Multiple Sclerosis

Key clinical point: Patients with multiple sclerosis (MS) are at an increased risk for cancer than the general population.

Major finding: Compared with the general population, patients with MS were at a significantly higher risk for cancer (hazard ratio [HR], 1.36; 95% CI, 1.29-1.43), particularly prostate cancer (HR, 2.08; 95% CI, 1.68-2.58), colorectal and anal cancer (HR, 1.35; 95% CI, 1.16-1.58), and trachea bronchus and lung cancer (HR, 2.36; 95% CI, 1.96-2.84).

Study details: This population-based matched-cohort study included 95,474 patients with MS matched with 95,474 individuals from the general population.

Disclosures: This study was sponsored by Merck Healthcare KGaA. Four authors including the lead author reported being employees of the Bordeaux PharmacoEpi, and the remaining authors reported being full-time employees of Merck Healthcare KGaA, Darmstadt, Germany. The lead author reported receiving speaker fees from Biogen.

Source: Bosco-Lévy P et al. Eur J Neurol. 2021 Dec 22. doi: 10.1111/ene.15226.

Key clinical point: Patients with multiple sclerosis (MS) are at an increased risk for cancer than the general population.

Major finding: Compared with the general population, patients with MS were at a significantly higher risk for cancer (hazard ratio [HR], 1.36; 95% CI, 1.29-1.43), particularly prostate cancer (HR, 2.08; 95% CI, 1.68-2.58), colorectal and anal cancer (HR, 1.35; 95% CI, 1.16-1.58), and trachea bronchus and lung cancer (HR, 2.36; 95% CI, 1.96-2.84).

Study details: This population-based matched-cohort study included 95,474 patients with MS matched with 95,474 individuals from the general population.

Disclosures: This study was sponsored by Merck Healthcare KGaA. Four authors including the lead author reported being employees of the Bordeaux PharmacoEpi, and the remaining authors reported being full-time employees of Merck Healthcare KGaA, Darmstadt, Germany. The lead author reported receiving speaker fees from Biogen.

Source: Bosco-Lévy P et al. Eur J Neurol. 2021 Dec 22. doi: 10.1111/ene.15226.

Key clinical point: Patients with multiple sclerosis (MS) are at an increased risk for cancer than the general population.

Major finding: Compared with the general population, patients with MS were at a significantly higher risk for cancer (hazard ratio [HR], 1.36; 95% CI, 1.29-1.43), particularly prostate cancer (HR, 2.08; 95% CI, 1.68-2.58), colorectal and anal cancer (HR, 1.35; 95% CI, 1.16-1.58), and trachea bronchus and lung cancer (HR, 2.36; 95% CI, 1.96-2.84).

Study details: This population-based matched-cohort study included 95,474 patients with MS matched with 95,474 individuals from the general population.

Disclosures: This study was sponsored by Merck Healthcare KGaA. Four authors including the lead author reported being employees of the Bordeaux PharmacoEpi, and the remaining authors reported being full-time employees of Merck Healthcare KGaA, Darmstadt, Germany. The lead author reported receiving speaker fees from Biogen.

Source: Bosco-Lévy P et al. Eur J Neurol. 2021 Dec 22. doi: 10.1111/ene.15226.

Key clinical point: Cognitive impairments may be evaluated up to 30 days before and up to 550 days after a relapse, beyond which they revert to prerelapse levels in patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: From 30 days prerelapse to 550 days postrelapse, there was a significant drop in the Symbol Digit Modalities Test (SDMT) score, with the largest decline occurring at 0-30 days postrelapse (β-coefficient, −4.00; 95% CI, −4.61 to −3.39) compared with the period of remission.

Study details: This nationwide cohort study recorded 31,529 SDMTs from among 3,877 patients with incident RRMS, each having a minimum of 2 SDMT scores recorded.

Disclosures: This study was funded by a postdoctoral fellowship award to KA McKay from the Swedish Research Council for Health, Working Life, and Welfare (Forte). The authors reported no conflict of interests.

Source: McKay KA et al. Ann Neurol. 2022 Jan 4. doi: 10.1002/ana.26301.

Key clinical point: Cognitive impairments may be evaluated up to 30 days before and up to 550 days after a relapse, beyond which they revert to prerelapse levels in patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: From 30 days prerelapse to 550 days postrelapse, there was a significant drop in the Symbol Digit Modalities Test (SDMT) score, with the largest decline occurring at 0-30 days postrelapse (β-coefficient, −4.00; 95% CI, −4.61 to −3.39) compared with the period of remission.

Study details: This nationwide cohort study recorded 31,529 SDMTs from among 3,877 patients with incident RRMS, each having a minimum of 2 SDMT scores recorded.

Disclosures: This study was funded by a postdoctoral fellowship award to KA McKay from the Swedish Research Council for Health, Working Life, and Welfare (Forte). The authors reported no conflict of interests.

Source: McKay KA et al. Ann Neurol. 2022 Jan 4. doi: 10.1002/ana.26301.

Key clinical point: Cognitive impairments may be evaluated up to 30 days before and up to 550 days after a relapse, beyond which they revert to prerelapse levels in patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: From 30 days prerelapse to 550 days postrelapse, there was a significant drop in the Symbol Digit Modalities Test (SDMT) score, with the largest decline occurring at 0-30 days postrelapse (β-coefficient, −4.00; 95% CI, −4.61 to −3.39) compared with the period of remission.

Study details: This nationwide cohort study recorded 31,529 SDMTs from among 3,877 patients with incident RRMS, each having a minimum of 2 SDMT scores recorded.

Disclosures: This study was funded by a postdoctoral fellowship award to KA McKay from the Swedish Research Council for Health, Working Life, and Welfare (Forte). The authors reported no conflict of interests.

Source: McKay KA et al. Ann Neurol. 2022 Jan 4. doi: 10.1002/ana.26301.

