The diagnosis of MS. - Free Online Library (2024)

Making the Diagnosis

Multiple sclerosis (MS) is traditionally a clinical diagnosis:evidence of at least two demyelinating lesions presenting as distinctevents affecting different areas of the central nervous system('separation in time and space'). It can be difficult todiagnose in the early stages: when the patient presents after a firstsolitary episode, could this be a one-off event, or the first which hasyet to be separated in time from another? How much reliance can beplaced on a history from the patient compatible with a previous event?What if this were literally decades ago with no intervening symptoms?Over time criteria have been devised, aiming to facilitate an early andaccurate diagnosis.

The Evolution of Diagnostic Criteria for MS

The lack of a specific diagnostic test for MS has frustratedneurologists since Charcot described the disease 140 years ago. (1)Although Charcot documented his classical 'triad' (dysarthria,ataxia and tremor), this disease was defined, and immortalized in name,by the post-mortem findings of multiple sclerose en plaques. The firstformal diagnostic criteria were set out 100 years later, by Schumacher,in 1965. (2) Diagnostic limitations meant that these were clinicalcriteria: the identification of separation in time and space ofneurological events through history-taking and/or objective neurologicalexamination. The next 20 years saw the development of paraclinical investigations (specifically cerebrospinal fluid [CSF] analysis andmagnetic resonance imaging [MRI]) which, whilst not providing theelusive diagnostic test, did allow some corroboration of the traditionalclinical diagnosis. In 1983 the Poser criteria (3) incorporated theseadvances and, though primarily intended for use in clinical trials,began to be used for diagnostic purposes.

In 2000 the International Panel on the Diagnosis of MultipleSclerosis met to review the Poser criteria. New criteria, named afterthe Chair, WI McDonald, were proposed which, whilst respecting thetime-honoured principle that MS is a clinical diagnosis, incorporatedthe growing importance of MRI. (4) A second attack in time or spacecould, it was proposed, be determined by appearances of new lesions onMRI, thus allowing earlier and possibly more accurate diagnosis, in turnfacilitating the initiation of treatments potentially more efficaciouswhen administered earlier in the disease process.

Common Clinical Presentations of MS

MS still remains predominantly a clinical diagnosis. The classicalpatient is a female (twice as often affected as males) in her third orfourth decade. (6) Attacks have been defined as 'neurologicaldisturbances of the kind seen in MS' (perhaps an unhelpful turn ofphrase but see below), subjectively reported or objectively observed,lasting a minimum of 24 h; and excluding so-called pseudoattacks andsingle paroxysmal episodes. (5) There must be a stipulated 30 daysbetween the onset of Event 1 and Event 2 for them to be regarded as'separated in time'. (5) Attacks are further typical of MS ifthe duration of deficit is days to weeks before they gradually abate.

Box 1. The revised McDonald criteria, 2005 (5)Clinical presentation Additional data for MS diagnosisTwo or more attacks; objective Noneclinical evidence of two or morelesionsTwo or more attacks; objective Dissemination in space,clinical evidence of one lesion demonstrated by: * MRI or * Two or more MRI-detected lesions consistent with MS plus positive CSF or * Await further clinical attack implicating a different siteOne attack; objective clinical Dissemination in time,evidence of two or more lesions demonstrated by: * MRI or * Second clinical attackOne attack; objective clinical Dissemination in space,evidence of one lesion demonstrated by:(monosymptomatic presentation;clinically isolated syndrome) * MRI or * Two or more MRI-detected lesions consistent with MS plus positive CSF and Dissemination in time, demonstrated by: * MRI or * Second clinical attackInsidious neurological progression One year of disease progressionsuggestive of MS (retrospectively or prospectively determined) and Two of the following: a. Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP) b. Positive spinal cord MRI (two focal T2 lesions) c. Positive CSF

Sensory Disturbances

Often the earliest symptoms, these are the presenting feature in21-55% of patients with MS. (7) They can be difficult to assess as theymay not respect usual anatomical boundaries and are often not associatedwith objective signs on examination. Classical sensory disturbancesinclude Lhermitte's symptom (an 'electric shock'sensation triggered by flexing the neck) and Uthoff's phenomenon(worsening of neurological symptoms with increased body temperature).

