Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

While working as a registered nurse on inpatient Stroke and Generalized Rehabilitation unit, she pursued for a degree in Adult and Gerontology Primary Care degree. She currently practices at UW Medicine/Harborview Medical Center for Sleep Medicine treating a variety of sleep disorders. She strives to provide quality and safe care to her patients.

1. According to the American Academy of Sleep Medicine, even in normal times, 30 to 35 % of the US population contends with acute, or short-term insomnia. As a board-certified nurse practitioner focusing on treating sleep disorders among older adults, can you discuss whether that percentage has increased during the coronavirus (COVID-19) pandemic, and if so, what would you say are the underlying reasons or causes?

As a sleep medicine nurse practitioner at UW (University of Washington) Medicine, I have seen quite a few patients with sleep disorders including acute and chronic insomnia. Since the start of  the COVID-19 pandemic there has been a noticeable increase in poor-sleep complaints -- the data indicate a 37% increase in the rate of clinical insomnia since the pandemic started.

Stress can worsen insomnia, and the pandemic has negatively affected most if not everyone’s life. It has changed lifestyles through social distancing, mask mandates, and stay-at-home orders. Many have been forced to balance working from home with household duties; parents are supervising their children’s schooling. This disruption in the workday environment and workload can be hard to manage. The uncertainty of the pandemic has increased worries – health related and financially related. Ready access to media can also increase stress. Moreover, the lack of structure in a person’s day can cause many problems. Working from home, quarantining, living a more sedentary lifestyle, losing a job, losing socialization, including attending events, all can cause a disruption in a person’s daily routine and induce later bed- and wake-up times. This disruption to the body’s biological or circadian rhythm can reduce sleep quality and INCREASE phase-delay insomnia. Moreover, the pandemic has been especially hard on people’s mental health.  One CDC study showed that 40% of adults are struggling with adverse mental health and substance-use issues due to COVID. Also, 13.3% of adults have responded to surveys saying they’ve started or increased their use of substances. As the pandemic continues, acute insomnia will likely turn into chronic insomnia.  

2. How can increased stress and lack of exercise cause insomnia? What risk factors contribute to lack of sleep and impact our overall health?

The incidence of anxiety disorder and depressive disorder has increased significantly as compared to pre-pandemic rates. Psychological stress, especially at bedtime, increases psychophysiological arousal. The hypothalamic- pituitary- adrenal (HPA) axis responds to stress by releasing cortisol. HPA activation is associated with poorer sleep quality – it increases sleep latency, frequency of awakening, decreases in slow-wave sleep, and degrades overall sleep efficiency. The result of poor quality and fragmented sleep can further activate the HPA axis, causing a positive feedback loop.

A deterrent to poor sleep is physical activity. It greatly improves sleep by improving sleep efficiency, decreasing light sleep, increasing REM sleep, and regulating circadian rhythm. Lack of physical activity has been  associated with increased sleep problems such as daytime sleepiness, an insufficient amount of sleep, snoring, sleep apnea symptoms, and restless sleep. And poor sleep further reduces physical activity which perpetuates the problem. The pandemic’s effect on physical activity is significant. It has caused people to stay home more often and therefore decreases in levels of exercise. and increased sedentary lifestyle. More than half of the adults in this country do not meet federal guidelines for aerobic physical activity.

Sleep deprivation can be dangerous, as sleepiness increases the likelihood of major occupational and road traffic accidents. Being awake for at least 18 hours is equivalent to having a blood alcohol content of 0.05% to 0.10% for 24 hours. Chronic sleep deprivation, defined as getting, on average, fewer than 7 hours per night negatively affects all systems of the body. Sleep deprivation therefore reduces quality of life and can reduce life expectancy.

Cardiovascular – Sleep deprivation can increase excessive heart age and reduce heart rate recovery after exercise. It is also linked to increases in heart rate, blood pressure, and death from cardiovascular issues.

Respiratory – Even one night of sleep deprivation can increase respiratory load. Studies have shown an association between sleep apnea and sleep deprivation. Sleep deprivation and respiratory disorders can perpetuate each other.

