79.1 Clinical Features
and Laboratory Investigations Multiple sclerosis (MS) is the most common demyeli- nating disorder of the CNS. The peak incidence is at 30 years of age. MS rarely commences in childhood or after the age of 50 years. Females are affected twice as often as males. MS shows a characteristic geographi- cal distribution. It is rare in tropical areas and in- creases in frequency at higher latitudes. It has been estimated, for example, that the prevalence in the United States varies from 6–14 per 100,000 inhabi- tants in the southern states to about 40–60 per 100,000 inhabitants in the northern states. No definite relationship has been established with the climatic characteristics of the latitude. Within this overall lat- itudinal distribution a rather large range of inci- dences of MS has been observed at the same latitudes.
Occasionally clusters of MS have been reported. In these instances a remarkable number of patients acquire MS within a short period of time (a few months). Etiological factors for these MS pockets are as yet unknown. Sometimes such clusters of MS as- sume the proportions of an epidemic, the incidence of MS rising over a period of several years in a large area. In these cases the nature of the introduced envi- ronmental factor or factors still remains to be eluci- dated. The importance of environmental factors is stressed by the findings of migrational studies. A de- crease in the risk of developing MS has been noted in young individuals migrating from high-risk to low- risk areas and an increase in risk after migration from low-risk to high-risk areas. Such changes in risk have not been found in older individuals, and the data sug- gest that the risk of acquiring MS is largely estab- lished around the age of 15. There is also strong evi- dence of a genetically influenced susceptibility to MS.
In general, first-degree relatives of probands have a risk that is 30–50 times greater than the risk for the general population.
A number of variants of MS can be distinguished:
classical MS (also called Charcot type), neuromyelitis optica (NMO, or Devic disease), concentric sclerosis (CS, or Baló disease), and diffuse sclerosis (DS, or Schilder disease).
The clinical presentation of classical MS is ex- tremely variable. The extreme acute progressive form (Marburg type) is rare. For the more slowly develop- ing forms it has become usual to distinguish four
main types. In most patients the disease starts with a relapsing-remitting course (RR), defined by the oc- currence of relapses clearly separated in time, with stable intervals in between. Disability in RR patients develops because recovery between relapses is in- complete; in two-thirds of the patients the relapsing- remitting phase is followed by a secondary progressive course (SP) with increasing disability as measured on a disability scale over a period of 12 months. Finally there is a primary progressive form in 10–15% of the patients, with progressive disability from the onset. In this group the disease usually starts later and the fe- male preponderance is less evident (Lublin and Rein- gold 1996). The term benign form (BF) is used when after initial relapses and remissions no further pro- gression occurs and the patient is neurologically fully functional 15 years after the first symptoms. Special attention has been given in the last decade to patients with a clinically isolated symptom (CIS) because of the potential to delay or prevent the possible progres- sion to MS with early treatment. Finally, tumefactive forms of MS present with symptoms of a space-occu- pying lesion. Medical history, the presence of other clinical symptoms or lesions on neuroimaging, and the therapeutic effect of corticosteroids may help in establishing the correct diagnosis.
In classical MS, clinical signs and symptoms are re- lated to lesions present in various tracts of the CNS.
Most last for days up to months or are permanent.
Sometimes symptoms of extremely short duration occur, lasting for seconds to hours. Common features are fatigue, impairment of vision due to optic neuri- tis, motor disturbances caused by pyramidal tract in- volvement, sensory disturbances including Lher- mitte’s symptom, cerebellar ataxia and dysarthria, diplopia, micturition problems, sexual disturbances, hearing loss, vertigo, and balance abnormalities. Less common are epileptic seizures, signs of peripheral neuropathy, trigeminal neuralgia, hemifacial spasms, and dementia, although some degree of cognitive im- pairment is present in up to half of MS patients. There is almost always a tendency for the frequency of episodes to decrease as time passes, or for the pro- gression in the progressive form to slow down.
The extent of the resulting disability is extremely variable. In general, it appears that the average life ex- pectancy in young patients after the onset of MS is about 35 years.About 60–70% of patients remain am- bulant. Long-term prognosis is not influenced by
Multiple Sclerosis
J. Valk, F. Barkhof
pregnancy, illness, or anesthesia. Patients with many relapses in the early phase more rapidly acquire a severe state of disability than those with less frequent relapses (Confavreux et al. 2000). A large number of hyperintense lesions on T
2-weighted images is also indicative of more rapid deterioration. When more than 10 lesions are present, the EDSS score within 4 years will be higher than 6, which means inability to walk without support. Abnormal evoked responses in the early phase of the disorder are also indicative of a poor prognosis. It should, however, be noted that these predictors are rather weak.
NMO (neuromyelitis optica or Devic disease) is a clinical syndrome consisting of optic neuritis, often bilateral with total blindness, in combination with transverse myelitis, which usually has a thoracic lo- calization. The optic neuritis and transverse myelitis either occur simultaneously or are separated by a brief interval of several days to several weeks. Men and women are affected more or less equally. The age of patients ranges from 5 to 65 years, but patients are rarely older than 50 years. The group most common- ly affected is young adults. This disease occurs most frequently in the Asian population, where the overall incidence of MS is low. The prognosis is rather poor.
Until recently, about 15–20% of patients died in the acute stage due to an ascending spinal disorder with respiratory paralysis; another 30% died with compli- cations after many months. A poor neurological out- come with severe disability is reported in another 15% of patients. Complete or nearly complete recov- ery is found in about 35%. Improved supportive care has reduced mortality and residual disability. About half of the surviving patients experience no recur- rence of neurological disease; about one-third of the remainder suffer a relapse of optic neuritis, one-third a relapse of optic neuritis and transverse myelitis, and one-third develop a multifocal white matter disease.
Wingerchuck et al. (1999) formulated absolute cri- teria and supportive criteria for the diagnosis NMO.
The absolute criteria are: optic neuritis, acute myelitis, and no evidence of clinical disease outside the optic nerve and spinal cord. Supportive criteria are subdi- vided into major and minor support criteria. Major support criteria are: negative brain MRI at onset; MRI lesions in the spinal cord extending over more than three vertebral segments; and CSF pleocytosis >50 white blood cells/mm
3. Minor supportive criteria are:
bilateral optic neuritis; severe optic neuritis with fixed visual acuity of less than 20/200 in at least one eye; and severe, fixed, attack-related weakness in one or more limbs.
CS (encephalitis periaxialis concentrica or Baló disease) is a very rare MS variant, which usually af- fects young adults. For unknown demographic rea- sons there is a much higher incidence in the Philip- pines. Both sexes are affected more or less equally.
Compared to classical MS, CS runs a more rapidly progressive, usually monophasic course. The initial symptoms are often suggestive of a stroke; less fre- quently psychiatric symptoms predominate. The neu- rological symptoms are sometimes associated with fever and headache and then resemble the clinical picture of an infection or tumor. The disease is pro- gressive and can be fatal, usually as a consequence of respiratory problems and infection. A more pro- longed survival for several years has also been report- ed.
DS (encephalitis periaxialis diffusa or Schilder dis- ease) is a demyelinating disease related to MS, which primarily affects children. Clinical features are intel- lectual impairment, epileptic seizures, signs of pyra- midal tract involvement (occasionally unilaterally with hemiplegia), cerebellar ataxia, visual impair- ment (caused by retrobulbar neuritis or demyelina- tion of the occipital lobes), pseudobulbar palsy (lead- ing to problems with speech and swallowing), deaf- ness, diplopia, extrapyramidal movement abnormali- ties, and incontinence. A predominantly psychiatric symptomatology is relatively frequent. In most cases there is rather rapid progression of neurological signs over the course of 1–2 years. In a minority, the de- myelinating process is fulminant and accompanied by cerebral edema. Rarely, the course of disease is characterized by exacerbations. In exceptional cases significant and prolonged improvement occurs; an arrest of the disease is observed in exceptional cases.
