Ana sayfa | MS’in Derinliği  | MS Slide Resource

The diagnosis of multiple sclerosis (MS) is fraught with difficulty. The symptoms seen at the onset of the disease, and during its subsequent course, vary widely between individuals. So marked is this variability that, in exceptional cases, it may take years to recognize and confirm the diagnosis. Furthermore, for many people the thought of MS is so terrifying that doctors prefer to be sure of the diagnosis before informing the patient. The diagnosis of MS must be based on accepted clinical criteria. It demands also the interpretation of supporting evidence, collected from several sources, by a neurologist with a particular knowledge of the disease.

Diagnostic criteria

Why are diagnostic criteria needed?

In essence, diagnostic criteria provide a reference guide that helps the neurologist to minimize the number of unconfirmed and misdiagnosed cases.

MS diagnosis is an extremely complex process. It begins once suspicion is aroused in the physician's mind that the patient has MS.¹

Several factors make the definite diagnosis of MS difficult, these include:

• the variability of symptoms

• the existence of symptoms common to MS and also to other conditions

• the inability of any existing laboratory test to exclude the possibility of many other conditions, or to confirm unequivocally the diagnosis of MS.

Therefore, there is a need to establish a framework of criteria on which to base the diagnosis of MS.

The essential diagnostic criteria for MS are:

• the demonstration of two or more central nervous system (CNS) lesions disseminated in time and space.

• the exclusion of other conditions that may produce a similar clinical picture.

Only if these two conditions are satisfied can the diagnosis of MS be considered definite, no matter what additional criteria are used. They are fundamental to all diagnostic criteria systems.

Diagnostic criteria systems

What uses can diagnostic criteria systems serve?

Several diagnostic criteria systems have been proposed. Apart from the obvious goal of establishing what is wrong with the patients involved, these systems were intended to serve a number of purposes:

• determining the best management strategy for the patient

• monitoring the patient's disease course

• obtaining comparable data in worldwide epidemiological studies

• differentiating between MS and other conditions with a similar pattern of presenting symptoms and/or course

• establishing how closely laboratory findings and clinical findings correlate

• ensuring that therapeutic trials include only patients with a definite diagnosis of MS.¹

Early diagnostic criteria systems

Some of these systems acknowledged the possibility of diagnostic error by accepting a definite diagnosis of MS only after post mortem examination, rather than on clinical evidence.¹ They gave little attention to laboratory findings unless doubt remained following consideration of the patient's history and physical signs.

These early diagnostic criteria systems had several drawbacks. The inclusion of disease categories such as 'early', 'latent', and 'possible', as well as 'probable' and 'definite', could leave the patient in a state of uncertainty and confusion. Ambiguities in the definitions of different categories of disease within a system could lead to misinterpretation by those not experienced in MS diagnosis.¹

Currently-used systems

The diagnostic criteria systems currently in use were designed to enable the identification of definite MS cases for inclusion in therapeutic trials.¹ However, they have since been applied more generally.

The criteria proposed by Schumacher et al. identify definite MS cases on the basis of clinical findings alone.² This system demands that the following six criteria must be met for the patient's condition to be regarded as clinically definite MS:

1. Objective abnormalities that are attributable to CNS dysfunction are present on neurological examination.

2. Neurological examination or the patient's history provides evidence of the involvement of two or more separate parts of the CNS.

3. Signs reflect the presence of lesions that are predominantly in the white matter.

4. Either, two or more episodes of worsening separated by at least one month and lasting for a minimum of 24 hours.

Or, slow or step-wise progression of signs and symptoms over a period of at least 6 months.

5. The patient's age at onset is between 10 and 50 years.

6. There is no better explanation for the patient's signs and symptoms.²

With this system, the observation of symptoms suggestive of MS, in the absence of neurological evidence of lesions, is insufficient to support a definite diagnosis of MS. Furthermore, care is needed to ensure that signs apparently caused by separate lesions do not result in reality from a single lesion.

In this system, laboratory findings are not used to confirm the diagnosis. However, they can lend support to the diagnosis, or help in excluding other conditions. Inevitably, some patients with MS fail to meet such strict criteria.

Poser's criteria

The latest revision of the diagnostic criteria for MS, Poser's criteria, increases reliance on laboratory and paraclinical tests.³ It incorporates evidence of subclinical involvement as shown by:

• measurement of evoked potentials

• magnetic resonance imaging (MRI) scans

• immunological tests on the cerebrospinal fluid (CSF).³

Poser's criteria allow cases to be divided into two major categories, definite or probable MS. Each of these categories can be subdivided into clinical and laboratory-supported groups, based on the type of evidence that supports the diagnosis.³ The use of Poser's criteria either overcomes or reduces two of the main problems associated with earlier diagnostic criteria systems. These are:

• confusion due to the various systems using the same term to describe different manifestations of disease

• the subjective element of diagnosis.³

It should be noted that Poser defines the term 'laboratory support' as examination of the CSF for the presence of oligoclonal bands or increased IgG production.³ Other special investigations (e.g. evoked responses, MRI scans etc.) are considered to be extensions of the clinical examination.³

How helpful are diagnostic criteria systems?

Despite their value as a means of rationalizing the diagnosis of MS, even the currently-used diagnostic criteria systems have their limitations (e.g. the handling of the primary progressive course is unclear). Furthermore, there are conditions other than MS that can satisfy the diagnostic criteria.

