Does MS Begin With Radiologically Isolated Syndrome?

BOSTON—Radiologically isolated syndrome (RIS) may be the first visible manifestation of multiple sclerosis (MS), according to an overview that was presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Not all neurologists accept RIS as a valid and distinct entity, however. Providing a firm, scientific basis for the diagnosis may require improved characterization of the syndrome and the lesions that define it.

An important question for researchers to answer is whether MS, similar to diseases such as high blood pressure, high cholesterol, and diabetes, should be treated early (eg, at RIS onset) to improve disability over time, said Darin T. Okuda, MD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern in Dallas. “We definitely need more scientific studies to answer this very important question: Would earlier treatment result in better long-term outcomes for patients?”

What Is RIS? A diagnosis of RIS may result from an MRI ordered to investigate a complaint unrelated to MS. “For the most part, these are individuals who were being worked up for migraine headache complaints, cerebrovascular accidents, [and] post-traumatic events,” said Dr. Okuda. A neurologist may diagnose RIS when the MRI reveals features within the brain and spinal cord that strongly suggest MS. Such features include periventricular, ovoid, circumscribed lesions within the cervical and thoracic spinal cord.

In addition, to diagnose RIS, a neurologist must confirm that the patient has never had clinical symptoms of MS. “We do our best to ensure that we are not missing another condition or disease process that could better explain why these structural anomalies are observed,” said Dr. Okuda.

The literature appears to provide evidence for asymptomatic MS. “Great scientific data support the presence of incidental anomalies [and] asymptomatic anomalies within the CNS from sporadic and familial MS cases,” said Dr. Okuda. Large collections of postmortem cases have identified and validated demyelinating changes within brain and spinal cord tissue, and researchers have described brain changes that are highly suggestive of MS. “Healthy subjects are definitely a group of interest because they appear asymptomatic and clearly possess features consistent with demyelinating disease,” said Dr. Okuda.

Skepticism About RIS
Neurologists have presented several arguments that RIS is not a distinct entity. One argument is that patients diagnosed with RIS have cryptogenic white matter changes but not MS. Many patients with RIS have changes in a brain region that MS does not typically affect, such as the subcortical or frontal region.

Another argument is that the patients, knowingly or not, have had clinical symptoms of MS. This objection often is directed against clinically isolated syndrome, too, said Dr. Okuda. Furthermore, some neurologists suggest that RIS is actually MS. The literature, however, appears to lend support to RIS as a diagnosis. Many MRI studies focusing on at-risk groups indicate the existence of presymptomatic disease, and recent scientific evidence suggests that deep gray matter volume changes may be present before the first clinical attack suggestive of MS, said Dr. Okuda.

Conventional Imaging May Lead to Overdiagnosis
Neurologists now use conventional imaging technology more often than novel techniques, but this tendency may result in the overdiagnosis of RIS, said Dr. Okuda. With conventional imaging, lesions may appear to be typical of MS when they are unrelated to the disease.

Future imaging efforts could prevent such mistakes. Newer techniques enable neurologists to see whether blood vessels traverse the lesions, and this feature is characteristic of MS-related changes, said Dr. Okuda. A preponderance of these features on brain MRI suggests that MS, rather than an unknown cause, is responsible for the findings. High-resolution imaging and qualitative imaging studies also could improve the diagnosis of RIS.

Treatment of RIS
No scientific data currently address the question of whether to treat a patient with RIS. One common reason that neurologists choose treatment is that the patient’s MRI scan has evolved and revealed more changes (eg, contrast enhancement or additional lesions) that are consistent with MS. Neurologists also may decide to treat RIS if the patient’s MRI has particularly negative findings such as tumefactive-like lesions, lesions involving the gray and white matter, or signs of old disease. Contrast enhancement within a specific brain region for an individual with features typical of MS also prompts some neurologists to initiate treatment.

Nevertheless, the effects of treating RIS with disease-modifying therapy (DMT) are unknown. “We need to treat these individuals under a controlled environment” in a prospective study, said Dr. Okuda. The RIS Consortium recently formed a strategic research alliance with Biogen Idec to assess the effect of dimethyl fumarate on extending the time to a first neurologic event associated with CNS demyelination. This study within the US will begin enrollment during the last quarter of 2014.