Definite diagnosis has always been a problem in MS. The clinical features may mimic many other neu- rological disorders, including ischemic disorders, neoplastic diseases, vasculitides, granulomatous dis- eases, and infections. Definitive diagnostic tests are lacking. This diagnostic uncertainty has led to the de- finition of diagnostic criteria. In 1965, Schumacher was the first to draw up clinical criteria for the diag- nosis of definite MS. The basic idea behind these cri- teria is that there must be symptoms and objective signs of multifocal white matter disease with dissem- ination in space and time, for which there is no better neurological explanation. These criteria have been re- peatedly modified, and clinical criteria for possible and probable MS have been added (Rose et al. 1976).
In 1983, Poser et al. were the first to draw up diagnos- tic criteria that were not completely clinical but incor- porated supportive laboratory data (CSF abnormali- ties) and paraclinical evidence of multifocal white matter lesions (CT and evoked responses). Since that time, MRI has become more generally used and has acquired a prominent role as a paraclinical test. MR has the possibility to prove dissemination in time (by new enhancing lesions or new T
2lesions) and dissem- ination in space (by multiple brain and spinal cord lo- calizations). In the most recently proposed diagnostic criteria for multiple sclerosis by McDonald et al.
79.1 Clinical Features and Laboratory Investigations 567
(2001), these MRI criteria have been formalized. The MRI criteria for dissemination in space are based on the Barkhof criteria (Barkhof et al. 1997) with a mod- ification as proposed by Tintoré et al. (2000). These new MRI criteria have been validated and make an earlier diagnosis of MS feasible without sacrificing accuracy (Barkhof et al. 2003; Dalton et al. 2003).
Table 79.1 summarizes the diagnostic criteria as rec- ommended by the International Panel on the Diagno- sis of Multiple Sclerosis.
Valuable laboratory findings supporting the diag- nosis of MS are oligoclonal bands in the CSF and an increased IgG index as a sign of increased synthesis of IgG within the blood–brain barrier. The sensitivity of assessment of the IgG index in MS is about 80% and
that of oligoclonal banding about 90%. The specifici- ty and predictive value of these CSF investigations are highly dependent on the so-called pretest probability of MS. The problem is that a number of diseases mim- icking MS, such as infections, acute disseminated en- cephalomyelitis, and vasculitis, are apt to lead to an increased production of IgG in the CSF with oligo- clonal banding. It should also be noted that some pa- tients with clinically definite MS have a normal IgG index and lack CSF oligoclonal bands. Levels of CSF IgM and IgA may also be elevated in MS. The CSF pro- tein content may be slightly raised, but very rarely exceeds the level of 1 g/l. The white cell count may be increased, but only in exceptional cases is it higher than 20 cells/ml. Another CSF abnormality may be an
Table 79.1. Criteria for diagnosis of MS (McDonald et al. 2001)
Clinical presentation Additional data needed for MS diagnosis
Two or more attacks; objective clinical evidence None of 2 or more lesions
Two or more attacks; objective clinical evidence of 1 lesion Dissemination in space, demonstrated by MRI or
Two or more MRI-detected lesions consistent with MS plus positive CSF
or
Await further clinical attack implicating a different site One attack; objective clinical evidence of 2 or more lesions Dissemination in time, demonstrated by MRI
or
Second clinical attack
One attack; objective clinical evidence of 1 lesion Dissemination in space, demonstrated by MRI (monosymptomatic presentation; clinically isolated syndrome) or
Two or more MRI-detected lesions consistent with MS plus positive CSF
and
Dissemination in time, demonstrated by MRI or
Second clinical attack Insidious neurological progression suggestive of MS Positive CSF
and
Dissemination in space, demonstrated by:
(1) Nine or more T2lesions in brain or
(2) 2 or more lesions in spinal cord or
(3) 4–8 brain lesions plus 1 spinal cord lesion or
Abnormal VEP associated with 4–8 brain lesions, or with fewer than 4 brain lesions plus 1 spinal cord lesion demonstrated by MRI
and
Dissemination in time, demonstrated by MRI or
(4) Continued progression for 1 year
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.”
No additional tests are required; however, if tests (MRI, 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.
MRI demonstration of space dissemination must fulfill the criteria derived from Barkhof et al. (1997) and Tintoré et al. (2000).
“Positive CSF” is determined by oligoclonal bands detected by established methods (preferably isoelectric focusing) different from any such bands in serum, or by a raised IgG index.
elevation of myelin basic protein in active MS. Its lev- el is normal in stable MS. The finding of increased amounts of myelin basic protein is indicative of active demyelination and as such not specific for MS. Re- cently analysis of antibodies against myelin oligoden- drocyte glycoprotein and myelin basic protein in pa- tients with clinically isolated symptoms predict for early conversion to clinically definite MS (Berger et al.
2003). Free light chains of immunoglobulins and the k:l light chain ratio may be increased in the CSF. In- creased CSF free k chains appear to be relatively spe- cific for MS. Abnormally high levels have been found in 85% of patients with clinically definite MS, in 20%
of patients with CNS infections, and only exceptional- ly in noninfectious controls. Concentrations of solu- ble adhesion molecules, sVCAM-1 and sICAM-1, in serum and CSF correlate with activity of MS, as indi- cated by gadolinium-enhancing lesions on MRI, and may possibly be used as a surrogate marker for dis- ease activity.
A number of changes in the subset distribution of T lymphocytes has been reported in the peripheral blood of MS patients. CD (cluster of differentiation markers on hematopoietic cells) 4+ T cells (T helper- inducer cells) can be subdivided in two mutually ex- clusive subsets: “naive” cells that have not yet been stimulated, and “memory” cells that have been stimu- lated before. These subsets can be recognized by dif- ferences in CD antigens. Memory cells can produce large amounts of cytokines after activation and show increased expression of a set of adhesion molecules, sVCAM-1 and sICAM-1. In the peripheral blood of patients with active MS, naive cells are decreased in number; in inactive MS this fraction is normal. In the peripheral blood of patients with active MS, lympho- cytes have been found with a higher expression of the activation marker CD26 than in patients with inactive MS and healthy controls. In CSF of active MS patients CD4+ T cells are relatively over-represented as com- pared to CD4+ T cells in peripheral blood.Among the CD4+ T cells in the CSF, memory cells are increased whereas naive cells are almost absent. Subset changes, therefore, may reflect disease activity and can be used for monitoring purposes. Increased numbers of TNF- producing T cells are associated with an enhanced rate of lesion development on MRI (Killestein et al.
2001). More recently, the role of CD8+ T cells (sup- pressor-cytotoxic cells) has been reinforced, and again relationships with MRI lesion development have been found (Killestein et al. 2003). Further ex- aminations are required to reveal the significance of these findings.
Other tests often used in the diagnostic assessment of MS are the visual, sensory and auditory evoked po- tentials (VEP, SSEP, and BAEP). These tests are helpful in detecting silent white matter lesions, thus provid- ing evidence of multifocal white matter involvement
in cases of clinically indefinite MS. VEPs and SSEPs appear to have a higher diagnostic yield than BAEPs.
However, abnormalities are nonspecific and must be interpreted with care in the context of the clinical pic- ture.
In NMO, CSF abnormalities are similar to those in MS, with the exception of a more common occur- rence of lymphocytic pleocytosis.
Laboratory examinations in CS rarely yield much information. CSF usually reveals no pleocytosis, sometimes an increased amount of red blood cells.
Total protein is only occasionally elevated.
