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Brain, Multiple Sclerosis
Article Last Updated: Jan 24, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 12  
Author: James A Wilson, MD, MSc, FRCPC, BSc(H), Neurologist and Clinical Neurophysiologist, Oconee Neurology Services
James A Wilson is a member of the following medical societies: American Academy of Neurology and Ontario Medical Association
Coauthor(s):
Omar Islam, MD, FRCP(C), Assistant Professor of Diagnostic Radiology, Queen's University; Consulting Staff, Department of Diagnostic Radiology, Division of Neuroradiology, Kingston General Hospital
Editors: Jeffrey L Creasy, MD, Associate Professor, Associate Section Head, Division of Neuroradiology, Director, Neuroradiology Fellowship, Department of Radiology, Vanderbilt University; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; James G Smirniotopoulos, MD, Professor of Radiology, Neurology, and Biomedical Informatics, Chairman, Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences
Author and Editor Disclosure
Synonyms and related keywords:
MS, brain lesions, MS lesions, brain plaques, MS plaques, autoimmune disease, cognitive impairment, neurologic deficit, relapsing-remitting MS, chronic-progressive MS, inactive MS, clinically definite multiple sclerosis, CDMS
Background
Multiple sclerosis (MS) is an inflammatory demyelinating condition of the central nervous system (CNS) that is generally considered to be autoimmune in nature. White matter tracts are affected, including those of the cerebral hemispheres, infratentorium, and spinal cord. MS lesions, known as plaques, may form in CNS white matter in any location; thus, clinical presentations may be diverse. Continuing lesion formation in MS often leads to physical disability and, sometimes, to cognitive decline.
For excellent patient education resources, visit eMedicine's Muscle Disorders Center. Also, see eMedicine's patient education article, Multiple Sclerosis.
Pathophysiology
As with other autoimmune conditions, in patients with MS, the immune system is triggered to attack its host, possibly as a result of exposure to a molecular sequence that mimics the molecular sequence found in the host tissue. In patients with MS, the immune trigger is unknown, but the targets are myelinated CNS tracts. In regions of inflammation, breakdown of the blood-brain barrier occurs, with perivascular lymphocytic and monocytic infiltration. Focal destruction of myelin ensues, with axonal damage, gliosis, and the formation of sclerotic plaques. Gradually, cumulative damage results in significant loss of white matter and a reduction in total brain volume.
Frequency
United States
The frequency of MS varies depending on both the population and the geographic location. MS is most prevalent in white persons of northern European descent and in persons living in temperate climates. This observation suggests that both genetic and environmental factors influence the frequency of MS.
In the United States, Anderson et al estimated a prevalence of approximately 250,000-350,000 cases in 1990 (Anderson, 1992). With a total population of approximately 250 million, this figure corresponds to a prevalence of approximately 1 case per 1000 population, which is half the prevalence of MS in northern Europe (2 cases per 1000 population). Americans of Japanese descent have a prevalence approximately one quarter that of white Americans, whereas Americans of African descent have approximately one third the prevalence of white Americans.
International
The highest prevalence of MS occurs in the Orkney Islands of Scotland at a rate of 250 cases per 100,000 population (Hauser, 1994). A rate of only 2 cases per 100,000 population is observed in Japan, and MS is exceedingly rare in Africa. However, Americans of Japanese descent have a prevalence approximately one quarter that of white Americans, whereas Americans of African descent have about one third the prevalence of white Americans. These figures suggest an environmental effect and genetic susceptibility.
Mortality/Morbidity
MS is the leading cause of neurologic disability in early-to-middle adulthood, second only to trauma. Thus, the lifelong cumulative disability burden of MS is enormous. Practically any neurologic function can be affected during the course of MS.
- The presence of sensory and motor dysfunction is almost ubiquitous in patients with MS, and visual loss resulting from optic neuritis is not uncommon. Estimates indicate that 15 years after the onset of disease, 50% of persons with MS require ambulatory assistance.
- Cognitive impairment is observed in approximately 43% of individuals with MS (Rao, 1991).
- Litwiller et al reported that more than 80% of MS patients have lower genitourinary tract dysfunction, which may range from bladder and urethral dysfunction to impotence (Litwiller, 1999).
Race
MS is most prevalent in white persons of northern European descent (Hauser, 1994).
Sex
Male-to-female ratio is approximately 1:2 (Noseworthy, 2000).
Age
MS is a disease of early adulthood.
- Onset has been documented in patients aged 2-74 years, although the disease usually appears between the late teenage years and the fourth decade of life, peaking at approximately age 35 years.
