Katz Sand, Ilana B. MD; Lublin, Fred D. MD, FAAN, FANA
DIAGNOSING MULTIPLE SCLEROSIS: CURRENT DIAGNOSTIC CATEGORIES AND CRITERIA
Relapsing-Remitting Multiple Sclerosis
The majority of patients diagnosed with multiple sclerosis (MS) (80% to 85%) follow an initial relapsing-remitting course characterized by episodes with fairly rapid onset of new or recurrent neurologic deficits followed by partial or complete recovery. Onset of disease is typically between ages 20 and 40, with a clear female preponderance.
Since Charcot first described “la sclérose en plaques disséminées” in 1868, the field has seen many iterations of proposed diagnostic criteria for MS.1 The McDonald criteria, which brought us into the modern era, were initially proposed by the International Panel on Diagnosis of Multiple Sclerosis in 2001,2 revised in 2005,3 and revised again in 2010.4 The concepts underlying the criteria have remained unchanged; what has changed over time is the way in which certain requirements are satisfied.
All recent formulations of the diagnostic criteria begin with an initial clinical presentation that includes symptoms typical for an MS attack (also called a relapse or exacerbation). Typical presentations usually involve the optic nerves (optic neuritis), brainstem (for example, internuclear ophthalmoplegia), or spinal cord (for example, partial transverse myelitis). This initial presentation has been termed the “clinically isolated syndrome” (CIS); the differential diagnoses of various presentations and the features typical for MS versus those that should raise the question of an alternative diagnosis are discussed below (see section on differential diagnosis).
The McDonald 2010 panel defined an attack as “patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection.”4 Naturally, patient-reported symptomatology should be correlated with objective findings on neurologic examination, although there may be some instances when this is not possible. For paroxysmal symptoms (such as paroxysmal dysarthria, tonic spasms, or paroxysmal sensory symptoms) to be considered an attack, symptoms must be recurrent over at least 24 hours.
The various iterations of McDonald criteria have all stressed that the criteria should only be applied to cases in which MS seems to be the best explanation for the clinical picture. Once MS has been established as the most likely etiology of the symptoms, the clinician must evaluate for evidence of dissemination in space (DIS), which requires involvement of multiple areas of the CNS, and for dissemination in time (DIT), which requires ongoing disease activity over time.
DIS criteria may be satisfied on clinical grounds alone if the patient has objective clinical evidence of involvement of at least two CNS sites, or objective clinical evidence of one lesion with reasonable historical evidence of another site being affected. Objective clinical evidence may include findings on neurologic examination, abnormal visual evoked potentials in a patient with a history of visual loss, or evidence of a demyelinating lesion on MRI that would explain prior symptoms. If there is only objective clinical evidence of one lesion, DIS may be established by applying the MRI criteria. Prior DIS MRI criteria, based on work by Barkhof and colleagues5 and Tintoré and colleagues,6 required many lesions if a gadolinium-enhanced lesion was not present and were somewhat difficult to apply because of their complexity.7 The revised McDonald 2010 DIS MRI criteria are based on recommendations from the European multicenter collaborative research network that studies MRI in MS (MAGNetic Resonance In Multiple Sclerosis, or MAGNIMS). This group demonstrated that in applying these new, less restrictive criteria, sensitivity was increased without an accompanying decrease in specificity.8 DIS MRI criteria now require at minimum only two lesions: at least one T2 lesion in at least two of the four sites typically affected by MS (periventricular, juxtacortical, infratentorial, or spinal cord), as illustrated in Table 2-1. Of note, in the case of a brainstem or spinal cord syndrome, the symptomatic lesion may not be used toward the MRI lesion count.
DIT criteria may be satisfied on clinical grounds alone if the patient has a history of at least two attacks. If the patient has a history of one attack, MRI criteria may be applied to establish DIT. The 2005 criteria specified that DIT could be established with any new T2 lesion on MRI compared to a baseline scan, with the caveat that the baseline scan be performed at least 30 days after onset of the clinical symptoms. However, work by the MAGNIMS group demonstrated that specificity was not compromised when this time frame was not applied.9 Under the 2010 criteria, DIT can therefore be established with the development of a new T2 lesion at any time, compared to a baseline scan performed at any time. In certain cases, DIT can actually be established with a single MRI scan, as outlined in Table 2-2. The MAGNIMS group was recently able to confirm earlier work demonstrating high specificity of a single MRI with simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions in patients with a typical CIS who satisfied DIS criteria (Case 2-1).10 A second clinical attack or new lesion on MRI is therefore only needed when the initial scenario does not satisfy these requirements.