In DS the CSF is often normal, but slight lympho- cytosis is occasionally found. The protein level is not infrequently elevated, as is the IgG index. Oligoclonal bands have been reported.
79.2 Pathology
Usually the external appearance of the brain is rela- tively normal in MS. In chronic cases slight atrophy may be present with widening of sulci and slight en- largement of the ventricular system. Occasionally firm, depressed lesions are seen on the surface of the brain stem, spinal cord, and in the optic nerves. On sectioning, numerous lesions of varying size become apparent in the white matter of CNS. Even more are revealed by microscopic examination, especially if MRI-guided. The distribution of plaques varies great- ly among MS patients, but the following are recog- nized as preferential localizations: the periventricular white matter, in particular the lateral angles of the lat- eral ventricles, floor of the fourth ventricle, cerebellar peduncles, cervical part of the spinal cord, and the optic nerves. In severe, long-standing cases, numer- ous lesions are found in most parts of the CNS. Al- though the distribution of lesions is not precisely symmetrical, predominant involvement of one hemi- sphere is rare. A significant proportion of the plaques are found in the border zone between gray and white matter. The extent of cortical involvement has been underestimated for a long time. They are found with rigorous myelin stains (e.g., using antibodies against myelin basic protein or proteolipid protein), because the normal amount of myelin in the cortex is minimal and classical inflammatory changes are lacking (Peterson et al. 2001). In many cases a diffuse subpial demyelination can be found (Bö et al. 2003).
Microscopically, the earliest stage of the MS plaque consists of perivenular lymphocytic infiltration. Such lesions are now found more easily using postmortem MRI as a guide (De Groot et al. 2001). The subsequent stage is characterized by more diffuse tissue infiltra- tion by inflammatory cells and macrophages associ- ated with edema, demyelination, proliferation, and hyperplasia of astrocytes, and appearance of in-
79.2 Pathology 569
creased numbers of lipid-laden macrophages and demyelinated axons. Axonal damage already occurs during the phase of acute demyelination. Loss of myelin and oligodendrocytes eventually becomes complete. As plaques enlarge and coalesce, the perivenular distribution becomes less apparent. Al- though variable between patients, axonal damage can be extensive from early on. In the course of time, axonal loss can become very substantial (Bjartmar et al. 2003). In the gray matter plaques, too, the myelin is predominantly affected and neuronal cell bodies are largely preserved. In lesions of several months’ dura- tion, inflammation is far less pronounced, fewer lipid- laden macrophages are seen, and fibrillary gliosis be- comes increasingly prominent. Chronic-inactive MS plaques have a sharply demarcated border and are hypocellular, demyelinated, and gliotic with almost total oligodendrocyte loss. Inflammatory cells and lipid-laden macrophages are no longer present. The remaining elements are axons and astrocytic process- es. Axonal damage has led to wallerian degeneration, which is most evident in the long tracts. Rarely is the damage sufficiently severe to produce a cyst. In the same patient lesions of different ages are present.
In MS, plaque-like areas are observed, in which myelin has not completely disappeared, and which do not have the appearance of the typical plaque. These lesions are called shadow plaques. The myelin sheaths in these plaques are abnormally thin and are of rela- tively uniform thickness. The internodes are short.
The number of oligodendrocytes is increased in the lesion. These features are characteristic of remyelina- tion, and so the shadow plaques probably represent areas of remyelination.
The description as given fits the relapsing-remit- ting form of MS. Histological examination is usually performed in patients who have suffered from the disease for a long time.An exception is the acute form of MS, in which the lesions are days to weeks old and show acute inflammatory and demyelinating changes.
As a consequence of the lack of early histological in- formation, there is no parallel description of histol- ogy in some clinical MS subtypes, such as benign MS.
In primary progressive MS more diffuse demyelina- tion with more diffuse and less intense inflammation is found.A mixture of the multiple lesions and the dif- fuse pattern is seen in patients in whom the disease was initially relapsing-remitting, but secondarily be- came progressive in its course.
Immunocytochemical studies have demonstrated that the inflammatory cells of acute MS plaques are mainly macrophages and lymphocytes, with few plas- ma cells. Macrophages stain positive for the major histocompatibility complex (MHC) class II, which implies a role for these cells in local antigen presenta- tion to T cells. The T cells present are a mixture of CD4+ (helper-inducer) and CD8+ (suppressor-cyto-
toxic) T lymphocytes. Initially these T lymphocytes are predominantly present in the center of the plaque, but as the lesion enlarges, T cells move to the periph- eral part of the lesion. The CD4+ cells invade the nor- mal white matter. The majority of the inflammatory T cells in MS are memory cells. The margins of the plaque contain predominantly CD8+ cells and in- creased numbers of oligodendrocytes and astrocytes.
With increasing age of the plaque, myelin and macrophages disappear from the central part; the plaque margins contain lymphocytes, oligodendro- cytes, lipid-laden macrophages, and astrocytes, sug- gestive of low-grade activity at these margins. In chronic-active MS, small numbers of inflammatory cells are scattered throughout the normal-appearing white matter, suggestive of a diffuse, slow demyelinat- ing process. Chronic-inactive MS lesions contain few inflammatory cells. In chronically affected tissue an interesting recent finding is the presence of T cells and their association with heat shock proteins ex- pressed on oligodendrocytes. These cells have previ- ously been implicated in the pathogenesis of rheuma- toid arthritis, but the presence of these cells with still unclear function now seems to be a more general finding in autoimmunity. They may play a role either in tissue repair or in perpetuating the inflammatory process.
In the review of Lassman et al. (2001) four different types of histopathological reactions were distin- guished, possibly reflecting four different types of MS lesions: (1) macrophage-mediated, with T-cell-medi- ated inflammation as a putative mechanism; (2) anti- body-mediated, with T-cell-mediated inflammation with complement-mediated lysis of antibody-target- ed myelin as a putative mechanism; (3) distal oligo- dendrogliopathy, with T-cell-mediated small vessel vasculitis with secondary ischemic damage of the white matter as a putative mechanism; and (4) prima- ry oligodendrocyte damage and secondary demyeli- nation, with T-cell-mediated inflammation and de- myelination induced by macrophage toxins on the background of metabolically impaired oligodendro- cytes as a putative mechanism. It is clear that such a postmortem classification does not easily translate into clinical practice, but it may help a better under- standing of the differences between subtypes of MS.
In NMO the spinal cord, optic nerves, and chiasm appear swollen and congested externally if the patient has died relatively early in the course of disease.
Demyelination and inflammation with perivascular
lymphocytic infiltration and fat granules are seen at
microscopy. In severe cases necrosis of gray and white
matter occurs, leading to cavitation. However, at the
periphery of such lesions the relative sparing of axons
is evident. Acute lesions may be hemorrhagic. The
spinal cord lesion is often large and extends over
many segments, usually in the low cervical and high
thoracic areas. Lesions in the conus may also occur. In the optic nerves and chiasm extensive loss of myelin, gliosis, and some loss of axons occur. As a rule, additional areas of demyelination are found in the predilectional regions of classical MS, such as peri- ventricular areas and brain stem.
The characteristic lesions in CS are areas of alter- nating zones of myelinated and demyelinated tissue, either with a concentric pattern or with a more irreg- ular arrangement. The size of lesions varies from tiny to about 4–5 cm in diameter. The location and num- ber of lesions vary widely. Sometimes large areas are almost completely involved. The lesions may occur anywhere in the CNS; only the spinal cord is rarely affected. The rings of the lesion terminate abruptly where they contact gray matter. The central core is the starting point of the lesion and consists of a venule with a cuff of inflammatory cells. In the course of time, the central core becomes intensely gliotic. The core is surrounded by zones of demyelination, in which axons are preserved and myelin is replaced by gliosis. With increasing distance from the core, the stage of myelin breakdown in the affected zones becomes less advanced, and the gliosis is less severe.