- In men, the onset is slightly later than in women (Hauser, 1994).
Anatomy
MS is a demyelinating CNS disorder, and it may affect any central white matter. Lesions are commonly located in the optic nerves and tracts, throughout the supratentorial and infratentorial white matter, and along the myelinated tracts of the spinal cord. Locations may include the corpus callosum, cerebellar white matter, and corticospinal tracts.
Clinical Details
Clinical diagnosis
A diagnosis of MS is made on the basis of clinical findings by using supporting evidence from ancillary tests such as cerebrospinal fluid (CSF) examination for oligoclonal banding and MRI.
Clinically, MS has historically been diagnosed with the demonstration of white matter dysfunction disseminated in time and space (Schumacher, 1965). With the advent of diagnostic laboratory investigations and imaging techniques, the Poser criteria (Poser, 1983) were proposed to establish a degree of certainty of diagnosis in the absence of the 2 clinical attacks by using terms such as possible MS and probable MS.
Even more recently, with increasing treatment options for MS, and better imaging techniques, newer diagnostic criteria have been suggested that allow diagnosis after a single attack coupled with appropriate positive test results. These criteria have been coined the MacDonald criteria (MacDonald, 2001). Essentially, they allow for the second attack in time to be defined by a new lesion appearing on MRI. Also, the MacDonald criteria allow the dissemination in space to be established on the basis of either 9 typical white matter lesions on MRI or 1 enhancing lesion. If CSF studies show increased immunoglobulin G (IgG) values or oligoclonal banding, the presence of only 2 typical MRI lesions satisfy the dissemination-in-time criteria.
With respect to the initial clinical presentation in MS, it may vary with the white matter tract involved, and it may include somatic sensory changes, optic neuritis, or weakness, to mention just a few possible neurologic presentations. After only a single attack, the diagnosis of MS is suggested if the first impairment is coupled with positive paraclinical test results, such as those on imaging or CSF studies. Furthermore, the attack must be compatible with the pattern of impairment found in patients with MS, which typically means that the duration of deficit is days to weeks. Worsening of vision due to optic neuritis and subsequent exercise is known as the Uhthoff phenomenon.
Clinical course
The clinical course of MS can follow different patterns, and this observation has led to the classification of distinct types of MS. The most common form of MS is termed relapsing-remitting MS, in which progression involves symptoms of neurologic dysfunction frequently followed by partial or complete clinical recovery. In relapsing-remitting MS, global clinical deterioration has traditionally been attributed to cumulative deficit due to incomplete recovery from repeated occurrences of individual relapses. Recently, however, this cumulative deficit has been questioned, because evidence increasingly suggests an ongoing background neurologic deterioration that is independent of the relapses.
Occasionally, the course of MS may be more indolent and exhibit a chronic persistent neurologic deficit without apparent ongoing deterioration or further impairment. Sometimes, this course of MS is called inactive or benign MS, and this form is often observed in patients with prior relapsing-remitting disease.
Another potentially complicating matter clinically is that highly active MS lesions may sometimes demonstrate significant mass effect. Rarely, mass effect can lead to midline shift, herniations, infarctions, and even death. Such a drastic clinical and radiological presentation can lead to an incorrect preliminary diagnosis and inappropriate neurosurgical intervention. When MS presents in a more fulminant, aggressive manner, it is frequently known as malignant MS or the Marburg variant.
See Multiple Sclerosis for a detailed discussion of the clinical aspects of MS.
Preferred Examination
Radiologically, the use of MRI is revolutionizing the investigation, diagnosis, and even the treatment of MS. Usually, MRI is the only imaging modality needed for imaging patients with MS, and it far surpasses all other tests with respect to its positive predictive value.
CSF analysis for oligoclonal banding or IgG levels is no longer routine in the investigation of MS, although this test may be of use when MRI is unavailable or MRI findings are nondiagnostic.
Limitations of Techniques
MRI is useful in the diagnosis of MS and in the treatment of patients. One of the limitations of using MRI in patients with MS is the discordance occurring between lesion location and the clinical presentation. In addition, depending on the number and location of findings, MRI can vary greatly in terms of sensitivity and specificity in the diagnosis of MS.
This is especially true of primary progressive MS, which may not show the classic discrete lesions of relapsing-remitting MS. A clinician presented with an MRI report that details a few "nonspecific white matter lesions" that are "compatible with MS" is often frustrated with the lack of sensitivity and specificity of such a description.
