New MS Criteria Aim to Simplify Diagnosis

An international panel has revised the McDonald criteria for the diagnosis of multiple sclerosis to simplify the use of imaging in determining the dissemination of central nervous system lesions both in space and time, while preserving sensitivity and specificity.

The new revisions also address the applicability of the criteria in non-Western Caucasian populations – specifically Asian and Latin American populations – and children and adolescents.

The changes update the 2005 version of the criteria based on new evidence and consensus, which "pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult population from which the criteria were derived," wrote lead author Dr. Chris H. Polman and his coauthors (Ann. Neurol. 2011;69:292-302).

In an accompanying editorial, Dr. Richard A. Rudick agreed (Ann. Neurol. 2011;69:234-6). "The McDonald criteria were not just for clinical trials, but for neurologists in practice. However, some neurologists found the McDonald criteria complex and difficult to use in the clinic, and even experienced MS specialists were uncertain about some aspects of the criteria." Dr. Rudick is the director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

The 2010 revisions to the McDonald criteria are intended to allow a more rapid diagnosis of MS in some instances, with equivalent or improved specificity or sensitivity, and will clarify and simplify the diagnostic process with fewer required MRI examinations, according to Dr. Polman of the neurology department at the Free University in Amsterdam, and his coauthors.

The International Panel on Diagnosis of MS reviewed published research related to the diagnosis of MS and to the original and revised McDonald criteria, gathered from literature searches of English-language publications.

The panel stressed that the updated criteria should only be applied to patients who present with a typical clinically isolated syndrome (CIS) suggestive of MS or symptoms consistent with a central nervous system (CNS) inflammatory demyelinating disease, because the development and validation of the criteria have been limited to patients with such presentations. It also remains imperative that alternative diagnoses be considered and excluded.

Neuromyelitis Optica and Spectrum Disorders. The panel focused on the differential diagnosis for MS of neuromyelitis optica (NMO) and NMO spectrum disorders, because "there is increasing evidence of relapsing CNS demyelinating disease characterized by involvement of optic nerves (unilateral or bilateral optic neuritis), often severe myelopathy with MRI evidence of longitudinally extensive spinal cord lesions, often normal brain MRI (or with abnormalities atypical for MS), and serum aquaporin-4 (AQP4) autoantibodies."

The panel agreed that this phenotype should be separated out because the clinical course, prognosis, and underlying pathophysiology are different from those of typical MS. The response of patients with NMO and its spectrum disorders to some available MS disease-modifying therapies is often poor.

The panel recommended that this disorder should be carefully considered in the differential diagnosis of all patients presenting with clinical and MRI features that are strongly suggestive of NMO or NMO spectrum disorder, especially if:

• myelopathy is associated with MRI-detected spinal cord lesions longer than three spinal segments and primarily involving the central part of the spinal cord on axial sections;

• optic neuritis is bilateral and severe or associated with a swollen optic nerve or chiasm lesion or an altitudinal scotoma; and

• intractable hiccough, nausea, or vomiting is present for more than 2 days with evidence of a periaqueductal medullary lesion on MRI.

AQP4 serum testing should be used to help make a differential diagnosis between NMO and MS.

Dissemination in Space and Time. While the panel agreed that the underlying concepts of the original (2001) and revised (2005) criteria are still valid, they recommended key changes related to the use and interpretation of imaging criteria for dissemination in space (DIS) and dissemination in time (DIT) as articulated by the recently published work from the Magnetic Imaging in MS (MAGNIMS) research group.

The European MAGNIMS multicenter collaborative research network compared the Barkhof/Tintoré criteria for DIS (Brain 1997;120:2059-69; Am. J. Neuroradiol. 2000;21:702-6) – used in previous McDonald criteria – with simplified criteria developed by Swanton and colleagues (Lancet Neurol. 2007;6:677-86; J. Neurol. Neurosurg. Psychiatry 2006;77:830-3).

Based on the MAGNIMS analysis, the panel said that DIS can be demonstrated with at least one T2 lesion in at least two of four locations considered characteristic for MS (juxtacortical, periventricular, infratentorial, and spinal cord), excluding lesions within the symptomatic region in patients with brainstem or spinal cord syndromes.

These new criteria for DIS can simplify the diagnostic process for MS, while preserving specificity and improving sensitivity.