Acute lesions are surrounded by edema. In chronic lesions the involved area becomes scarred and at- rophic. The concentric lesion may become so disinte- grated that it is difficult to recognize. Ultrastructural examination of the myelinated zones reveals that they are largely composed of thinly myelinated fibers. A few normally myelinated and some demyelinated axons are also present. These bands contain many cells, including oligodendrocytes, lymphocytes, and astrocytes. These changes are reminiscent of those seen at the edge of a chronic-active MS plaque and are interpreted by some as zones of remyelination.
Throughout the white matter, numerous venules show cuffs of inflammatory cells. Very often there are also lesions characteristic of classical MS.
In DS widespread demyelination is found, with variable axonal damage in the centrum semiovale of both cerebral hemispheres, most often involving the occipital lobes. Usually the corpus callosum is also af- fected and interconnects the lesions of the two sides.
The lesions are not completely symmetrical. They have a sharp edge. A rim of subcortical white matter is commonly preserved, but a lesion may also spread into the gray matter. In the acute stage demyelination is associated with dense perivascular infiltrates of lymphocytes, plasma cells, and lipid-filled macro- phages. The myelin disintegration leads to the forma- tion of sudanophilic material. Areas may be become frankly necrotic, and cavitation may occur. Glial reac- tion is present, with giant multinucleated and hyper- trophied astrocytes. In cases of long duration, inflam- matory cells and macrophages containing sudano- philic material disappear. Evidence of wallerian de-
generation is common. There are not only naked ax- ons but also axons partially covered with thin layers of myelin as signs of abortive remyelination.
79.3 Chemical Pathology
Chemical analysis of the composition of MS plaques reveals a number of alterations: increase in water, de- crease in total lipid, in particular in cholesterol, cere- brosides, sulfatides, ethanolamine plasmalogens, and serine phosphoglycerides. Cholesterol esters are in- creased. In the lesion the major myelin proteins – myelin basic protein, proteolipid protein, and myelin- associated glycoprotein – are reduced. Myelin basic protein is in fact virtually absent from the center of most plaques, and the decrease in concentration of myelin-associated glycoprotein extends into the nor- mal-appearing white matter around the plaque, sug- gesting that this protein disappears or is altered be- fore myelin breakdown starts. The protein losses in the plaque are accompanied by an increase in pro- teins of a lower molecular weight, which may be pro- teolytic breakdown products. In and around the MS lesion proteinases and other hydrolytic enzymes are increased. The observed chemical changes in the MS plaques are variable and depend on the extent of demyelination. An early MS lesion contains more myelin and more sudanophilic material, which is bio- chemically defined as cholesterol esters. Old plaques have no or little myelin left and lack sudanophilic material.
Myelin isolated from the plaque has a composition typical of abnormal myelin during aspecific degrada- tion. No myelin abnormalities specific for MS have been demonstrated.
Much effort has been devoted to the study of the chemical composition of normal-appearing white matter in MS. In the first place, the myelin yield of the normal-appearing white matter is strikingly low.
There is a decrease in total lipid, in phospholipids (particularly ethanolamine plasmalogens), in both galactolipids (cerebroside, and sulfatide), and in myelin proteins. Frequently, cholesterol esters are found. Several investigators found an elevation of hydrolytic enzymes in normal-appearing white mat- ter. These findings are qualitatively similar to those observed in MS plaques, but are considerably smaller in magnitude. All these data together provide strong evidence for the presence of minor microscopic ab- normalities of the MS type in the white matter that appears macroscopically normal. This suggestion has been confirmed by microscopic examination of sam- ples of normal-appearing white matter. It is clear that the disease process is widespread and not simply re- stricted to plaques. There is a general myelin deficit throughout the white matter.
79.3 Chemical Pathology 571
79.4 Pathogenetic Considerations
The search for the cause of MS has engaged many in- vestigators for many years. Three main lines can be distinguished in theories about the etiology of MS:
one line stressing the importance of immunological reactions, the second line pointing to the evidence for genetic factors, the third one advocating environmen- tal factors. These lines are complementary and not mutually exclusive.
A major theory proposes that MS results from al- terations in the immune system. A suggestion in this direction came from the observation of some similar- ity between MS and experimental allergic encephalo- myelitis (EAE) in animals. EAE is induced by immu- nizing animals with antigens normally present in the CNS myelin, such as myelin basic protein (MBP), pro- teolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), with an adjuvant containing heat-killed mycobacterium to stimulate the innate immune system. In about 1–2 weeks the animals de- velop encephalomyelitis with perivascular infiltrates composed of lymphocytes and macrophages in the white matter, followed by demyelination. In mice EAE is caused by activated CD4+ T cell lymphocytes spe- cific for MBP, PLP or MOG, as proven in vitro and in cloning experiments. The lesions of EAE and of MS have the character of delayed hypersensitivity reac- tions. The sequence of events in EAE and possibly by analogy MS could be as follows: autoreactive T cells specific for myelin proteins may be present in the cir- culation of normal individuals. Immunization with a myelin antigen together with an adjuvant leads to T cell activation against epitopes of autologous myelin proteins. Activated T cells stick to the endothelial lin- ing and cross into the cerebral parenchyma. In the CNS the activated T cells encounter myelin proteins and release cytokines that recruit and activate macrophages and other T cells that lead to myelin de- struction. EAE has been used to analyze the specifici- ty of myelin-reactive T cells and help to define im- munodominant regions of myelin proteins that may be relevant to MS in humans.
Abnormalities of immunoregulation and of hu- moral and cellular immunity appear to be an impor- tant part of the disease process in MS. Inflammatory cells – lymphocytes, plasma cells, and macrophages – are present in perivascular areas in the CNS in active disease and take part in the disease process. In nearly all MS patients, there is evidence for an increased syn- thesis of immunoglobulins within the blood–brain barrier. A low CD8+ T suppressor cell activity and a high ratio of CD4+ T helper to CD8+ T suppressor cells is present in the blood during exacerbations of MS, and also chronically progressive MS patients have similar abnormalities of peripheral blood T lympho- cyte subsets. The high levels of antiviral antibodies,
indicative of hyperactive B lymphocytes, and the de- ficiency of suppressor T lymphocyte function may be signs of a fundamental defect in immunoregulation.
The role of CD8+ suppressor-cytotoxic cells versus CD4+ helper cells has been a point of discussion.
These subsets interact with specific MHC molecules to regulate the immune response. MHC class II restricted CD4+ T cells are the major producers of cytokines and are associated with delayed-type hy- persensitivity and antibody response. MHC class I re- stricted CD8+ T cells are associated with cytotoxicity.
There is evidence that CD4+ cells are the key initia- tors of tissue destruction in MS. CD8+ T cells have re- ceived less attention, but there is growing evidence that MHC class I restricted CD8+ T cell responses may have a critical role in the pathogenesis of MS. In addition to CD4+ cells, CD8+ lymphocytes are pre- sent in active demyelinating lesions, and in fact pre- dominate in many lesions. CD8+ T cells recognize peptides presented by MHC class I molecules. Adult oligodendrocytes express class I MHC molecules and do not express class II MHC molecules, even when stimulated by interferon-g. This implies that when adult oligodendrocytes are targets for T cell reactivi- ty, they will probably be recognized by MHC class I restricted CD8+ T cells and not by class II restricted CD4+ T cells.