Neurologic – Sleep is crucial in brain development. Lack of sleep is associated with low grade neuroinflammation, memory and cognitive function decline, and acceleration of Alzheimer’s disease. Sleep deprivation can increase pain sensitivity, the risk of stroke, aggressive behavior, cognitive instability, hyperactivity, and socialization problems.

Endocrine – Sleep deprivation increases appetite stimulation causing excessive food intake and weight gain. It can also impair metabolism, which leads to obesity and insulin resistance.

Reproductive – Studies on sleep deprivation and the human reproduction system are limited. A study in male rats shows a relation between less sleep and overall lower reproductive health such as alteration of spermatic function, “decreased sexual behavior, lower testosterone level, and lower sperm viability level”. Studies also show renal dysfunction and high blood pressure in the offspring of sleep deprived rats in the last week of pregnancy.

3. Please discuss coronasomnia and its symptoms. Also, will you discuss your thoughts on the diagnosis and provide examples of the types of stressors associated with coronasomnia.

Coronasomnia is the term used to describe the increase in sleep problems associated with the COVID-19 pandemic. Coronasomnia is associated with increased sleep onset, maintenance insomnia, delayed sleep schedule, nocturnal awakening, sleep deprivation, and worsened pre-existing sleep issues. The worst insomnia and psychological symptoms are among those who are in the center of the pandemic, such as frontline workers and people living in areas more impacted by COVID-19.

During the pandemic, anxiety, depression, stress, and poor sleep have significantly increased. Anxiety and depression can be accompanied by intrusive thoughts which interfere with falling asleep. Patients with depression have a twofold risk of sleep disruption. Lack of daily routine may be associated with an increase in poor dental hygiene, such as lower rates of flossing and brushing.There’s also an increased rate in snacking (weight gain) and avoidance of visits to the dentists.

More time at home leads to more time spent on TV or social media. Increased screen time and media use at night, especially close to bedtime, are linked to poorer sleep. Blue light emitted by electronic devices can suppress the release of melatonin, making it more difficult to fall asleep. In addition, viewing or listening to content that is distressing or exciting right before bedtime negatively affects sleep quality. Following pandemic news for more than 3 hours a day has been found to be associated with increased levels of anxiety.

Health care providers are especially susceptible to coronasomnia. Those who work directly with COVID -19 patients are twice as likely to report disrupted sleep, anxiety, and depression. An increased work and patient load, the shortage of both fellow providers and supplies, all contribute to increased anxiety and disrupted sleep. Poor sleep, especially coupled with longer work hours and shift work, are associated with a worsened immune system and poor work performance. 

4. In looking at the overall challenges pertaining to pandemic-induced sleep problems, what are your guideline recommendations to help ensure we sleep well during this outbreak?

Poor sleep can be detrimental to physical and mental health, and poor sleep hygiene practices can significantly impact sleep quality. Below are some general sleep-hygiene recommendations.

Caffeine – Caffeine consumed  close to bedtime can disrupt sleep. Caffeine should be avoided 6 hours prior to bedtime. Everyone’s tolerance to caffeine is different so timing and caffeine dosage may need to be individually tailored.

Alcohol – Alcohol consumed  close to bedtime can decrease sleep latency. However, it increases arousal during the second half of the night. It can also worsen snoring and sleep apnea. The effect can be alcohol level dependent.

Exercise – Regular exercise, as already discussed, is linked to better sleep quality. It is typically recommended to exercise earlier in the day; research has shown conflicting results on nighttime exercise. One study of  patients with insomnia who exercised at night showed that aerobic exercise of moderate intensity improved polysomnography patient-reported sleep latency, and total sleep time.

Routine – An irregular sleep schedule is associated with poor sleep and daytime sleepiness. Following a consistent sleep schedule promotes stable circadian rhythm. A familiar relaxing routine should be established before bedtime.

Stress – To lower stress, patients should be advised to schedule brief meditation sessions so they can reflect on stressful situations. Patients also should limit the amount of exposure to pandemic news. Writing down and talking about stress, relaxation, and mindfulness techniques may reduce stress. However, stress and anxiety significantly differ case by case and interventions from health care providers may be needed.

Time in bed – Limit the amount of time in bed only for sleep and sex. Limit the use of electronics before bed and avoid use of electronics in bed. Turning off devices or silencing notifications can all help in reducing sleep disruption. 