The presence of both gadolinium-enhancing and nonenhancing lesions on the baseline MRI can substitute for a follow-up scan to confirm DIT, as long as it can be reliably determined that the gadolinium-enhancing lesion is not due to non-MS pathology.

Based on these changes, a diagnosis of MS can be made in some CIS patients on the basis of a single MRI. The panel stated that this change simplifies the diagnostic process without reducing accuracy.

Cerebrospinal Fluid. The panel still agreed that positive cerebrospinal fluid (CSF) findings – elevated immunoglobulin G (IgG) index or two or more oligoclonal bands – can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict clinically definite MS. However, when applying the simplified MAGNIMS imaging criteria for DIS and DIT, the panel believes that changing the MRI requirements in CSF-positive patients is not appropriate.

Primary Progressive MS. The panel recommended replacing previous brain imaging criteria for primary progressive MS (PPMS) with the new MAGNIMS criteria for DIS. In addition to 1 year of disease progression, the new criteria for PPMS require two of the following: at least one T2 lesion in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial); at least two T2 lesions in the cord; or positive CSF (isoelectric focusing evidence of oligoclonal bands with or without an elevated IgG index).

Pediatric Patients. The panel agreed that the proposed MAGNIMS-based MRI revisions for DIS will also work well for most pediatric MS patients – especially those with acute demyelination, presenting as CIS – because most pediatric patients will have more than two lesions and are very likely to have lesions in two of the four specified CNS locations.

However, an estimated 15%-20% of pediatric MS patients (most younger than 11 years) present with encephalopathy and multifocal neurological deficits, which are difficult to distinguish from acute disseminated encephalomyelitis.

For these patients, the panel concluded that application of the revised MAGNIMS-based criteria for DIS and DIT on initial MRI would be inappropriate. Instead, serial clinical and MRI observations are required to confirm a diagnosis of MS. In this young age group, there can be marked lesion resolution following an initial attack prior to emergence over time of new lesions and attacks leading to a diagnosis of MS, the panel noted.

Other Populations. A phenotype characterized by NMO, longitudinally extensive spinal cord lesions, and AQP4 autoantibody seropositivity has been relatively more common among Asian patients with CNS inflammatory demyelinating disease than in Western populations. However, there is some uncertainty – especially in Asia – about whether MS and NMO are distinct. If so, it is unclear how these patients should be distinguished. "Failure to make the correct diagnosis in patients with NMO may impact treatment," the panel noted.

The panel recommended testing for AQP4 autoantibodies with validated assays in patients who are suspected of having NMO or NMO spectrum disorders, especially in patients with an Asian or Latin American genetic background because of the higher prevalence of the disease in these populations.

However, the current evidence suggests that once NMO and NMO spectrum disorders have been excluded, Western-type MS in Asia or Latin America is not fundamentally different from typical MS in the Caucasian population, the panel concluded. The MAGNIMS MRI criteria would apply to such patients, although confirmatory studies should be done.

Dr. Polman, Dr. Rudick, and several other panelists reported significant financial relationships with several pharmaceutical companies.

An international panel has revised the McDonald criteria for the diagnosis of multiple sclerosis to simplify the use of imaging in determining the dissemination of central nervous system lesions both in space and time, while preserving sensitivity and specificity.

The new revisions also address the applicability of the criteria in non-Western Caucasian populations – specifically Asian and Latin American populations – and children and adolescents.

The changes update the 2005 version of the criteria based on new evidence and consensus, which "pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult population from which the criteria were derived," wrote lead author Dr. Chris H. Polman and his coauthors (Ann. Neurol. 2011;69:292-302).

In an accompanying editorial, Dr. Richard A. Rudick agreed (Ann. Neurol. 2011;69:234-6). "The McDonald criteria were not just for clinical trials, but for neurologists in practice. However, some neurologists found the McDonald criteria complex and difficult to use in the clinic, and even experienced MS specialists were uncertain about some aspects of the criteria." Dr. Rudick is the director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

The 2010 revisions to the McDonald criteria are intended to allow a more rapid diagnosis of MS in some instances, with equivalent or improved specificity or sensitivity, and will clarify and simplify the diagnostic process with fewer required MRI examinations, according to Dr. Polman of the neurology department at the Free University in Amsterdam, and his coauthors.

The International Panel on Diagnosis of MS reviewed published research related to the diagnosis of MS and to the original and revised McDonald criteria, gathered from literature searches of English-language publications.