Key clinical point: Treatment with interferon (IFN)-beta 1A improved the SARS-CoV-2-mRNA vaccine-specific humoral response in patients with multiple sclerosis (MS), which was significantly reduced in patients treated with cladribine, fingolimod, or ocrelizumab.

Major finding: Antispike immunoglobulin (Ig)G levels were significantly higher in IFN-treated patients with MS vs healthy controls (median, 1,916 vs 1,089; P = .029); however, antispike IgG levels were significantly lower in patients treated with cladribine (P = .002), fingolimod (P < .0001), or ocrelizumab (P < .0001).

Study details: This was a prospective monocentric study involving 149 patients with MS treated with disease-modifying therapies who were age- and gender-matched to 26 healthy controls, all of whom had no history of SARS-CoV-2 infection and received 2 doses of BNT162b2-mRNA COVID-19 vaccine.

Disclosures: This study was supported by Fondazione Italiana Sclerosi Multipla and others. The authors declared no conflict of interests.

Source: Maniscalco GT et al. Mult Scler Relat Disord. 2021 Dec 18. doi: 10.1016/j.msard.2021.103455.

Key clinical point: Treatment with interferon (IFN)-beta 1A improved the SARS-CoV-2-mRNA vaccine-specific humoral response in patients with multiple sclerosis (MS), which was significantly reduced in patients treated with cladribine, fingolimod, or ocrelizumab.

Major finding: Antispike immunoglobulin (Ig)G levels were significantly higher in IFN-treated patients with MS vs healthy controls (median, 1,916 vs 1,089; P = .029); however, antispike IgG levels were significantly lower in patients treated with cladribine (P = .002), fingolimod (P < .0001), or ocrelizumab (P < .0001).

Study details: This was a prospective monocentric study involving 149 patients with MS treated with disease-modifying therapies who were age- and gender-matched to 26 healthy controls, all of whom had no history of SARS-CoV-2 infection and received 2 doses of BNT162b2-mRNA COVID-19 vaccine.

Disclosures: This study was supported by Fondazione Italiana Sclerosi Multipla and others. The authors declared no conflict of interests.

Source: Maniscalco GT et al. Mult Scler Relat Disord. 2021 Dec 18. doi: 10.1016/j.msard.2021.103455.

Key clinical point: Treatment with interferon (IFN)-beta 1A improved the SARS-CoV-2-mRNA vaccine-specific humoral response in patients with multiple sclerosis (MS), which was significantly reduced in patients treated with cladribine, fingolimod, or ocrelizumab.

Major finding: Antispike immunoglobulin (Ig)G levels were significantly higher in IFN-treated patients with MS vs healthy controls (median, 1,916 vs 1,089; P = .029); however, antispike IgG levels were significantly lower in patients treated with cladribine (P = .002), fingolimod (P < .0001), or ocrelizumab (P < .0001).

Study details: This was a prospective monocentric study involving 149 patients with MS treated with disease-modifying therapies who were age- and gender-matched to 26 healthy controls, all of whom had no history of SARS-CoV-2 infection and received 2 doses of BNT162b2-mRNA COVID-19 vaccine.

Disclosures: This study was supported by Fondazione Italiana Sclerosi Multipla and others. The authors declared no conflict of interests.

Source: Maniscalco GT et al. Mult Scler Relat Disord. 2021 Dec 18. doi: 10.1016/j.msard.2021.103455.

Key clinical point: Discontinuation of natalizumab seemed safe in patients with multiple sclerosis (MS), who converted to secondary MS during treatment, with a high annual relapse rate (ARR) before natalizumab treatment being a risk factor for early relapse posttreatment discontinuation.

Major finding: After natalizumab discontinuation, conversion to secondary MS during treatment was protective for disease reactivation (odds ratio [OR], 0.08; P = .03), whereas ARR before treatment was the only risk factor for early relapse (OR, 1.46; P = .014).

Study details: This was a retrospective analysis of 235 patients with MS who were treated with natalizumab, of whom 105 discontinued the treatment.

Disclosures: No information on funding was provided. E Fava reported no conflict of interests, and the other authors reported receiving fees for acting as an advisor/speaker/consultant or receiving grants for travel/research from various sources.

Source: Auer M et al. Sci Rep. 2021 Dec 2. doi: 10.1038/s41598-021-02665-6.

Key clinical point: Discontinuation of natalizumab seemed safe in patients with multiple sclerosis (MS), who converted to secondary MS during treatment, with a high annual relapse rate (ARR) before natalizumab treatment being a risk factor for early relapse posttreatment discontinuation.

Major finding: After natalizumab discontinuation, conversion to secondary MS during treatment was protective for disease reactivation (odds ratio [OR], 0.08; P = .03), whereas ARR before treatment was the only risk factor for early relapse (OR, 1.46; P = .014).

Study details: This was a retrospective analysis of 235 patients with MS who were treated with natalizumab, of whom 105 discontinued the treatment.

Disclosures: No information on funding was provided. E Fava reported no conflict of interests, and the other authors reported receiving fees for acting as an advisor/speaker/consultant or receiving grants for travel/research from various sources.

Source: Auer M et al. Sci Rep. 2021 Dec 2. doi: 10.1038/s41598-021-02665-6.

Key clinical point: Discontinuation of natalizumab seemed safe in patients with multiple sclerosis (MS), who converted to secondary MS during treatment, with a high annual relapse rate (ARR) before natalizumab treatment being a risk factor for early relapse posttreatment discontinuation.

Major finding: After natalizumab discontinuation, conversion to secondary MS during treatment was protective for disease reactivation (odds ratio [OR], 0.08; P = .03), whereas ARR before treatment was the only risk factor for early relapse (OR, 1.46; P = .014).

Study details: This was a retrospective analysis of 235 patients with MS who were treated with natalizumab, of whom 105 discontinued the treatment.

Disclosures: No information on funding was provided. E Fava reported no conflict of interests, and the other authors reported receiving fees for acting as an advisor/speaker/consultant or receiving grants for travel/research from various sources.