Cognitive behavioral therapy for insomnia (CBT-I) should be considered for patients with chronic insomnia. This therapy often includes sleep hygiene education, sleep restriction therapy, and relaxation training.  Benefits of CBT-I treatment are long-term and reduce the need for additional pharmacologic therapies.

While many patients are experiencing insomnia these days, other underlying sleep disorders also should be  considered. Patients should be evaluated to see if a sleep specialist is needed to diagnose and treat their sleep disorders.

While working as a registered nurse on inpatient Stroke and Generalized Rehabilitation unit, she pursued for a degree in Adult and Gerontology Primary Care degree. She currently practices at UW Medicine/Harborview Medical Center for Sleep Medicine treating a variety of sleep disorders. She strives to provide quality and safe care to her patients.

1. According to the American Academy of Sleep Medicine, even in normal times, 30 to 35 % of the US population contends with acute, or short-term insomnia. As a board-certified nurse practitioner focusing on treating sleep disorders among older adults, can you discuss whether that percentage has increased during the coronavirus (COVID-19) pandemic, and if so, what would you say are the underlying reasons or causes?

As a sleep medicine nurse practitioner at UW (University of Washington) Medicine, I have seen quite a few patients with sleep disorders including acute and chronic insomnia. Since the start of  the COVID-19 pandemic there has been a noticeable increase in poor-sleep complaints -- the data indicate a 37% increase in the rate of clinical insomnia since the pandemic started.

Stress can worsen insomnia, and the pandemic has negatively affected most if not everyone’s life. It has changed lifestyles through social distancing, mask mandates, and stay-at-home orders. Many have been forced to balance working from home with household duties; parents are supervising their children’s schooling. This disruption in the workday environment and workload can be hard to manage. The uncertainty of the pandemic has increased worries – health related and financially related. Ready access to media can also increase stress. Moreover, the lack of structure in a person’s day can cause many problems. Working from home, quarantining, living a more sedentary lifestyle, losing a job, losing socialization, including attending events, all can cause a disruption in a person’s daily routine and induce later bed- and wake-up times. This disruption to the body’s biological or circadian rhythm can reduce sleep quality and INCREASE phase-delay insomnia. Moreover, the pandemic has been especially hard on people’s mental health.  One CDC study showed that 40% of adults are struggling with adverse mental health and substance-use issues due to COVID. Also, 13.3% of adults have responded to surveys saying they’ve started or increased their use of substances. As the pandemic continues, acute insomnia will likely turn into chronic insomnia.  

2. How can increased stress and lack of exercise cause insomnia? What risk factors contribute to lack of sleep and impact our overall health?

The incidence of anxiety disorder and depressive disorder has increased significantly as compared to pre-pandemic rates. Psychological stress, especially at bedtime, increases psychophysiological arousal. The hypothalamic- pituitary- adrenal (HPA) axis responds to stress by releasing cortisol. HPA activation is associated with poorer sleep quality – it increases sleep latency, frequency of awakening, decreases in slow-wave sleep, and degrades overall sleep efficiency. The result of poor quality and fragmented sleep can further activate the HPA axis, causing a positive feedback loop.

A deterrent to poor sleep is physical activity. It greatly improves sleep by improving sleep efficiency, decreasing light sleep, increasing REM sleep, and regulating circadian rhythm. Lack of physical activity has been  associated with increased sleep problems such as daytime sleepiness, an insufficient amount of sleep, snoring, sleep apnea symptoms, and restless sleep. And poor sleep further reduces physical activity which perpetuates the problem. The pandemic’s effect on physical activity is significant. It has caused people to stay home more often and therefore decreases in levels of exercise. and increased sedentary lifestyle. More than half of the adults in this country do not meet federal guidelines for aerobic physical activity.

Sleep deprivation can be dangerous, as sleepiness increases the likelihood of major occupational and road traffic accidents. Being awake for at least 18 hours is equivalent to having a blood alcohol content of 0.05% to 0.10% for 24 hours. Chronic sleep deprivation, defined as getting, on average, fewer than 7 hours per night negatively affects all systems of the body. Sleep deprivation therefore reduces quality of life and can reduce life expectancy.

