Ana sayfa | MS’in Derinliği  | MS Slide Resource

Ideally, the role of the neurologist should not end once a diagnosis of MS has been made. In practice, most diagnosed patients are handed back to the care of their family doctor and are referred to an MS clinic only when there is a particular need. Usually, only those patients attending a MS research centre are monitored systematically throughout the entire course of their disease. Such monitoring involves a combination of clinical assessment of the patients' disabilities and the recording of pathological changes using MRI.

Why monitor disease progression?

MS is the most common cause of chronic neurological disability among young adults. Nevertheless, it remains a disease of uncertain cause that is accompanied by unpredictable changes in disability.^1,51 Therefore, it is essential to monitor the effects of the disease as it progresses in order to:

• increase the understanding of the disease

• assess the efficacy of existing symptomatic treatments

• evaluate new treatments in clinical trials

• make patient management decisions

• generate data to give a more reliable prognosis.

The manifestations of MS vary so widely between patients that it is often difficult to relate the clinical symptomatology of the disease to scientific data. However, the study of disease progression in individual patients provides a means of accumulating data that may give important insights into the natural history of the disease. Such studies may contribute also to an eventual understanding of disease aetiology, since the variability of MS could be related in some way to its cause.

It is only by referring to the accumulated data on disease progression that the efficacy of new and existing treatments can be assessed. There are no certainties in MS, and it is impossible to state unequivocally what would have happened to a particular patient if left untreated. Neither is it possible to be certain that a given response can be attributed to the therapy. However, MRI may change all this. Performed at regular intervals, this technique is a sensitive measure of disease etkinligini and may provide a useful therapeutic indicator for monitoring the effectiveness of new treatments.

Decisions regarding patient management must rely largely on experience gained with similar cases. In addition, an understanding of the patterns of disease progression makes an important contribution to the accuracy of the prognoses offered to patients.

How is disease progression monitored?

The clinical state of an MS patient can vary rapidly: one day they may be able to walk only slowly and the next their walking speed may be near normal. Symptoms can disappear as rapidly as they came. What appears to be an improvement may only be transitory. In some patients changes are not lasting. Such observations do not enable evaluation of whether the patient is improving or deteriorating. To determine this, the clinical condition of the patient, and the rate at which it is changing, must be recorded in a way that allows comparisons to be made with other patients - and with the same patient over time.¹

Objective methods have been developed that allow the clinical and pathological status of the patient to be monitored. Using these, it is now possible to measure both acute and chronic changes.

Monitoring dynamic acute changes

Clinical monitoring

Clinically, the acute changes in MS can be recorded as relapses. A clinical relapse can be defined as:

• the appearance of a new symptom accompanied by appropriate neurological signs, or

• the reappearance of an old symptom, or

• the worsening of an existing symptom at any time after the initial attack.

True relapses last longer than 24 to 48 hours. Also, it is generally accepted that all fresh symptoms occurring within a period of one month can be considered as part of the same relapse. A new relapse can only be diagnosed after one month has passed from the onset of the previous relapse.¹

In order to quantify relapse rates, clinical etkinligini can be measured as the number of relapses occurring in a specified period of time, e.g. relapses/year. Relapses can also be rated according to severity, (mild, moderate, or severe) using clinical rating scales such as the Neurological Rating System (NRS or Scripps Scale).⁵² (See later.)

Acute MRI monitoring

MRI is the most sensitive technique for visualizing lesions in the CNS. With its introduction, disease etkinligini has become evident in patients who display no clinical evidence of relapse.²¹

The most reliable indicator of acute disease etkinligini in MS is the occurrence of new and active neurological lesions. Serial MRI studies (bi-weekly or monthly) show dramatic disease etkinligini that is often subclinical.⁵³ MRI evidence allows lesions to be classified as follows:

• new lesions - those not visible on previous scans

• enlarging lesions - those showing a significant enlargement from a previously stable state, (significant enlargement means an increase of approximately 70% in small lesions, i.e. lesions of ¾1 cm; in larger lesions a 10% increase is significant)

• recurring lesions - those that appear in the same site as an earlier lesion that disappeared

• resolving lesions - those showing a significant reduction in size.