The cause of the immunological alterations in MS
and their role in the pathogenesis of MS have not yet
been elucidated. The antibody response in the CSF
may be an expression of an autoimmune process
against normal or altered brain constituents. This
autoimmune process may be idiopathic, or triggered
by a viral infection or other exogenous or endo-
genous antigens that cross-react with brain con-
stituents. Low concentrations of antibodies have been
demonstrated in the CSF reacting with myelin pro-
teins, oligodendroglia, glycolipids, and nuclear anti-
gens, but no single MS-specific antigen that reacts
with most of the IgG has ever been identified. It is not
excluded that the observed antibodies are epiphe-
nomena without pathogenetic importance. Another
explanation may be that T helper-inducer lympho-
cytes in MS are activated and autoreactive. Many
other changes in immune-related factors have been
observed, such as circulating immune complexes,
altered levels of cytokines and complement compo-
nents, and increased prostaglandin synthesis, but the
significance of these findings is not known. A con-
vincing observation about the role of immune re-
sponses in MS has been the decrease in MS-activated
lesions in pregnant women. There is a sharp decrease
in lesions in all cases, with a return to the prepregnant
status in the months after delivery. In another study,
the beneficial effect of pregnancy was indicated by
the finding that the mean disease duration before be-
coming wheelchair-dependent was 50% longer in pa-
tients who became pregnant after the first symptoms of MS.
Lymphocytes become activated by an unidentified cause and by a multistep process penetrate the blood–brain barrier. The capillary endothelial cells in the CNS are not fenestrated and are connected through tight junctions. The capillary endothelial cells express cellular adhesion molecules (V-CAM) and class II molecules of the MHC.Activated lympho- cytes can pass the endothelial barrier assisted by adhesion molecules such as integrins, in particular a
4integrin, which binds to V-CAM. Once the activated lymphocytes have extravasated, they still need help in passing through a barrier of extracellular matrix con- sisting of type IV collagen. T cells are then targeted to proteins of the myelin sheath, myelin basic protein, myelin oligodendroglial glycoprotein, and prote- olipid protein, as well as stress proteins like aB crys- tallin, present in the myelin sheath after activation by the inflammatory response. T cells produce cyto- kines, notably TNF-b and TNF-a, and then influence macrophages, microglial cells and astrocytes to pro- duce nitric oxide, a major mediator in inflammatory reactions, and osteopontin, a multifunctional protein abundantly expressed during inflammation. Macro- phages and microglia are induced to phagocytose large pieces of the myelin sheath.
This short and incomplete summary of the initia- tion of the inflammatory process is intended to give an impression of the complexity of the process, in which the role of the many players only gradually be- comes clear. Knowledge of this process in detail has already opened therapeutic windows and will open more in the future. It helps us to understand why many therapeutic interventions only yield partial re- sults. Much still depends on the unraveling of the pri- mary cause of the inflammatory reaction.
The evidence for genetic factors comes from re- ports of familial cases and unusually high-risk fami- lies, and from studies which consistently show higher concordance rates for MS in monozygotic twins than in dizygotic twins. The concordance rate in monozy- gotic twins reported in the literature varies from 10%
to 70%, and that in dizygotic twins from 2.3% to 20%.
Selection bias probably leads to overestimation of the rate of concordance among twins. On the other hand, however, a twin sample collected at one point in time probably underestimates the concordance rate, as more individuals will develop MS in the course of time, and the concordance rate will increase with in- creased duration of follow-up. The prevalence of MS among relatives of MS patients is increased, and the increase becomes more pronounced the closer the de- gree of kinship to the propositus. This observation is consistent with a genetic hypothesis, but common en- vironmental experiences with relatives, and especial- ly twins, may also play a role. The low overall twin
concordance rate (a concordance rate of 100% would be expected among monozygotic twins if MS were ex- clusively genetically determined), and the increased prevalence of MS in dizygotic twins as compared to siblings (1–6% of the siblings of MS patients are also affected) strongly suggests the involvement of envi- ronmental as well as genetic factors.
Further evidence for a genetic component in the etiology of MS comes from the observation of associ- ations between MS and specific human leukocyte antigen (HLA) alleles. The HLA genes encoding for these antigens, which are expressed on cell surfaces of lymphocytes, are found on the short arm of chromo- some 6. The HLA system consists of five loci – A, B, C, D, and DR – and each of the HLA loci has a large num- ber of alleles. The HLA region can be used as an excel- lent genetic marker with known chromosomal loca- tion. There is a highly significant association between HLA-DR2 and MS and a less strong association be- tween HLA-A3 and B7 and MS in Caucasians. How- ever, there are great differences in observed HLA as- sociations in populations of different racial back- ground, and it is clear that the mentioned HLA alleles in themselves are neither necessary nor sufficient to lead to the development of MS. The meaning of the HLA associations is not entirely understood. A likely explanation is that the MS-related gene or genes lie on the same chromosome as the HLA genes and are in linkage disequilibrium with specific HLA alleles. This means that certain combinations of alleles occur sig- nificantly more frequently than would be expected by chance. It is also possible that specific HLA alleles are directly involved in the etiology of MS. The HLA sys- tem is part of the immune response system. Alleles of certain class II genes, HLA DR and HLA DQ, confer the strongest risk of MS. In addition to the well-estab- lished MHC association, genome-wide screens of families with multiple cases of MS also suggest a role for several additional unidentified genes, each with a modest effect. Transcriptional profiling using gene microarrays and large-scale sequencing of tran- scripts from MS lesion material reveal expression of genes involved in the pathogenesis of acute disease, like immunoglobulins, interleukin 6, and osteopon- tin.
It is clear that MS is not a genetically determined disease with a Mendelian mode of inheritance. It is more probable that multiple susceptibility genes for MS exist, and that the expression of subtle changes in these genes (polymorphisms) depends on environ- mental factors. The chromosomal localization of some of the genes determining susceptibility to MS is probably in or near the HLA region, or their expres- sion depends on the action of certain HLA alleles. A method consisting of pooling DNA from MS individ- uals and typing these pools for around 60,000 mi- crosatellite markers, suggested by Barcellos et al.
79.4 Pathogenetic Considerations 573
(1997), was realized in an extensive study known as Genetic Analysis of Multiple Sclerosis in EuropeanS (GAMES), described by Sawcer and Compston (2003).
GAMES is essentially an indirect screen for associa- tion and is therefore dependent on the assumption that at least some of the markers tested will have alle- les in linkage disequilibrium with gene variants that influence the susceptibility to MS. All previous ge- nomic screens in MS families only suggested linkage with 6p21, the area containing the genes for the major histocompatibility complex. Although its approach has limits and flaws, GAMES may have the potential of identifying one or more novel associations outside the MHC region at 6p21.
Epidemiological studies of migrants suggest that environmental factors, particularly when present be- fore the age of 15 years, are involved in the etiology of MS. One of the most important theories about the na- ture of the environmental factors speculates on a viral etiology. However, a causative virus has never been reproducibly isolated from the CNS of MS patients, nor has viral antigen been demonstrated in a consis- tent fashion. Ultrastructural examination of brain tis- sue has never unequivocally revealed virus particles.
Antibodies to multiple viruses are elevated in the CSF of MS patients. It is probable that these antibodies re- sult from a nonspecific immunostimulation. It is commonly accepted that relapses in MS are often trig- gered by infection with viruses. Viruses, such as her- pes virus-6, influenza, measles, papilloma virus, and Epstein–Barr virus, have genes encoding peptides containing amino acid sequences similar to those found in the major structural proteins of myelin. An- tibodies reacting with protein sequences from these microbes may cross-react with components of the myelin sheath. T cells also recognize peptide se- quences in the myelin sheath that are shared with mi- crobial sequences. Once an immune cell is activated, either by a foreign microbe or a self-protein, it may penetrate the blood–brain barrier and the inflamma- tory cascade as described above will follow (Buljevac et al. 2002).
