Clinical Presentation

Symptoms range from isolated cranial nerve palsy, optic neuritis, and vague sensory complaints, to paresis and paraplegia of limbs, and myelopathy. Subtle and obvious changes in intellectual capacity are also identified in patients with MS.

Clinical Criteria

The diagnosis of MS is presently still based on clinical and paraclinical criteria alone. These parameters were initially proposed to select patients for treatment trials. The clinical diagnosis of MS (according to the Schumacher criteria) is made by history or neurologic examination resulting from two or more white matter lesions with either (1) two or more episodes of worsening, each lasting at least 24 hours and each at least a month apart, or (2) slow stepwise progression of signs or symptoms for at least 6 months.

The criteria accepted by the International Panel in 2005 has been adopted by the mainstream neurology community and is outlined in Table 7-1 and Box 7-3. It advances a greater role for MR imaging in supporting the diagnosis of MS and now requires radiologists to count lesions and to determine if they are infratentorial, supratentorial, or spinal; if they are juxtacortical; and if they enhance. MR is also used to demonstrate when lesions are distributed over time to differentiate MS from acute disseminated encephalomyelitis (ADEM) and other monophasic diseases that have a different course and prognosis.

Table 7-1 International Panel Criteria (McDonald Criteria) for the Diagnosis of Multiple Sclerosis

Laboratory Tests

Laboratory tests, including visual, auditory, and somatosensory evoked responses, can confirm the presence of lesions, but they are nonspecific and provide no clue to the cause of the abnormal finding. Approximately 70% of patients with MS have elevated cerebrospinal fluid (CSF) levels of IgG index and approximately 90% have elevated oligoclonal bands.

Clinical Course

MS is a disease characterized by a variety of clinical courses. Terminology about clinical classification can be confusing and even contradictory. Relapsing remitting MS is the most common course of the disease, initially occurring in up to 85% of cases. At the beginning, exacerbations are followed by remissions. However, over years, additional exacerbations result in incomplete recovery. Within 10 years 50% (and within 25 years, 90%) of these cases enter a progressive phase, termed secondary progressive (or relapsing progressive) MS. During this phase deficits are progressive without much remission in the disease. Less commonly, the disease is progressive from the start. This entity, first distinguished in 1952, has been termed primary progressive (or chronic progressive) MS. These patients (5% to 10% of the MS population) may present at a later age with progressive neurologic findings, including paraparesis, hemiparesis, brain stem syndromes, or visual loss, and typically have a more severe disability. They may have occasional plateaus and temporary improvements but do not have distinct relapses. Primary progressive patients tend to have a smaller lesion load, fewer new lesions on monthly T2-weighted images (T2WI), and fewer enhancing lesions when compared to patients with secondary progressive disease, despite progressive declining neurologic status. Progressive relapsing MS, a rare clinical course, is defined as progressive disease with clear acute relapses, with or without full recovery, and with the periods between relapses characterized by continuing progression. All of these groups also have been lumped together and identified as chronic progressive MS; however, some experts believe the term should be abandoned because of its vague nature and the variable clinical courses and corresponding MR patterns. Benign MS describes those cases in which, after initial clinical symptomatology, there is no clinical progression over, approximately, a 10- to 15-year course. Conversely, a rapid progressive disease leading to significant disability or death in a short time after the onset has been termed malignant MS.

Monosymptomatic Patient

In addition to these well-described clinical patterns of the disease, there exists the dilemma of the monosymptomatic patient. This presentation consists of a single episode of neurologic deficit, such as optic neuritis, transverse myelitis, or brain stem syndrome. Seventy-seven percent of patients presenting with an isolated brain stem syndrome have been reported to have asymptomatic supratentorial white matter abnormalities. Progression to MS occurs in about 57% of patients with isolated brain stem syndrome and in 42% of patients with spinal cord syndrome. Fifty percent of patients with optic neuritis had lesions in their brain 3 weeks to 7 years after their attack. The risk of a patient with MS having an episode of optic neuritis at some point in the disease course is 80%. The presence as well as the number of asymptomatic lesions on MR markedly increases the risk of progression to MS not only in cases presenting with optic neuritis, but also in isolated brain stem or spinal cord syndromes. Those patients presenting with isolated acute syndromes without brain lesions are at lower risk of progressing to MS. MR, thus, possesses good predictive power in patients presenting with clinically isolated syndromes suggestive of MS.