For this reason, imaging findings need to be described in detail, and preferably referenced to one of the published set of diagnostic criteria such as those by Paty or Barkhof (see the CAT Scan and MRI sections below). Finally, the specific patient's neurological history and clinical findings must be correlated with the imaging to establish an accurate diagnosis.
Brain, Stroke
Optic Neuritis
Progressive Multifocal Leukodystrophy
Other Problems to be Considered
Acute demyelinating encephalomyelitis
Acute disseminated encephalomyelitis
Atypical facial pain
Brainstem gliomas
Central pontine myelinolysis
Essential tremor
CNS complications (related to opportunistic infections, opportunistic neoplasms, vacuolar myelopathy, and encephalopathy due to HIV)
AIDS-dementia complex
Hemifacial spasm
Inherited metabolic disorders
Lyme disease
Lysosomal storage disease
Metabolic disease and stroke
Myokymia
Paraneoplastic encephalomyelitis
Primary CNS lymphoma
Primary lateral sclerosis
Spinal cord infarction
Sudden visual loss
Neuromyelitis optica (Devic disease)
Diffuse cerebral sclerosis of Schilder (encephalitis periaxialis diffusa)
Concentric sclerosis of Balo
Findings
Plain radiographic studies have no positive predictive value in the diagnosis of MS. Occasionally, plain radiographs may be used to exclude mechanical bony lesions.
Degree of Confidence
Plain images cannot demonstrate MS-specific lesions.
Findings
Similar to radiography, CT has had a limited role in the diagnosis of MS and in the treatment of patients since the advent of MRI. CT scans may be used to exclude other causes for neurologic impairment, but they have a low positive predictive value in the diagnosis of MS.
Prior to MRI, CT was used in an attempt to identify active MS lesions with the injection of double or triple doses of intravenous contrast material. However, the scans were insensitive for the detection of chronic lesions. CT scans can help in assessing the degree of cerebral atrophy associated with advanced MS, but given the plethora of additional information provided by MRI, CT is no longer used for this purpose.
Degree of Confidence
CT has a low positive predictive value in the diagnosis of MS.
In a cohort of 200 patients, Paty et al found that of the 19 who went on to develop clinically definite MS (CDMS), abnormal CT findings were demonstrated in only 9 (47%). In contrast, abnormal MRI findings were demonstrated in 18 (95%). All of the abnormal CT findings were also demonstrated on MRIs.
False Positives/Negatives
CT imaging in MS is nonspecific and insensitive; thus, the false-negative rate is high. An acute MS lesion may enhance and appear simply as an enhancing white matter lesion on CT scans, but the appearance is highly nonspecific. When a highly active MS lesion is observed to enhance and possibly exerts mass effect, it can be termed tumefactive due to the potential for misidentification as a tumor. Because CT scans typically do not help identify the more chronic lesions, the tumefactive MS lesion may appear as a solitary enhancing mass, which leads to neurosurgical intervention. Fortunately, this situation is relatively uncommon.
Findings
The advent of MRI has revolutionized the diagnosis and monitoring of MS. Typical findings and pulse sequences Because of the inflammation and breakdown of the blood-brain barrier in MS lesions, the presence of extravascular fluid leads to hyperintensity on T2-weighted images. Thus, in a patient with MS, MRIs typically demonstrate more than 1 hyperintense white matter lesion. Lesions may be observed anywhere in the CNS white matter, including the supratentorium, infratentorium, and spinal cord; however, more typical locations for MS lesions include the periventricular white matter, brainstem, cerebellum, and spinal cord. Ovoid lesions perpendicular to the ventricles are common in MS and occasionally are called Dawson bars or fingers, which occur along the path of the deep medullary veins. Perhaps the most specific lesions in MS are noted in the corpus callosum at the interface with the septum pellucidum (Gean-Marton, 1991). Proton density (PD)–weighted MRI has an advantage over standard T2 imaging because, on PD series, MS lesions remain hyperintense while CSF signal is suppressed. Therefore, the lesions are easily identified. Depending on the PD technique, CSF signal is suppressed to a variable degree, rendering it isointense to hypointense relative to the brain parenchyma. This sequence results in substantial suppression of Virchow-Robin spaces, which are perivascular CSF spaces that may penetrate to the subcortical white matter. These spaces may appear as hyperintense spots on standard T2-weighted MRIs. Compared with other techniques, nonenhanced T1-weighted MRI is far less sensitive in detecting MS lesions. Acute lesions usually are not depicted at all. With T1-weighted MRI, the clinician can gain a general appreciation of