Source: Auer M et al. Sci Rep. 2021 Dec 2. doi: 10.1038/s41598-021-02665-6.

Key clinical point: COVID-19 vaccines are safe and elicit a protective humoral response in most patients with multiple sclerosis (MS) who were treated with disease-modifying treatments (DMTs) or remained untreated, except for some patients treated with fingolimod or ocrelizumab.

Major finding: Overall, 86.8% of patients developed a positive humoral response against SARS-CoV-2, with only some patients treated with fingolimod (22.2%) or ocrelizumab (66%) failing to produce a significant humoral response (P < .01). Moreover, immunoglobulin G levels against SARS-CoV2 were significantly lower in patients treated with fingolimod or ocrelizumab than those treated with other DMTs or those who remained untreated (P < .01). None of the patients experienced any adverse events requiring hospitalization.

Study details: This was a prospective cohort study involving 140 patients with MS who were treated with different DMTs and had received vaccination for COVID-19 (mostly BNT162b2).

Disclosures: No source of funding was declared.

Source: Capone F et al. Neurotherapeutics. 2021 Dec 3. doi: 10.1007/s13311-021-01165-9.

Key clinical point: COVID-19 vaccines are safe and elicit a protective humoral response in most patients with multiple sclerosis (MS) who were treated with disease-modifying treatments (DMTs) or remained untreated, except for some patients treated with fingolimod or ocrelizumab.

Major finding: Overall, 86.8% of patients developed a positive humoral response against SARS-CoV-2, with only some patients treated with fingolimod (22.2%) or ocrelizumab (66%) failing to produce a significant humoral response (P < .01). Moreover, immunoglobulin G levels against SARS-CoV2 were significantly lower in patients treated with fingolimod or ocrelizumab than those treated with other DMTs or those who remained untreated (P < .01). None of the patients experienced any adverse events requiring hospitalization.

Study details: This was a prospective cohort study involving 140 patients with MS who were treated with different DMTs and had received vaccination for COVID-19 (mostly BNT162b2).

Disclosures: No source of funding was declared.

Source: Capone F et al. Neurotherapeutics. 2021 Dec 3. doi: 10.1007/s13311-021-01165-9.

Key clinical point: COVID-19 vaccines are safe and elicit a protective humoral response in most patients with multiple sclerosis (MS) who were treated with disease-modifying treatments (DMTs) or remained untreated, except for some patients treated with fingolimod or ocrelizumab.

Major finding: Overall, 86.8% of patients developed a positive humoral response against SARS-CoV-2, with only some patients treated with fingolimod (22.2%) or ocrelizumab (66%) failing to produce a significant humoral response (P < .01). Moreover, immunoglobulin G levels against SARS-CoV2 were significantly lower in patients treated with fingolimod or ocrelizumab than those treated with other DMTs or those who remained untreated (P < .01). None of the patients experienced any adverse events requiring hospitalization.

Study details: This was a prospective cohort study involving 140 patients with MS who were treated with different DMTs and had received vaccination for COVID-19 (mostly BNT162b2).

Disclosures: No source of funding was declared.

Source: Capone F et al. Neurotherapeutics. 2021 Dec 3. doi: 10.1007/s13311-021-01165-9.

Epstein-Barr virus (EBV) is the likely cause of multiple sclerosis (MS), new research confirms. Investigators found the risk of MS increased 32-fold following EBV infection.

This study is the first to provide compelling evidence of a causal link between EBV and MS, principal investigator Alberto Ascherio, MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health, and professor of medicine, Harvard Medical School, Boston, told this news organization.

The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Dr. Ascherio. “Now we know MS is a complication of a viral infection.” With this knowledge, he added, “we can redirect research” to find antiviral drugs to treat the disease.

The study was published online Jan. 13 in Science.
 

Unique dataset

A chronic disease of the central nervous system, MS involves an inflammatory attack on the myelin sheath and the axons it insulates. The disease affects 2.8 million people worldwide.

EBV is a human herpesvirus that can cause infectious mononucleosis. After infection, it persists in latent form in B-lymphocytes.

EBV is common and infects about 95% of adults. Most individuals are already infected with the virus by age 18 or 20 years, making it difficult to study uninfected populations, said Dr. Ascherio.

However, access to a “huge” database of more than 10 million active-duty U.S. service personnel made this possible, he said.

Service members are screened for HIV at the start of their service care and biennially thereafter. The investigators used stored blood samples to determine the relation between EBV infection and MS over a 20-year period from 1993 to 2013.

Researchers examined 801 MS case patients and 1,566 matched controls without MS. Most individuals were under 20 at the time of their first blood collection. Symptom onset for those who developed MS was a median of 10 years after the first sample was obtained.

Only one of the 801 MS case patients had no serologic evidence of EBV. This individual may have been infected with the virus after the last blood collection, failed to seroconvert in response to infection, or was misdiagnosed, the investigators note.

The hazard ratio for MS between EBV seroconversion versus persistent EBV seronegative was 32.4 (95% CI, 4.3-245.3; P < .001).
 

An MS vaccine?

MS risk was not increased after infection with cytomegalovirus, a herpesvirus that is transmitted through saliva, as is EBV.

Researchers measured serum concentrations of neurofilament light chain (sNflL), a biomarker of neuroaxonal degeneration, in samples from EBV-negative individuals at baseline. There were no signs of neuroaxonal degeneration before EBV seroconversion in subjects who later developed MS.

This indicates that “EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS,” the investigators note.

The very magnitude of increased MS risk of MS observed EBV almost completely rules out confounding by known risk factors. Smoking and vitamin D deficiency double the risk, and genetic predisposition and childhood obesity also only raise the risks of MS to a “moderate” degree, said Dr. Ascherio.

It’s not clear why only some people infected with EBV go on to develop MS, he said.