One-Third of Patients With RIS Had an Attack
Dr. Okuda and colleagues performed a retrospective analysis of individuals with RIS in the United States, Spain, France, Italy, and Turkey. The researchers’ goal was to collect cases and assess for risk factors for first symptom onset. They identified 451 subjects with RIS, the majority of whom were from the US. Most patients were young (mean age, 37.2), Caucasian, and female.

The most common reason the patients underwent MRI was for headache evaluation. Approximately 10% of subjects had a family history of MS, and about 65% had an abnormal CSF profile. These results indicate the specificity of the criteria that the researchers used to identify subjects­­, said Dr. Okuda. Approximately 17% of patients were exposed to a DMT before first symptom onset.

During the five-year study period, 34% of the cohort had a first attack suggestive of MS. This result “provided further validation that asymptomatic MS exists,” said Dr. Okuda. The investigators identified spinal cord lesions within the cervical or thoracic region, age younger than 37, and male sex as risk factors for a first attack. Having more than one risk factor was associated with a greater risk than having only one risk factor.

Among patients who had a first attack, 11% were identified with a primary progressive MS phenotype. This finding provides evidence for an asymptomatic form of progressive MS, said Dr. Okuda. In addition, for those subjects with an initial MRI study performed after 2008 that revealed anomalies suggestive of MS, 40% demonstrated worsening on MRI and had an increased risk for a seminal clinical event, but further scientific efforts would be needed to confirm these data, said Dr. Okuda.

—Erik Greb

BOSTON—Radiologically isolated syndrome (RIS) may be the first visible manifestation of multiple sclerosis (MS), according to an overview that was presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Not all neurologists accept RIS as a valid and distinct entity, however. Providing a firm, scientific basis for the diagnosis may require improved characterization of the syndrome and the lesions that define it.

An important question for researchers to answer is whether MS, similar to diseases such as high blood pressure, high cholesterol, and diabetes, should be treated early (eg, at RIS onset) to improve disability over time, said Darin T. Okuda, MD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern in Dallas. “We definitely need more scientific studies to answer this very important question: Would earlier treatment result in better long-term outcomes for patients?”

What Is RIS? A diagnosis of RIS may result from an MRI ordered to investigate a complaint unrelated to MS. “For the most part, these are individuals who were being worked up for migraine headache complaints, cerebrovascular accidents, [and] post-traumatic events,” said Dr. Okuda. A neurologist may diagnose RIS when the MRI reveals features within the brain and spinal cord that strongly suggest MS. Such features include periventricular, ovoid, circumscribed lesions within the cervical and thoracic spinal cord.

In addition, to diagnose RIS, a neurologist must confirm that the patient has never had clinical symptoms of MS. “We do our best to ensure that we are not missing another condition or disease process that could better explain why these structural anomalies are observed,” said Dr. Okuda.

The literature appears to provide evidence for asymptomatic MS. “Great scientific data support the presence of incidental anomalies [and] asymptomatic anomalies within the CNS from sporadic and familial MS cases,” said Dr. Okuda. Large collections of postmortem cases have identified and validated demyelinating changes within brain and spinal cord tissue, and researchers have described brain changes that are highly suggestive of MS. “Healthy subjects are definitely a group of interest because they appear asymptomatic and clearly possess features consistent with demyelinating disease,” said Dr. Okuda.

Skepticism About RIS
Neurologists have presented several arguments that RIS is not a distinct entity. One argument is that patients diagnosed with RIS have cryptogenic white matter changes but not MS. Many patients with RIS have changes in a brain region that MS does not typically affect, such as the subcortical or frontal region.

Another argument is that the patients, knowingly or not, have had clinical symptoms of MS. This objection often is directed against clinically isolated syndrome, too, said Dr. Okuda. Furthermore, some neurologists suggest that RIS is actually MS. The literature, however, appears to lend support to RIS as a diagnosis. Many MRI studies focusing on at-risk groups indicate the existence of presymptomatic disease, and recent scientific evidence suggests that deep gray matter volume changes may be present before the first clinical attack suggestive of MS, said Dr. Okuda.

Conventional Imaging May Lead to Overdiagnosis
Neurologists now use conventional imaging technology more often than novel techniques, but this tendency may result in the overdiagnosis of RIS, said Dr. Okuda. With conventional imaging, lesions may appear to be typical of MS when they are unrelated to the disease.