Perhaps it is unrealistic to expect the existing diagnostic criteria to comprehensively describe all possible presentations of such a variable disease as MS. This will remain the case until a diagnostic test specific to MS is available. In the meantime, the judgement of a neurologist experienced in MS remains a key factor in establishing a firm diagnosis.¹

The symptoms and signs of MS

MS can affect any part of the CNS, hence patients can display a wide variety of neurological signs and symptoms. However, areas of demyelination are not distributed completely randomly, and some sites are particularly vulnerable to attack. Therefore, the symptoms and signs most commonly seen at disease onset result from demyelination of these vulnerable areas. (Note: In general, the term symptom is used to include both symptoms and signs in the text that follows.)

Symptoms at disease onset

Isolated instances of visual, sensory, or motor disturbances are often the first reported symptoms of MS. These symptoms may be typical and easily recognisable, or atypical and difficult to relate to MS.

Some symptoms appear to be more common at disease onset than others.¹ Broad agreement exists between several study groups regarding which symptoms are seen most frequently at presentation.⁵ These are:

• optic neuritis

• sensory or motor disturbance of the limbs

• syndromes referable to the brainstem and cerebellum

• syndromes referable to the brainstem and cerebellum:

• most reports of the initial symptoms are collected retrospectively

• early symptoms may go unrecognized

• medical records may be incomplete

• comparison between studies may be difficult due to differences in selection methods

• diagnostic criteria may vary between studies, e.g. 'possible' cases may or may not be included

• the headings under which particular symptoms are listed may vary between studies.

Recently, Poser has proposed a list of symptoms that is intended to standardize the method of pinpointing clinical onset of MS (only in cases diagnosed as definite or probable MS).⁶ The symptoms that can be regarded as associated with MS onset are divided into two classes, definite and possible.

• Definite symptoms (e.g. unilateral optic/retrobulbar neuritis, transient scanning speech, sensory useless hand syndrome) must last for a minimum of 24 hours.

• Possible symptoms (e.g. unilateral facial palsy, painful tonic seizures, organic erectile dysfunction) can be used as onset markers only if definite symptoms follow within 2 years.

It is difficult to be sure of the frequency of specific symptoms and signs at particular stages of the disease. Certainty could be achieved only by observing the symptoms and signs of MS throughout its entire course in a vast number of clinically definite cases.¹

Nevertheless, a relationship does seem to exist between age at disease onset and the presenting symptoms.⁷ Optic neuritis is characteristic of patients presenting when they are under 30 years of age. Insidious motor symptoms (e.g. chronic progressive myelopathy) are more frequently seen in patients presenting in their thirties and forties.⁷ Such differences in presenting symptoms may reflect the variation in disease form that is apparent in patients with late compared with early MS onset (see later).

The relationship between initial MS symptoms and prognosis

According to the recent literature there is a correlation between the type of symptoms seen at MS onset and the subsequent course of the disease: sensory and visual symptoms at onset having the best prognosis, motor and cerebellar symptoms the worst.^8,9

Symptoms throughout the entire course of MS

As MS progresses, different symptoms and signs appear. These depend mainly on the function of the CNS areas affected by lesions. Common MS symptoms arise from lesions affecting the sensory nerve pathways, optic nerves, and pyramidal tracts (motor nerve pathways).

Sensory symptoms

Sensory symptoms, although seen throughout the course of MS, are especially common at the onset of disease and in early relapse.¹ Often the patient experiences paraesthesiae, or abnormal sensations. These may take the form of 'pins and needles', tingling, or a variety of other strange sensations.

Complete loss of sensation is rare. Usually the patient can feel light touch and pinpricks. but these are perceived to be different from normal in some way.¹

Lhermitte's sign (which is a symptom rather than a sign) is common in MS but can occur in other conditions. Usually, it takes the form of a brief, tingling, electric shock-like sensation that passes down the spine and legs following neck flexion. This symptom seems to result from the combination of a spinal cord lesion and a mechanical factor, probably stretching of the cord.^1,10

Chronic pain is frequently associated with MS. However, the nature of the pain is rarely specified. Often, pain occurs as an indirect result of MS, e.g. pain in the lower back can result from abnormal posture or to osteoporosis due to immobility and/or to frequent treatment with corticosteroids. Dyaesthetic limb pain (abnormal and unpleasant sensation felt when the skin is touched) is common, and may last for years. This symptom may worsen at night, or be aggravated by heat.

Acute pain is less common. It occurs in the eyes (optic neuritis), face (trigeminal neuralgia, or tic douloureux), or as a paroxysmal burning sensation in the limbs.¹

Optic neuritis

Inflammation of the optic nerve, or optic neuritis, is another of the symptoms that occurs with conditions other than MS. An isolated episode of optic neuritis may be due to any one of several diseases, e.g. systemic lupus erythematosus. However, recurrent episodes are almost always due to MS.¹

The visual symptoms of optic neuritis vary from very mild to severe. Typically, it begins with pain when moving the eye, this is followed by a gradual loss of vision. Sight continues to deteriorate for up to a week.¹ The severity of visual loss varies from none to total blindness.¹¹ Examination of the eye often reveals a swollen optic nerve, and visual evoked potentials (VEPs) are often, but not invariably, abnormal (see below).^1,10

Generally, the pain of optic neuritis resolves after a few days, and recovery of vision follows in most patients. Reports vary regarding the mean time to achieve a return to normal vision. In most cases improvement does not continue for more than 3 months, and there is little likelihood of further recovery after 6 months.¹ In some cases, visual acuity remains reduced.