Optic Neuritis

Acute optic nerve inflammation typically presents with suddenmonocular visual loss and eye pain. (8) It is a common presentingsymptom, the initial experience of 14-23% of MS patients. (7) The OpticNeuritis Study Group recently published data on the 15-year follow-up of389 patients who presented with acute optic neuritis: (8) the presenceof brain MRI abnormalities at the time of an optic neuritis attack was astrong predictor of the 15-year risk of MS, conversely the absence ofsuch lesions was associated with a low likelihood of developing MS. (8)

Motor Abnormalities

Corticospinal tract involvement occurs with initial attack in32-41% patients. (7) Ataxia is present at onset in 11% of patients, andis experienced by 82% at some point during the course of the disease.(9) Spasms, paroxysmal motor symptoms and the upper motor neuronesyndrome are other common motor presentations of MS.

Diplopia

Inter-nuclear ophthalmoplegia may cause horizontal diplopia.Oscillopsia can occur with ataxic nystagmus; more rarely there arenuclear or infranuclear III, IV or VI nerve palsies and gaze palsies.

Others

Trigeminal neuralgia, brainstem and sphincter dysfunction are rarerpresenting features of MS.

MRI Findings

Charcot's sclerose en plaques are visible on MRI ashyper-intense T2 lesions with a characteristic distribution in the cord,corpus callosum and juxtacortical region. McDonald's criteriaspecify gadolinium (Gd)-enhanced MRI which highlights activeinflammatory lesions in the central nervous system (CNS), allowing earlyidentification of new lesions.

Whilst more than 95% of MS patients have MRI lesions atpresentation, (6) this does mean that 5% have a normal scan. Thus a'negative' result does not rule out MS: the National Institutefor Health and Clinical Excellence (NICE) guidelines stress that thediagnosis of MS is clinical and that MRI should not be used in isolationfor diagnosis. (10) The major practical use of MRI is thus toinvestigate individuals with clinically isolated lesions or progressivedisease at a single site (6)--and, of course, to help exclude otherdisorders.

Box 2. Definition of a positive MRI5* One Gd-enhancing brain or cord lesion or 9 T2hyperintense brain and/or cord lesions if there is noGd-enhancing lesion* One or more brain infratentorial or cord lesion* One or more juxtacortical lesion* Three or more periventricular lesions* A Gd-enhancing lesion detected in a scan done atleast 3 months after onset of initial clinical event at asite different from the initial event or a new T2 lesiondetected in a scan done at any time compared witha reference scan done at least 30 days after initialclinical event.

Other Investigations CSF Analysis

A positive result demonstrates oligoclonal IgG bands in CSF (andnot serum) or elevated IgG index. (5)

Neurophysiological Measurements

Evoked potentials support the diagnosis: (5) demyelination delaysthe latencies of visual, auditory and somatosensory evoked potentials,as well as central motor conduction times; (6) wave form is wellpreserved.

Summary of Diagnostic Procedures

Diagnostic criteria may assist uniformity in the diagnosis of earlyMS, but whether they have been widely adopted outside clinical trials,or have had any clinical impact in reducing the misdiagnosis of MS, hasnot been studied. NICE recommends formal documentation of the supportingevidence and its degree of certainty, allowing the diagnosis to becritically reviewed and reinvestigated if appropriate. (10)

Differential Diagnoses

The list of disorders which can mimic MS is extensive, and anunexpected symptom or sign, raised erythrocyte sedimentation rate (ESR)', or atypical MRI can raise suspicions. (11)

Syndromes of Non-disseminated Demyelination

A number of disorders are clearly related to MS, but neverthelessremain distinct. The underlying pathogenic processes may appearidentical, but ultimately fail to manifest with dissemination in time orspace. Whether these disorders signal the onset of MS is often foremostin the minds of both the informed patient, and their clinician.

