commonly used for treatment of acute relapses of MS.

Disease-Modifying Agents Currently, there are six FDA-approved disease-modifying agents for treatment of MS: (1) low-dose, low-frequency interferon-β1a (Avonex); (2) high-dose, highfrequency interferon-β1a (Rebif); (3) high-frequency interferon-β1b; (4) glatiramer acetate (GA), also known as copolymer 1, Cop-1, or Copaxone; (5) natalizumab (Tysabri), a monoclonal antibody against the cellular adhesion molecule a4-integrin; and (6) mitoxantrone (Table 1.4).

Beta-Interferons Beta-interferons decrease the number of contrast (Gd)-enhancing lesions on brain MRI, reduce severe relapses by 50%, and delay disease progression. The mechanisms of the beneficial effects of beta-interferons in the management of MS patients are only partially known. Proposed mechanisms of action for these agents include reduction of antigen presentation [48], decreasing the expression of co-stimulatory molecules on the dendritic and other cells [49,50], suppressing the proliferation of pro-inflammatory Th1 lymphocytes and upregulation of production of IL-10 [51], shifting of the cytokine environment from pro-inflammatory to anti-inflammatory [52,53], preventing transendothelial migration of autoreactive T lymphocytes by decreasing the production of matrix metalloproteinases [54,55], and restoring BBB integrity by upregulating the expression of occludin and VE-cadherin [22]. IFN-β1b also decreases serum levels of IL-12 and IL-23 [27]. Adverse effects of IFN-β1b include injection site reactions. The flu-like syndrome that occurs within hours of the injection usually resolves within 24 h. However, the severity of the flu-like syndrome may decrease with more injections over several weeks. Various techniques can be used to reduce the severity and duration of the flu-like symptoms. One recommendation is to inject IFN-β1b at bedtime and to use a titration schedule to increase the dose slowly, starting at 25% of the recommended dose and progressing to the full dose within 4–6 weeks. Patients should be instructed to take noncorticosteroid anti-inflammatory agents such as ibuprofen or acetaminophen prior to and after the injection. In severe cases, use of low-dose corticosteroids (prednisone 10 mg prior

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Table 1.4  Therapeutic Drugs Approved by the FDA for Treatment of MS Drug

Dosage

Route of Side Effects Administration

Safety Blood Work

Avonex (INF-β1a)

30 μg weekly Intramuscular

Flu-like syndrome

LFT/CBC Redness, necrosis

Rebif (INF-β1a)

8.0 million Subcutaneous units 3 times weekly

Flu-like syndrome

LFT/CBC Redness, necrosis

Betaseron (INF-β1b)

44 μg

Subcutaneous

Flu-like syndrome

LFT/CBC Redness, necrosis

Glatiramer acetate (Copaxone)

20 mg

Subcutaneous

None

None

Tysabri 300 mg once Intravenous (natalizumab) every 28 days

None A number of cases of progressive multifocal leukoencephalopathy have been reported in association with it

Mitoxantrone 12 mg/m2 Intravenous body surface once every 3 months, not to exceed 140 mg in lifetime

Cardiomyopathy, opportunistic infections, acute myeloid leukemia

Skin Reaction

Redness, lipodystrophy None

LFT/CBC Skin necrosis upon accidental skin exposure

LFT, liver function tests; CBC, complete blood count.

to injection) is recommended. Uncommonly, depression and suicidal ideation occur in patients being treated with IFN-β1b. The most common laboratory abnormalities associated with IFN-β1b are lymphopenia and elevated liver enzymes. Injection site reactions are common and typically occur when patients inject themselves at the same place frequently. This reaction ranges from redness of the skin to skin necrosis. Skin necrosis usually requires discontinuation of the IFN-β1b.