The idea that reverse causation – that immune dysregulation during the preclinical phase of MS increases susceptibility to EBV infection – is unlikely, the investigators note. For instance, EBV seroconversion occurs before elevation of sNfL levels, an early marker of preclinical MS.

Since most MS cases appear to be caused by EBV, a suitable vaccine might thwart the disease. “A vaccine could, in theory, prevent infection and prevent MS,” said Dr. Ascherio, adding that there’s ongoing work to develop such a vaccine.

Another approach is to target the virus driving MS disease progression. Developing appropriate antivirals might treat and even cure MS, said Dr. Ascherio.
 

‘Compelling data’

In an accompanying commentary, William H. Robinson, MD, PhD, professor, Division of Immunology and Rheumatology, department of medicine, Stanford (Calif.) University, and a colleague said the study findings “provide compelling data that implicate EBV as the trigger for the development of MS.”

The mechanism or mechanisms by which EBV leads to MS “remain elusive,” the commentary authors write.

“Possibilities include molecular mimicry, through which EBV viral protein sequences mimic human myelin proteins and other CNS proteins and thereby induce autoimmunity against myelin and CNS antigens,” they note.

As other factors, including genetic susceptibility, are important to MS, EBV infection is likely necessary but not sufficient to trigger MS, said the commentary. “Infection with EBV is the initial pathogenic step in MS, but additional fuses must be ignited for the full pathophysiology.”

The commentary authors query whether there may be “new opportunities” for therapy with vaccines or antivirals. “Now that the initial trigger for MS has been identified, perhaps MS could be eradicated.”

In a statement from the Science Media Center, an independent venture promoting views from the scientific community, two other experts offered their take on the study.

Paul Farrell, PhD, professor of tumor virology, Imperial College London, said the paper “provides very clear confirmation of a causal role for EBV in most cases of MS.”

While there’s evidence that a vaccine can prevent the EBV disease infectious mononucleosis, no vaccine candidate has yet prevented the virus from infecting and establishing long-term persistence in people, noted Dr. Farrell.

“So, at this stage it is not clear whether a vaccine of the types currently being developed would be able to prevent the long-term effects of EBV in MS,” he said.

Daniel Davis, PhD, professor of immunology, University of Manchester, United Kingdom, commented that the value of this new discovery is not an immediate medical cure or treatment but is “a major step forward” in understanding MS.

The study “sets up new research working out the precise details of how this virus can sometimes lead to an autoimmune disease,” said Dr. Davis. “There is no shortage of ideas in how this might happen in principle and hopefully the correct details will emerge soon.”

The study received funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Multiple Sclerosis Society, the German Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute. Dr. Ascherio reports no relevant financial relaitonships. Dr. Robinson is a coinventor on a patent application filed by Stanford University that includes antibodies to EBV. Dr. Farrell reports serving on an ad hoc review panel for GSK on EBV vaccines in 2019 as a one off. He has a current grant from MRC on EBV biology, including some EBV sequence variation, but the grant is not about MS. Dr. Davis reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Epstein-Barr virus (EBV) is the likely cause of multiple sclerosis (MS), new research confirms. Investigators found the risk of MS increased 32-fold following EBV infection.

This study is the first to provide compelling evidence of a causal link between EBV and MS, principal investigator Alberto Ascherio, MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health, and professor of medicine, Harvard Medical School, Boston, told this news organization.

The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Dr. Ascherio. “Now we know MS is a complication of a viral infection.” With this knowledge, he added, “we can redirect research” to find antiviral drugs to treat the disease.

The study was published online Jan. 13 in Science.
 

Unique dataset

A chronic disease of the central nervous system, MS involves an inflammatory attack on the myelin sheath and the axons it insulates. The disease affects 2.8 million people worldwide.

EBV is a human herpesvirus that can cause infectious mononucleosis. After infection, it persists in latent form in B-lymphocytes.

EBV is common and infects about 95% of adults. Most individuals are already infected with the virus by age 18 or 20 years, making it difficult to study uninfected populations, said Dr. Ascherio.

However, access to a “huge” database of more than 10 million active-duty U.S. service personnel made this possible, he said.

Service members are screened for HIV at the start of their service care and biennially thereafter. The investigators used stored blood samples to determine the relation between EBV infection and MS over a 20-year period from 1993 to 2013.

Researchers examined 801 MS case patients and 1,566 matched controls without MS. Most individuals were under 20 at the time of their first blood collection. Symptom onset for those who developed MS was a median of 10 years after the first sample was obtained.

Only one of the 801 MS case patients had no serologic evidence of EBV. This individual may have been infected with the virus after the last blood collection, failed to seroconvert in response to infection, or was misdiagnosed, the investigators note.

The hazard ratio for MS between EBV seroconversion versus persistent EBV seronegative was 32.4 (95% CI, 4.3-245.3; P < .001).
 

An MS vaccine?

MS risk was not increased after infection with cytomegalovirus, a herpesvirus that is transmitted through saliva, as is EBV.

Researchers measured serum concentrations of neurofilament light chain (sNflL), a biomarker of neuroaxonal degeneration, in samples from EBV-negative individuals at baseline. There were no signs of neuroaxonal degeneration before EBV seroconversion in subjects who later developed MS.

This indicates that “EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS,” the investigators note.

The very magnitude of increased MS risk of MS observed EBV almost completely rules out confounding by known risk factors. Smoking and vitamin D deficiency double the risk, and genetic predisposition and childhood obesity also only raise the risks of MS to a “moderate” degree, said Dr. Ascherio.

It’s not clear why only some people infected with EBV go on to develop MS, he said.

The idea that reverse causation – that immune dysregulation during the preclinical phase of MS increases susceptibility to EBV infection – is unlikely, the investigators note. For instance, EBV seroconversion occurs before elevation of sNfL levels, an early marker of preclinical MS.