The precise nature of the relationship between MS, CS, NMO, and DS is not known. The frequent occur- rence of histopathological typical MS lesions in CS, NMO, and DS provides evidence for essential similar- ities in etiology and pathogenesis. In NMO, it is im- portant to distinguish the MS-related disease from acute disseminated encephalomyelitis and a vas- culitic process, especially lupus erythematosus, both of which may produce an identical clinical picture and a rather similar pathological picture. As NMO is relatively frequent in Asian populations, it has been suggested that racial-genetic factors lead to a modi- fied appearance of MS.
In CS, some consider the concentric lesion to be a variant of an MS plaque in which the center of the le- sion represents the initial small focus of acute de- myelination, and in which the concentric rings are formed by a centrifugal progression of episodes of demyelination and remyelination. The zones of pre- served myelin within the concentric lesions are sup- posed to be formed by episodic remyelination at the borders of demyelinating foci, which is followed by further centrifugal spread of the demyelination. A remarkable difference with MS is that the concentric lesion never invades gray matter structures, unlike MS plaques. There is, as yet, no explanation for the higher incidence of CS in the Philippines.
Loose and indiscriminate use of the term “diffuse sclerosis” (DS) has led to a great deal of confusion in nomenclature. Schilder was the first to describe the disease in three cases of what he called “encephalitis periaxialis diffusa.” However, on closer inspection of clinical data and neuropathological findings, it was concluded that one of these patients probably had X- linked adrenoleukodystrophy and another acute dis- seminated encephalomyelitis. Only one patient is now considered to be an example of DS. After Schilder many authors used the name “diffuse sclerosis” for a wide range of unrelated demyelinating disorders. It is true that a number of diseases, especially X-linked adrenoleukodystrophy, may be difficult to differenti- ate from DS on clinical and pathological grounds alone. In these cases, assessment of various enzyme activities and ultrastructural examination are indis- pensable in establishing the correct diagnosis. In the course of time, an increasing number of diseases could be distinguished from DS, and some investiga- tors have suggested abandoning the term “Schilder DS.” However, we are of the opinion that the term
“Schilder DS” should be reserved for myelinoclastic
diffuse sclerosis as a variant of MS. The pathology of
DS does not differ substantially in its light or electron
microscopic appearances from the classical dissemi-
nated form of MS. The only difference involves the di-
mension of the demyelinating lesions and the rapid
progression of the process. In 1985, Poser offered the
following definition of DS: the disease is a subacute or
chronic myelinoclastic disorder resulting in the for-
mation of one or more, commonly two, roughly sym-
metrical plaques measuring at least 2 ¥ 3 cm in two of
the three dimensions, involving the centrum semio-
vale of the cerebral hemispheres. Other diseases that
can lead to a similar picture should be excluded. Ac-
cording to this view, the pathogenesis of DS is largely
identical with that of MS, and the question is which
factor is responsible for the difference. It has been
suggested that the large areas of demyelination may
be due to the fact that the child’s nervous system, be-
ing still immature, is more susceptible to an injurious agent. It is improbable, however, that the immaturity of the brain alone accounts for the difference com- pared to classical MS, as classical MS can also occur during childhood.
The correlation between neuropathological lesions and clinical signs and symptoms is rather poor in MS.
There are many silent lesions. Clinically silent lesions probably occur when demyelination affects some but not all fibers of a pathway, or when remyelination occurs. A conduction block occurs in demyelinated fibers, but conduction remains intact in unaffected fibers. The very transient symptoms in MS are proba- bly related to a reduction of the functional reserve of a fiber tract for the conduction of nerve impulses be- cause of demyelination. Slight alterations of conduc- tion capacities, e.g., those due to a rise in body tem- perature, may result in the appearance of symptoms from a fiber tract in which a plaque has reduced the functional reserve but not to less than the minimum number of fibers necessary for normal function. Im- provement occurs as soon as conduction of electrical impulses is restored. Recovery after a relapse is prob- ably largely related to remyelination, which leads to abolition of the conduction block.
79.5 Therapy
The interest in an immunological basis for MS has led to the development of a variety of treatments de- signed to alter or suppress the immune response. One of the first of these studies advocated the use of adrenocorticotropic hormone (ACTH) in acute exac- erbations. It was demonstrated that ACTH shortens the recovery time but does not alter the eventual lev- el of recovery. More recent studies indicate that high- dose intravenous methylprednisolone also hastens recovery, but that the effect on suppression of gadolinium-enhancing lesions, used as surrogate marker of MS activity, is short-lived. Intrathecal cor- ticosteroids did not prove to be any more helpful than orally administered corticosteroids.
More aggressive immunosuppressive agents have also been used, such as azathioprine, cyclophos- phamide, cyclosporin A, and total lymphoid irradia- tion. Plasma exchange has been used in limited stud- ies. However, the limited beneficial effects of these treatment modalities usually do not outweigh the of- ten serious side effects. Recently the intravenous ad- ministration of immunoglobulins has been the sub- ject of interest.
Success has been reported with interferon beta-1b (IFNB) in relapsing-remitting MS, with significant fa- vorable effects on exacerbation rates, times between first and second exacerbations, severity of exacerba- tions, MS activity, and lesion load as determined by
MRI. However, IFNB is only partially effective at the tested doses. Patients in the high-dose group contin- ued to have exacerbations, although at a reduced rate and of milder clinical severity. The beneficial effect of IFNB is probably due to its ability to inhibit interfer- on-g (IFNG) synthesis, to improve defective suppres- sor activity in MS patients, and to inhibit MHC class II antigen expression induced by IFNG on the sur- faces of antigen-presenting cells. Patients in the chronic progressive phase still with relapses also benefit from continuous IFNB treatment. The indica- tions for INFB are relapsing-remitting forms of MS and clinically isolated syndromes. Interferons are less effective in primary progressive MS and secondary progressive MS.
Mitoxantrone (Novantrone in the US and Canada), which belongs to the group of tumor antibiotics, has been evaluated in a number of studies. Patients were treated with intravenous administration every 3 months for 24 months. Mitoxantrone was found to de- lay the time to first treated relapse and time to disabil- ity progression in patients with secondary progres- sive disease or progressive relapsing-remitting dis- ease. Monitoring of white blood cells and liver func- tion remained necessary because of an increased risk of infection.
Copolymer 1, known as glatimer acetate, is a mix- ture of polypeptides (
L-alanine,
L-lysine,
L-glutamine, and
L-tyrosine) that acts as an immunological agent and appears to simulate myelin basic protein. It has been reported to reduce the number of relapses with possible improvement of functional abilities. Its greatest advantage is its low toxicity. Glatimer acetate stimulates antigen-specific suppressor cells. T cells activated by glatimer acetate protect against inflam- matory damage by the production of anti-inflamma- tory cytokines. It reduces the number of relapses. It is effective in MS patients under the age of 16 years.
Long-term studies indicate that the EDSS score in pa- tients treated with glatimer acetate hardly increases over the years and that outcome parameters such as brain atrophy and black holes show favorable results.
In MRS studies the N-acetylaspartate (NAA) increas- es with treatment. Probably this effect is due to the in- crease of brain-derived neurotrophic factor under glatimer acetate treatment.
The glycoprotein a
4b
1integrin, also known as very late antigen 4 (VLA-4) is expressed on the surface of lymphocytes and monocytes and is an important me- diator of cell adhesion and transendothelial migra- tion. Treatment with an antibody against a
4integrin reduced signs of disease activity and inflammation in mice and gave positive results in a small, placebo- controlled clinical trial with a humanized monoclon- al antibody (natalizumab) (Miller et al. 2003).