Optic Neuritis

50% of those presenting with optic neuritis (ON) develop adiagnosis of MS during the subsequent 15 years.8 Bilateral simultaneousor rapidly sequential ON should activate a search for an alternativediagnosis: Leber's hereditary optic neuropathy (typically severe,and usually permanent, in young men), toxins (tobacco and methanol);[B.sub.12] deficiency; other inflammatory disorders (sarcoidosis,vasculitis and lupus); infections; ischaemia (usually abrupt onset,painless, horizontal altitudinal field defect); and optic nerve,chiasmal or other local tumours.

Transverse Myelitis

'Idiopathic' transverse myelitis usually affects thethoracic cord. Rapidly progressing paralysis, sensory loss andincontinence, suggest involvement of the whole transverse extent of thecord compared with the more typical partial cord lesions seen in MS.Primary causes to be considered include post-infection (varicella,Epstein-Barr virus [EBV], mycoplasma, herpes zoster), post-vaccination(e.g. influenza) and systemic inflammatory disorders (sarcoidosis, SLE,Sjogren's syndrome, antiphospholipid syndrome, giant cellarteritis). (12) CSF analysis may reveal moderate pleocytosis and araised protein level, but only a minority have positive oligoclonalbands. (11)

Devic's Disease or Neuromyelitis Optica

Devic's syndrome refers to acute or sub-acute ON associatedwith a severe transverse myelitis. (13) It can occur in at least threeseparate contexts: in MS, if spinal cord and optic nerve diseasedominate the clinical picture; in other systemic inflammatory disorders,(SLE, sarcoidosis and Behcet's Disease); and in those with noclinical or paraclinical evidence of disease elsewhere in the CNS, inwhom other systemic or vasculitic disorders have been excluded. The termDevic's disease should be reserved for the latter. Oligoclonalbands are usually absent and brain MRI is normal in 50%. (14) Diagnosisincreasingly relies on the presence of serum anti-aquaporin-4 IgGantibodies. (15)

Diffuse or Disseminated Syndromes

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) occurs predominantly inchildren and young adults, and carries significant morbidity andmortality. Common precipitants include viral exanthemata andvaccination, but in some no prior immunological challenge isidentifiable. A prodrome of fever, myalgia and malaise is followed by anacutely progressing meningitic and enchephalomyelitic syndromesuggestive of severe simultaneous or rapidly sequential multifocal CNSdisease. Similarities in CSF and MRI findings make distinction from MSdifficult, although, if present, oligoclonal bands rarely persist, andMRI lesions are often more extensive and symmetrical. (16) Rarely, ADEMrelapses persistently, making the distinction from MS very difficult.

Apparent Variants of MS

These disorders are now considered clinicopathological variants ofMS. Marburg Disease essentially represents an aggressive course of MS,often leading to death in weeks to months. Schilder's diffusesclerosis usually begins in childhood. A progressive course withintermittent accelerated activity in which cortical features (dementia,hemiplegia, cortical blindness and deafness) predominate, may lead toconfusion with intracranial neoplasm or abscess. Balo's concentricsclerosis is characterized pathologically by alternating concentricrings of demyelination and apparently normal myelin. Several theorieshave been proposed to explain this unusual architecture. (17)

Primary Progressive MS

The clinical picture of primary progressive multiple sclerosis(PPMS) is not particularly distinctive, and alternative diagnoses arewisely sought. Progressive paraparesis should always trigger brain andcord MRI, which will exclude many (surgically relevant) causes.[B.sub.12] deficiency can cause similar clinical and MRI findings, inaddition, [B.sub.12] levels can be low in patients with MS, thusmonitoring of [B.sub.12] levels is advised. (18)

Inherited Disorders

Adrenoleukodystrophy and metachromatic leukodystrophy can resembleprogressive MS. A family history, abdominal symptoms, Addisonianfeatures and absent oligoclonal bands should prompt testing for verylong chain fatty acids and/or leukocyte enzyme abnormalities. (11)Mitochondrial disease has a heterogeneous clinical phenotype whichincludes a relapsing-remitting multifocal neurological picture.Oligoclonal bands are mostly negative.