Since most MS cases appear to be caused by EBV, a suitable vaccine might thwart the disease. “A vaccine could, in theory, prevent infection and prevent MS,” said Dr. Ascherio, adding that there’s ongoing work to develop such a vaccine.

Another approach is to target the virus driving MS disease progression. Developing appropriate antivirals might treat and even cure MS, said Dr. Ascherio.
 

‘Compelling data’

In an accompanying commentary, William H. Robinson, MD, PhD, professor, Division of Immunology and Rheumatology, department of medicine, Stanford (Calif.) University, and a colleague said the study findings “provide compelling data that implicate EBV as the trigger for the development of MS.”

The mechanism or mechanisms by which EBV leads to MS “remain elusive,” the commentary authors write.

“Possibilities include molecular mimicry, through which EBV viral protein sequences mimic human myelin proteins and other CNS proteins and thereby induce autoimmunity against myelin and CNS antigens,” they note.

As other factors, including genetic susceptibility, are important to MS, EBV infection is likely necessary but not sufficient to trigger MS, said the commentary. “Infection with EBV is the initial pathogenic step in MS, but additional fuses must be ignited for the full pathophysiology.”

The commentary authors query whether there may be “new opportunities” for therapy with vaccines or antivirals. “Now that the initial trigger for MS has been identified, perhaps MS could be eradicated.”

In a statement from the Science Media Center, an independent venture promoting views from the scientific community, two other experts offered their take on the study.

Paul Farrell, PhD, professor of tumor virology, Imperial College London, said the paper “provides very clear confirmation of a causal role for EBV in most cases of MS.”

While there’s evidence that a vaccine can prevent the EBV disease infectious mononucleosis, no vaccine candidate has yet prevented the virus from infecting and establishing long-term persistence in people, noted Dr. Farrell.

“So, at this stage it is not clear whether a vaccine of the types currently being developed would be able to prevent the long-term effects of EBV in MS,” he said.

Daniel Davis, PhD, professor of immunology, University of Manchester, United Kingdom, commented that the value of this new discovery is not an immediate medical cure or treatment but is “a major step forward” in understanding MS.

The study “sets up new research working out the precise details of how this virus can sometimes lead to an autoimmune disease,” said Dr. Davis. “There is no shortage of ideas in how this might happen in principle and hopefully the correct details will emerge soon.”

The study received funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Multiple Sclerosis Society, the German Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute. Dr. Ascherio reports no relevant financial relaitonships. Dr. Robinson is a coinventor on a patent application filed by Stanford University that includes antibodies to EBV. Dr. Farrell reports serving on an ad hoc review panel for GSK on EBV vaccines in 2019 as a one off. He has a current grant from MRC on EBV biology, including some EBV sequence variation, but the grant is not about MS. Dr. Davis reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Epstein-Barr virus (EBV) is the likely cause of multiple sclerosis (MS), new research confirms. Investigators found the risk of MS increased 32-fold following EBV infection.

This study is the first to provide compelling evidence of a causal link between EBV and MS, principal investigator Alberto Ascherio, MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health, and professor of medicine, Harvard Medical School, Boston, told this news organization.

The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Dr. Ascherio. “Now we know MS is a complication of a viral infection.” With this knowledge, he added, “we can redirect research” to find antiviral drugs to treat the disease.

The study was published online Jan. 13 in Science.
 

Unique dataset

A chronic disease of the central nervous system, MS involves an inflammatory attack on the myelin sheath and the axons it insulates. The disease affects 2.8 million people worldwide.

EBV is a human herpesvirus that can cause infectious mononucleosis. After infection, it persists in latent form in B-lymphocytes.

EBV is common and infects about 95% of adults. Most individuals are already infected with the virus by age 18 or 20 years, making it difficult to study uninfected populations, said Dr. Ascherio.

However, access to a “huge” database of more than 10 million active-duty U.S. service personnel made this possible, he said.

Service members are screened for HIV at the start of their service care and biennially thereafter. The investigators used stored blood samples to determine the relation between EBV infection and MS over a 20-year period from 1993 to 2013.

Researchers examined 801 MS case patients and 1,566 matched controls without MS. Most individuals were under 20 at the time of their first blood collection. Symptom onset for those who developed MS was a median of 10 years after the first sample was obtained.

Only one of the 801 MS case patients had no serologic evidence of EBV. This individual may have been infected with the virus after the last blood collection, failed to seroconvert in response to infection, or was misdiagnosed, the investigators note.

The hazard ratio for MS between EBV seroconversion versus persistent EBV seronegative was 32.4 (95% CI, 4.3-245.3; P < .001).
 

An MS vaccine?

MS risk was not increased after infection with cytomegalovirus, a herpesvirus that is transmitted through saliva, as is EBV.

Researchers measured serum concentrations of neurofilament light chain (sNflL), a biomarker of neuroaxonal degeneration, in samples from EBV-negative individuals at baseline. There were no signs of neuroaxonal degeneration before EBV seroconversion in subjects who later developed MS.

This indicates that “EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS,” the investigators note.

The very magnitude of increased MS risk of MS observed EBV almost completely rules out confounding by known risk factors. Smoking and vitamin D deficiency double the risk, and genetic predisposition and childhood obesity also only raise the risks of MS to a “moderate” degree, said Dr. Ascherio.

It’s not clear why only some people infected with EBV go on to develop MS, he said.

The idea that reverse causation – that immune dysregulation during the preclinical phase of MS increases susceptibility to EBV infection – is unlikely, the investigators note. For instance, EBV seroconversion occurs before elevation of sNfL levels, an early marker of preclinical MS.

Since most MS cases appear to be caused by EBV, a suitable vaccine might thwart the disease. “A vaccine could, in theory, prevent infection and prevent MS,” said Dr. Ascherio, adding that there’s ongoing work to develop such a vaccine.

Another approach is to target the virus driving MS disease progression. Developing appropriate antivirals might treat and even cure MS, said Dr. Ascherio.
 