New treatment modalities are based upon the un- derstanding of T cell activation and cytokine produc-
79.5 Therapy 575
tion in autoimmune diseases. From a therapeutic point of view there are several ways in which exces- sive effector functions of activated T cells can be counteracted, for instance by injection of monoclon- al antibodies against T cell membrane molecules. The presence of excessive intrathecal immunoglobulins in MS may be related to the activation of CD4+ T lym- phocytes, also inducing B lymphocyte production. A large multicenter anti-CD4+ antibody trial was start- ed, but the lack of efficacy has ended this trial in an early phase. As monoclonal antibodies act more se- lectively, they may be more effective in suppressing disease activity.
Far fewer therapeutic trials have been performed in CD, NMO, and DS. In these groups no reports on the effects of INFB or glatimer acetate are available. In CD a beneficial effect of prednisone therapy has been described, but not consistently. In NMO remarkable improvement has been reported under treatment with corticosteroids, immunosuppressants, and lym- phocyte plasmapheresis. However, due to the very low incidence of NMO, no controlled trial has provided proof of such favorable effects. In DS a good clinical reaction to corticosteroids, ACTH, and immunosup- pressants is generally observed.
Many other attempts have been made to control the progress of MS. In this section we discuss some prominent endeavors – certainly not all of them – to demonstrate the many possible entries to the disease process.
Finally, and also importantly, there are many pal- liative measures to ease the problems of MS patients:
physiotherapy is helpful in keeping the patient mobile as long as possible; spasmolytic drugs have a place in combating spasticity and bladder dysfunction; and antibiotics are necessary in intercurrent infections.
79.6 Magnetic Resonance Imaging
MR has obtained a prominent role in diagnosis, fol- low-up, therapy monitoring, and research in MS. MRI protocols for patients with or suspected of having MS depend on the clinical symptoms and the information required from the MRI. Different techniques yield different information (Table 79.2).
The most common MRI appearance of the relaps- ing-remitting and secondary progressive forms of MS consists of multiple lesions with intermediate or low signal intensity on T
1-weighted images, high signal intensity on T
2-weighted images, isolated or confluent or both, with a bilateral but usually not entirely sym- metrical distribution, and preferentially located along the lateral angles of the ventricles in the efferent and afferent tracts of the corpus callosum (Figs. 79.1–
79.5). Some of these lesions have a typical ovoid form, pointing towards the convexity of the brain, known as Dawson’s fingers (Figs. 79.1, 79.5). This is the result of the perivenular distribution of MS lesions. This is known from histopathology, but can now also be illustrated by high-resolution MR venography (Fig. 79.1). The corpus callosum is thinner than usual and the inner rim has an irregular border related to the presence of lesions. Parasagittal and sagittal T
2- weighted and FLAIR images show this to best advan- tage (Fig. 79.5). Other lesions are spread over the frontal, parietal, and occipital white matter and, less frequently, the temporal lobes. There are no or few le- sions in the basal ganglia. Lesions may occur in the midbrain (8%), pons (12%), cerebellar hemispheres (4%), and medulla oblongata (1–2%). Specific struc- tures may be involved, such as the medial longitudi- nal fasciculus (clinically presenting as internuclear ophthalmoplegia), the trigeminal nucleus or emerg-
Table 79.2. MR sequences that may be included in a protocol with an indication of the MS features in which they are effective.
This list serves as a general orientation and is not intended to be a protocol applicable to all MS patients.
Conventional:
T1-weighted, transverse “Black holes”,“gray” holes, prognosis T2-weighted and proton density, transverse T2lesions, distribution, lesion load
FLAIR (2D, 3D) Most sensitive for T2 lesions
T1-weighted with gadolinium Active lesions, blood-brain barrier disruption
FLAIR sagittal Corpus callosum lesions
STIR Visual pathways, optic neuritis
Proton density, T1-weighted, cardiac gated Spinal cord lesions
Special:
MTR or histograms Structural integrity, follow-up, research, study of normal appearing white matter
DWI, DTI Structural changes, ADC, FA, fiber tracking
MRS Chemical composition
FLAIR, fluid-attenuated inversion recovery; STIR, short tau inversion recovery; DWI, diffusion-weighted imaging; DTI, diffusion tensor imaging
ing nerve (presenting as trigeminal neuralgia), and the vestibular nucleus (presenting with vertigo) (Figs. 79.6 and 79.7). Cortical lesions are often present but are difficult to appreciate on MRI. Cortical lesions extending into the white matter or lesions located in the U fibers are well detectable (Fig. 79.8). Such juxta- cortical lesions form an important hallmark of MS on MRI and have been incorporated into new diagnostic criteria (McDonald et al. 2001, see Table 79.1).
Depending on the clinical request, contrast may be given. Active lesions may enhance. Enhancement in- dicates disruption of the blood–brain barrier, proba- bly the first local change of a developing MS plaque.
Inflammation and edema will follow. The enhance- ment lasts between 2 and 6 weeks. MRI provides the possibility to identify acute, new or reactivated, lesions (Fig. 79.9). Enhancing lesions are often used in clinical trials as surrogate markers for disease activi- ty. Contrast-enhanced MRI can help, not only by demonstrating “dissemination in space” with the presence of more than one lesion in the CNS at differ- ent locations, but by also demonstrating “dissemina- tion in time” in showing older nonenhancing or no
longer enhancing lesions together with new or reacti- vated lesions that enhance. The most important role of gadolinium-enhanced MRI has emerged as moni- toring the efficacy of drug treatment (Figs. 79.10 and 79.11). Long-term follow-up studies have shown that newly appearing gadolinium-enhancing lesions are far more frequent than clinical exacerbations in re- lapsing-remitting and secondary progressive forms of MS. If one accepts gadolinium enhancement as a sign of new disease activity, this can serve as a means of monitoring the therapeutic response of the disease to new drugs. It has been shown that changes in the number of gadolinium-enhancing lesions during the course of the disease correspond better to changes in the EDSS than changes in lesion load on T
2-weighted images. The apparent advantage for therapeutic trials is the gain in time and the smaller study population one has to examine to obtain statistical significance of results. The eventual clinical trial based on clinical re- sults can in this way be limited to the most promising therapeutic compounds.
Two manifestations of MS outside the brain de- serve special mention: optic neuritis and spinal cord
79.6 Magnetic Resonance Imaging 577 Fig. 79.1. The upper row of images
shows left a proton density image with a typical ovoid lesion and right a T1-weighted image with intravenous contrast, with enhancement of the lesion. The lower row of images shows a special high-resolution technique that allows submillimeter venography of the CNS. The image on the right shows the lesion extending from the frontal horn towards the convexity in its relation to the local perforating vein. From Tan et al. (2000), with permission
lesions, because they both require special MRI tech- niques.
The STIR sequence in particular has been effective in demonstrating optic neuritis. Other fat saturation techniques, using a saturation pulse to suppress the fat signal, can be combined with gadolinium en- hancement (Fig. 79.12).
The majority of MS lesions of the spinal cord occur in the cervical spinal cord and the conus medullaris.
In some patients lesions are solely present in the spinal cord. They appear most often as high-signal- intensity lesions on proton density and T
2-weighted images and may enhance with contrast (Fig. 79.13).
There is, as a rule, no or very little mass effect. Mass effect can, however, occasionally be considerable and
Fig. 79.2. The classical MR pattern of MS. The transverse T2- weighted series in this 42-year-old woman shows lesions in the centrum semiovale, around the lateral upper borders of
the ventricles, in the corpus callosum, in the mesencephalon, the pons, around the fourth ventricle, and in the medulla ob- longata. There are no lesions in the basal ganglia
the lesion may then mimic an intramedullary tumor.