In practice, factors such as differences in patient positioning, motion artefacts, difficulty in perceiving subtle changes, and in clearly identifying enlarging lesions can cause problems in defining lesions with confidence.

Gadolinium enhancement - Gd-DTPA (Magnevist^®) is a contrast medium that modifies the MR image. It can be used to differentiate acute from chronic lesions in MS patients.⁵⁴

One of the earliest events in the formation of new MS lesions is the breakdown of the blood-brain barrier.¹ It is through these areas of damage that Gd-DTPA leaks into the brain following intravenous injection. Hence, Gd-DTPA-enhanced MRI can detect the formation of new lesions. Because Gd-DTPA also detects reactivation in old lesions, it is essential when monitoring disease etkinligini always to record whether the enhancement is new, recurrent or persistent (i.e. persisting from one scan to the next).⁵⁵ Careful standardization of the method is required so that lesions can be identified on future scans.

For disease etkinligini assessment, experts now recommend serial examination with Gd-DTPA enhanced MRI scans. This is because unenhanced scans fail to detect a proportion of active lesions.⁵⁶

Gd-DTPA enhanced MRI is the most promising technique for monitoring treatment in patients with relapsing/remitting or secondary progressive MS. However, its use is not recommended in primary progressive MS, where a much lower frequency of enhancing lesions is seen (lesions are fewer and smaller than in secondary progressive MS).⁵⁷ Measuring Gd-DTPA-enhancing lesions may also be a useful outcome measure in the assessment of experimental therapies in early MS.⁵⁸

Ultimately, however, therapeutic efficacy is determined clinically, so regular clinical assessments to measure disability and to record relapses should be carried out in parallel with MRI.⁵⁸

Measuring disease etkinligini - Calculation of the rate of appearance of new enhancing lesions on MRI can be used to assess acute dynamic etkinligini. Scans should be performed monthly as lesions may be missed with less frequent scanning. Scans can be classified as either active (one or more new, enlarging or recurring lesions) or inactive (no new, enlarging or recurring lesions). Patient analysis can be based on a variety of parameters, such as the number of scans with active lesions, or the total number of active lesions. A new lesion etkinligini rate, or a total etkinligini rate, can then be calculated over a given period of time (e.g. etkinligini rate in lesions/year).^53,57

Measuring dynamic chronic changes

Chronic clinical monitoring

Periodic assessment of clinical status provides a means of monitoring the changing clinical picture of MS over time. It can be used also to classify the type of disease course a patient is experiencing. However, the physical manifestations of MS may bear little relationship to the site and extent of lesions in the CNS. Nevertheless, attempts have been made to quantify physical dysfunction in a way that will enable comparisons to be made between patients.

The International Federation of Multiple Sclerosis Societies has published guidelines for a Minimal Record of Disability (MRD) in MS.⁵⁹ These are based on the World Health Organization classification of neurological dysfunction, and evaluate neurological disorders under three headings:

• impairment - clinical signs and symptoms produced by damage to the CNS

• disability - personal limitations imposed on daily living by neurological impairment

• handicap - social and environmental effects of the disability.

However, this system has not been extensively used in clinical trials.

Many methods have been proposed for assessing the clinical severity of MS. These can be divided into disability scales and scoring systems. The most widely used disability scales are the Kurtzke Disability Status Scale (DSS), and, more often, its modified form the Expanded Disability Status Scale (EDSS).^60,61 These measure clinical impairment (rather than disability) in MS.

The DSS is a simple, 10-step scale, originally developed to measure the maximal function of each patient. The EDSS incorporates eight 'functional systems' (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, mental, and 'other'). In this scale each of the 10 steps from the DSS is divided into two sub-groups to improve sensitivity. The scale ranges from 0 (normal neurological examination) through to 10 (death). A physician is required to perform the assessment.^60,61,62

The Neurological Rating System (NRS or Scripps Scale), allocates a single score to the patient that reflects their overall neurological function. Mental status, cranial nerves, motor system, sensation and tendon reflexes are graded and totalled to give an overall score from 0 to 100.⁵² The higher the score, the less impairment the patient has. It is a straightforward system for scoring motor and sensory function in each limb but lacks precision in defining the degree of impairment.⁶² Both the EDSS and NRS have been used in recent clinical trials.⁴¹

Other systems used include: the Incapacity Status Scale (ISS), a modified form of the DSS, that is recommended in the MRD for assessing disability; and the Environmental Status Scale, which measures handicap (social and environmental limitations).⁶¹ These scales are more time consuming to use than the EDSS or NRS, and do not provide a direct record of disease severity.

