Ana sayfa | MS’in Derinliği  | MS Slide Resource

The symptoms and signs of MS

MS can affect any part of the central nervous system (CNS), consequently patients can display a wide variety of neurological symptoms and signs.¹ Some of these are typical of MS; others can occur in MS but are more common in other diseases. (See below for a more detailed examination of these and other related topics.)

Typical symptoms and signs

Common MS symptoms arise from disease affecting the optic nerves, pyramidal tracts (motor nerve pathways) and sensory nerve pathways.

Optic neuritis (inflammation of the optic nerve) is one of the most common features of MS. It causes impaired vision and eye pain. Muscle weakness and fatigue are also typical, especially in the legs. On examination the legs may show spasticity, other signs of pyramidal tract damage (e.g. weakness) or muscle wasting. Sensory symptoms and signs are also more common in the legs. They include paraesthesia and numbness. Lhermitte's sign, an electric shock sensation running down the spine and legs on neck flexion, is another frequent occurrence in MS. Brainstem and cerebellar damage often causes nystagmus, double vision, vertigo and altered speech. Autonomic nervous system involvement can result in bladder or sexual dysfunction.^2,3

Other symptoms and signs

Many other symptoms and signs occur. They include:

• mental changes

• cranial nerve symptoms and signs

• paroxysmal symptoms (brief episodes that usually last only seconds or minutes but occur as many as 50 times per day e.g. trigeminal neuralgia and dysarthria/ataxia)

• other autonomic nervous system symptoms and signs (e.g. sweating, cardiovascular system abnormalities and Horner's syndrome)

• restless leg syndrome

• pain of various kinds

• altered level of consciousness

• narcolepsy.³

Symptoms and signs atypical for MS

Some symptoms and signs are not usually found in MS and their presence may suggest an alternative diagnosis. They include aphasia, hemianopia, extrapyramidal movement disturbances, severe muscle wasting and muscle fasciculation.

Clinical course

In most patients with MS, symptoms and signs tend to come and go (relapse and remit), especially early in the disease course.¹ However, patients can follow either a relapsing/remitting course, or a primary progressive course in which symptoms and signs gradually accumulate without remission. A relapsing/remitting course may develop into a secondary progressive course with time.²

A characteristic clinical state usually develops in patients with established disease. They have pale optic discs, nystagmus, slurred speech, tremor, weakness and a spastic/ataxic gait. Later, in the terminal stages, patients become incontinent and totally dependent on carers.¹ The mean survival time after diagnosis is 35 years, but there is much variation. The terminal event is most often a bacterial infection in the urine or lungs, or a cause unrelated to MS.²

The speed with which a patient's condition proceeds from initial symptoms to death is very variable. Some develop crippling disability after the first attack, others, following their first remission, experience decades with no symptoms. A few patients never develop significant disabilities.²

Diagnosis and monitoring

Doctors often suspect that a patient has MS before a definite diagnosis can be made.⁴ For a clinical diagnosis to be made there must be evidence of CNS white matter lesions, on two or more occasions, at least 1 month apart, in a patient aged between 10 and 60 years, and differential diagnoses must be excluded.² Paraclinical evidence such as magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) samples and evoked potential measurements may aid the diagnosis.

Diagnostic imprecision causes difficulty when deciding which patients to include in clinical trials. Poser and his colleagues have developed diagnostic criteria to help classify patients for clinical trials.⁴ In modern trials, paraclinical evidence should be used with Poser's criteria to confirm that patients entering the trial have MS.

Scales exist which can be used to monitor a patient's disease progression/remission objectively during a trial - e.g. the Expanded Disability Status Scale (EDSS) and the Neurologic Rating Scale (NRS).⁵ These scales score components of a patient's neurological examination, and so can precisely define a patient's neurological state.

Overview of normal CNS histology

Neurones

Neurones are the most important components of the CNS. They connect to form a complex intricate network of pathways that conduct electrical impulses. The grey matter is composed principally of neuronal cell bodies; the white matter mainly of nerve fibres (axons) covered by myelin.⁶

Oligodendrocytes and myelin

Oligodendrocytes are responsible for the myelination of axons in the CNS. A single oligodendrocyte may be responsible for myelinating up to 50 axons. Myelin insulates nerve axons, allowing faster conduction of electrical impulses than is possible with non-myelinated fibres.⁷

Astrocytes

Astrocytes provide structural support for the neurones and other cells within the CNS. Also, they repair damage to CNS tissue by replicating tissue and forming scars in areas of damage.⁷ This repair process is variously known as astrocytosis, gliosis or sclerosis.