the global cerebral atrophy that occurs with advanced chronic MS. Global atrophy has been suggested to have the strongest imaging correlation with disability. Chronic MS lesions usually result in localized leukomalacia, and they may appear as hypointense lesions that represent loss of tissue. Gadolinium-enhanced T1-weighted MRIs can depict acute active MS lesions. These appear as enhancing white matter lesions, and the presence of an enhancing lesion has been shown to increase the specificity for MS (Barkhof, 1997; Tintoré, 2000). Newer pulse sequences and techniques Newer MRI pulse sequences and techniques have emerged, and these are potentially useful in the evaluation of patients with MS. Fluid-attenuated inversion recovery (FLAIR) MRI is a heavily T2-weighted technique that dampens ventricular (ie, free water) CSF signal. Thus, the highest signals on the sequence are from certain brain parenchymal abnormalities, such as MS lesions, while the CSF appears black. This appearance is different from that on PD-weighted MRIs, on which periventricular MS lesions may appear nearly isointense to the adjacent CSF. The greater relative suppression of CSF on FLAIR images compared with PD-weighted series increases the contrast between periventricular lesions and CSF, enhancing their detection. FLAIR has been shown to be superior to PD-weighted sequences in the detection of MS lesions in the cerebral hemispheres. However, PD-weighted imaging remains the investigation of choice for infratentorial lesions (Hashemi, 1995). Magnetic resonance (MR) spectroscopy uses the characteristic spectra of specific biochemical markers to quantitate organic compounds in vivo. N-acetylaspartate (NAA) is a relatively specific neuronal marker that is in sufficient concentrations in the brain to be revealed on MR spectroscopic images. By comparing the spectral signal of NAA with that of creatinine (Cr), MR spectroscopic can be useful in assessing neuronal and axonal loss. Arnold et al noted that the CNS NAA-Cr ratio was decreased in moderate-to-advanced MS. In addition, white matter that appeared normal on T1- and T2-weighted images also demonstrated the reduction (Arnold, 1990). In addition, a normal ratio was noted in the area of a recently active lesion associated with clinical deficits that subsequently resolved. The findings led the authors to propose that MRS findings may be able to help identify irreversible axonal damage. In a study involving 88 patients with MS, De Stefano et al found a strong correlation between disability scores and NAA-Cr ratios (De Stefano, 2001). The ratio exhibited a stronger correlation in MS patients with milder disability scores. Because MR spectroscopy appears to be capable of depicting changes in white matter that are not detected with routine pulse sequences and because the findings are correlated with disability scores, the use of MR spectroscopy may prove valuable in monitoring patients after treatment and in formulating their prognosis. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA.
NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.
Degree of Confidence
In patients with CDMS, MRI demonstrates a high rate of abnormal findings compatible with the diagnosis. In a study by Lukes et al, lesions were demonstrated in 10 patients with CDMS (Lukes, 1983). In a larger study by Robertson et al, MRI findings were abnormal in 124 of 133 patients with CDMS (Robertson, 1985). Ormerod et al found that 112 of 114 patients with CDMS had abnormal MRI findings and that 102 of 114 had discrete white matter lesions (Ormerod, 1987).
MRI is well established as the preferred imaging modality for depicting MS lesions. Another major use of MRI has been the evaluation of patients who have had only one episode of neurologic impairment and who do not meet the clinical criteria for the diagnosis. The overall risk of developing MS after a single episode of neurologic impairment is estimated to be as low as 12% (2-y follow-up study by Beck et al in 1993) to as high as 45% (12.9-y follow-up study by Sandberg-Wollheim et al in 1990) or 58% (14.9-y follow-up study by Rizzo et al in 1988).
MRI has been proven to be the most useful investigation for predicting the progression to MS. In a 10-year follow-up study of patients with a clinically isolated event, 45 (83%) of 54 patients with abnormal MRI findings went on to develop clinical MS, whereas only 3 of 27 with normal MRI findings developed MS (O'Riordan, 1998).
Tintoré et al followed up 70 patients for an average of 28.3 months after an isolated neurologic event and compared various MRI criteria for the diagnosis MS, as defined by Paty et al, Fazekas et al, and Barkhof et al (Tintoré, 2000; Paty, 1988; Fazekas, 1985; Barkhof, 1997). With the method of Paty et al, which requires 3 or 4 lesions (1 of which is periventricular), the authors reported a sensitivity of 86% but a specificity of only 54%.