The panel stressed that the updated criteria should only be applied to patients who present with a typical clinically isolated syndrome (CIS) suggestive of MS or symptoms consistent with a central nervous system (CNS) inflammatory demyelinating disease, because the development and validation of the criteria have been limited to patients with such presentations. It also remains imperative that alternative diagnoses be considered and excluded.

Neuromyelitis Optica and Spectrum Disorders. The panel focused on the differential diagnosis for MS of neuromyelitis optica (NMO) and NMO spectrum disorders, because "there is increasing evidence of relapsing CNS demyelinating disease characterized by involvement of optic nerves (unilateral or bilateral optic neuritis), often severe myelopathy with MRI evidence of longitudinally extensive spinal cord lesions, often normal brain MRI (or with abnormalities atypical for MS), and serum aquaporin-4 (AQP4) autoantibodies."

The panel agreed that this phenotype should be separated out because the clinical course, prognosis, and underlying pathophysiology are different from those of typical MS. The response of patients with NMO and its spectrum disorders to some available MS disease-modifying therapies is often poor.

The panel recommended that this disorder should be carefully considered in the differential diagnosis of all patients presenting with clinical and MRI features that are strongly suggestive of NMO or NMO spectrum disorder, especially if:

• myelopathy is associated with MRI-detected spinal cord lesions longer than three spinal segments and primarily involving the central part of the spinal cord on axial sections;

• optic neuritis is bilateral and severe or associated with a swollen optic nerve or chiasm lesion or an altitudinal scotoma; and

• intractable hiccough, nausea, or vomiting is present for more than 2 days with evidence of a periaqueductal medullary lesion on MRI.

AQP4 serum testing should be used to help make a differential diagnosis between NMO and MS.

Dissemination in Space and Time. While the panel agreed that the underlying concepts of the original (2001) and revised (2005) criteria are still valid, they recommended key changes related to the use and interpretation of imaging criteria for dissemination in space (DIS) and dissemination in time (DIT) as articulated by the recently published work from the Magnetic Imaging in MS (MAGNIMS) research group.

The European MAGNIMS multicenter collaborative research network compared the Barkhof/Tintoré criteria for DIS (Brain 1997;120:2059-69; Am. J. Neuroradiol. 2000;21:702-6) – used in previous McDonald criteria – with simplified criteria developed by Swanton and colleagues (Lancet Neurol. 2007;6:677-86; J. Neurol. Neurosurg. Psychiatry 2006;77:830-3).

Based on the MAGNIMS analysis, the panel said that DIS can be demonstrated with at least one T2 lesion in at least two of four locations considered characteristic for MS (juxtacortical, periventricular, infratentorial, and spinal cord), excluding lesions within the symptomatic region in patients with brainstem or spinal cord syndromes.

These new criteria for DIS can simplify the diagnostic process for MS, while preserving specificity and improving sensitivity.

The presence of both gadolinium-enhancing and nonenhancing lesions on the baseline MRI can substitute for a follow-up scan to confirm DIT, as long as it can be reliably determined that the gadolinium-enhancing lesion is not due to non-MS pathology.

Based on these changes, a diagnosis of MS can be made in some CIS patients on the basis of a single MRI. The panel stated that this change simplifies the diagnostic process without reducing accuracy.

Cerebrospinal Fluid. The panel still agreed that positive cerebrospinal fluid (CSF) findings – elevated immunoglobulin G (IgG) index or two or more oligoclonal bands – can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict clinically definite MS. However, when applying the simplified MAGNIMS imaging criteria for DIS and DIT, the panel believes that changing the MRI requirements in CSF-positive patients is not appropriate.

Primary Progressive MS. The panel recommended replacing previous brain imaging criteria for primary progressive MS (PPMS) with the new MAGNIMS criteria for DIS. In addition to 1 year of disease progression, the new criteria for PPMS require two of the following: at least one T2 lesion in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial); at least two T2 lesions in the cord; or positive CSF (isoelectric focusing evidence of oligoclonal bands with or without an elevated IgG index).

Pediatric Patients. The panel agreed that the proposed MAGNIMS-based MRI revisions for DIS will also work well for most pediatric MS patients – especially those with acute demyelination, presenting as CIS – because most pediatric patients will have more than two lesions and are very likely to have lesions in two of the four specified CNS locations.

However, an estimated 15%-20% of pediatric MS patients (most younger than 11 years) present with encephalopathy and multifocal neurological deficits, which are difficult to distinguish from acute disseminated encephalomyelitis.