Cardiovascular – Sleep deprivation can increase excessive heart age and reduce heart rate recovery after exercise. It is also linked to increases in heart rate, blood pressure, and death from cardiovascular issues.

Respiratory – Even one night of sleep deprivation can increase respiratory load. Studies have shown an association between sleep apnea and sleep deprivation. Sleep deprivation and respiratory disorders can perpetuate each other.

Neurologic – Sleep is crucial in brain development. Lack of sleep is associated with low grade neuroinflammation, memory and cognitive function decline, and acceleration of Alzheimer’s disease. Sleep deprivation can increase pain sensitivity, the risk of stroke, aggressive behavior, cognitive instability, hyperactivity, and socialization problems.

Endocrine – Sleep deprivation increases appetite stimulation causing excessive food intake and weight gain. It can also impair metabolism, which leads to obesity and insulin resistance.

Reproductive – Studies on sleep deprivation and the human reproduction system are limited. A study in male rats shows a relation between less sleep and overall lower reproductive health such as alteration of spermatic function, “decreased sexual behavior, lower testosterone level, and lower sperm viability level”. Studies also show renal dysfunction and high blood pressure in the offspring of sleep deprived rats in the last week of pregnancy.

3. Please discuss coronasomnia and its symptoms. Also, will you discuss your thoughts on the diagnosis and provide examples of the types of stressors associated with coronasomnia.

Coronasomnia is the term used to describe the increase in sleep problems associated with the COVID-19 pandemic. Coronasomnia is associated with increased sleep onset, maintenance insomnia, delayed sleep schedule, nocturnal awakening, sleep deprivation, and worsened pre-existing sleep issues. The worst insomnia and psychological symptoms are among those who are in the center of the pandemic, such as frontline workers and people living in areas more impacted by COVID-19.

During the pandemic, anxiety, depression, stress, and poor sleep have significantly increased. Anxiety and depression can be accompanied by intrusive thoughts which interfere with falling asleep. Patients with depression have a twofold risk of sleep disruption. Lack of daily routine may be associated with an increase in poor dental hygiene, such as lower rates of flossing and brushing.There’s also an increased rate in snacking (weight gain) and avoidance of visits to the dentists.

More time at home leads to more time spent on TV or social media. Increased screen time and media use at night, especially close to bedtime, are linked to poorer sleep. Blue light emitted by electronic devices can suppress the release of melatonin, making it more difficult to fall asleep. In addition, viewing or listening to content that is distressing or exciting right before bedtime negatively affects sleep quality. Following pandemic news for more than 3 hours a day has been found to be associated with increased levels of anxiety.

Health care providers are especially susceptible to coronasomnia. Those who work directly with COVID -19 patients are twice as likely to report disrupted sleep, anxiety, and depression. An increased work and patient load, the shortage of both fellow providers and supplies, all contribute to increased anxiety and disrupted sleep. Poor sleep, especially coupled with longer work hours and shift work, are associated with a worsened immune system and poor work performance. 

4. In looking at the overall challenges pertaining to pandemic-induced sleep problems, what are your guideline recommendations to help ensure we sleep well during this outbreak?

Poor sleep can be detrimental to physical and mental health, and poor sleep hygiene practices can significantly impact sleep quality. Below are some general sleep-hygiene recommendations.

Caffeine – Caffeine consumed  close to bedtime can disrupt sleep. Caffeine should be avoided 6 hours prior to bedtime. Everyone’s tolerance to caffeine is different so timing and caffeine dosage may need to be individually tailored.

Alcohol – Alcohol consumed  close to bedtime can decrease sleep latency. However, it increases arousal during the second half of the night. It can also worsen snoring and sleep apnea. The effect can be alcohol level dependent.

Exercise – Regular exercise, as already discussed, is linked to better sleep quality. It is typically recommended to exercise earlier in the day; research has shown conflicting results on nighttime exercise. One study of  patients with insomnia who exercised at night showed that aerobic exercise of moderate intensity improved polysomnography patient-reported sleep latency, and total sleep time.