The blood-brain barrier and cerebral blood vessels

The blood-brain barrier controls the passage of cells and molecules into the CNS.⁸

Cerebral microvessels differ structurally and functionally from blood vessels in other organs. There is a complex relationship between their endothelial cells, basement membranes, and associated cells (e.g. perivascular macrophages and astrocytes). The endothelia of the blood-brain barrier are joined together by tight junctions that have extremely high electrical resistance. Also, there is little, if any, passage of molecules through endothelial cells in transport vesicles. In addition to this, the endothelial cells are almost completely surrounded by the foot processes of astrocytes, and some microglia. Perivascular macrophages, being highly phagocytic, act as a further line of defence.^9,10

The pathological lesions of MS

General features

MS produces abnormalities that are easily visible to the naked eye at post-mortem. The overall appearance is of a shrunken (atrophic) brain and, with widening of the cerebral sulci and dilated ventricles.¹¹

At post mortem, plaques vary in appearance, size and age, even within one patient. Old lesions appear grey, translucent and firm (sclerosed); the newer lesions appear soft and pink. During life, new lesions continue to appear in different parts of the nervous system for many years. Plaques grow by either coalescence of adjacent lesions, or finger-like extensions (Dawson's fingers) from the plaque edge.^11,12

The pattern of plaque distribution varies considerably from patient to patient, but is often symmetrical. All white matter is susceptible; but grey matter can be involved too, and its involvement is frequently underestimated. Typical sites for plaques include the spinal cord, medulla, pons, cerebellar white matter, optic nerves and corpus callosum. Plaques are particularly common close to the ventricular system - especially at the lateral angles of the lateral ventricles. Also, they tend to occur around veins.^11,12

The blood-brain barrier and cerebral blood vessels

Recurrent episodes of blood-brain barrier disruption play a major role in MS,¹³ and explain why plaques are generally perivenous. Blood-brain barrier damage can be seen in new lesions in vivo on Gd-DTPA (Magnevist^®) enhanced MRI scans (Gd-DTPA will only enter the brain where the blood-brain barrier is abnormal). Lymphocytes and macrophages enter the CNS at these points of damage.¹⁴

Inflammation

MS plaques contain large numbers of inflammatory cells arranged around veins: T-lymphocytes, plasma cells (producing antibody), large mononuclear cells and macrophages.^13,15 However, the inflamed areas are dominated by T-lymphocytes and macrophages. The type and amount of inflammation varies depending on the form (active or inactive) and stage (early or late) of the disease.¹⁴

Other non-plaque areas are affected also. Inflammation occurs throughout the brains of MS patients.¹⁴ The meninges are involved in this diffuse inflammatory process, and macrophages, lymphocytes and plasma cells can be identified in the patient's subarachnoid spaces.¹¹

Oligodendrocytes/myelin

Myelin and oligodendrocytes appear to be the principal targets of attack in MS.¹² Their destruction leaves confluent areas of intact but naked axons. This process is known as periaxial primary demyelination.^11,14

Some of the early structural changes that lead to demyelination are splitting of the sheets of myelin, the formation of intramyelinic vesicles, and the interaction of macrophages with myelin sheaths.¹⁵

More diffuse lesions not visible to the naked eye, with abnormally thin myelin, have been reported outside plaques.¹¹ These are called shadow plaques, and are areas of remyelination by oligodendrocytes.¹⁵ As with inflammation, demyelination and remyelination occur to varying degrees depending on the form and stage of MS.¹⁴

Astrocytes/sclerosis

Astrocytes fill the defects resulting from demyelination, causing gliosis and sclerosis (hence the name multiple sclerosis).¹⁵ In addition, areas of diffuse gliosis can occur in white matter that appears normal to the naked eye. These areas correspond to the areas of abnormally thin myelin (shadow plaques) where remyelination has occurred.¹¹

Active and inactive MS

Plaques may be inflamed and demyelinating (active), or dormant (inactive). Active and inactive plaques display the general features of MS plaques to different degrees.