For these patients, the panel concluded that application of the revised MAGNIMS-based criteria for DIS and DIT on initial MRI would be inappropriate. Instead, serial clinical and MRI observations are required to confirm a diagnosis of MS. In this young age group, there can be marked lesion resolution following an initial attack prior to emergence over time of new lesions and attacks leading to a diagnosis of MS, the panel noted.

Other Populations. A phenotype characterized by NMO, longitudinally extensive spinal cord lesions, and AQP4 autoantibody seropositivity has been relatively more common among Asian patients with CNS inflammatory demyelinating disease than in Western populations. However, there is some uncertainty – especially in Asia – about whether MS and NMO are distinct. If so, it is unclear how these patients should be distinguished. "Failure to make the correct diagnosis in patients with NMO may impact treatment," the panel noted.

The panel recommended testing for AQP4 autoantibodies with validated assays in patients who are suspected of having NMO or NMO spectrum disorders, especially in patients with an Asian or Latin American genetic background because of the higher prevalence of the disease in these populations.

However, the current evidence suggests that once NMO and NMO spectrum disorders have been excluded, Western-type MS in Asia or Latin America is not fundamentally different from typical MS in the Caucasian population, the panel concluded. The MAGNIMS MRI criteria would apply to such patients, although confirmatory studies should be done.

Dr. Polman, Dr. Rudick, and several other panelists reported significant financial relationships with several pharmaceutical companies.

An international panel has revised the McDonald criteria for the diagnosis of multiple sclerosis to simplify the use of imaging in determining the dissemination of central nervous system lesions both in space and time, while preserving sensitivity and specificity.

The new revisions also address the applicability of the criteria in non-Western Caucasian populations – specifically Asian and Latin American populations – and children and adolescents.

The changes update the 2005 version of the criteria based on new evidence and consensus, which "pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult population from which the criteria were derived," wrote lead author Dr. Chris H. Polman and his coauthors (Ann. Neurol. 2011;69:292-302).

In an accompanying editorial, Dr. Richard A. Rudick agreed (Ann. Neurol. 2011;69:234-6). "The McDonald criteria were not just for clinical trials, but for neurologists in practice. However, some neurologists found the McDonald criteria complex and difficult to use in the clinic, and even experienced MS specialists were uncertain about some aspects of the criteria." Dr. Rudick is the director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

The 2010 revisions to the McDonald criteria are intended to allow a more rapid diagnosis of MS in some instances, with equivalent or improved specificity or sensitivity, and will clarify and simplify the diagnostic process with fewer required MRI examinations, according to Dr. Polman of the neurology department at the Free University in Amsterdam, and his coauthors.

The International Panel on Diagnosis of MS reviewed published research related to the diagnosis of MS and to the original and revised McDonald criteria, gathered from literature searches of English-language publications.

The panel stressed that the updated criteria should only be applied to patients who present with a typical clinically isolated syndrome (CIS) suggestive of MS or symptoms consistent with a central nervous system (CNS) inflammatory demyelinating disease, because the development and validation of the criteria have been limited to patients with such presentations. It also remains imperative that alternative diagnoses be considered and excluded.

Neuromyelitis Optica and Spectrum Disorders. The panel focused on the differential diagnosis for MS of neuromyelitis optica (NMO) and NMO spectrum disorders, because "there is increasing evidence of relapsing CNS demyelinating disease characterized by involvement of optic nerves (unilateral or bilateral optic neuritis), often severe myelopathy with MRI evidence of longitudinally extensive spinal cord lesions, often normal brain MRI (or with abnormalities atypical for MS), and serum aquaporin-4 (AQP4) autoantibodies."

The panel agreed that this phenotype should be separated out because the clinical course, prognosis, and underlying pathophysiology are different from those of typical MS. The response of patients with NMO and its spectrum disorders to some available MS disease-modifying therapies is often poor.

The panel recommended that this disorder should be carefully considered in the differential diagnosis of all patients presenting with clinical and MRI features that are strongly suggestive of NMO or NMO spectrum disorder, especially if:

• myelopathy is associated with MRI-detected spinal cord lesions longer than three spinal segments and primarily involving the central part of the spinal cord on axial sections;

• optic neuritis is bilateral and severe or associated with a swollen optic nerve or chiasm lesion or an altitudinal scotoma; and

• intractable hiccough, nausea, or vomiting is present for more than 2 days with evidence of a periaqueductal medullary lesion on MRI.