Pyramidal symptoms

Muscle weakness due to pyramidal lesions occurs eventually in almost all MS patients. Although it is usual for both legs to be affected to different degrees, sometimes there is weakness of one leg only, or of one leg and one arm (often on the same side of the body).¹ Frequently, the initial report is of weakness or fatigue on exertion. This gradually increases until weakness is continual. Occasionally, onset of weakness is sudden, causing diagnostic confusion with stroke.¹

Pyramidal lesions are responsible also for spasticity (increased muscle tone), which is a major cause of disability in MS patients. They have difficulty in walking because of the stiffness of their legs.¹ The tone and deep tendon reflexes are increased, the abdominal reflexes are decreased or absent, and the plantar responses are extensor. With ongoing disease the spastic pareses may progress so that the patient needs a stick, a walking frame, or a wheelchair. Flexor spasms can cause pain and considerable distress.¹

Cerebellar symptoms

The earliest sign of cerebellar involvement is unsteadiness in walking. This gait ataxia may become so severe that walking is impossible. Intention tremor of the upper extremities (disclosed upon examination by the 'finger to nose' test) is a very frequent finding and might increase to an involuntary movement of such wide range that use of the arms is difficult. Dysarthria varies from temporary slurring or indistinctness of speech to an explosive form of utterance that may be difficult to understand.

Paroxysmal symptoms

Paroxysmal dysarthria and ataxia may occur. These attacks last about 10 to 20 seconds, and recur many times a day. Tonic seizures are another manifestation of paroxysmal attacks (rapid onset and spread of tonic spasm of one side of the body).¹

Autonomic nervous system disorders

Disruption of bladder function is very common in MS. Symptoms include urgency, hesitancy, excessive frequency of micturition, and incontinence.¹⁰ The degree of bladder disorder is related, in general terms, to the severity of motor and sensory impairment, and overall disability.¹

Bowel disorders are less common than those affecting the bladder. However, constipation can be a problem in many cases of MS.¹ The tendency for patients to limit their fluid intake in an attempt to reduce their urinary problems can exacerbate constipation.¹⁰

Sexual dysfunction is a common problem for MS patients. However, it is often overlooked or under-reported.⁵ Both male and female patients experience difficulties that they may be reluctant to discuss.

In men, the main problem is erectile impotence, but difficulty with ejaculation and orgasm are common also. In women, lack of lubrication and failure of orgasm are common problems. Fatigue, sensory defects and diminished libido contribute to the problem in both sexes.¹⁰ No correlation is apparent between age or duration of disease and sexual difficulties. Instead, sexual dysfunction in MS was strongly correlated with bladder and bowel disorders and a frequent and unexplained complaint of coldness of the legs.¹

Non-specific and mental symptoms

Fatigue is one of the most frequently reported and disabling symptoms of MS.⁵ It may be continuous, or apparent only following exertion. Sometimes it can be difficult to differentiate between fatigue, depression and weakness that occurs as a result of pyramidal symptoms.¹

Cognitive dysfunction, resulting from lesions in the cerebral cortex, involves deficits in many functions. These include memory, ability to sustain concentration, abstract reasoning, and thinking speed. In MS the defects are usually less severe than in other cognitive disorders such as Alzheimer's disease.¹

Among the psychiatric disorders, depression is the most common problem, but anxiety also occurs.^1,5 The association between MS and euphoria (inappropriate cheerfulness), which was sometimes regarded as an early diagnostic sign, is a late phenomenon in advanced disease.

Other clinical features

Brainstem lesions can cause disorders of eye movement, such as nystagmus (jerky, involuntary movements) and diplopia (double vision). A typical finding in MS patients with diplopia is internuclear ophthalmoplegia - a delay or complete loss of adduction on attempted horizontal gaze to one side, accompanied by nystagmus in the abducting eye. Convergence is preserved. More serious brainstem lesions can damage vital cardiorespiratory centres. In exceptional cases, this can cause respiratory difficulties, and may lead to death unless the patient is artificially ventilated.¹

Reversibility of symptoms

Natural remissions, and symptomatic treatments, mean that MS symptoms are not neces sarily permanent. Most are reversible, although the degree of reversibility varies. Some symptoms never disappear completely, but their intensity fluctuates.

Where the data are available, it is possible to estimate the reversibility of particular symptoms. This can be done by comparing the percentage of a cohort of patients who have exhibited a specific symptom earlier in their disease course with the percentage who have that symptom at their latest examination. For example, if 31% of patients have experienced diplopia during the course of their disease, but only 13% have this symptom at the latest examination, then the estimated reversibility of diplopia is 18%.¹²

The ability to predict the potential reversibility of a symptom is of practical importance for:

• assessing a patient's prognosis

• planning long-term management

• assessing the possibilities and limitations of rehabilitation.

All of these are matters of importance to both the physician and the patient.¹²

In addition, an understanding of the relative reversibility and pattern of occurrence of different symptoms in MS, and in diseases that can be confused with MS, can help in differential diagnosis.¹²

Disease course in MS

Despite the variability of the natural course of MS, it is possible to recognize broad categories of disease and to classify MS patients accordingly. From the variety of terms used to describe the different patterns of disease three concepts are particularly useful: relapsing/remitting, chronic progressive, and 'benign' MS.

The terms relapsing/remitting and chronic progressive are defined by the evolution and course of the disease. Either one can be benign or malignant - terms which characterize the prognosis. Hence, the use of the term 'benign' to describe a disease category is controversial.

Relapsing/remitting MS

This form of MS begins with the acute or sub-acute onset of neurological symptoms, from which most patients recover either completely or partially.^1,5 Further attacks (relapses or exacerbations) occur at irregular intervals.

A relapse is the appearance of a new symptom, the reappearance of an old symptom, or worsening of an existing symptom at any time after the initial attack. True relapses last longer than 24 to 48 hours. Recovery from such relapses may be complete, but if it is not the patient's disability will increase over time. Therefore, the category of relapsing/remitting MS includes patients with varying levels of disability.