Chronic MRI monitoring

Using serial MRI, it is possible to quantify the total area or volume of brain lesions and to determine 'burden of disease' (lesion load) and how this changes over time. Several computer-assisted methods are available for quantifying the area of abnormality in the brain.

The first step involves defining the borders of individual lesions. These areas are summed, slice by slice, to give a total lesion area, recorded in mm².⁴² Alternatively, total lesion volume can be calculated and expressed in mm³.⁶³ These measurements of lesion load are more accurate if performed by a single observer (reproducibility varies from 5% to 20%, depending on observer experience).⁵⁶ It is critical that the patient is repositioned accurately at each examination.⁶⁴

The degree of clinical expression of a lesion is probably due to its location, plus a combination of additional factors including degree of axonal loss within the lesion. Serial examination enables the extent and evolution of pathology to be followed with some accuracy. However, as yet this cannot be related to the fluctuating severity of the clinical impairment or to the patients' level of disability.^53,56

The impact of MRI

How MRI works

MRI is a non-invasive method of obtaining images of the body. It depends on artificially altering the spins of the nuclei of hydrogen atoms (protons).⁶⁵

When a strong magnetic field is applied, the spinning nuclei in the tissue under examination act like small magnets and align themselves within the field. If a pulse of radio-frequency (RF) is then directed at the tissue, the orientation and speed of the nuclear spins are altered. When the RF is turned off, the protons return to their 'relaxed' position in the magnetic field, and energy is emitted from the tissue as a weak RF signal.⁶⁵

Nuclei relax more quickly in some tissues than in others. The scanner converts these different relaxation times into a visual image of the tissues in the section of the body being examined.⁶⁵

Tissues have two different kinds of relaxation time, called T1 and T2. The T1, (also known as the longitudinal relaxation time or spin-lattice relaxation time) is the time taken for the majority of the nuclei to return to their original direction after displacement by a RF pulse. The T1 time of a tissue depends mainly on its physical characteristics, e.g. whether it is fluid or solid.

The second type of magnetic relaxation, the T2 (also known as the transverse relaxation time or spin-spin relaxation time), takes place at the same time as (but independently of) T1. This is the time taken for the nuclei to return to their original 'out-of-phase' state after synchronization by a RF pulse. The chemical composition of tissue has a greater effect on T2 time than on T1.⁶⁵

By adjusting the scanner settings, images can be produced to emphasize either the T1 or T2 relaxation times of the tissues.⁶⁵ Whether a particular tissue appears bright or dark depends on whether a T1- or a T2-weighted scan is performed.

T2-weighted images

T2-weighted scans of the brain are usually used to show MS lesions. The lesions tend to be multiple, giving a typical 'lumpy-bumpy' appearance, and are often adjacent to the ventricles.

MRI of the spinal cord is technically more difficult, due to the small size of the cord, artefacts caused by breathing movements and technological limitations. Lesions of the spinal cord may cause swelling, bright patches may occur, and atrophy of the cord is seen in long-standing disease.²¹

Within the brain, white matter with a normal appearance has a dark, low intensity signal on T2-weighted images. In MS lesions water is freed by the breakdown of the myelin layers. 'Free' water has a long relaxation time, producing an increased signal on T2-weighted images. Other pathological processes such as oedema, gliosis and inflammation can also increase the signal on T2-weighted images.

Enhanced T1-weighted images

The earliest detectable events in the formation of MS lesions are characterized by inflammation and breakdown of the blood-brain barrier.^54,66 Inflammation can be detected exclusively on T1-weighted images. When used in conjunction with the contrast agent Gd-DTPA (Magnevist^®), T1 scans reveal areas of breakdown in the blood-brain barrier. Such contrast agents markedly shorten the T1 relaxation time of nearby hydrogen nuclei and are most effective when they accumulate in a particular tissue.