The criteria of Fazekas et al resulted in the same sensitivity and specificity. These criteria require 3 lesions with 2 of the 3 following characteristics: infratentorial location, periventricular location, and lesion greater than 6 mm. The criteria of Barkof require 1 infratentorial lesion, 1 juxtacortical lesion, 3 periventricular lesions, and either 1 gadolinium-enhanced lesion or more than 9 lesions on T2-weighted MRIs. These criteria resulted in a sensitivity of 73% and a specificity of 73%. Thus, as the MRI criteria become more stringent in the diagnosis of MS, specificity increases at the expense of decreasing sensitivity.
False Positives/Negatives
In virtually all patients with clinically well-established MS, MRIs demonstrate the corresponding changes. False-negative findings occur more frequently in patients with early MS and a minimal clinical history of neurologic impairment than in other patients.
O'Riordan et al prospectively found that, in 3 of 27 patients with normal MRI findings, MS subsequently developed (O'Riordan, 1998). The patients with normal MRI findings all developed lesions detectable on MRIs when the disease became established. Similarly, as patients are followed for longer periods, the rate of false-positive findings decreases because, in many patients with abnormal MRI findings after a single neurologic event, the clinical criteria for MS eventually develop.
Findings
Ultrasonography is not currently used in the investigation of MS. Recently, however, Berg et al used transcranial sonography to determine the size of the ventricles in patients with MS (Berg, 2000). The authors found that an increasing size is correlated with the MRI-determined brain volume, as well as cognitive dysfunction and clinical disability. Further studies may establish a role for ultrasonography in the prognosis and treatment of patients with MS.
Findings
Nuclear medicine studies are not used in the diagnosis or management of MS.
Findings
Angiography has a limited role in the diagnosis and management of MS. Occasionally, when CNS vasculitis is considered in a patient with undifferentiated findings, angiography may be considered.
Degree of Confidence
No positive angiographic findings are specific to MS.
No radiologic interventions are applicable in patients with MS, with the exception of the occasional fluoroscopic-guided lumbar puncture to obtain CSF for oligoclonal banding assessment.
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Sagittal T1-weighted MRI depicts multiple hypointense lesions in the corpus callosum; this finding is characteristic of multiple sclerosis. |
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Axial T2-weighted MRI in a patient with multiple sclerosis demonstrates numerous white matter plaques in a callosal and pericallosal white matter distribution. |
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Axial T1-weighted gadolinium-enhanced MRI in a patient with multiple sclerosis demonstrates several intensely enhancing pericallosal white matter lesions compatible with active disease. |
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Axial diffusion-weighted MRI in a patient with multiple sclerosis shows several hyperintense lesions, a feature of inflammatory disease activity. |
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Axial proton density–weighted MRI through the posterior fossa in a patient with multiple sclerosis demonstrates multiple bright foci in the brainstem and cerebellum. Proton density–weighted sequences are highly sensitive for the detection of plaques in multiple sclerosis, especially in the posterior fossa. |
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Coronal fluid-attenuated inversion recovery (FLAIR) MRI in a patient with multiple sclerosis demonstrates periventricular high signal intensity lesions, which exhibit a typical distribution for multiple sclerosis. FLAIR MRI is a highly sensitive sequence for lesion detection, particularly supratentorially. |
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Axial proton density–weighted MRI demonstrates multiple lesions in a distribution characteristic of multiple sclerosis. Specifically, the periventricular lesions and the more peripheral white matter lesions near the gray matter–white matter junction are typical MRI findings in multiple sclerosis. |
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Axial T1-weighted gadolinium-enhanced MRI in a patient with multiple sclerosis depicts enhancement of a plaque in the right temporo-occipital lobe, signifying disease activity. Note the C-shaped or arclike enhancement, which is fairly characteristic of multiple sclerosis. |
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Point-resolved spectroscopic study performed in a patient with multiple sclerosis demonstrates a slightly decreased N-acetylaspartate peak and a mildly elevated choline peak; these findings are compatible with demyelination with neuronal loss and increased cell membrane turnover. |
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Sagittal proton density–weighted MRI in a patient with multiple sclerosis demonstrates the characteristic corpus callosum and pericallosal white matter lesions. |
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Axial T1-weighted gadolinium-enhanced MRI in a patient with multiple sclerosis depicts several enhancing lesions, at least 2 of which show characteristic C-shaped or arclike peripheral enhancement. |
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Axial diffusion-weighted MRI in a patient with multiple sclerosis shows several hyperintense lesions, a feature of inflammatory disease activity. |
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Brain, Multiple Sclerosis excerpt Article Last Updated: Jan 24, 2007
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