A 23-year-old man with no significant medical history presented for evaluation of horizontal diplopia, which began 3 days ago. He had no other neurologic complaints and denied recent systemic illness. On neurologic examination, when he looked to the right there was an adduction lag in the left eye as well as dissociated abducting nystagmus in the right eye, consistent with an internuclear ophthalmoplegia. The remainder of his neurologic examination was unremarkable. MRI of the brain showed a right frontal juxtacortical lesion, two left periventricular lesions, and a very small lesion in the pons. The frontal lesion enhanced with gadolinium (Figure 2-1).
Comment. This patient’s presentation is typical for an inflammatory CNS demyelinating event and therefore qualifies him for a potential diagnosis of multiple sclerosis (MS). Because he has only had one clinical event (clinically isolated syndrome, or CIS), dissemination in space (DIS) and dissemination in time (DIT) must both be demonstrated for the diagnosis to be made. The pontine lesion is not considered in applying DIS and DIT criteria using MRI because it is presumably the symptomatic lesion in a patient who presented with a brainstem syndrome. He meets DIS criteria, which require at least one T2 lesion in at least two typical regions, because he has one juxtacortical as well as two periventricular lesions. He meets DIT criteria because he has both asymptomatic gadolinium-enhancing (right frontal) and nonenhancing (periventricular) lesions on this initial MRI. The diagnosis is therefore relapsing-remitting MS, in contrast to the CIS diagnosis he would have received under the 2005 criteria. Lumbar puncture is not necessary for diagnosis in this case because of the typical clinical and imaging features of MS.
It should be noted that CSF examination is not a required element of the 2010 diagnostic criteria. In prior years, positive CSF (at least two oligoclonal bands not present in the serum or elevated IgG index) could be used to reduce the number of lesions needed to satisfy DIS MRI criteria. The 2010 panel determined that this would not be appropriate under the new DIS and DIT criteria because the MRI criteria have already been liberalized and the specific contribution of CSF findings in this setting have not been adequately studied. The panel did, however, assert the importance of CSF studies as potential supporting evidence for the diagnosis of MS as well as in evaluating for other potential etiologies in the case of a diagnostic question.
Primary Progressive Multiple Sclerosis
While the majority of MS patients follow an initial relapsing-remitting course, approximately 10% to 15% of patients experience a progressive course from the onset. Primary progressive MS is characterized by the insidious onset of symptoms followed by gradual deterioration over time. Clinical disease in these patients typically presents as a progressive myelopathy, and less frequently as a brainstem or cerebellar syndrome. It is characterized by difficulties with gait, balance, spasticity, weakness, and bladder and/or bowel, with sensory symptoms occurring much less commonly than in relapsing-remitting MS.11 Patients diagnosed with primary progressive MS tend to be older than those with relapsing-remitting MS (mean age approximately 40 years for primary progressive MS compared to 30 years for relapsing-remitting MS), and there is no clear gender predominance, in contrast to the overwhelmingly female population affected by relapsing-remitting MS.12 MRI lesions are similar in appearance, although they tend to be fewer in number and less likely to enhance with gadolinium compared to relapsing-remitting MS.
The criteria for diagnosing primary progressive MS were also revised under the McDonald 2010 panel. The only substantive change from 2005 was to incorporate the MAGNIMS work regarding DIS to more closely align the brain MRI DIS section with the new relapsing-remitting MS criteria.13 The 2010 primary progressive MS criteria require at least 1 year of disease progression as well as at least two of the following: (1) at least one T2 lesion in at least one area characteristic for MS (periventricular, juxtacortical, infratentorial); (2) at least two T2 lesions in the spinal cord; or (3) positive CSF (oligoclonal bands or elevated IgG index), as outlined in Table 2-3. Occasional plateaus and minor improvements in clinical status are permitted. The complete set of McDonald 2010 criteria are shown in Table 2-4.