Glatiramer Acetate GA, which is administered 20 mg/day subcutaneously, reduces relapses by one third. GA is a synthetic random polymer of four amino acids (with a molecular weight of 6.4 kDa) that exist in the MBP. It is currently used for treatment of patients with RRMS. The four amino acids are tyrosine, glutamate, alanine, and lysine. Previous experiments demonstrated that GA was an effective therapy for preventing and

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ameliorating experimental allergic encephalomyelitis [56]. GA was approved in 1997 by the FDA for treatment of patients with RRMS. The mechanisms of the beneficial effects of GA on MS patients are not completely understood. Based on the proposed mechanism of action of GA, this medication induces a Th2/anti-inflammatory response in up to 50% of treated patients. The Th2 T cells in turn induce immunosuppressive type 2 monocytes and microglia, which also promote a switch to a Th2 environment. Currently, GA is not indicated for treatment of patients with SPMS and PPMS. Two recent head-to-head clinical trials comparing the clinical efficacy of IFN-β1a and IFN-β1b did not establish any difference between the efficacy of the beta-interferons and GA [57,58].

Natalizumab Natalizumab (Tysabri) is a humanized monoclonal antibody that targets the α4 chain of α4β1and α4β7 integrins. The α4β1 integrin very late antigen-4 (VLA-4) is expressed on all leukocytes except neutrophils and binds to the vascular cell adhesion molecule-4 (VCAM-4), which is expressed by the cerebral inflamed endothelium [59]. Natalizumab blocks the binding of the VLA-4 and VCAM-1, which in turn either blocks or significantly reduces transendothelial migration of the activated leukocytes into the CNS. The results of clinical trials of natalizumab in MS patients indicate that administration of this monoclonal antibody reduced the annual relapse rate by 68% and decreased the rate of disability progression by 42%, the number of brain contrastenhancing T1-weighted lesions by 92%, and the number of T2-weighted lesions by 83% [60,61]. Natalizumab is infused intravenously 300 mg once every 28 days. Its major adverse event is development of progressive multifocal leukoencephalopathy. Other monoclonal antibodies under clinical investigation for treatment of MS include daclizumab, rituximab, and alemtuzumab.

Mitoxantrone Mitoxantrone (Novantrone), an antineoplastic agent with profound immunosuppressive effects, is chemically related to the anthracyclines such as doxorubicin and acts as a potent immunosuppressive agent for treatment of MS. Mechanisms of action of mitoxantrone include intercalation with the DNA molecule, which in turn causes single- and double-stranded disruptions and suppresses DNA repair via inhibition of topoisomerase II. Mitoxantrone potently inhibits proliferation of B and T lymphocytes as well as macrophages. Other cells, such as antigen-presenting cells, are also killed and migration of the activated leukocytes is suppressed. Other modes of action for mitoxantrone include lowering the secretion of IFN-γ, TNF-α, and IL-2 [62]. Administration of mitoxantrone causes apoptosis of B and T lymphocytes [63]. Mitoxantrone is administered 12 mg/m2 every 3 months. It significantly reduces clinical relapses, disease progression, and MRI lesions in MS patients. Mitoxantrone has three significant side effects: severe leukopenia, acute myelogenous leukemia, and cardiac toxicity. In addition, patients treated with mitoxantrone are always at high risk for opportunistic infections.

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Prognosis MS is an unpredictable disease and in many cases, even with standard treatment, patients progress toward irreversible disability. Prognostic factors that indicate a better outcome include female gender, younger age at disease onset, initial disease presentation with optic neuritis or sensory symptoms, the presence of little residual disability after each relapse, a prolonged interval between the demyelinating attacks, a lower lesion load on the baseline brain scan at the onset, a progressive course from the beginning of the disease, poor recovery from relapses, and cerebellar or motor deficits.

Conclusion MS remains a very complicated and incurable disease with many as yet unrecognized features. Ongoing basic science and clinical research into the pathophysiology of MS has altered our view of the fundamental mechanisms of disease process and had led to the discovery of disease-modifying agents. With introduction of these agents, the natural course of MS has changed forever and our clinical practice has moved toward more rapid diagnosis and earlier treatment of these patients. It is hoped that more effective therapies with fewer side effects will translate into a better quality of life for MS patients. The authors hope this chapter will encourage readers to continue research into the nature of this enigmatic disease.

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