Clear guidelines exist for the use of MRI in monitoring MS treatment trials. They address many aspects of scanning, from magnetic field strengths to analysis of trial outcomes. The guidelines are based on the use of T2-weighted unenhanced MRI and T1-weighted Gd-DTPA enhanced MRI.⁵⁷

Benefits and limitations

The use of MRI for monitoring changes in MS is increasing because:

• MRI is a more sensitive indicator of disease etkinligini than clinical assessment: active MRI lesions are detected 5 to 10 times more frequently than are clinical exacerbations⁵⁷

• it is easier to quantify MRI changes than clinical changes

• MRI assessments are more objective and reproducible than clinical assessments.

However, MRI still has its limitations, e.g. used alone, it cannot provide a definite diagnosis of MS. Neither can current conventional MRI give much information about pathological changes in MS lesions. Also, it is difficult to correlate MRI findings (lesion load) with clinical assessment methods like EDSS.

The future of disease monitoring

Clinical monitoring

Currently, clinical assessment systems rate the severity of neurological abnormalities rather than the extent of underlying pathology. Therefore, despite their usefulness to neurologists, the existing assessment systems are not perfect. Nevertheless, clinical rating scales will continue to be important in the future. In particular they will be necessary to monitor whether reductions in MRI etkinligini translate into a long-term slowing in the rate of accumulation of clinical disability.²⁵

However, current scales may need modification so that:

• they are based on signs (objective findings on standard neurological examination) rather than symptoms (subjective observations made by patients)

• 'functional systems' are selected on the basis of ease and reliability of clinical assessment

• grades within each functional system are more precisely described (not simply as mild, moderate or severe)

• increased impairment is reflected by an increase in score

• the method for combining subscales to form an overall score becomes clear and simple.⁶²

Computerization of clinical data is important to research, and should include essential clinical information such as relapse history, and clinical impairment scores (EDSS, NRS). Also, it should include disease course classification (i.e. relapsing/ remitting, primary progressive, etc.), since MRI disease etkinligini varies between clinical subgroups.

A database for serial MRI in MS has already been established and includes essential clinical information to allow proper interpretation of the MRI data.⁶⁷ Computerization of clinical information also allows retrospective analysis of data in the light of new hypotheses.

MRI monitoring

MRI enables the detailed study of MS in vivo and has greatly increased our understanding of the disease. However, to date it has provided little information about the underlying pathology. Imaging techniques which detect demyelination and axonal loss (processes that probably account for much of the permanent disability in MS) are particularly needed. Several techniques are being developed to differentiate these pathologies.²²

Studies suggest that T2-relaxation measurements may have identified a reservoir of water in the brain with a relatively short T2 time. This could prove to be a useful marker for the water trapped within the normal myelin layers, and may help to identify normal myelin.⁶⁸

Proton magnetic resonance spectroscopy (MRS) allows non-invasive measurement of cerebral metabolites and can be used to give information on the biochemical make-up of lesions in vivo.

N-acetyl aspartate (NAA) is a metabolite located primarily within lesions; mildly decreased or normal levels are seen in acute lesions, with lower levels occurring in older irreversible lesions.²¹ Several studies have shown that low NAA peaks in MS lesions are reliable markers for irreversible axonal loss.⁶⁹

An increase in inositol seen with MRS is thought to be associated with active gliosis, whilst free lipids and choline may be markers for demyelination.⁶⁸ Preliminary evidence suggests that MRS may detect differences in resonances (e.g. lipids, lactate) that could potentially be used to differentiate MS from other brain diseases.⁵⁴

New techniques such as magnetization transfer imaging (MTI) may also increase sensitivity for detecting demyelination, and help to differentiate between oedema and demyelination.

In summary

The ultimate aim of elucidating the pathological mechanisms in MS is to devise rational therapy which will:

• arrest the disease by preventing new lesions from occurring, or

• halt the progression of new inflammatory lesions into permanent lesions (demyelination with or without axonal loss).

Defining the pathology in MS may strengthen the correlation between clinical and MRI outcomes and provide a highly sensitive and clinically relevant measure of disease etkinligini. Although some progress has been made, there remains a need for further studies to investigate other applications for this powerful research tool.

Bu sayfadaki bilginin en son güncellendiği/doğrulandığı tarih:

11/09/2001

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