The active lesion

The blood-brain barrier is more leaky in active than in inactive plaques. This allows macrophages and T-lymphocytes to enter the brain and cause inflammation (macrophages greatly outnumbering T-lymphocytes). The macrophages may be the key cells in the pathogenesis of active lesions, promoting active demyelination by secreting cytokines and presenting antigen to the T-lymphocytes.^9,15

In actively demyelinating plaques, myelin sheaths and other cells are constantly under attack. Their destruction leaves abundant myelin and lipid degradation products. The degree of oligodendrocyte destruction (as opposed to myelin destruction) is variable.^11,14

Many macrophages occur at the edges of active plaques and astrocytes extend several centimetres into the tissue surrounding a plaque. Both of these cell types may be involved in plaque enlargement. If such plaques remain active for several months they can enlarge. Long-standing active lesions often become hypocellular and gliosed (sclerosed) at their centres, developing some of the features of old inactive plaques.¹¹

The inactive lesion

Inactive plaques are areas that have been affected by the disease process in the past and, although no longer active, they show residual damage. They are demyelinated (but do not contain myelin breakdown products), they show oligodendrocyte loss, are hypocellular, and gliosed (sclerosed). Naked axons with modified astrocyte contacts (resulting from lost myelin) run through these plaques. Venules in inactive plaques have thickened hyalinized walls, but perivenous inflammatory infiltrates may persist. Large inactive plaques are particularly common in the periventricular areas.¹¹

Early and late phases of MS

There appear to be some important pathological differences between the plaques of early and late MS.

Early MS

In the active plaques of early MS, blood-brain barrier breakdown is accompanied by the accumulation of lymphocytes and macrophages around the blood vessels in the plaques (there are fewer plasma cells in the plaques of early MS compared with late MS). Myelin sheaths disintegrate, and infiltrating macrophages phagocytose the myelin. Axons remain intact, and astrocytes are present also, causing glial scar tissue to form around the demyelinated axons.^11,14,16

Myelin destruction occurs before there is obvious damage to oligodendrocytes in early MS. The plaques contain almost normal numbers of oligodendrocytes, although some of those present may be new oligodendrocytes differentiated from progenitor cells to replace those destroyed. The frequent finding of shadow plaques, produced by the remyelinating etkinligini of oligodendrocytes, emphasizes the relative normality of this cell population in early disease.¹⁴

Late (chronic) MS

In contrast to early MS, the plaques of late (chronic) MS show extensive oligodendrocyte loss. Also, remyelination is sparse and restricted to the borders of plaques. Moreover, in some cases, oligodendrocyte destruction appears to occur before myelin destruction.¹⁴

Astrocyte activation may be a very early feature of plaque formation in late MS, often occurring simultaneously with active demyelination, even in the surrounding white matter.¹⁵

Other characteristic features include:

• marked brain and spinal cord atrophy, wide cerebral sulci and dilated ventricles

• extensive demyelination

• loss of axons (especially at plaque centres)

• gliotic scars (sclerosis)

• lymphatic-vessel-like structures in perivascular connective tissue spaces.^11,14,15

The plaques in late MS are probably caused by inflammation, although the signs of this are less obvious than in early MS. Typically, the blood-brain barrier is less damaged, and the intensity of the perivenous inflammatory reaction less pronounced. However, inflammatory cells do occur in actively demyelinating plaques of late MS and are found even in unaffected white matter.¹⁵ Also, significantly more immunoglobulin producing plasma cells are present compared with early disease. In the long-standing plaques of late MS, signs of cell degeneration are restricted to the plaque borders.¹⁴

Acute (Marburg type) MS

This is a severe form of MS that causes extensive neurological deficits, which lead to death within about 1 year.¹⁴

Plaques in acute MS are intensely inflammatory. The inflammation clearly precedes the demyelination, and gliosis (sclerosis) occurs secondary to the demyelination. There is more damage to the blood-brain barrier than with typical late MS, and the perivenous accumulation of debris-containing phagocytic cells is much more pronounced.¹⁵ There are fewer plasma (antibody producing) cells in acute, compared with late MS plaques.¹⁴

This type of MS leads to marked destruction of brain architecture. Post mortems show extensive myelin destruction and severe axon loss. The areas of demyelination are surrounded by wide zones of oedema, which contain many macrophages. Degenerating cells (oligodendrocytes, T-lymphocytes, macrophages and astrocytes) are common in these cases. Despite the aggressive nature of this type of MS, remyelinating shadow plaques are frequently found.^11,14

A similar acute fulminant phase may occur as the terminal event of late MS.¹¹

Conclusion

The reasons for the differences between early, late and acute (Marburg type) MS are not clear. The differences could be due simply to variations in speed and severity of plaque development. Alternatively, there may be differences in the pathological mechanisms of tissue damage.¹⁵

Remyelination

General features

Until recently, most researchers thought that remyelination could not occur in MS.¹⁷ It is now known that whole plaque remyelination can take place, leaving an increased density of glial cells in otherwise normal white matter.¹⁵