Future imaging efforts could prevent such mistakes. Newer techniques enable neurologists to see whether blood vessels traverse the lesions, and this feature is characteristic of MS-related changes, said Dr. Okuda. A preponderance of these features on brain MRI suggests that MS, rather than an unknown cause, is responsible for the findings. High-resolution imaging and qualitative imaging studies also could improve the diagnosis of RIS.

Treatment of RIS
No scientific data currently address the question of whether to treat a patient with RIS. One common reason that neurologists choose treatment is that the patient’s MRI scan has evolved and revealed more changes (eg, contrast enhancement or additional lesions) that are consistent with MS. Neurologists also may decide to treat RIS if the patient’s MRI has particularly negative findings such as tumefactive-like lesions, lesions involving the gray and white matter, or signs of old disease. Contrast enhancement within a specific brain region for an individual with features typical of MS also prompts some neurologists to initiate treatment.

Nevertheless, the effects of treating RIS with disease-modifying therapy (DMT) are unknown. “We need to treat these individuals under a controlled environment” in a prospective study, said Dr. Okuda. The RIS Consortium recently formed a strategic research alliance with Biogen Idec to assess the effect of dimethyl fumarate on extending the time to a first neurologic event associated with CNS demyelination. This study within the US will begin enrollment during the last quarter of 2014.

One-Third of Patients With RIS Had an Attack
Dr. Okuda and colleagues performed a retrospective analysis of individuals with RIS in the United States, Spain, France, Italy, and Turkey. The researchers’ goal was to collect cases and assess for risk factors for first symptom onset. They identified 451 subjects with RIS, the majority of whom were from the US. Most patients were young (mean age, 37.2), Caucasian, and female.

The most common reason the patients underwent MRI was for headache evaluation. Approximately 10% of subjects had a family history of MS, and about 65% had an abnormal CSF profile. These results indicate the specificity of the criteria that the researchers used to identify subjects­­, said Dr. Okuda. Approximately 17% of patients were exposed to a DMT before first symptom onset.

During the five-year study period, 34% of the cohort had a first attack suggestive of MS. This result “provided further validation that asymptomatic MS exists,” said Dr. Okuda. The investigators identified spinal cord lesions within the cervical or thoracic region, age younger than 37, and male sex as risk factors for a first attack. Having more than one risk factor was associated with a greater risk than having only one risk factor.

Among patients who had a first attack, 11% were identified with a primary progressive MS phenotype. This finding provides evidence for an asymptomatic form of progressive MS, said Dr. Okuda. In addition, for those subjects with an initial MRI study performed after 2008 that revealed anomalies suggestive of MS, 40% demonstrated worsening on MRI and had an increased risk for a seminal clinical event, but further scientific efforts would be needed to confirm these data, said Dr. Okuda.

—Erik Greb

BOSTON—Radiologically isolated syndrome (RIS) may be the first visible manifestation of multiple sclerosis (MS), according to an overview that was presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Not all neurologists accept RIS as a valid and distinct entity, however. Providing a firm, scientific basis for the diagnosis may require improved characterization of the syndrome and the lesions that define it.

An important question for researchers to answer is whether MS, similar to diseases such as high blood pressure, high cholesterol, and diabetes, should be treated early (eg, at RIS onset) to improve disability over time, said Darin T. Okuda, MD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern in Dallas. “We definitely need more scientific studies to answer this very important question: Would earlier treatment result in better long-term outcomes for patients?”

What Is RIS? A diagnosis of RIS may result from an MRI ordered to investigate a complaint unrelated to MS. “For the most part, these are individuals who were being worked up for migraine headache complaints, cerebrovascular accidents, [and] post-traumatic events,” said Dr. Okuda. A neurologist may diagnose RIS when the MRI reveals features within the brain and spinal cord that strongly suggest MS. Such features include periventricular, ovoid, circumscribed lesions within the cervical and thoracic spinal cord.

In addition, to diagnose RIS, a neurologist must confirm that the patient has never had clinical symptoms of MS. “We do our best to ensure that we are not missing another condition or disease process that could better explain why these structural anomalies are observed,” said Dr. Okuda.