Infectious Diseases

Neurological sequelae of Borreliosis (Lyme disease) includemyelitis, cerebellar ataxia and recurrent cranial neuropathies. MRI canshow multifocal white matter lesions, and CSF can contain oligoclonalbands. Diagnosis, however, relies on a combination of history(characteristic skin rash), examination and antibody studies of serumand CSF. (19) Neurosyphilis is increasing in frequency but rarely causesa picture easily confused with MS, particularly in the MRI era.HTLV-related myelopathy (tropical spastic paraparesis) can cause similarbrain MRI changes and oligoclonal bands are common: HTLV serology shouldtherefore be considered. (11)

Unrelated Inflammatory Disorders

These disorders can provoke neurological events similar to MS.Distinctive treatment strategies demand their identification. Inisolation, neither history, examination, CSF analysis nor MRIconfidently discriminate; however, taken together, a diagnosis isusually possible.

Cerebral Vasculitis

This rare and serious disorder continues to present significantdiagnostic and therapeutic challenges. (20) Three broad clinicalphenotypes have been proposed for both isolated CNS vasculitis and CNSinvolvement in systemic vasculitis: (21) (i) 'MS-plus' with arelapsing-remitting course and events such as optic neuropathy and brainstem episodes; (ii) acute or sub-acute encephalopathy; and (iii) masslesion. Once suspected, diagnosis can be difficult: serologicalbiomarkers are commonly negative, and CSF analysis, though oftenabnormal, lacks specificity. Contrast angiography (revealing segmentalnarrowing and localized dilatation which, although not specific tovasculitis, are not seen in MS) and biopsy are often required. Thedistinction is important: the use of cyclophosphamide, with steroids,improves outcome.

Systemic Lupus Erythematosus

Neurological involvement is seen in 50% of cases, and can beserious: second only to renal disease as a cause of death. (22)Neurological presentation is seen in around 3% cases. (22) A variety ofCNS complications can occur (headache, epilepsy, ischaemic events,encephalopathy, meningitis), some similar to MS (myelopathy and opticneuropathy). A persistently raised ESR should not be ignored. CSFanalysis may reveal raised protein, pleocytosis and positive oligoclonalbands in around 50%, although like sarcoidosis and vasculitis, butunlike MS, these may resolve with successful immunotherapy. (11)

Sjogren's Syndrome

CNS complications include an MS-like picture (optic neuropathy,cerebellar ataxia, internuclear ophthalmoplegia). To help distinguishfrom MS, systemic symptoms such as dry mouth and eyes should be sought.Peripheral features (neuropathy or myositis), and CNS disturbances(seizures, stroke-like events, encephalopathy with or without an asepticmeningitis, and/or psychiatric abnormalities) help point away from MS.(11)

Neurosarcoidosis (Besnier-Boeck-Schaumann Disease)

Sarcoidosis affects the nervous system in around 5%; (23) isolatedneurosarcoidosis is rare. Cranial nerve involvement is most common. (23)Unlike MS, optic nerve disease follows a progressive course and haspersistent steroid sensitivity.11 Cognitive and neuropsychiatricabnormalities, and peripheral nervous system involvement also contrastwith MS. Serum and CSF ACE levels may be elevated, but are not specific,nor are raised protein and/or cell counts in the CSF. (23) Oligoclonalbands may be present, but their presence varies when serially assessed.Cranial MRI may show multiple white matter lesions and/orlepto-meningeal enhancement. Diagnosis may further rely on biopsy,ophthalmological examination, chest X-ray, bronchial lavage. (23)

Behcet's Disease

Behcet's disease is a chronic, relapsing, multi-system,inflammatory disorder. Around 5% develop neurological complications;most commonly affecting the 'parenchyma' with hemisphere,brainstem and spinal cord pathology. (24) Oligoclonal bands are uncommonand MRI abnormalities are non-specific. Brain biopsy may be required.

