Relatives of Patients With MS Show Early Signs of Disease

Asymptomatic first-degree relatives of patients with multiple sclerosis (MS) who are at high risk for developing the disease are significantly more likely to show subclinical signs of MS than family members at lower risk, according to data published online ahead of print January 17 in JAMA Neurology. In addition, evidence from neuroimaging and clinical tests indicates that individuals with the highest risk for MS are more likely to develop the disease than relatives with the lowest risk. Of all of the tests, simple vibration threshold testing may give the best results, said Zongqi Xia, MD, PhD, Associate Neurologist at Brigham and Women’s Hospital in Boston.

 

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

 

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Asymptomatic first-degree relatives of patients with multiple sclerosis (MS) who are at high risk for developing the disease are significantly more likely to show subclinical signs of MS than family members at lower risk, according to data published online ahead of print January 17 in JAMA Neurology. In addition, evidence from neuroimaging and clinical tests indicates that individuals with the highest risk for MS are more likely to develop the disease than relatives with the lowest risk. Of all of the tests, simple vibration threshold testing may give the best results, said Zongqi Xia, MD, PhD, Associate Neurologist at Brigham and Women’s Hospital in Boston.

 

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

 

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Asymptomatic first-degree relatives of patients with multiple sclerosis (MS) who are at high risk for developing the disease are significantly more likely to show subclinical signs of MS than family members at lower risk, according to data published online ahead of print January 17 in JAMA Neurology. In addition, evidence from neuroimaging and clinical tests indicates that individuals with the highest risk for MS are more likely to develop the disease than relatives with the lowest risk. Of all of the tests, simple vibration threshold testing may give the best results, said Zongqi Xia, MD, PhD, Associate Neurologist at Brigham and Women’s Hospital in Boston.

 

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

 

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].