AQP4 serum testing should be used to help make a differential diagnosis between NMO and MS.

Dissemination in Space and Time. While the panel agreed that the underlying concepts of the original (2001) and revised (2005) criteria are still valid, they recommended key changes related to the use and interpretation of imaging criteria for dissemination in space (DIS) and dissemination in time (DIT) as articulated by the recently published work from the Magnetic Imaging in MS (MAGNIMS) research group.

The European MAGNIMS multicenter collaborative research network compared the Barkhof/Tintoré criteria for DIS (Brain 1997;120:2059-69; Am. J. Neuroradiol. 2000;21:702-6) – used in previous McDonald criteria – with simplified criteria developed by Swanton and colleagues (Lancet Neurol. 2007;6:677-86; J. Neurol. Neurosurg. Psychiatry 2006;77:830-3).

Based on the MAGNIMS analysis, the panel said that DIS can be demonstrated with at least one T2 lesion in at least two of four locations considered characteristic for MS (juxtacortical, periventricular, infratentorial, and spinal cord), excluding lesions within the symptomatic region in patients with brainstem or spinal cord syndromes.

These new criteria for DIS can simplify the diagnostic process for MS, while preserving specificity and improving sensitivity.

The presence of both gadolinium-enhancing and nonenhancing lesions on the baseline MRI can substitute for a follow-up scan to confirm DIT, as long as it can be reliably determined that the gadolinium-enhancing lesion is not due to non-MS pathology.

Based on these changes, a diagnosis of MS can be made in some CIS patients on the basis of a single MRI. The panel stated that this change simplifies the diagnostic process without reducing accuracy.

Cerebrospinal Fluid. The panel still agreed that positive cerebrospinal fluid (CSF) findings – elevated immunoglobulin G (IgG) index or two or more oligoclonal bands – can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict clinically definite MS. However, when applying the simplified MAGNIMS imaging criteria for DIS and DIT, the panel believes that changing the MRI requirements in CSF-positive patients is not appropriate.

Primary Progressive MS. The panel recommended replacing previous brain imaging criteria for primary progressive MS (PPMS) with the new MAGNIMS criteria for DIS. In addition to 1 year of disease progression, the new criteria for PPMS require two of the following: at least one T2 lesion in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial); at least two T2 lesions in the cord; or positive CSF (isoelectric focusing evidence of oligoclonal bands with or without an elevated IgG index).

Pediatric Patients. The panel agreed that the proposed MAGNIMS-based MRI revisions for DIS will also work well for most pediatric MS patients – especially those with acute demyelination, presenting as CIS – because most pediatric patients will have more than two lesions and are very likely to have lesions in two of the four specified CNS locations.

However, an estimated 15%-20% of pediatric MS patients (most younger than 11 years) present with encephalopathy and multifocal neurological deficits, which are difficult to distinguish from acute disseminated encephalomyelitis.

For these patients, the panel concluded that application of the revised MAGNIMS-based criteria for DIS and DIT on initial MRI would be inappropriate. Instead, serial clinical and MRI observations are required to confirm a diagnosis of MS. In this young age group, there can be marked lesion resolution following an initial attack prior to emergence over time of new lesions and attacks leading to a diagnosis of MS, the panel noted.

Other Populations. A phenotype characterized by NMO, longitudinally extensive spinal cord lesions, and AQP4 autoantibody seropositivity has been relatively more common among Asian patients with CNS inflammatory demyelinating disease than in Western populations. However, there is some uncertainty – especially in Asia – about whether MS and NMO are distinct. If so, it is unclear how these patients should be distinguished. "Failure to make the correct diagnosis in patients with NMO may impact treatment," the panel noted.

The panel recommended testing for AQP4 autoantibodies with validated assays in patients who are suspected of having NMO or NMO spectrum disorders, especially in patients with an Asian or Latin American genetic background because of the higher prevalence of the disease in these populations.

However, the current evidence suggests that once NMO and NMO spectrum disorders have been excluded, Western-type MS in Asia or Latin America is not fundamentally different from typical MS in the Caucasian population, the panel concluded. The MAGNIMS MRI criteria would apply to such patients, although confirmatory studies should be done.

Dr. Polman, Dr. Rudick, and several other panelists reported significant financial relationships with several pharmaceutical companies.