Reported prevalence rates for this pattern of disease differ from study to study, depending on the precise definition of relapsing/remitting MS used by the investigators. However, Weinshenker et al. provide a useful guide: they found that, in the early phase of the disease, 66% to 85% of their patients had relapsing/ remitting disease (the variation in percentage depends on the population studied).⁷

Chronic progressive MS

There are two forms of chronic progressive MS: primary and secondary. Some patients never improve following disease onset. Instead, disability becomes steadily worse, with no relapses or remissions. This is primary progressive MS. Estimates of its prevalence vary, but most reviewers quote a prevalence of around 10%.^5,13

With time, relapsing/remitting MS usually converts to a disease pattern of gradual accumulation of irreversible disability. This is termed secondary progressive (or relapsing/ progressive) MS.⁵ The proportion of patients developing progressive disease increases with time. Weinshenker et al. found that 41% of relapsing/remitting patients had entered the secondary progressive phase within 6 to 10 years of disease onset.⁷ When examined between 11 and 15 years after onset, 68% of the original population had converted to a progressive course.⁷

Secondary progression proceeds in different ways in different patients. Most commonly, there is a slow, steady deterioration, but sometimes an initial rapid progression is followed by a slower accumulation of disability. Alternatively, disability may remain static for long periods, and several other variations are possible. Whatever the pattern of slow progression, once established, disability infrequently remits.

Some researchers suggest that primary and secondary progressive MS are biologically distinct.⁵ In practice, however, the two may not always be differentiated. Onset of primary progressive MS tends to occur later (around 37 years of age) than relapsing/remitting disease.¹

'Benign' MS

The term 'benign' MS is used to describe a form of MS characterized by either little disability many years after diagnosis, or very slow accumulation of disability over time.¹ In the mildest cases, MS is discovered only at post-mortem examination. However, the definition of 'benign' MS is arbitrary, and there is no compelling reason to think of it as a distinct entity.

Regardless of how 'benign' MS is defined, all studies show that some patients have only slight disability after a long disease duration. Conversely, MS experts recognize that long-standing 'benign' disease can become more aggressive, leading to severe disability.⁷ However, when and if this will happen is not predictable. At 10 years post-diagnosis, one-third of patients have 'benign' disease (little or no disability); this proportion decreases to one-fifth by 20 years.⁵

In summary

The variability of MS makes it very difficult to predict how individual patients will be affected by their disease. There is an imperfect correlation between disease etkinligini and symptoms. The severity of the clinical manifestation of MS is determined by the function of the affected region(s) of the CNS as much as by the size and number of lesions. Particular regions will more readily produce symptoms and signs than others.¹⁴

Case history

The following account describes the progression of a 'typical' case of moderately severe MS. However, it is important to remember that for many patients their experience of MS will differ from the following example.¹⁵

Within a few weeks of an initial attack of sensory disturbance, the patient, perhaps a woman of about 24 years of age, recovers completely. At this stage it is unlikely that a diagnosis has been made.

The disease becomes latent, and there may be an interval of several months to several years before further symptoms develop. These symptoms usually, but not always, differ from those of the initial attack.¹⁵ Once again, recovery is complete.

A further relapse occurs within the next two years. This time the symptoms may include weakness in both legs.¹⁵ Permanent, slightly disabling symptoms persist after this attack (e.g. weakness in one leg when tired, and an inability to run).¹⁵

For a further three or four years, relapses occur at a rate of one every 6 to 24 months. Each time recovery is less complete and the symptoms that remain are more severe. Eventually, there is persistent difficulty in walking, perhaps ataxia, and probably a loss of normal bladder control.¹⁵

Following the active stage of relapse and remission, which lasts for several years, the pattern of disease is likely to change. Acute attacks and spontaneous recovery no longer occur. The severity of symptoms remains static, although there may be some fluctuation from day to day, and during the course of a day. Many patients remain at this stage for many years.¹⁵

In more severe MS, this period of relative stabilitesini eventually gives way to the progressive stage, when disability increases over time until the patient needs constant nursing care. This may continue for many years until complications, such as renal infection or pneumonia, cause death.¹⁵

The outcome of MS

Most patients with MS die from the complications of immobility (such as infection), or from unrelated disease. Although death may, very rarely, occur within 1 to 2 years, the average duration of disease is at least 25 years. One study found that 50% of men with MS survive for more than 35 years after disease onset.^15,16

Diagnostic methods

History

As with any other disease, the first step in the diagnosis of MS is to take a detailed medical history. This should include the mode of onset and course of the present illness, and details of previous illnesses. Note should also be taken of the family history and social and personal history.¹⁷

The patient is the obvious source of this history, but sometimes the evidence of other family members, or of friends, can be valuable in establishing when the first symptoms became apparent. Also, third parties can often bring to notice symptoms that the patient considered unimportant or has forgotten.

When the patient describes neurological symptoms, great care must be taken to ensure that their meaning is clearly understood. It is difficult to communicate the nature of an altered sensation to a listener who has not experienced it. And, although terms like 'pins and needles' are generally understood, the patient may have profound difficulty in describing the more complex sensory disturbances. It is vital that the clinician should exercise patience. He or she should allow time for the patient to elaborate and modify their descriptions until they find the words that are most appropriate.¹⁷ Patients should always be asked directly whether they have (or have had) bladder, bowel and/or sexual disturbances, since many 'forget' to mention these spontaneously.