Routine – An irregular sleep schedule is associated with poor sleep and daytime sleepiness. Following a consistent sleep schedule promotes stable circadian rhythm. A familiar relaxing routine should be established before bedtime.

Stress – To lower stress, patients should be advised to schedule brief meditation sessions so they can reflect on stressful situations. Patients also should limit the amount of exposure to pandemic news. Writing down and talking about stress, relaxation, and mindfulness techniques may reduce stress. However, stress and anxiety significantly differ case by case and interventions from health care providers may be needed.

Time in bed – Limit the amount of time in bed only for sleep and sex. Limit the use of electronics before bed and avoid use of electronics in bed. Turning off devices or silencing notifications can all help in reducing sleep disruption. 

Cognitive behavioral therapy for insomnia (CBT-I) should be considered for patients with chronic insomnia. This therapy often includes sleep hygiene education, sleep restriction therapy, and relaxation training.  Benefits of CBT-I treatment are long-term and reduce the need for additional pharmacologic therapies.

While many patients are experiencing insomnia these days, other underlying sleep disorders also should be  considered. Patients should be evaluated to see if a sleep specialist is needed to diagnose and treat their sleep disorders.

While working as a registered nurse on inpatient Stroke and Generalized Rehabilitation unit, she pursued for a degree in Adult and Gerontology Primary Care degree. She currently practices at UW Medicine/Harborview Medical Center for Sleep Medicine treating a variety of sleep disorders. She strives to provide quality and safe care to her patients.

1. According to the American Academy of Sleep Medicine, even in normal times, 30 to 35 % of the US population contends with acute, or short-term insomnia. As a board-certified nurse practitioner focusing on treating sleep disorders among older adults, can you discuss whether that percentage has increased during the coronavirus (COVID-19) pandemic, and if so, what would you say are the underlying reasons or causes?

As a sleep medicine nurse practitioner at UW (University of Washington) Medicine, I have seen quite a few patients with sleep disorders including acute and chronic insomnia. Since the start of  the COVID-19 pandemic there has been a noticeable increase in poor-sleep complaints -- the data indicate a 37% increase in the rate of clinical insomnia since the pandemic started.

Stress can worsen insomnia, and the pandemic has negatively affected most if not everyone’s life. It has changed lifestyles through social distancing, mask mandates, and stay-at-home orders. Many have been forced to balance working from home with household duties; parents are supervising their children’s schooling. This disruption in the workday environment and workload can be hard to manage. The uncertainty of the pandemic has increased worries – health related and financially related. Ready access to media can also increase stress. Moreover, the lack of structure in a person’s day can cause many problems. Working from home, quarantining, living a more sedentary lifestyle, losing a job, losing socialization, including attending events, all can cause a disruption in a person’s daily routine and induce later bed- and wake-up times. This disruption to the body’s biological or circadian rhythm can reduce sleep quality and INCREASE phase-delay insomnia. Moreover, the pandemic has been especially hard on people’s mental health.  One CDC study showed that 40% of adults are struggling with adverse mental health and substance-use issues due to COVID. Also, 13.3% of adults have responded to surveys saying they’ve started or increased their use of substances. As the pandemic continues, acute insomnia will likely turn into chronic insomnia.  

2. How can increased stress and lack of exercise cause insomnia? What risk factors contribute to lack of sleep and impact our overall health?

The incidence of anxiety disorder and depressive disorder has increased significantly as compared to pre-pandemic rates. Psychological stress, especially at bedtime, increases psychophysiological arousal. The hypothalamic- pituitary- adrenal (HPA) axis responds to stress by releasing cortisol. HPA activation is associated with poorer sleep quality – it increases sleep latency, frequency of awakening, decreases in slow-wave sleep, and degrades overall sleep efficiency. The result of poor quality and fragmented sleep can further activate the HPA axis, causing a positive feedback loop.

A deterrent to poor sleep is physical activity. It greatly improves sleep by improving sleep efficiency, decreasing light sleep, increasing REM sleep, and regulating circadian rhythm. Lack of physical activity has been  associated with increased sleep problems such as daytime sleepiness, an insufficient amount of sleep, snoring, sleep apnea symptoms, and restless sleep. And poor sleep further reduces physical activity which perpetuates the problem. The pandemic’s effect on physical activity is significant. It has caused people to stay home more often and therefore decreases in levels of exercise. and increased sedentary lifestyle. More than half of the adults in this country do not meet federal guidelines for aerobic physical activity.