Caveats to the McDonald 2010 Criteria
The main caveats to the McDonald 2010 criteria presented by the panel are their application to Latin, Asian, and pediatric populations, as the studies supporting the criteria are based largely on adult white patients. The panel’s conclusion with respect to Latin and Asian populations is that the criteria are likely applicable once care has been taken to exclude neuromyelitis optica (NMO), which occurs with greater frequency and proportion to MS in these populations than in the white population. The panel suggested that confirmatory work be done in this arena. Similarly, the panel concluded that the criteria are likely applicable to pediatric patients (especially adolescents, who often present similarly to adults) but that care must be taken in young children with acute disseminated encephalomyelitis (ADEM)–like presentations. For further discussion regarding this topic, please see Dr Tanuja Chitnis’ article “Pediatric Demyelinating Diseases” in this issue of CONTINUUM.
Secondary Progressive Multiple Sclerosis
Various natural history studies have suggested that approximately 25% to 40% of patients with relapsing-remitting MS go on to a secondary progressive course after an average of about 20 years, although a wide range of time frames for this conversion has been described.14 Secondary progressive MS is diagnosed when, after an initial relapsing-remitting course, a patient demonstrates disease progression independent of relapses for at least 6 months.15 Typically, patients report gradual deterioration with respect to gait, balance, spasticity, and bladder function. Many patients experience cognitive decline as well. Relapses may or may not continue to occur, and minor improvements or plateaus are permitted.
Progressive Relapsing Multiple Sclerosis
A very small number of patients demonstrate disease progression from the time of onset but also have clear acute relapses sometime later during their disease course. These patients are diagnosed as having progressive relapsing MS. There has been some debate in the literature regarding whether these patients are truly different from primary progressive MS patients,16 but currently this diagnostic category remains.
PATIENTS WITH EVIDENCE SUGGESTIVE OF MULTIPLE SCLEROSIS WHO DO NOT MEET MCDONALD 2010 CRITERIA
Clinically Isolated Syndrome
Despite the liberalization of the diagnostic criteria, there remain patients who present with a typical, convincing CIS yet do not quite meet relapsing-remitting MS criteria. The diagnosis in these cases remains CIS until such time that relapsing-remitting MS criteria are met. However, because several studies have correlated the presence of MRI abnormalities with high risk of goingonto meet criteria for MS in the coming years,17 MS specialists often treat these patients similarly to those who already meet relapsing-remitting MS criteria and offer them disease-modifying therapy at the outset, although this varies by provider. This decision becomes less clear when the MRI is normal. In these cases, positive CSF may help support the diagnosis.
Radiologically Isolated Syndrome
Increasing use of MRI in recent years for conditions such as headache or after motor vehicle accidents has resulted in the identification of incidental abnormalities in the CNS. While many of these are nonspecific in appearance, some demonstrate a pattern highly suggestive of underlying demyelinating pathology. Okuda and colleagues proposed the term “radiologically isolated syndrome” (RIS) to describe patients with imaging findings suggestive of MS (in the absence of clinical symptoms) that are not better explained by another medical condition.18 The proposed RIS criteria are listed in Table 2-5. Barkhof criteria include (1) one gadolinium-enhancing lesion or at least nine total T2 lesions, (2) one juxtacortical lesion, (3) one infratentorial lesion, and (4) three periventricular lesions.5 Three of thesefour are currently required for the diagnosis of RIS by Okuda’s proposed criteria. Further revisions of the criteria for MS diagnosis will likely bring RIS in line with CIS as far as MRI criteria are concerned, but the present McDonald 2010 revisions do not speak to this issue.
In Okuda’s initial study, radiologic progression was identified in 24 of 41 patients (59%) over a median follow-up time of 2.7 years. Conversion to CIS or clinically definite MS (relapsing-remitting MS or primary progressive MS) occurred in 10 of 30 patients (30%) over a median interval of 5.4 years. The presence of spinal cord lesions seems to be a risk factor for conversion to clinical disease.19 Further studies investigating prognostic factors to help guide treatment decisions are currently underway.
DIFFERENTIAL DIAGNOSIS: WHEN SHOULD A DIAGNOSIS OTHER THAN MULTIPLE SCLEROSIS BE CONSIDERED?