Clinical examination

The next stage in the diagnosis of MS is a complete clinical examination. This involves a detailed physical and neurological evaluation using the standard methods. Intellectual function, speech, gait, motor power, coordination, reflexes, sensation, function of cranial nerves etc. should all be tested.¹⁸ Based on the functional deficits observed, the clinician may be able to establish which nerve pathways are affected. However, some signs are more difficult to interpret than others and, when considered in isolation, little reliance can be placed on them. Their significance should be re-evaluated as further abnormalities are discovered in the course of the examination.¹⁷

Although the clinical examination often enables lesions of the CNS to be localized with precision, it may not be possible to fulfil the demands of Poser's criteria (see above).³ In such cases, evidence to support the clinical diagnosis, or to aid in differentiation of ambiguous cases, should be sought from paraclinical or laboratory tests.

Paraclinical tests

According to Poser's criteria, paraclinical tests are an extension of the clinical examination.³ These tests are, therefore, accepted as aiding in the definite diagnosis of MS. They are not diagnostic of MS in isolation - they must always be accompanied by evidence of at least one MS attack and one CNS lesion. It should be borne in mind that these criteria were originally proposed to restrict therapeutic trials and research protocols to patients with definite MS (see above).³

Evoked potentials

The measurement of evoked potentials (EPs) provides a non-invasive means of detecting the existence of 'silent' CNS lesions (lesions not apparent on clinical examination).¹

EP techniques measure the electrical etkinligini that takes place in specific CNS pathways in response to sensory stimuli. Electrical etkinligini is measured via electrodes attached to the skin. In areas of demyelination, conduction may be markedly delayed, even where no neurological deficit is apparent. Such delays are detected by comparison with normal control data.¹⁹

In MS diagnosis, the most widely used, and clinically useful, tests are the visual (VEP), somatosensory (SSEP), and brain stem auditory (BAEP) evoked potentials. However, abnormal evoked potentials are not specific to MS; they must be interpreted in relation to the overall clinical picture.¹⁹

VEPs measure conduction through the visual pathways. An array of scalp electrodes placed over the occipital region of the skull record the signals evoked in response to a visual stimulus. The most widely used stimulus is a television-generated checkerboard pattern that reverses at regular intervals. The dominant response from a normal eye is a positive wave with a peak at about 100-110 milliseconds. Lesions of the retina, optic nerve, optic chiasm, optic tract, optic radiation or occipital cortex may all disrupt or delay the response. Demyelinating lesions of the optic nerve often cause marked delay (>110 milliseconds) with relatively good preservation of the wave form. Therefore, such a finding in a patient with clinically normal vision can help in the diagnosis of MS. Abnormal VEPs have been recorded in 75-97% of patients with clinically definite MS.¹

SSEPs measure the sensory reaction of the body to touch. They are recorded over the parietal cortex in response to electrical stimulation of a peripheral nerve (e.g. the median nerve). Additional electrodes sited at various points along the sensory pathway record the ascending etkinligini. The conduction time between any two sites can be found by subtracting the latencies between the peaks recorded from these sites. Patients with MS often display SSEP abnormalities, including loss of etkinligini, prolonged latency of components of the response and prolonged interpeak latencies.¹⁹ In various studies, up to 96% of patients with clinically definite MS have been found to have abnormal SSEPs.¹

BAEPs measure conduction through the auditory pathways in the VIII nerve and nucleus, and in the pons and midbrain. Electrical etkinligini evoked in the first 10 milliseconds following a 'click' stimulus produces a multi-wave pattern related to conduction through this pathway. Disruption or delays in response may provide evidence of acoustic nerve or brain stem disorders. Mean BAEP abnormality rates of 67%, 41%, and 30% have been recorded for patients with clinically definite, probable, or possible MS, respectively.¹⁹ The proportion of EP abnormalities found in definite cases of MS is sufficiently high to warrant the use of the technique in patients in whom the diagnosis is in doubt.

Motor EPs have been introduced in the diagnostic process of MS lately. They indicate an involvement of pyramidal pathways. In respect to diagnosis, they are helpful only in patients without clinical evidence of disturbed pyramidal function or in patients with equivocal motor signs.²⁰

In many specialist neurology departments, modern CSF and MRI studies have replaced the use of EPs in the diagnosis of MS. However, these sophisticated techniques are neither universally available nor infallible.¹ Hence, the simpler, and non-invasive, EP tests may still have a role to play.

MRI

MRI is the first imaging technique that allows the visualization of MS plaques in the CNS. It is a highly sensitive technique: 90-97% of clinically definite MS patients have positive brain scans.²¹ It is possible, when using MRI in conjunction with the contrast agent gadolinium (Gd-DTPA, Magnevist^®), to detect brain lesions at a very early inflammatory stage.²¹ MRI can detect spinal cord lesions also, although the resolution is not yet optimal and the technique cannot be used in patients with metallic implants (e.g. those with cardiac pacemakers).^19,22,23

(See the later section on Disease Monitoring for a fuller explanation of MRI.)