Pathologic Findings

MS is believed to be an autoimmune disease; however, other mechanisms have been proposed. At this time, its etiology is still unknown. The pathology of MS is manifest by a chronic inflammatory process resulting in myelin loss. Active lesions demonstrate axonal transactions, infiltration with lipid-laden macrophages (Gitter cells), perivascular inflammatory cuffing with T and B lymphocytes, and plasma cells associated with perivascular demyelination. Attempts by the oligodendroglia at remyelination have been observed in both acute and chronic plaques. The extent of this process can vary from a narrow rim around silent lesions to macroscopic satellite zones contiguous with demyelinated lesions, the latter having been termed a shadow plaque. Remyelination and its relationship, if any, to clinical recovery is still problematic. Inactive plaques are hypocellular without perivascular inflammation.

MR Findings

On T1WI, plaques are isointense or low-intensity regions, whereas on T2WI the lesions are high intensity (Fig. 7-1). The hypointense lesions on T1WI have been termed black holes and have been reported to be associated with areas of greatest myelin loss and to correlate with patient disability scores/clinical symptoms. On T2WI, tiny nodules or large confluent high-intensity lesions are seen. MS lesions have a predilection for certain regions of the brain, including the periventricular region, corpus callosum (best visualized on sagittal fluid-attenuated inversion recovery [FLAIR] or proton density-weighted images [PDWI]), subcortical region (best seen on FLAIR), optic nerves and visual pathways, posterior fossa (including the brain stem and cerebellar peduncles, best seen on T2WI), and cervical region of the spinal cord. However, MS lesions can and do occur in any location in the brain. This includes the cortex (6%), where white matter fibers track up to the superficial cortical cells, and the deep gray matter (5%). CAUTION: FLAIR imaging does not detect lesions in the posterior fossa, brain stem, and spinal cord as well as conventional T2WI. In addition, very hypointense lesions on T1WI may look similar to CSF on FLAIR; that is, not bright. High-intensity lesions at the callosal-septal interface (sagittal FLAIR) have been suggested to have 93% sensitivity and 98% specificity in differentiating MS lesions from vascular disease (Fig. 7-2). The shape of these MS plaques may be variable. However, ovoid lesions are believed to be more specific for MS. Their morphology has been attributed to inflammatory changes around the long axis of a medullary vein (Dawson’s fingers) (Fig. 7-3).

Figure 7-1 Multiple sclerosis. A, Sagittal T1-weighted image (T1WI) with hypointense lesions or so-called “black holes”(arrows). B, Axial T2WI showing multiple hyperintense lesions (arrows).

Figure 7-2 Sagittal FLAIR image with high intensity lesions emanating from the septal-callosal interface.

Figure 7-3 Dawson’s finger on 4-Tesla magnetic resonance. Note the vein (open black arrows) courses through the middle of the ovoid lesion.

Lesions may display mass effect that can mimic a tumor (tumefactive MS) and have been associated with seizures (Fig. 7-4). Several hints aid in suggesting this diagnosis, including the history, which is usually acute or subacute in onset in a young adult, and other white matter abnormalities unassociated with the mass lesion (check the spinal cord) and the callosal-septal interface. Tumefactive MS lesions have a leading edge of enhancement and often an incomplete horseshoe-shaped ring of enhancement. Perfusion in tumors is usually increased and in MS it is normally not. Veins are displaced by neoplasms but course through MS lesions. There also have been rare reports of hemorrhage into demyelinating lesions, but this is more common in tumors and strokes. Some of the many faces of MS are displayed in Figure 7-5.

Figure 7-4 Tumefactive multiple sclerosis. A, Axial FLAIR image with large mass compressing the left ventricle with extension into the corpus callosum. B, T1-weighted image with irregular enhancement extending into the corpus callosum.

Figure 7-5 MS from top to bottom. A, Subcortical lesions on FLAIR. B, Same as A only inferior slice with corresponding diffusion-weighted image. C, Diffusion image with high intensity from possible cytoxic edema (?acute demyelination). D, Periventricular lesions on FLAIR. E, Brain stem lesion on FLAIR. F, Vermian multiple sclerosis with mass and ring enhancement (G).

Other findings include atrophy of the brain and spinal cord. In general, the longer the course of the disease, the greater the accumulation of MS lesions. This can average between 8% and 10% of the disease burden a year in relapsing remitting MS. The greater the loss of myelin and axons, the more likely the lesion is to be hypointense on T1WI. High intensity on unenhanced T1WI can be observed infrequently, most often in the periphery of the plaque. The cause of this phenomenon is undetermined, but hypotheses include a small amount of paramagnetic accumulation from hemorrhage; myelin catabolites, including fat; free radical production from the inflammatory response; or focally increased regions of protein.