For patients who present with symptoms that are typical for MS, have typical imaging findings, and meet relapsing-remitting MS criteria, often no further diagnostic evaluation is necessary. However, if any element of the clinical history, examination, or imaging is atypical, additional testing to exclude other etiologies is warranted. This section will review common presentations consistent with CIS and for each will describe what features are typical for MS compared withwhat features may suggest an alternative diagnosis. General clinical features will then be reviewed, followed by select imaging features that should prompt additional diagnostic workup.
Common Presentations Suggestive of a Clinically Isolated Syndrome
Optic neuritis. Patients with optic neuritis related to underlying MS typically present with painful, subacute, unilateral visual loss that manifests as visual blurring or a scotoma. Pain may precede the onset of the visual loss, is variable in intensity, and typically lasts for only a few days. In the Optic Neuritis Treatment Trial (ONTT), pain was present 92.2% of the time, and 87.1% of patients reported a relationship to eye movements.20 Progression of visual loss usually occurs over a few days and typically does not continue for more than 2 weeks before spontaneous recovery begins.21 Visual loss is usually unilateral but may be bilateral at times. An additional common feature is the presence of phosphenes or photopsias (light flashes) with eye movements, which were reported by 30.4% of patients in the ONTT.
The severity of the visual loss ranges from very mild to very severe, although complete visual loss with lack of light perception is rare.20 Decreased contrast and color vision are common, as are a variety of visual field defects. A relative afferent pupillary defect is usually present except in cases that are very mild or in which the other eye has been previously affected. On funduscopic examination, the optic disc may appear swollen (Figure 2-2), although it is more often normal. Hemorrhages and retinal exudates are rarely seen.20
The presence of any features that are not typical for optic neuritis associated with underlying MS merits consideration of alternative diagnoses and may require additional evaluation, dependent on the remainder of the clinical picture. For example, a patient who denies pain associated with the visual loss but otherwise demonstrates features typical for optic neuritis and has imaging findings typical for MS may not require further testing. However, a patient with severe bilateral visual loss with poor recovery after several weeks will certainly require testing for NMO as well as consideration of sarcoidosis, inherited optic neuropathies, infections such as Lyme and syphilis, and other etiologies depending on the remainder of the clinical scenario. The differential diagnosis for optic neuropathy, with clinical features atypical for optic neuritis associated with MS as well as suggested additional diagnostic testing, is outlined in Table 2-6.21
Brainstem or cerebellar syndrome. A classic presentation of a brainstem syndrome suggestive of CIS is diplopia due to internuclear ophthalmoplegia, which is often bilateral. A sixth nerve palsy is another common potential source of diplopia. Other typical symptoms of a brainstem or cerebellar CIS include ataxia with gaze-evoked nystagmus, facial sensory symptoms, vertigo, and paroxysmal symptoms. Paroxysmal symptoms, such as paroxysmal dysarthria or vertigo, typically consist of stereotyped events lasting seconds to minutes that recur over at least 24 hours.22 As is the case in optic neuritis, the onset of symptoms is typically subacute, over hours to days, with at least partial spontaneous recovery often beginning within a few weeks. Onset that is acute should raise the question of a vascular process. The onset of brainstem symptoms that are insidiously progressive, especially with persistent enhancement on MRI, should raise suspicion for etiologies such as sarcoidosis, histiocytosis, Behçet syndrome, malignancy, infections including Whipple disease and tuberculosis, or chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) (Figure 2-323). Progressive cerebellar symptoms should raise questions regarding hereditary spinocerebellar ataxias or paraneoplastic syndromes. Brainstem and cerebellar symptoms that are typical, less common, and atypical for CIS are shown in Table 2-724, and Figure 2-4 provides an algorithm for evaluating patients who present with brainstem syndromes that are potentially demyelinating.