‘Compelling data’

In an accompanying commentary, William H. Robinson, MD, PhD, professor, Division of Immunology and Rheumatology, department of medicine, Stanford (Calif.) University, and a colleague said the study findings “provide compelling data that implicate EBV as the trigger for the development of MS.”

The mechanism or mechanisms by which EBV leads to MS “remain elusive,” the commentary authors write.

“Possibilities include molecular mimicry, through which EBV viral protein sequences mimic human myelin proteins and other CNS proteins and thereby induce autoimmunity against myelin and CNS antigens,” they note.

As other factors, including genetic susceptibility, are important to MS, EBV infection is likely necessary but not sufficient to trigger MS, said the commentary. “Infection with EBV is the initial pathogenic step in MS, but additional fuses must be ignited for the full pathophysiology.”

The commentary authors query whether there may be “new opportunities” for therapy with vaccines or antivirals. “Now that the initial trigger for MS has been identified, perhaps MS could be eradicated.”

In a statement from the Science Media Center, an independent venture promoting views from the scientific community, two other experts offered their take on the study.

Paul Farrell, PhD, professor of tumor virology, Imperial College London, said the paper “provides very clear confirmation of a causal role for EBV in most cases of MS.”

While there’s evidence that a vaccine can prevent the EBV disease infectious mononucleosis, no vaccine candidate has yet prevented the virus from infecting and establishing long-term persistence in people, noted Dr. Farrell.

“So, at this stage it is not clear whether a vaccine of the types currently being developed would be able to prevent the long-term effects of EBV in MS,” he said.

Daniel Davis, PhD, professor of immunology, University of Manchester, United Kingdom, commented that the value of this new discovery is not an immediate medical cure or treatment but is “a major step forward” in understanding MS.

The study “sets up new research working out the precise details of how this virus can sometimes lead to an autoimmune disease,” said Dr. Davis. “There is no shortage of ideas in how this might happen in principle and hopefully the correct details will emerge soon.”

The study received funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Multiple Sclerosis Society, the German Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute. Dr. Ascherio reports no relevant financial relaitonships. Dr. Robinson is a coinventor on a patent application filed by Stanford University that includes antibodies to EBV. Dr. Farrell reports serving on an ad hoc review panel for GSK on EBV vaccines in 2019 as a one off. He has a current grant from MRC on EBV biology, including some EBV sequence variation, but the grant is not about MS. Dr. Davis reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

All of the above conditions can have ophthalmic manifestations, but the majority of optic neuritis cases seen in clinical practice are either sporadic or MS related. Optic neuritis is the first demyelinating event in approximately 20% of patients with MS. It develops in approximately 40% of MS patients during the course of their disease. 

Optic neuritis is characterized by loss of vision (or loss of color vision) in the affected eye and pain on movement of the eye (painful ophthalmoplegia). Less often, patients with optic neuritis may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Phosphenes may occur before or during an optic neuritis event or even several months after recovery.

The diagnosis of optic neuritis is usually made clinically, with direct imaging of the optic nerves showing evidence of optic disc swelling with blurred margins. The real contribution of imaging in the setting of optic neuritis, however, is made by imaging of the brain, not of the optic nerves themselves. MRI of the brain provides information that can change the management of optic neuritis and yields prognostic information regarding the patient's future risk of developing MS. The most valuable predictor of the development of subsequent MS is the presence of white matter abnormalities. Between 27% and 70% of patients (in various studies) with isolated optic neuritis showed abnormal MRI brain findings, as defined by the presence of two or more white matter lesions on T2-weighted images. Patients with two or more lesions may have up to an 80% chance of meeting criteria for MS within the next 5 years. 

A gradual recovery of visual acuity with time is characteristic of optic neuritis, although permanent residual deficits in color vision and contrast and brightness sensitivity are common. The symptoms of optic neuritis will usually resolve without medical treatment, although continuing to take regular MS disease-modulating medication is usually helpful. An intravenous steroid or oral prednisone is sometimes recommended to speed recovery. A 3- to 5-day course of high-dose (1 g) IV methylprednisolone, followed by a rapid oral taper of prednisone, has been shown to provide rapid recovery of symptoms in the acute phase. However, IV steroids do little to affect the ultimate visual acuity in patients with optic neuritis.

Typically, patients begin to recover 2-4 weeks after the onset of the vision loss. The optic nerve may take up to 6-12 months to heal completely, but most patients recover as much vision as they are going to within the first few months.

For patients with optic neuritis whose brain lesions on MRI indicate a high risk of developing clinically definite MS, treatment with immunomodulators may be considered. IV immunoglobulin treatment of acute optic neuritis has been shown to have no beneficial effect. In severe cases, plasma exchange may be considered.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ.

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme.

All of the above conditions can have ophthalmic manifestations, but the majority of optic neuritis cases seen in clinical practice are either sporadic or MS related. Optic neuritis is the first demyelinating event in approximately 20% of patients with MS. It develops in approximately 40% of MS patients during the course of their disease. 

Optic neuritis is characterized by loss of vision (or loss of color vision) in the affected eye and pain on movement of the eye (painful ophthalmoplegia). Less often, patients with optic neuritis may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Phosphenes may occur before or during an optic neuritis event or even several months after recovery.

The diagnosis of optic neuritis is usually made clinically, with direct imaging of the optic nerves showing evidence of optic disc swelling with blurred margins. The real contribution of imaging in the setting of optic neuritis, however, is made by imaging of the brain, not of the optic nerves themselves. MRI of the brain provides information that can change the management of optic neuritis and yields prognostic information regarding the patient's future risk of developing MS. The most valuable predictor of the development of subsequent MS is the presence of white matter abnormalities. Between 27% and 70% of patients (in various studies) with isolated optic neuritis showed abnormal MRI brain findings, as defined by the presence of two or more white matter lesions on T2-weighted images. Patients with two or more lesions may have up to an 80% chance of meeting criteria for MS within the next 5 years. 