The literature appears to provide evidence for asymptomatic MS. “Great scientific data support the presence of incidental anomalies [and] asymptomatic anomalies within the CNS from sporadic and familial MS cases,” said Dr. Okuda. Large collections of postmortem cases have identified and validated demyelinating changes within brain and spinal cord tissue, and researchers have described brain changes that are highly suggestive of MS. “Healthy subjects are definitely a group of interest because they appear asymptomatic and clearly possess features consistent with demyelinating disease,” said Dr. Okuda.

Skepticism About RIS
Neurologists have presented several arguments that RIS is not a distinct entity. One argument is that patients diagnosed with RIS have cryptogenic white matter changes but not MS. Many patients with RIS have changes in a brain region that MS does not typically affect, such as the subcortical or frontal region.

Another argument is that the patients, knowingly or not, have had clinical symptoms of MS. This objection often is directed against clinically isolated syndrome, too, said Dr. Okuda. Furthermore, some neurologists suggest that RIS is actually MS. The literature, however, appears to lend support to RIS as a diagnosis. Many MRI studies focusing on at-risk groups indicate the existence of presymptomatic disease, and recent scientific evidence suggests that deep gray matter volume changes may be present before the first clinical attack suggestive of MS, said Dr. Okuda.

Conventional Imaging May Lead to Overdiagnosis
Neurologists now use conventional imaging technology more often than novel techniques, but this tendency may result in the overdiagnosis of RIS, said Dr. Okuda. With conventional imaging, lesions may appear to be typical of MS when they are unrelated to the disease.

Future imaging efforts could prevent such mistakes. Newer techniques enable neurologists to see whether blood vessels traverse the lesions, and this feature is characteristic of MS-related changes, said Dr. Okuda. A preponderance of these features on brain MRI suggests that MS, rather than an unknown cause, is responsible for the findings. High-resolution imaging and qualitative imaging studies also could improve the diagnosis of RIS.

Treatment of RIS
No scientific data currently address the question of whether to treat a patient with RIS. One common reason that neurologists choose treatment is that the patient’s MRI scan has evolved and revealed more changes (eg, contrast enhancement or additional lesions) that are consistent with MS. Neurologists also may decide to treat RIS if the patient’s MRI has particularly negative findings such as tumefactive-like lesions, lesions involving the gray and white matter, or signs of old disease. Contrast enhancement within a specific brain region for an individual with features typical of MS also prompts some neurologists to initiate treatment.

Nevertheless, the effects of treating RIS with disease-modifying therapy (DMT) are unknown. “We need to treat these individuals under a controlled environment” in a prospective study, said Dr. Okuda. The RIS Consortium recently formed a strategic research alliance with Biogen Idec to assess the effect of dimethyl fumarate on extending the time to a first neurologic event associated with CNS demyelination. This study within the US will begin enrollment during the last quarter of 2014.

One-Third of Patients With RIS Had an Attack
Dr. Okuda and colleagues performed a retrospective analysis of individuals with RIS in the United States, Spain, France, Italy, and Turkey. The researchers’ goal was to collect cases and assess for risk factors for first symptom onset. They identified 451 subjects with RIS, the majority of whom were from the US. Most patients were young (mean age, 37.2), Caucasian, and female.

The most common reason the patients underwent MRI was for headache evaluation. Approximately 10% of subjects had a family history of MS, and about 65% had an abnormal CSF profile. These results indicate the specificity of the criteria that the researchers used to identify subjects­­, said Dr. Okuda. Approximately 17% of patients were exposed to a DMT before first symptom onset.

During the five-year study period, 34% of the cohort had a first attack suggestive of MS. This result “provided further validation that asymptomatic MS exists,” said Dr. Okuda. The investigators identified spinal cord lesions within the cervical or thoracic region, age younger than 37, and male sex as risk factors for a first attack. Having more than one risk factor was associated with a greater risk than having only one risk factor.

Among patients who had a first attack, 11% were identified with a primary progressive MS phenotype. This finding provides evidence for an asymptomatic form of progressive MS, said Dr. Okuda. In addition, for those subjects with an initial MRI study performed after 2008 that revealed anomalies suggestive of MS, 40% demonstrated worsening on MRI and had an increased risk for a seminal clinical event, but further scientific efforts would be needed to confirm these data, said Dr. Okuda.

—Erik Greb