Spinal cord syndrome. Patients with a spinal cord syndrome suggestive of CIS characteristically present with a partial transverse myelitis, which is usually dominated by sensory symptoms.25 At times, sensory symptoms may be in the form of a partial Brown-Séquard syndrome. Sphincter symptoms are often present, with bladder involvement occurring more commonly than bowel. Lhermitte sign is commonly reported as well.24 Symptom onset and progression typically occurs over several days but should not continue longer than 3 weeks.26 As with the other syndromes, at least partial recovery should then begin. If symptoms are hyperacute, especially if the deficit is in the distribution of the anterior spinal artery and recovery is poor, this should raise suspicion for a vascular etiology. Patients with a more progressive myelopathy often need to be evaluated for etiologies such as vitamin B12 or copper deficiency, structural lesions such as in cervical spondylosis, infections such as HIV and human T-lymphotropic virus (HTLV), and others, depending on the remainder of the clinical picture.
On MRI, spinal cord lesions due to MS are typically peripheral, with the dorsolateral cord being the most common plaque location. MS lesions are usually less than two vertebral segments in length and occupy less than half of the cross-sectional cord area.27 Lesions that are centrally located or longitudinally extensive (three or more vertebral segments in length) should raise suspicion for NMO.28
A suggested algorithm regarding the evaluation of patients who present with myelopathy is presented in Figure 2-5.
Neurologic and Systemic Features Suggestive of an Alternative Diagnosis
In 2008, an international panel of MS experts convened to develop consensus perspectives regarding the differential diagnosis of MS.24 They identified a set of “red flags” along with examples of suggested alternative diagnoses. These include neurologic features ranging from the presence of diabetes insipidus (Case 2-2) to extrapyramidal symptomsto headache. They also examined systemic features, such as the presence of arthralgias and gastrointestinal symptoms. Their findings are adapted in Table 2-8.
A 54-year-old man presented to the emergency department with paroxysmal sensations of electricity going into his arms and legs, which had been accompanied by the subacute onset of hoarseness, a sense of disequilibrium, and weakness in the legs. Significant medical history included the onset of diabetes insipidus 5 years before this event; brain imaging findings had been normal at the time.
The patient was found to have T2 hyperintensity involving the brainstem, with patchy contrast enhancement (Figure 2-6). Initial workup, which included various serologies and lumbar puncture, was unrevealing. He was told that he might have multiple sclerosis (MS), and it was recommended that he begin treatment. Over the coming months he reported slow worsening of ataxia and developed intermittent dysarthria and diplopia. Repeat imaging showed an increase in the involved area, again with patchy areas of enhancement. He was treated empirically with steroids but did not improve. Further testing included repeat CSF sample; CT of the chest, abdomen, and pelvis; positron emission tomography (PET) scan; bone scan; and gallium scan, all of which were unrevealing. Because of his rapidly progressive course and unclear diagnosis, a brain biopsy was performed but unfortunately was nondiagnostic.
In the coming months, the brainstem lesion took on a more masslike appearance. Because of this and the history of diabetes insipidus, bone scan was repeated and now showed increased uptake in the long bones. Bone biopsy was consistent with Erdheim-Chester disease. The patient was treated with high-dose methotrexate, with good initial response. Unfortunately, treatment had to be stopped because of medical complications, and he ultimately died of complications of his neurologic disease.
Comment. A history of diabetes insipidus is a major “red flag” that should prompt additional evaluation. The potential for neurosarcoidosis should be evaluated, beginning with a careful history and physical examination looking for signs of systemic sarcoidosis, followed by testing to include lumbar puncture, chest CT, and PET scan (which may be more accurate than gallium scan)29 if needed. Biopsy of an extracranial site is preferred when possible. If meningeal thickening or enhancement is noted, this is a reasonable site as well. Most patients with histiocytosis involving the CNS will have symptoms or signs of systemic disease and will usually have an abnormal bone scan,30 which provides a biopsy site. Skin biopsy can also be diagnostic if a skin lesion is present. Persistent enhancement of lesions over many months was another indication that this case was not likely to be MS.