Sleep deprivation can be dangerous, as sleepiness increases the likelihood of major occupational and road traffic accidents. Being awake for at least 18 hours is equivalent to having a blood alcohol content of 0.05% to 0.10% for 24 hours. Chronic sleep deprivation, defined as getting, on average, fewer than 7 hours per night negatively affects all systems of the body. Sleep deprivation therefore reduces quality of life and can reduce life expectancy.

Cardiovascular – Sleep deprivation can increase excessive heart age and reduce heart rate recovery after exercise. It is also linked to increases in heart rate, blood pressure, and death from cardiovascular issues.

Respiratory – Even one night of sleep deprivation can increase respiratory load. Studies have shown an association between sleep apnea and sleep deprivation. Sleep deprivation and respiratory disorders can perpetuate each other.

Neurologic – Sleep is crucial in brain development. Lack of sleep is associated with low grade neuroinflammation, memory and cognitive function decline, and acceleration of Alzheimer’s disease. Sleep deprivation can increase pain sensitivity, the risk of stroke, aggressive behavior, cognitive instability, hyperactivity, and socialization problems.

Endocrine – Sleep deprivation increases appetite stimulation causing excessive food intake and weight gain. It can also impair metabolism, which leads to obesity and insulin resistance.

Reproductive – Studies on sleep deprivation and the human reproduction system are limited. A study in male rats shows a relation between less sleep and overall lower reproductive health such as alteration of spermatic function, “decreased sexual behavior, lower testosterone level, and lower sperm viability level”. Studies also show renal dysfunction and high blood pressure in the offspring of sleep deprived rats in the last week of pregnancy.

3. Please discuss coronasomnia and its symptoms. Also, will you discuss your thoughts on the diagnosis and provide examples of the types of stressors associated with coronasomnia.

Coronasomnia is the term used to describe the increase in sleep problems associated with the COVID-19 pandemic. Coronasomnia is associated with increased sleep onset, maintenance insomnia, delayed sleep schedule, nocturnal awakening, sleep deprivation, and worsened pre-existing sleep issues. The worst insomnia and psychological symptoms are among those who are in the center of the pandemic, such as frontline workers and people living in areas more impacted by COVID-19.

During the pandemic, anxiety, depression, stress, and poor sleep have significantly increased. Anxiety and depression can be accompanied by intrusive thoughts which interfere with falling asleep. Patients with depression have a twofold risk of sleep disruption. Lack of daily routine may be associated with an increase in poor dental hygiene, such as lower rates of flossing and brushing.There’s also an increased rate in snacking (weight gain) and avoidance of visits to the dentists.

More time at home leads to more time spent on TV or social media. Increased screen time and media use at night, especially close to bedtime, are linked to poorer sleep. Blue light emitted by electronic devices can suppress the release of melatonin, making it more difficult to fall asleep. In addition, viewing or listening to content that is distressing or exciting right before bedtime negatively affects sleep quality. Following pandemic news for more than 3 hours a day has been found to be associated with increased levels of anxiety.

Health care providers are especially susceptible to coronasomnia. Those who work directly with COVID -19 patients are twice as likely to report disrupted sleep, anxiety, and depression. An increased work and patient load, the shortage of both fellow providers and supplies, all contribute to increased anxiety and disrupted sleep. Poor sleep, especially coupled with longer work hours and shift work, are associated with a worsened immune system and poor work performance. 

4. In looking at the overall challenges pertaining to pandemic-induced sleep problems, what are your guideline recommendations to help ensure we sleep well during this outbreak?

Poor sleep can be detrimental to physical and mental health, and poor sleep hygiene practices can significantly impact sleep quality. Below are some general sleep-hygiene recommendations.

Caffeine – Caffeine consumed  close to bedtime can disrupt sleep. Caffeine should be avoided 6 hours prior to bedtime. Everyone’s tolerance to caffeine is different so timing and caffeine dosage may need to be individually tailored.