Shadow plaques (originally thought to be areas of partial demyelination but now known to be remyelinating areas) are a characteristic and widespread finding in MS.^15,18 They contain uniformly thin myelin. In addition, the length of internodes (distance between nodes of Ranvier) is shorter in shadow plaques than in normal myelin. These two features are characteristic of remyelinating nerve fibres.¹⁷

The type and amount of remyelination varies between different forms of MS and at different stages of the disease, possibly reflecting different pathogenic mechanisms. The circumstances that determine whether a plaque will or will not remyelinate are not known. However, there seems to be a direct correlation between the extent of remyelination and the preservation of oligodendrocytes during active demyelination.^14,18

It is paradoxical that myelin degeneration may occur at the same time as remyelination. This may be because of a feedback mechanism in which factors, such as myelin breakdown products, stimulate oligodendrocytes to produce myelin.¹⁹

Remyelination in early MS

Remyelination is a prominent feature of active lesions in early MS. This may be because oligodendrocytes are not the primary target (there is evidence that, after an attack, oligodendrocytes survive). Consequently, new lesions usually remyelinate unless interrupted by recurrent etkinligini. Often entire plaques remyelinate.^14,18

Remyelination in late (chronic) MS

The longer a patient has had MS, the less remyelination occurs. Shadow plaques are rare in late compared with early MS.¹⁵ This may be because, in late MS, demyelination is accompanied by extensive destruction of oligodendrocytes. Any oligodendrocytes present appear to be recruited from the pool of progenitor cells.¹⁴ In addition, recurrent demyelination and destruction of oligodendrocytes in the same area will eventually deplete not only the pre-existing oligodendrocytes, but also the pool of progenitor cells. This may contribute to a failure of remyelination late in the disease course.^20,21

Remyelination in acute (Marburg's type) MS

In acute MS (Marburg's type) shadow lesions are frequent.¹⁵ As with early MS, this may be because oligodendrocytes are not the primary target of the inflammatory response. Even in the highly destructive lesions characteristic of acute MS, many oligodendrocytes are preserved and available to induce rapid remyelination.¹⁴

Schwann cells in spinal cord MS

Usually, Schwann cells are responsible for peripheral nerve myelination, while oligodendrocytes are responsible for CNS myelination. However, spinal cord MS lesions often contain regenerating myelin sheaths formed by Schwann cells. This results in peripheral type myelin formation in the CNS.^22,23

One site of Schwann cell remyelination is near spinal-nerve-root entry zones where they form sheaths around fibres continuous with the peripheral nervous system. However, numerous myelin-forming Schwann cells occur far from nerve-root entry zones and other CNS surface regions. These may originate from Schwann cells that have migrated into the CNS e.g. along blood vessels. Alternatively, they could represent the few Schwann cells that exist in the normal spinal cord, or they may even be derived from multipotential stem cells.²²

How does MS pathology relate to symptoms and signs?

The functional consequences of the features of MS plaques

The symptoms of MS are due to slow, absent or abnormal conduction of nerve impulses along CNS pathways. Plaque location (blocking specific pathways) often accounts for the neurological symptoms.

However, the relationship between plaques and symptoms is unexpectedly complex. The site of a lesion is not the only factor that determines symptoms and signs. Large MS plaques can occur in important parts of the brain without causing symptoms.²⁴ Similarly, other effects require explanation, such as paroxysmal symptoms and the effect of heat and exercise.

The most significant feature that produces symptoms and signs is demyelination. However, clinical symptoms and signs in MS are also caused by oedema and toxic inflammatory mediators (both the result of inflammation), and loss of axons. Those induced by oedema or toxic mediators often resolve rapidly after the onset of corticosteroid therapy. Those due to axonal destruction tend to be permanent.

Demyelination

Myelination of nerves allows saltatory conduction to occur. This means that nerve impulses 'jump' down the fibre from node to node. The advantage of this is that it increases the velocity of impulse conduction.²⁵

Demyelination impairs impulse conduction by preventing saltatory conduction, and also by exposing potassium channels in axon membranes normally covered by myelin. Impulse conduction and clinical performance can be improved by the potassium channel blocker 4-aminopyridine.^26,27

In plaques with small stretches of demyelination, electrical impulses can pass over the short gaps in the myelin to the next normal node. In these cases conduction is simply slowed. However, the degree of slowing may vary in different fibres of a functional pathway. This may result in asynchronous arrival of impulses at their target, causing failure of their intended effect.²⁴

Once the demyelinated stretch reaches a certain length, conduction block occurs (complete loss of conduction). In small lesions, conduction block may affect only a small percentage of fibres in a functional pathway. However, multiple, consecutive small plaques causing conduction blocks in the same pathway may together lead to functional deficit.²⁴