Imaging Features Typical for Multiple Sclerosis and Differential Diagnosis of Atypical Features
As suggested by the McDonald criteria, common areas for MS lesions include periventricular, juxtacortical, and infratentorial regions, as well as the spinal cord. Although periventricular lesions are commonly seen in other conditions, such as in microvascular ischemic disease, those associated with MS often display characteristic features such as an ovoid shape and radial orientation away from the ventricles, giving rise to the classic Dawson fingers appearance on sagittal imaging.31 Involvement of the paracentral corpus callosum, particularly at the callosal-septal interface (but not the midline corpus callosum), is common in MS,32 whereas this region is not typically affected by ischemic disease. Juxtacortical lesions are also commonly seen in MS and not commonly seen in microvascular disease.33 Infratentorial lesions are typically seen along the floor of the fourth ventricle or at the surface of the pons, in contrast to the central pontine location typically seen in microvascular disease.34 Typical MS spinal cord lesions are described above (see section on spinal cord syndrome). Newly formed MS lesions usually enhance with gadolinium, and this enhancement typically lasts 4 to 6 weeks. Enhancement that persists beyond 3 months should raise the question of an alternative diagnosis34 such as sarcoidosis, vasculitis, lymphoma or other neoplasm, or (particularly in the spinal cord) vascular malformations. Examples of typical-appearing MS lesions are shown in Figure 2-7.35Table 2-9 demonstrates the imaging red flags defined by the same panel of MS experts as the clinical features described above.
Patients who present with clinical and imaging features typical for MS may not require further diagnostic evaluation, especially if they already meet the revised 2010 McDonald criteria for a diagnosis of MS at the time of presentation. For patients in whom an MS diagnosis is being considered but atypical clinical or imaging features are present, additional testing is necessary to explore other alternatives before a diagnosis of MS can be made.
- All recent formulations of the diagnostic criteria begin with an initial clinical presentation that includes symptoms typical for a multiple sclerosis attack (also called a relapse or exacerbation). Typical presentations usually involve the optic nerves (optic neuritis), brainstem (for example, internuclear ophthalmoplegia), or spinal cord (for example, partial transverse myelitis).
- Once multiple sclerosis has been established as the most likely etiology of the symptoms, the clinician must evaluate for evidence of dissemination in space, which requires involvement of multiple areas of the CNS, and for dissemination in time, which requires ongoing disease activity over time.
- Dissemination-in-space MRI criteria now require at minimum only two lesions: at least one T2 lesion in at least two of the four sites typically affected by multiple sclerosis (periventricular, juxtacortical, infratentorial, or spinal cord).
- Dissemination in time can be demonstrated with a single MRI if simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions are present.
- Primary progressive multiple sclerosis is characterized by the insidious onset of symptoms followed by gradual deterioration over time. Clinical disease in these patients typically presents as a progressive myelopathy, and less frequently as a brainstem or cerebellar syndrome.
- Secondary progressive multiple sclerosis is diagnosed when, after an initial relapsing-remitting course, a patient demonstrates disease progression independent of relapses for at least 6 months.
- Radiologically isolated syndrome is diagnosed when a patient is incidentally found to have imaging findings suggestive of multiple sclerosis, which are not better explained by another medical condition, in the absence of clinical symptoms.
- For patients who present with symptoms that are typical for multiple sclerosis, have typical imaging findings, and meet relapsing-remitting multiple sclerosis criteria, often no further diagnostic evaluation is necessary. However, if any element of the clinical history, examination, or imaging is atypical, additional testing to exclude other etiologies is warranted.
- Patients with optic neuritis related to underlying multiple sclerosis typically present with painful, subacute, unilateral visual loss that manifests as visual blurring or a scotoma.
- The presence of any features that are not typical for optic neuritis associated with underlying multiple sclerosis merits consideration of alternative diagnoses and may require additional evaluation, dependent on the remainder of the clinical picture.
- A classic presentation of a brainstem syndrome suggestive of clinically isolated syndrome is diplopia due to internuclear ophthalmoplegia, which is often bilateral.
- Patients with a spinal cord syndrome suggestive of clinically isolated syndrome characteristically present with a partial transverse myelitis, which is usually dominated by sensory symptoms.
- On MRI, spinal cord lesions due to multiple sclerosis are typically peripheral, with the dorsolateral cord being the most common plaque location. Multiple sclerosis lesions are usually less than two vertebral segments in length and occupy less than half of the cross-sectional cord area.
- Common areas for multiple sclerosis lesions include periventricular, juxtacortical, and infratentorial regions, as well as the spinal cord.
- Involvement of the paracentral corpus callosum, particularly at the callosal-septal interface (but not the midline corpus callosum), is common in multiple sclerosis.
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