A gradual recovery of visual acuity with time is characteristic of optic neuritis, although permanent residual deficits in color vision and contrast and brightness sensitivity are common. The symptoms of optic neuritis will usually resolve without medical treatment, although continuing to take regular MS disease-modulating medication is usually helpful. An intravenous steroid or oral prednisone is sometimes recommended to speed recovery. A 3- to 5-day course of high-dose (1 g) IV methylprednisolone, followed by a rapid oral taper of prednisone, has been shown to provide rapid recovery of symptoms in the acute phase. However, IV steroids do little to affect the ultimate visual acuity in patients with optic neuritis.

Typically, patients begin to recover 2-4 weeks after the onset of the vision loss. The optic nerve may take up to 6-12 months to heal completely, but most patients recover as much vision as they are going to within the first few months.

For patients with optic neuritis whose brain lesions on MRI indicate a high risk of developing clinically definite MS, treatment with immunomodulators may be considered. IV immunoglobulin treatment of acute optic neuritis has been shown to have no beneficial effect. In severe cases, plasma exchange may be considered.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ.

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme.

All of the above conditions can have ophthalmic manifestations, but the majority of optic neuritis cases seen in clinical practice are either sporadic or MS related. Optic neuritis is the first demyelinating event in approximately 20% of patients with MS. It develops in approximately 40% of MS patients during the course of their disease. 

Optic neuritis is characterized by loss of vision (or loss of color vision) in the affected eye and pain on movement of the eye (painful ophthalmoplegia). Less often, patients with optic neuritis may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Phosphenes may occur before or during an optic neuritis event or even several months after recovery.

The diagnosis of optic neuritis is usually made clinically, with direct imaging of the optic nerves showing evidence of optic disc swelling with blurred margins. The real contribution of imaging in the setting of optic neuritis, however, is made by imaging of the brain, not of the optic nerves themselves. MRI of the brain provides information that can change the management of optic neuritis and yields prognostic information regarding the patient's future risk of developing MS. The most valuable predictor of the development of subsequent MS is the presence of white matter abnormalities. Between 27% and 70% of patients (in various studies) with isolated optic neuritis showed abnormal MRI brain findings, as defined by the presence of two or more white matter lesions on T2-weighted images. Patients with two or more lesions may have up to an 80% chance of meeting criteria for MS within the next 5 years. 

A gradual recovery of visual acuity with time is characteristic of optic neuritis, although permanent residual deficits in color vision and contrast and brightness sensitivity are common. The symptoms of optic neuritis will usually resolve without medical treatment, although continuing to take regular MS disease-modulating medication is usually helpful. An intravenous steroid or oral prednisone is sometimes recommended to speed recovery. A 3- to 5-day course of high-dose (1 g) IV methylprednisolone, followed by a rapid oral taper of prednisone, has been shown to provide rapid recovery of symptoms in the acute phase. However, IV steroids do little to affect the ultimate visual acuity in patients with optic neuritis.

Typically, patients begin to recover 2-4 weeks after the onset of the vision loss. The optic nerve may take up to 6-12 months to heal completely, but most patients recover as much vision as they are going to within the first few months.

For patients with optic neuritis whose brain lesions on MRI indicate a high risk of developing clinically definite MS, treatment with immunomodulators may be considered. IV immunoglobulin treatment of acute optic neuritis has been shown to have no beneficial effect. In severe cases, plasma exchange may be considered.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ.

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme.

The patient has probably transitioned to the secondary progressive form of multiple sclerosis (MS). Four phenotypes have been identified in MS, with relapsing-remitting MS (RRMS) representing the most common and secondary progressive MS (SPMS) the second most common. RRMS is thought to begin as an inflammatory disease that over time becomes primarily neurodegenerative. The course of RRMS is marked by episodes of neurologic deficit followed by periods of remission which may be asymptomatic. When symptoms do not resolve — becoming fixed without remission — this is a sign of progression to SPMS. One in two RRMS patients will develop SPMS within 15 years of their diagnosis, leading to a progressive decrease of neurologic function and limitation of daily activities. Risk factors for developing SPMS include older age at onset of RRMS, longer duration of RRMS, and more cortical inflammatory lesions at baseline.

RRMS is diagnosed through clinical findings and laboratory results, the main approaches being MRI of the brain and spinal cord, and examination of cerebrospinal fluid. Neurologic symptoms must be consistent with those typically seen in MS, with deficit lasting for days to weeks. MRI is useful in monitoring disease progression (ie, new lesions that develop during relapses in RRMS). There are no universally accepted diagnostic criteria for SPMS, however. A patient usually can be diagnosed upon meeting these criteria: The patient was previously diagnosed with RRMS; the patient's symptoms are gradually worsening; this worsening is not tied to a relapse; and this worsening has been observed for 6 months or longer. Of note, SPMS' symptom-worsening characteristics can be subtle and difficult for patients to detect, and delays in diagnosis of up to several years are common.

Recognizing the onset of transition to SPMS is critical, as early initiation of therapy is thought to slow disease progression, the primary goal of treatment. In patients with SPMS, adhering to a holistic health program and managing comorbidities, especially vascular risk factors, can help preserve the health and functions of both the central nervous system and brain. Patients with SPMS who experience relapses or demonstrate new lesion formation as captured on MRI are thought to have active SPMS (aSPMS) and generally benefit from disease-modifying therapy (DMT). There is generally a transition period of about 5 years during which SPMS patients will still have a relapsing form of the disease, meaning that DMTs have proven to be effective in managing progressive MS should theoretically be beneficial for SPMS during this period. There are FDA-approved treatments for aSPMS, but off-label use is acceptable of those medications indicated for relapsing MS in those patients with evidence of relapses or new MRI activity.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme

The patient has probably transitioned to the secondary progressive form of multiple sclerosis (MS). Four phenotypes have been identified in MS, with relapsing-remitting MS (RRMS) representing the most common and secondary progressive MS (SPMS) the second most common. RRMS is thought to begin as an inflammatory disease that over time becomes primarily neurodegenerative. The course of RRMS is marked by episodes of neurologic deficit followed by periods of remission which may be asymptomatic. When symptoms do not resolve — becoming fixed without remission — this is a sign of progression to SPMS. One in two RRMS patients will develop SPMS within 15 years of their diagnosis, leading to a progressive decrease of neurologic function and limitation of daily activities. Risk factors for developing SPMS include older age at onset of RRMS, longer duration of RRMS, and more cortical inflammatory lesions at baseline.