When patients present with symptoms indicative of a spinal cord lesion, MRI of the spinal cord may be the first requested examination. If a lesion indicative of MS is found, an MRI of the brain should follow to look for corroborative evidence, in the form of lesions in the brain, to support the diagnosis of MS. The great- est technical problems in detecting spinal cord MS lesions are encountered in the thoracic region. Phased array coils have increased the signal-to-noise ratio and detail in studies of the spinal cord. Conventional dual-echo spin echo sequences with cardiac gating yield the best results (Fig. 79.14) (Lycklama á Nijeholt et al. 1996). In more than 90% of patients with MS, spinal lesions can thus be identified (Figs. 79.15–
79.17). The detection of spinal lesions also helps in the differentiation of MS from vascular lesions (Table 79.3; Bot et al. 2002).
Indications, techniques, and the role of asympto- matic spinal cord lesions in the differential diagnosis from MS versus other diseases such as vascular dis- orders have recently been summarized (Lycklama á Nijeholt et al, 2003).
Many patients with definite MS do not fit the “typ- ical” description given above. Nearly anything goes with MS. Lesions may show mass effect or become cystic. The distribution may not be typical. Criteria as suggested by Barkhof et al. (1997), incorporated in the McDonald criteria (see Table 79.1), are often helpful in establishing the diagnosis.
Sometimes MS presents with clinical signs of raised intracranial pressure and a tumefactive lesion on MRI, often enhancing. In quite a few patients this observation has prompted a brain biopsy. The pres- ence of other white matter lesions and the “open ring”
sign may lead to the correct diagnosis and manage- ment of the patient (Fig. 79.18). The open ring sign is often present in large, contrast-enhancing demyeli- nating lesions and consists of a partly enhancing ring around the lesion (Masden et al. 2000).
Much attention has also been given to clinical iso- lated symptoms (CIS) that may or may not progress to MS. This isolated symptom is often optic neuritis, but other signs are possible. MRI is a powerful predic- tor of the later diagnosis of definite MS, better than the presence of HLA-DR2 or CSF oligoclonal bands.
79.6 Magnetic Resonance Imaging 579 Fig. 79.3. Same patient as
in Fig. 79.2. It is useful in patients suspected of having MS to include the spinal cord in the examination. The disability of the patient is often also or mainly related to the spinal cord lesions
Table 79.3. Spinal lesions in patients with MS and patients with other neurological disorders. The difference is statistical- ly significant (Bot et al. 2002)
Spinal cord Normal Abnormal
Other neurological disorders 39 4 (n = 43)
MS (n = 25) 2 23
Normal-appearing white matter (NAWM) has be- come an important issue in MRI of MS. MR tech- niques have confirmed the histopathological and chemical observations that white matter that appears normal on T
1-weighted, T
2-weighted, and FLAIR im- ages show diminished structural integrity when mag- netization transfer ratios (MTRs) are estimated (Fig. 79.19). With diffusion tensor imaging, ADC val-
ues of normal-appearing white matter are increased and FA values lower as compared to normal white matter in non-MS patients. Changes in metabolite concentrations on MR spectra lead to the same con- clusion.
The relationship between the lesions demonstrat- ed on MRI and clinical findings is generally speaking poor. In patients with advanced disease of the sec-
Fig. 79.4. A 38-year-old woman suspected of having MS. The MR picture is compatible with this diagnosis. The transverse T2-weighted images show lesions around the lateral borders
of the ventricles and the corpus callosum.There are no lesions elsewhere in the brain
ondary progressive type, the correspondence be- tween the developing atrophy and the number of white matter lesions and the EDSS disability score is better.
In estimating the prognosis of MS, so-called black holes have been proven to have a special place.“Black holes” are MS lesions that appear very dark on T
1- weighted images and bright on T
2-weighted images (Fig. 79.20). The presence of black holes correlates better with a poor prognosis than the presence of le- sions on T
2-weighted images and gadolinium en-
hancement of lesions (Van Walderveen et al, 1995, 1998). Histopathologically, they correspond to areas with severe matrix destruction and axonal loss (Van Waesberghe et al. 1999).
There is a growing interest in remyelination, part of the healing process of MS. Some lesions disappear from MRI in MS patients with follow-up MRI, where- as others do not. The question is whether the disap- pearing lesions remyelinate and therefore become in- visible, or shrink and turn into little gliotic scars. New MR methods may be helpful in answering this ques-
79.6 Magnetic Resonance Imaging 581
Fig. 79.5. Same patient as in Fig. 79.4. The upper two rows dis- play sagittal and parasagittal proton density images, revealing the shape and extent of the lesions in the corpus callosum and
around the lateral ventricular borders. In this patient, too, mul- tiple lesions in the spinal cord confirm the diagnosis
tion, for example by demonstrating changes in the MTR or ADC. Not all lesions that remyelinate neces- sarily disappear from the MR image; many maintain a high signal on T
2-weighted images. In a post- mortem study, MRI of the 1-cm-thick slices was used to detect lesions (Barkhof et al. 2003). In this study re- myelination was found in 42% of the lesions, the re- myelination being partial in 19% and full in 23%. The
conclusion of this study was that T
1-weighted images and MTRs have additional value in distinguishing le- sions with and without remyelination (Barkhof et al.
2003). In addition, ADC values and contrast-en- hanced T
1-weighted images may also hold informa- tion in patients with remitting MS (Fig. 79.21). MR data obtained in demyelinating lesions induced by lysophosphatidyl choline in animals showed high
Fig. 79.6. Transverse FLAIR series of a 40-year-old woman pre- senting with a 6-week history of vertigo attacks. She had pre- viously undergone operations on both ears for cholesteato-
mas. The surprise finding in this patient consisted of lesions supratentorially suggestive of MS and a distinct lesion on the left side in the vestibular nucleus and nerve
ADC values in the peripheral edema and moderately low values in the center of the lesions in the early phase of the lesions. Substantial reduction of ADC values occurs in both parts of the lesions with re- myelination (Degaonkar et al. 2002).
Several special MR techniques have been shown to be effective in extracting more information on the na- ture and degree of structural damage of brain tissue.
They are mainly applied in research settings and in protocols of clinical trials.
Diffusion-weighted imaging usually reveals a high to very high signal in hyperacute lesions and some- times low ADC values (Fig. 79.22). It is difficult to draw conclusions from that, because the underlying mechanism of the signal change in these cases is not completely understood. Low ADC values do not cor- respond entirely with enhancement, probably be- cause enhancement depends on leakage through the blood–brain barrier, whereas low ADC values in MS lesions more likely reflect the initial inflammatory reaction. Low ADC values in MS are not indicative of cytotoxic edema. Diffusion tensor imaging and fiber tracking may be helpful in demonstrating the repair
in fiber tracts when remyelination occurs. Other tech- niques may also be considered, such as functional MRI in combination with fiber tracking.
Magnetization transfer ratios (MTRs) are often used in follow-up studies. Changes in MTR reflect changes in structural integrity and correlate with axonal damage. MTR histograms of the whole brain or segments (white matter, gray matter) are used as a tool to measure progression or regression of the dis- ease.
Proton MR spectroscopy (
1H-MRS) has added con- siderably to the understanding of the pathophysiolo- gy of MS.
1H-MRS has been performed as a single voxel technique or as chemical shift imaging (CSI) in acute, subacute, and chronic lesions, and also in nor- mal-appearing white and gray matter, in particular in patients with relapsing-remitting MS and secondary progressive MS. MRS can analyze the biochemical changes and their time course. In acute lesions choline and lactate increase early in the demyelinat- ing process, reflecting inflammation and demyelina- tion, followed in most lesions by a decrease in NAA, reflecting axonal loss. The amount of NAA loss (be-
79.6 Magnetic Resonance Imaging 583
Fig. 79.7. T1-weighted contrast enhanced images in the same patient as in Fig. 79.6.The two enlarged images on the right show the enhancement of the lesions in the vestibular nucleus and tract (ring and arrow)