Increased iron deposition (in the thalamus and basal ganglia) producing low intensity on T1WI and T2WI has been reported in patients with long-standing MS. This latter finding is nonspecific, having been described in a variety of different conditions, including Parkinson disease, multisystem atrophy, and other degenerative conditions.

There is a significant incidence of high-intensity abnormalities in the brains of healthy individuals without MS. This number varies depending on the exact report and the cohort’s age. In one study of healthy volunteers, white matter abnormalities were noted in 11% of subjects age 0 to 39 years, in 31% age 40 to 49 years, 47% age 50 to 59 years, 60% age 60 to 69 years, and in 83% of those age 70 years and older. Rudimentary MR criteria may have a role in prioritizing differential diagnoses; however, with all of the caveats related to high-intensity abnormalities, the use of MR criteria alone is open to criticism and fraught with error. Most radiologists provide a broad disclaimer when identifying a few white matter lesions in a young patient with a nonclassical appearance, such as, “These lesions are nonspecific in appearance and may be seen with accelerated small-vessel ischemic disease, vasculopathies, migraine headaches, Lyme disease, and as the residua from inflammatory and traumatic insults to the brain.” No, it does not cover everything. If there is an elevated erythrocyte sedimentation rate, include vasculitis, not just vasculopathy. Vasculitides (see Chapters 4 and 6) including primary angiitis of the central nervous system, polyarteritis nodosa, Behçet’s disease, syphilis, Wegener’s granulomatosis, Sjogren syndrome, and lupus should be in the differential diagnosis of MS both clinically and radiographically.

Enhancement in MS

The enhancement pattern of the initial lesion is usually in the shape of a nodule, which may be ovoid in appearance. Nodular enhancement can evolve to a ring or arc shape (Fig. 7-6). If lesions recrudesce, they usually have an arc or ring appearance. Many times the center of this type of lesion is lower intensity on T1WI. On T2WI, lesions generally wax and wane in size. Most often, one is left with a residual high-intensity lesion on T2WI. If a lesion is enhancing as a nodule for more than 3 months, be a little suspicious—it can happen, but consider other possible diagnoses. Cranial nerves (besides the optic nerve) can also enhance, but make sure the patient has MS (Fig. 7-7). Enhancement is more sensitive than either clinical examination or T2WI in detecting disease activity and potentially can separate clinical groups. The normal window of enhancement is from 2 to 8 weeks; however, plaques can enhance for 6 months or more. Enhancement cannot be viewed as an “all or none” phenomenon; rather it is dependent on the time from injection to imaging, the dosage of contrast agent, the magnitude of the blood-brain barrier abnormality, and the size of the space where it accumulates. Delayed imaging (usually 15 to 60 minutes after injection) increases the detection of enhancing MS lesions. Triple doses of gadolinium (0.3 mmol/kg) or a single dose (0.1 mmol/kg) with magnetization transfer (MT) (also see discussion in the New Methods section of this chapter) to suppress normal brain can increase the number of detectable MS lesions.

Figure 7-6 Patterns of enhancement in multiple sclerosis (MS). A, Axial T2-weighted image (T2WI) of a patient with MS showing a variety of shaped lesions. B, Axial enhanced T1WI with arc (arrow) and ring enhancement (open arrows). C, Axial enhanced T1WI with nodular enhancement (arrows).

Figure 7-7 Neural enhancement in multiple sclerosis. A, Coronal postcontrast T1-weighted image revealing enhancement of cranial nerve V (white arrows). B, Coronal enhanced image with enhancement of right cranial nerve III (arrow).

(Courtesy of Robert Quencer, MD, Miami, Florida).

Normal-appearing White Matter

We have just covered combinations and permutations of visible lesions but the normal-appearing white matter (NAWM) is also abnormal. Yes, the term is quite relative. There are many new MR methods (see New Methods in this chapter) that clearly demonstrate that the NAWM in MS is not normal; that is, there are lesions that we cannot detect by conventional MR. This is important, because the extent of disease in MS patients is generally greater than the visible T2 lesion load. In addition, MS lesions tend to have fuzzy borders; that is, even the visible lesions have abnormalities that extend beyond the visible boundaries on T2WI.