MRI can often, but not always, identify the lesions responsible for particular clinical symptoms in MS patients. In addition, serial MRI scans detect the appearance, evolution and, sometimes, resolution of both symptomatic and asymptomatic lesions. Serial scans show that MS lesions may appear and disappear five to ten times more frequently than recognized clinical relapses.²⁴

The primary role of MRI in MS diagnosis is to confirm the presence of multiple white matter lesions. It provides evidence of the dissemination of lesions in space (i.e. in different parts of the CNS), thus satisfying Poser's diagnostic criteria.²⁵ In patients who have experienced two or more documented attacks but with clinical evidence of only one CNS lesion, MRI evidence of multiple lesions characteristic of MS makes possible a clinically definite (CDMS) diagnosis.²⁵ Abnormal MRI findings can permit a more certain diagnosis of clinically probable MS (CPMS) or laboratory-supported definite MS (LSDMS) to be made, but are not in themselves diagnostic.²⁵

Several attempts have been made to formulate criteria to be applied when assessing MRI scans in support of MS diagnosis.²⁴ Among the most widely applied of these are those of Paty et al., according to which an MRI scan is strongly suggestive of MS (in patients <40 year of age) if:

• > four lesions are present (at least 3 mm in diameter), or

• > three lesions are present, one of which is periventricular.²⁶

A follow-up study that applied these criteria showed a sensitivity of 94%, but diagnostic specificity was lower (57%).²⁷

In patients of 50 years of age or older vascular events produce lesions indistinguishable from those of MS. In an attempt to eliminate this problem, Fazekas et al. developed criteria that improved diagnostic specificity in such patients. They proposed that an MRI scan is strongly suggestive of MS when any two of the following are present:

• a lesion >6 mm in diameter

• a lesion abutting the bodies of the lateral ventricles (i.e. giving a 'lumpy-bumpy' ventricular interface)

• an infratentorial lesion.²⁸

When tested retrospectively, the apparent specificity of these criteria was 96% and the sensitivity 88% in patients with clinically definite or probable MS.²⁹ However, no consensus has yet been reached on the criteria to be applied when assessing MRI scans in MS diagnosis.²⁴

Laboratory tests

Despite clinical examination and the use of paraclinical tests, the diagnosis of MS may remain uncertain. In such cases laboratory tests may provide additional evidence to support the diagnosis.

CSF studies

CSF and MRI tests are complementary. Although MRI allows visualization of white matter lesions and their dissemination in space, these abnormalities can be caused by a variety of pathological processes. CSF analysis can provide evidence that the disease process is inflammatory in nature and involves the CNS. However, no CSF abnormalities are specific for MS.³⁰

The basic CSF tests used to support, or to reject, a diagnosis of MS are:

• determination of the immunoglobulin G (IgG) levels in the serum and CSF

• determination of antibodies against measles, rubella, and zoster viruses in the serum and CSF

• comparison of the IgG profile in the serum and CSF, detection of oligoclonal bands

• determination of total protein and albumin concentrations in the serum and CSF

• determination of the CSF cell count.

IgG synthesis in the CSF - selective increase in IgG levels due to synthesis within the CNS-CSF compartment is the most characteristic abnormality in MS patients.³⁰ The IgG index (CSF IgG/serum IgG: CSF albumin/serum albumin), which compensates for the influence of serum levels of IgG and albumin, provides a simple and widely used method of measuring intrathecal IgG synthesis. In more than 80% of clinically definite cases of MS the IgG index exceeds 0.7.^19,31 Corticosteroids induce a reduction in the levels of CSF IgG, however they have no effect on oligoclonal bands.³²

Virus-specific antibodies - Intrathecal synthesis of antibodies against a variety of antigens occurs in MS. For diagnostic purposes tests for the presence of antibodies against measles, rubella, and zoster viruses are most helpful.³³

IgG profile - In 95% of patients with clinically definite MS, oligoclonal IgG bands are present in the CSF but not in the serum.³⁴ The most sensitive method of comparing the IgG profiles of CSF and serum is an electrophoretic technique, known as isoelectric focusing. This technique separates proteins on the basis of ionic charge alone. Once separated, special staining techniques allow the protein bands to be visualized and compared.³⁵

Positive CSF samples contain two or more IgG-specific bands that are not seen in the serum.¹⁹ However, this result is not specific to MS; similar results can be found in a variety of inflammatory neurological disorders.¹⁹

CSF and serum albumin concentrations - The most effective method for detection of blood-CSF barrier dysfunction is the albumin quotient (CSF albumin/serum albumin).³⁵ CSF albumin is derived from the serum, and not synthesized in the CNS/CSF compartment. An increased albumin quotient indicates a blood-CSF barrier dysfunction, a finding that is rare in MS (less than 20% of clinically definite MS patients have a slightly elevated albumin quotient).

More severe barrier dysfunctions with quotients >20 x 10-3 may suggest that alternative diagnoses should be considered. Hence the greatest value of the albumin quotient is in helping to exclude a diagnosis of MS.

CSF white cell count - Approximately 50% of patients with clinically definite MS have a higher than normal CSF white cell count. Normal values are <4 white cells/mm³; in MS patients the cell count usually falls within the range 5-35 cells/mm³. Counts of 35-50 cells/mm³ are rare and may cast doubt on a diagnosis of MS.³⁵

In summary

Each of the tests discussed here has its strengths and weaknesses. However, it must be emphasized that none is diagnostic for MS. Currently, a definite diagnosis relies on clinical evidence plus accumulated data, and (perhaps most importantly) sound clinical judgement and experience. Paraclinical and laboratory tests are aids to diagnosis only - each must be carefully controlled and needs expert interpretation.

Differential diagnosis

Numerous conditions can produce symptoms and signs, and follow a course, that can be mistaken for MS. Although most of these can be eliminated during the normal diagnostic procedure, some conditions may mimic MS so closely that they satisfy the diagnostic criteria.³⁶ Therefore, even an apparently established diagnosis of MS should not blind the investigator to other possibilities. It must always be borne in mind that the exclusion of other conditions that produce a similar clinical picture is one of the essential diagnostic criteria for MS.^2,3

Why is differential diagnosis important?