Whipple's Disease

Ten per cent have neurological involvement; in 5% the disease maybe confined to the nervous system. (25) Imaging and CSF analysis arenon-specific. PCR against Tropheryma whippelii has facilitated diagnosisin recent years. Neurological disease may be reversible if treatedpromptly; but rapidly fatal if not.

Vascular Disease

Arteriovenous malformations, once classic confounding sources ofrelapsing remitting single-sited syndromes, no longer are with theadvent of MRI. Endocarditis and atrial myxoma can cause a multifocalpicture, but the context should raise suspicions.

Malignancy

Paraneoplastic leukocytoclastic vasculitis, lymphomatoidgranulomatosis and neoplastic angioendotheliosis, can all resemble MS,but are usually accompanied by systemic features such as low-grade orundulating fever, weight loss and pruritis. Several CNS malignancies(meningiomata, epidermoid cysts and foramen magnum tumours) havereputations as mimics of MS, but MRI now identifies most of these.Multifocal glioma is one of the few primary CNS malignancies that canevade MRI diagnosis. (11)

Giving the Diagnosis

In reality, having excluded other disorders as mentioned above, thediagnosis is commonly one of two options: MS or possible MS. Whetherand/or when to indicate the latter is a concern: most would rather notgive the diagnosis of an incurable and disabling disease unlessabsolutely confident that this is correct. The diagnostic uncertaintydiscussed above may preclude this. One large study has shown that themajority of MS patients (91%) would prefer to be given the diagnosis assoon as it is suspected. (26) This study, however, was performed inpatients who ultimately did have a diagnosis of MS.

NICE guidelines recommend that patients should be informed of thepossibility of MS. (9) Familiarity with the natural history andprognosis of MS can help to reassure the patient. Further support forthe patient, their families and friends, can be obtained from specialistMS nurses, the established societies and their websites.

Acknowledgements

Elizabeth Mallam is funded by a generous grant from the MyelinProject.

Conflicts of Interest

No conflicts of interest were declared in relation to this article.

Key Points

* The diagnosis of MS is clinical: requiring the separation in timeand space of neurological events

* MS can present in a variety of ways; there is no singlediagnostic test, and the list of potential differential diagnoses islegion

* Difficulty can arise when the patient presents after a singleepisode

* The use of paraclinical investigations and internationaldiagnostic criteria may assist in making a diagnosis

* Uncertainty regarding diagnosis should be discussed with patients

Received: 19 August 2008

Accepted: 10 September 2008

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E Mallam, N Scolding

University of Bristol Institute of Clinical Neurosciences, BurdenNeurological Institute, Frenchay Hospital, Bristol,

UK

Address for correspondence:

Neil Scolding, The MS Labs, The Burden Centre, Frenchay Hospital,Bristol, BS16 1JB, UK E-mail [emailprotected]

Table 1. Features which might lead to doubt concerninga diagnosis of MS (11)Unfortunately, all of the features shown in italics canoccur in MS!Systemic Family historyfeatures Fever/night sweats, weight loss, arthropathy, rash, ulcers, dry mouth and eyes, ocular diseaseNeurological Persistent headache, fits,features encephalopathy, meningism, movement disorders, stroke-like events, peripheral neuropathyInvestigations Raised ESR and/or CRP, serology; abnormal CXR Absent oligoclonal bands or persistent CSF pleocytosis Normal MRI or pronounced meningeal enhancementTable 2. Inflammatory demyelinating diseases. (11)Benign focal inflammatory demyelination (BFID) * Optic neuritis Partial cord syndromes, etc.Non-benign, non-disseminated syndromes Transverse myelitis Devic's diseaseDisseminated diseases Acute disseminated encephalomyelitis (ADEM) Acute haemorrhagic encephalomyelitis Multiple sclerosis Relapsing-remitting (Charcot-type) multiple sclerosis Primary progressive multiple sclerosis Marburg disease Schilder's disease (Balo's disease)* 'Benign focal inflammatory demyelination' has been proposedas a term to cover monophasic and monofocal syndromes seenin MS. The term 'Clinically Isolated Syndrome' or 'CIS' iscurrently more commonly used and well understood by MS-ologists,but arguably rather vague for the non-specialist