Spinal Cord Disease

MS can affect the spinal cord alone (5% to 24%) or, more commonly, both the brain and the spinal cord. Approximately 60% of spinal cord lesions occur in the cervical region. In one study, most patients had only one spinal lesion, whereas in another large study, 56% of cases had more than one spinal lesion. Spinal cord MS tends not to involve the entire cord, is peripherally located, generally does not respect boundaries between white and gray matter, and can range in length from 2 to 60 mm. Ninety percent of MS lesions are less than two vertebral body segments in length. Spinal cord swelling associated with lesions occurs in 6% to 14% of cases, whereas atrophy ranges from 2% to 40%. Many lesions in patients referred for imaging of spinal cord MS symptoms demonstrate enhancement. In terms of clinical categories spinal cord lesion load is highest in relapsing remitting and secondary progressive MS. Primary progressive patients (who have overall low lesion load) have a higher proportion of their lesion load within the spinal cord than secondary progressive patients. Nonetheless, no correlation is found between spinal cord lesion load and the Kurtzke Expanded Disability Status Scale. Clinical disability has been correlated with spinal cord atrophy.

MS Syndromes

Many syndromes are associated with MS. Devic disease, or neuromyelitis optica (Fig. 7-8), represents either an acute variant of MS or a separate demyelinating disease. The disease consists of both transverse myelitis and bilateral optic neuritis (Fig. 7-9). Symptoms may occur simultaneously or be separated by days or weeks. The clinical manifestations can be severe.

Figure 7-8 Devic disease. A, High intensity on sagittal T2-weighted image (T2WI) involving more than seven vertebral body segments (arrows). B, Enhancement throughout the upper area of abnormality. C, Axial T2WI with central hyperintensity.

Figure 7-9 Optic neuritis. The T2-weighted image shows bright signal within the left optic nerve (arrow).

Balo disease (concentric sclerosis) represents a histologic MS lesion with alternating concentric regions of demyelination and normal brain (Fig. 7-10). Diffuse sclerosis (Schilder disease) is an acute, rapidly progressive form of MS with bilateral relatively symmetric demyelination. It is seen in childhood and rarely after age 40 years. It is characterized by large areas of demyelination that are well circumscribed, often involving the centrum semiovale and occipital lobes. Marburg variant of MS is defined as repeated relapses with rapidly accumulating disability, producing immobility, lack of protective pharyngeal reflexes, and bladder involvement.

Figure 7-10 Balo sclerosis. A, Left frontal high intensity lesion. There are alternating rings of different intensities (arrows). B, Note the rings of intensity on this postgadolinium T1-weighted image (arrows).

Magnetic Resonance Spectroscopy

N-acetyl aspartate (NAA) is decreased in MS, indicating that MS is more than a white matter disease. Axonal-neuronal loss occurs both early and often. It is suggested that the neuronal loss is associated with irreversible neurologic impairment. Choline (Cho) is increased and is associated with membrane (myelin) breakdown, inflammation, and remyelination. Creatine (Cr) may also be decreased. Lipid resonances have been observed in acute lesions using short echo times (TE ≤ 30 ms). Myoinositol and lactate have also been reported to be present in some lesions. Citrulline peaks at 3.15 ppm between Cho and Cr from citrullination of myelin basic protein can be seen in 50% of brains with early-onset MS.

Magnetization Transfer

Magnetization transfer (MT) results from the transfer of magnetization from protons attached to rigid macromolecules (such as myelin) to free water protons. The effect is observed by noting a decrease in intensity on MR images (particularly PDWI) performed with an off resonance MT pulse. Injury resulting in demyelination causes a decrease in MT. Usually, MT effects are noted as one minus the ratio of the image intensity with a saturation pulse on divided by the intensity with the saturation pulse off:

This is termed the magnetization transfer ratio (MTR). Thus, (for the physicly challenged) low MTR equates with myelin loss. Remember, we are not referring to MT in the setting of enhancement. Rather, we are attempting to look at tissue specificity.

There is decreased MT in MS, including in plaques and in NAWM. MTR is highest in homogeneously enhancing lesions, lower in nonenhancing lesions, and lowest in the central portion of ring-enhancing lesions, suggesting possible evolutionary patterns for lesions. Correlation with clinical disability has been found using MT. Histogram analysis using MT enables interrogation of the entire brain. Combined with techniques that segment the brain into gray and white matter, one can tease out the effect of disease on specific brain components.