Misdiagnosis in MS falls into two categories: diagnosis of another disease process as MS, and diagnosis of MS as another condition.³⁷ The rate of misdiagnosis in patients referred to MS clinics is approximately 10% - indicating that about one in every ten patients thought to have MS in reality has a condition that resembles MS.³⁸ Similarly, a proportion of patients who do have MS are diagnosed as suffering from other conditions.

It is important for both the physician and the patient that misdiagnosis is minimized, since it is only when a correct diagnosis is achieved that:

• the physician can make appropriate patient management decisions, and

• the patient can be offered appropriate advice, which for patients with some of the conditions mistaken for MS, may mean the possibility of definitive therapy.³⁷

Correct diagnosis is important also to avoid the inclusion of non-MS patients in epidemiological studies and in clinical trials, as this could confuse research findings.

Reasons for misdiagnosis

The reasons for misdiagnosis in MS have changed dramatically since the introduction of MRI, but the overall percentage of misdiagnosis remains around 10%. In the past, tumours were the major source of misdiagnosis, a problem that has been largely eliminated by advances in imaging techniques. Currently, the most common cause of misdiagnosis appears to be overinterpretation of, and over reliance on, MRI.³⁷

It seems that patients are being referred to MS clinics or to a neurologist as already diagnosed cases of MS - just because they complain of tingling and a radiologist has found some 'white spots' on MRI..³⁷

"Nothing shuts off critical neurological thought processes faster than a diagnosis of multiple sclerosis" (RM Herndon. Neurology grand rounds, Johns Hopkins Hospital, 1974).³⁸

Once patients are referred on this basis, the diagnosis may be accepted and alternative diagnoses may be overlooked.³⁸ Subsequently, features of the patients' condition that are atypical for MS may be accepted as examples of the wide spectrum of manifestations of the disease.

When is differential diagnosis necessary?

When is differential diagnosis necessary.^37,38

These features are:

• absence of objective neurological deficits in patients who are referred with vague complaints of fatigue and weakness, but no verifiable neurological deficit;

• absence of objective evidence for dissemination of lesions in time or space - additional evidence may be found later, but until then the diagnosis remains in doubt;

• strongly positive family history of MS - especially if the course is of progressive spinal or spinocerebellar disease (this can lead to the assumption that the patient has MS when they have another condition);

• progressive disease from the outset in patients <35 years old - such a disease course is unusual in young MS patients;

• absence of eye involvement and normal VEPs - visual disturbance and disorders of eye movement are so frequent in MS that their absence should cast doubt on a diagnosis of MS;

• localized disease - dissemination within the CNS is the rule in MS. Lack of evidence of dissemination raises suspicion of localized structural abnormality;

• absence of CSF abnormalities - as the majority of MS patients display CSF abnormalities, their permanent lack suggests that the diagnosis needs re-evaluation;

• pain as the predominant symptom - MS is not a painless disease but pain is rarely the predominant symptom in the absence of other typical MS findings.

The presence of any of the above features would be considered atypical of MS and should signal the need for differential diagnosis.

Similarly, certain symptoms are atypical for MS and their presence suggests that an alternative diagnosis is likely.¹ Back pain and areflexia are two such symptoms.

• Back pain, particularly if this involves the cervical and thoracic regions, is unusual in MS.

• Areflexia (absence of the ankle jerk reflex) and flaccid pareses as presenting symptoms suggest that the patient is unlikely to have MS. The ankle jerk reflex is affected only in the later stages of MS (due to spasticity).

However, it must be remembered that some patients with MS may have a co-existing disease, and this could confuse the clinical picture.¹

As well as allowing the visualization of lesions in the CNS, the development of MRI has brought new problems to the diagnosis of MS. Early MS lesions may have the appearance of space occupying lesions on MRI scans and be mistaken for tumours, as may the ring enhancing lesions sometimes seen on Gd-DTPA enhanced MRI scans.³⁷

Conditions that can be mistaken for MS

Many disorders can produce a multifocal CNS syndrome with a relapsing/remitting course in young adults.³⁹ Conditions more commonly confused with MS, and therefore early candidates for differential diagnosis, include autoimmune disorders such as

• systemic lupus erythematosus

• primary Sjögren's syndrome

• Behçet's disease

• polyarteritis nodosa

• acute disseminated encephalomyelitis,

as well as infectious diseases:

• Lyme disease

• syphilis

• AIDS;

and a variety of other disorders, for example:

• adult onset leucodystrophy (adrenomyeloneuropathy)

• mitochondrial encephalopathy

• Arnold-Chiari malformation

• olivopontocerebellar atrophy

• cardiac embolic event.

Some conditions are less similar to MS, but still require investigation. These include granulomatous disorders such as:

• sarcoidosis

• Wegener's granulomatosis;

isolated spinal cord syndromes, like:

• compressive lesions, either intrinsic or extrinsic

• vitamin B12 deficiency

• HTLV-1 infection;

and also:

• Leber's optic atrophy

• intracranial tumour.⁵

Several of the above diseases, as well as a number of others (e.g. viral encephalitis, Guillian-Barré syndrome), produce CSF oligoclonal bands. MRI findings can add to the confusion also, since many diseases exhibit 'typical' MS lesions on MRI. MS variants such as Devic type MS (neuromyelitis optica, which is more common in people of Japanese origin) and Schilder type MS (diffuse cerebral sclerosis, generally occurring in patients <35 years and with a progressive, spinal disease course from the outset) can also be diagnosed as 'classical' MS.^1,40

How is differential diagnosis achieved?