Alcohol – Alcohol consumed  close to bedtime can decrease sleep latency. However, it increases arousal during the second half of the night. It can also worsen snoring and sleep apnea. The effect can be alcohol level dependent.

Exercise – Regular exercise, as already discussed, is linked to better sleep quality. It is typically recommended to exercise earlier in the day; research has shown conflicting results on nighttime exercise. One study of  patients with insomnia who exercised at night showed that aerobic exercise of moderate intensity improved polysomnography patient-reported sleep latency, and total sleep time.

Routine – An irregular sleep schedule is associated with poor sleep and daytime sleepiness. Following a consistent sleep schedule promotes stable circadian rhythm. A familiar relaxing routine should be established before bedtime.

Stress – To lower stress, patients should be advised to schedule brief meditation sessions so they can reflect on stressful situations. Patients also should limit the amount of exposure to pandemic news. Writing down and talking about stress, relaxation, and mindfulness techniques may reduce stress. However, stress and anxiety significantly differ case by case and interventions from health care providers may be needed.

Time in bed – Limit the amount of time in bed only for sleep and sex. Limit the use of electronics before bed and avoid use of electronics in bed. Turning off devices or silencing notifications can all help in reducing sleep disruption. 

Cognitive behavioral therapy for insomnia (CBT-I) should be considered for patients with chronic insomnia. This therapy often includes sleep hygiene education, sleep restriction therapy, and relaxation training.  Benefits of CBT-I treatment are long-term and reduce the need for additional pharmacologic therapies.

While many patients are experiencing insomnia these days, other underlying sleep disorders also should be  considered. Patients should be evaluated to see if a sleep specialist is needed to diagnose and treat their sleep disorders.

 Stephanie J. Estes, MD is a board certified Obstetrician/Gynecologist and Professor of Reproductive Endocrinology and Infertility at the Penn State Hershey Medical center in Hershey, Pennsylvania.  As a subspecialist, she has a focus on endometriosis and fibroid research and also advances the care of women through advanced reproductive surgery techniques and robotic surgery. 

Q: At what point do you consider medical therapies in your approach to a patient with endometriosis?

Dr. Estes: I consider medical therapies for every patient that I see. There are 3 categories that I think about:

• Are they a candidate for medical therapy?
• Are they a candidate for surgical therapy?
• Lastly, are they a candidate for fertility treatment?

The difference between the plans is if the patient desires fertility. Next, I consider the advantages and disadvantages of medical therapy. The pros of medical therapy are avoiding the risks of surgery, with known and unknown complications or adhesions. And the cons are side effects of medical therapy. Also, medical therapy does not address treating hydrosalpinges, endometriomas, or other deep infiltrating nodules and, clearly, it also inhibits fertility treatment. So, my overall process is looking at the patient’s goal of symptom management and how best to limit their number of surgical procedures. My approach spans many options, and I look at all of those to make an appropriate decision for each patient.

Q: How do you determine what options would be best suited for the patient?

Dr. Estes: The first line of symptom treatment best suited for the patient is always NSAIDs, which are nonsteroidal anti-inflammatory drugs. These are an appropriate first start in managing the dysmenorrhea and pelvic pain that can be associated with endometriosis. If there are no contraindications, the next most common way to manage endometriosis symptoms is combined oral contraceptive pills, transdermal patches, or rings. A key principle, especially when selecting a pill, is to look at the type of estrogen and progestin you’re choosing. Some practitioners may see these pills as equals, but there are differences. I always select a 20-µm ethinyl estradiol pill for my endometriosis patients. Then, I select a progestin, such as norethindrone or levonorgestrel, which provide good suppressive treatment.

The preferred hormonal therapy for endometriosis symptoms not only should be easy for the patient to use but also accomplish management of the symptoms that they are coming in for. Hormonal therapies have a low side-effect profile, which allows the patient to feel well for a long time. We know that endometriosis is a chronic disease, so this is something that the patient is going to need to manage for a long time. I really like to help my patients because they have other things to do in life. They want to take care of their kids, or they’re in school, or have other goals. Patients want to feel well while doing all these activities of life, and so an individualized approach is important. Some of my patients love taking pills, and they are perfectly happy to do so. Other people would prefer a more long-acting treatment so that they do not have to deal with remembering to take a medication every day.