Demyelination can cause a prolonged refractory period (time needed by a depolarized section of nerve to recover before it can depolarize again). This impairs the ability of nerves to transmit trains of impulses at high frequencies. It may contribute to the rapid fatigue often experienced by patients with MS during exercise. Similarly, poor vision in bright light (another symptom of MS) may occur because a bright background causes rapid trains of impulses that the demyelinated optic nerve fibres cannot transmit.^24,28

A well known feature of MS is that heat tends to make symptoms worse (e.g. a patient collapses in a hot shower). Improved function in response to cold is less often observed. This heat effect can be explained by demyelination. In normal fibres, conduction velocity decreases with rising temperature until conduction block occurs. The thinner the myelin, the lower the temperature at which this occurs.²⁴ Demyelinated fibres are particularly temperature sensitive. An increase in body temperature of only 0.5°C can result in conduction block.²⁸

Some other symptoms and signs of MS can be explained by the effects of demyelination. Paroxysmal symptoms may be caused by the lateral spread of nerve impulses to neighbouring demyelinated axons. Lhermitte's sign may occur because demyelinating fibres are sensitive to bending.²⁴

Remyelination

Conduction through a nerve fibre can sometimes be re-established before the onset of remyelination. This is more likely in small diameter fibres (e.g. in the optic nerve), than large diameter fibres (e.g. in the dorsal columns of the spinal cord).²⁸

Remyelination is especially prominent in early MS. However, this does not necessarily lead to improved function, because the new myelin may be physiologically abnormal. Nevertheless, remyelination is probably a cause of symptom remission. Progressive disease may be caused by a failure to remyelinate.^15,24

The effects of plaque distribution

Asymptomatic plaques

Asymptomatic plaques are common in MS. Post mortem studies show this clearly. Extensive lesions can be found that were completely asymptomatic during life. Similarly, MRI scans show that plaques are much more frequent than clinical evidence would suggest. Scans often show large asymptomatic plaques. Serial scans reveal that these increase and then decrease in size over months.^24,29

There are several reasons why plaques may be asymptomatic. They may be in areas that are clinically silent (have no clinically identifiable function). This is particularly common with cerebral hemisphere plaques. Alternatively, plasticity of the nervous system may preserve function (i.e. another nerve pathway can adapt to perform the same function as one that has been destroyed, leaving no recognisable functional deficit). Again, this is common with cerebral hemisphere lesions. Finally, effective impulse transmission through chronic plaques sometimes occurs.²⁴

Although the effects of plaques on neurological function is unexpectedly complex, and some plaques remain asymptomatic, many produce symptoms that correspond directly with their anatomical site within the CNS.²⁴ Typical sites include the cerebral hemispheres, spinal cord, optic nerves, medulla, pons, and cerebellar white matter.^11,30,31

Cerebral hemispheres

The cerebral hemispheres of an MS patient may contain hundreds of plaques. All lobes and both hemispheres are equally vulnerable. Most plaques tend to occur close to the ventricles, or in the white matter or white/grey matter junction. Forty percent of plaques occur in the periventricular white matter.³¹

The cerebral hemispheres have many functions, so symptoms resulting from cerebral hemisphere plaques are wide and varied. They range from upper motor neurone and sensory signs to mental changes.

Spinal cord

Plaques are common in the spinal cord of MS patients. They are about twice as common in the cervical region than at lower levels. Typically, they are fan shaped and occur in the lateral columns of the cord. These lesions are responsible for some of the most disabling symptoms in MS.³²

The most disabling consequence of spinal cord disease is paraplegia.²⁴ In less severe cases, lesions in the lateral columns cause leg weakness, which may be partly responsible for the fatigue commonly experienced by patients with MS. Lesions in the pyramidal tracts cause spasticity. Posterior column and spinothalamic tract plaques are probably the cause of tingling paraesthesia and numbness. Lhermitte's sign is a consequence of mechanical deformation of demyelinated fibres in cervical cord plaques. Involvement of autonomic nerves in the spinal cord can cause bladder and sexual dysfunction.³

Other sites

Optic neuritis causes impaired visual acuity and eye pain. This is one of the most common clinical presentations of MS. Plaques in the medulla and pons can cause double vision, vertigo, dysarthria or nystagmus. Plaques in the cerebellar white matter can cause cerebellar ataxia, intention tremor, dysarthria or nystagmus.³

Bu sayfadaki bilginin en son güncellendiği/doğrulandığı tarih:

11/09/2001

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