RRMS is diagnosed through clinical findings and laboratory results, the main approaches being MRI of the brain and spinal cord, and examination of cerebrospinal fluid. Neurologic symptoms must be consistent with those typically seen in MS, with deficit lasting for days to weeks. MRI is useful in monitoring disease progression (ie, new lesions that develop during relapses in RRMS). There are no universally accepted diagnostic criteria for SPMS, however. A patient usually can be diagnosed upon meeting these criteria: The patient was previously diagnosed with RRMS; the patient's symptoms are gradually worsening; this worsening is not tied to a relapse; and this worsening has been observed for 6 months or longer. Of note, SPMS' symptom-worsening characteristics can be subtle and difficult for patients to detect, and delays in diagnosis of up to several years are common.

Recognizing the onset of transition to SPMS is critical, as early initiation of therapy is thought to slow disease progression, the primary goal of treatment. In patients with SPMS, adhering to a holistic health program and managing comorbidities, especially vascular risk factors, can help preserve the health and functions of both the central nervous system and brain. Patients with SPMS who experience relapses or demonstrate new lesion formation as captured on MRI are thought to have active SPMS (aSPMS) and generally benefit from disease-modifying therapy (DMT). There is generally a transition period of about 5 years during which SPMS patients will still have a relapsing form of the disease, meaning that DMTs have proven to be effective in managing progressive MS should theoretically be beneficial for SPMS during this period. There are FDA-approved treatments for aSPMS, but off-label use is acceptable of those medications indicated for relapsing MS in those patients with evidence of relapses or new MRI activity.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme

The patient has probably transitioned to the secondary progressive form of multiple sclerosis (MS). Four phenotypes have been identified in MS, with relapsing-remitting MS (RRMS) representing the most common and secondary progressive MS (SPMS) the second most common. RRMS is thought to begin as an inflammatory disease that over time becomes primarily neurodegenerative. The course of RRMS is marked by episodes of neurologic deficit followed by periods of remission which may be asymptomatic. When symptoms do not resolve — becoming fixed without remission — this is a sign of progression to SPMS. One in two RRMS patients will develop SPMS within 15 years of their diagnosis, leading to a progressive decrease of neurologic function and limitation of daily activities. Risk factors for developing SPMS include older age at onset of RRMS, longer duration of RRMS, and more cortical inflammatory lesions at baseline.

RRMS is diagnosed through clinical findings and laboratory results, the main approaches being MRI of the brain and spinal cord, and examination of cerebrospinal fluid. Neurologic symptoms must be consistent with those typically seen in MS, with deficit lasting for days to weeks. MRI is useful in monitoring disease progression (ie, new lesions that develop during relapses in RRMS). There are no universally accepted diagnostic criteria for SPMS, however. A patient usually can be diagnosed upon meeting these criteria: The patient was previously diagnosed with RRMS; the patient's symptoms are gradually worsening; this worsening is not tied to a relapse; and this worsening has been observed for 6 months or longer. Of note, SPMS' symptom-worsening characteristics can be subtle and difficult for patients to detect, and delays in diagnosis of up to several years are common.

Recognizing the onset of transition to SPMS is critical, as early initiation of therapy is thought to slow disease progression, the primary goal of treatment. In patients with SPMS, adhering to a holistic health program and managing comorbidities, especially vascular risk factors, can help preserve the health and functions of both the central nervous system and brain. Patients with SPMS who experience relapses or demonstrate new lesion formation as captured on MRI are thought to have active SPMS (aSPMS) and generally benefit from disease-modifying therapy (DMT). There is generally a transition period of about 5 years during which SPMS patients will still have a relapsing form of the disease, meaning that DMTs have proven to be effective in managing progressive MS should theoretically be beneficial for SPMS during this period. There are FDA-approved treatments for aSPMS, but off-label use is acceptable of those medications indicated for relapsing MS in those patients with evidence of relapses or new MRI activity.

Krupa Pandey, MD, Director, Multiple Sclerosis Center, Department of Neurology & Neuroscience Institute, Hackensack University Medical Center; Neurologist, Department of Neurology, Hackensack Meridian Health, Hackensack, NJ

Krupa Pandey, MD, has serve(d) as a speaker or a member of a speakers bureau for: Bristol-Myers Squibb; Biogen; Alexion; Genentech; Sanofi-Genzyme

Good data is lacking on best first-line MS drug strategies

Personalized medicine is just about the biggest buzzword in health. But neurologist Ellen M. Mowry, MD, of Johns Hopkins University, Baltimore, steers patients with multiple sclerosis (MS) away from the concept when she first starts talking to them about initial therapy options and possible ways to forestall disability down the line.

Learn More

Good data is lacking on best first-line MS drug strategies

Personalized medicine is just about the biggest buzzword in health. But neurologist Ellen M. Mowry, MD, of Johns Hopkins University, Baltimore, steers patients with multiple sclerosis (MS) away from the concept when she first starts talking to them about initial therapy options and possible ways to forestall disability down the line.

Learn More

Good data is lacking on best first-line MS drug strategies

Personalized medicine is just about the biggest buzzword in health. But neurologist Ellen M. Mowry, MD, of Johns Hopkins University, Baltimore, steers patients with multiple sclerosis (MS) away from the concept when she first starts talking to them about initial therapy options and possible ways to forestall disability down the line.

Learn More