Laboratory tests

Many misdiagnoses made on the basis of MRI alone can be resolved by applying the standard range of tests: CSF, EPs, and further MRI scans. In cases where doubt remains differential diagnosis should be carried out. Differential diagnosis involves working through a series of tests specific for particular conditions that can be mistaken for MS. And, since some conditions are more often misdiagnosed as MS than others, it is logical to investigate these before the less common conditions.

There are many differential tests that can help to distinguish between MS and other diseases.¹ These include:

• Detailed family history - with medical findings in other family members with MS.

• Measurement of antibodies to the bacteria Borrelia burgdorferi and Treponema pallidum - the organisms that, respectively, cause Lyme disease and syphilis. Both of which are diseases that, once diagnosed, can be treated with antibiotics.

• Tests for HIV antibodies in serum - which could indicate that the patient has developed AIDS.

• Estimation of very long chain fatty acids in the plasma - their presence establishes the diagnosis of adrenomyelo-neuropathy.

Diagnosis and the patient

Achieving a diagnosis is only the beginning of a new set of problems for physicians. Afterwards they must address a complex dilemma - when and how much to tell their patients. Their decisions can have far-reaching effects for their patients. This is especially true now, as the first opportunities arise for more than purely symptomatic treatments.^41,42

For patients, diagnosis means the beginning of a new life - one in which they have a name for, and must come to terms with, their disease and all it entails. To some extent every aspect of their lives will be affected. And the way in which the diagnosis is revealed to them can have a profound influence on how they cope with the future.

When should the patient be told?

In the past patients were often kept in ignorance of their diagnosis. Sometimes this decision was made by the physicians and sometimes by the patients' families. Generally, the basis of the decision was a desire to protect the patient. But the question remains: had they a right to make that decision?

Evidence from studies in which patients' opinions were canvassed suggest that most patients prefer to know their diagnosis.^43,44,45 However, it is also clear that they want, perhaps more than anything else, an end to uncertainty about their diagnosis and their future. The realization that patients want to be informed leads to a completely new set of problems:

• How definite must the diagnosis be before the patient is told?

• What is the effect of delaying the diagnosis?

If patients think they are being deliberately kept in ignorance they may lose trust in their physicians, which could cause permanent damage to the doctor-patient relationship.

Whatever the decision, it should be borne in mind that many patients discover the diagnosis for themselves. Whether they find out by accident (maybe by overhearing a discussion of their case) or by design (perhaps by reading notes left out by their physician) they are likely to feel let down. Furthermore, a valuable opportunity to discuss both their condition and their future will be lost.

Who should tell the patient?

Patients need to be given the best information and advice that is available. Therefore, the neurologist who made the diagnosis is probably the best person to tell the patient.⁴⁴ Generally, the neurologist will be experienced in giving MS diagnoses, and he or she will be able to adapt their approach to suit the reaction of the individual patient. When and if it is appropriate, the patient's family (and/or friends) should be told of the diagnosis also.

How should the patient be told?

Patients want to be able to give their disease a name.⁴³ Not knowing, or being denied information, increases the patients' sense of frustration.⁴⁶ Patients prefer to be given the diagnosis in as straightforward and informative a manner as possible, and often experience a sense of relief that speculation is at an end.⁴³

Giving the diagnosis in a sympathetic, tactful, considerate, and positive way can help patients to take a positive attitude to their future. Also, if they have a good understanding of what to expect, they can begin to accept their disease. Acceptance is the key to adapting to this new phase of their lives. Gradually they can begin to look forward instead of back.

The importance of counselling the patient

Even when patients express relief at being told their diagnosis, it can still be a shock. They need to be given the time to assimilate all the new information, and to ask the multitude of questions that will begin to occur to them. Many patients react to their diagnosis with grief. They may go through a period of mourning before they can come to terms with the loss of their previous life, and maybe of their expectations.

At this time, counselling is vital to MS patients. Initially this should come from those most closely involved in their diagnosis. Input from other MS patients and MS societies is important too, but only when the time is right for the individual. If it comes too soon, the patient may be resentful, regarding it as an intrusion: alternatively, they may become upset by meeting patients with very advanced disease. Counselling will be better accepted when the patient has accepted their diagnosis.⁴⁶

Disease markers: the future of diagnosis

There are numerous tests that can help in the diagnosis of MS, but still there is no test that is specific for the disease. However, research is continuing and hope remains that the development of a truly diagnostic test may eventually prove possible.

Currently, several research groups are searching for disease markers for MS. Since MS is almost universally accepted to be an autoimmune disease, components of the immune system are the focus of investigations.

The aim is to identify markers that are specific for MS, and most of the candidate molecules relate to disease etkinligini. However, even the identification of non-specific markers of MS etkinligini may contribute to a better understanding of the disease processes. This may indirectly aid the search for a disease marker.

Potential disease markers

The growing knowledge of the immunological processes and pathology of MS has directed the search for disease markers into areas of particular interest. These include:

• Cytotoxic T-cell subsets found in the region of active chronic MS lesions.⁴⁷

• T-cells specific for myelin basic protein (MBP) found in the blood and CSF of MS patients.

• Soluble adhesion molecules (e.g. vascular cell adhesion molecule 1, VCAM-1; and intercellular adhesion molecule 1, ICAM-1), which possibly interact with activated T-cells as they cross the blood-brain barrier.⁴⁸

• Cytokines, inflammatory and anti-inflammatory mediators, which are potential indicators of disease etkinligini.^49,50

In summary

Although advances are being made, the search continues for a marker that will enable MS to be diagnosed unequivocally, and preferably early in its course. Already the signs are encouraging, especially in the identification of molecules that will help in monitoring disease progression.

Bu sayfadaki bilginin en son güncellendiği/doğrulandığı tarih:

11/09/2001

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