Q: Explain how you would apply the use of an intrauterine device (IUD) to manage endometriosis. 

Dr. Estes: I use many IUDs with progestin because evidence has shown them to be effective in managing endometriosis symptoms, specifically by decreasing dysmenorrhea. I will usually insert them during a patient’s surgery in the operating room. If I identify endometriosis and can place the IUD at the same time of the surgery, this see-and-treat philosophy maximizes the efficiency of patient care—and the patient avoids the discomfort of an in-office insertion. During the patient’s post-operative check, I evaluate how they feel and how the IUD is working for them. I think many patients are candidates for progestin IUDs, especially those who cannot take an estrogen-containing compound.

Q: Where do newly available therapies for endometriosis fit into your overall management approach?

Dr. Estes: Norethindrone 5 mg is an effective treatment for endometriosis and it is US Food and Drug Administration (FDA)‒approved for that cause. And then, the other medications that Penn State Hershey was part of the clinical trials for include Gonadotropin-releasing hormone (GnRH) antagonists such as elagolix. I saw the improvement in symptoms not only in the trial but also in continued follow-up of patients. GnRH antagonists are a group of medications that have a very good side-effect profile. Patients typically do not have significant side effects, however, hot flashes can me common. Hot flashes that can be ameliorated with some add back hormone therapy. The other drugs in the pipeline are relugolix and linzagolix. Relugolix is FDA approved for prostate cancer treatment. Endometriosis trials are expensive, and they are long and hard to do because of the pain factor—people do not want to stop their other medications to do the trial; however, the use of these medications will continue to be studied, and I look further to continuing to fine tune treatment options

Q: Is cost to the patient a consideration during management counseling, and should it be? 

Dr. Estes: Absolutely. It comes up in every conversation because endometriosis is a long-term disease process that needs to be managed throughout the life cycle of a woman; you cannot have something that is going to be so expensive that will have to be taken for years and years or is not going to be continued. Because cost is critical, I use Lupron Depot as well as letrozole, and goserelin implants are also approved for endometriosis treatment. I also occasionally use danazol, which is a very different mechanism of action in select patients, so multiple options are all present. We have streamlined our pre-approval process for the GnRH antagonists to make it fairly easy.

It used to be a little bit harder, but now, if a patient has found that other medications did not offer relief for her endometriosis, then GnRH antagonists are much easier to obtain.

Q: Is there anything else you’d like to add?

Dr. Estes: Our patient involvement in clinical trials is just so valuable for endometriosis disease research. So, anyone out there living with endometriosis who would like to help medical science—wherever you live, wherever you are—get involved because this can help not only you but also the next person who comes after you. We are currently participating in a study right now on quinagolide. It is a vaginal ring that is not hormonal.

Again, we want to keep all options open and see what works and does not work. Science is so fantastic, and it is one of those summary points to note that we always need more information in terms of endometriosis. We really are aspiring to develop and apply treatment options that are effective throughout the lifespan of those affected by endometriosis.

 Stephanie J. Estes, MD is a board certified Obstetrician/Gynecologist and Professor of Reproductive Endocrinology and Infertility at the Penn State Hershey Medical center in Hershey, Pennsylvania.  As a subspecialist, she has a focus on endometriosis and fibroid research and also advances the care of women through advanced reproductive surgery techniques and robotic surgery. 

Q: At what point do you consider medical therapies in your approach to a patient with endometriosis?

Dr. Estes: I consider medical therapies for every patient that I see. There are 3 categories that I think about:

• Are they a candidate for medical therapy?
• Are they a candidate for surgical therapy?
• Lastly, are they a candidate for fertility treatment?

The difference between the plans is if the patient desires fertility. Next, I consider the advantages and disadvantages of medical therapy. The pros of medical therapy are avoiding the risks of surgery, with known and unknown complications or adhesions. And the cons are side effects of medical therapy. Also, medical therapy does not address treating hydrosalpinges, endometriomas, or other deep infiltrating nodules and, clearly, it also inhibits fertility treatment. So, my overall process is looking at the patient’s goal of symptom management and how best to limit their number of surgical procedures. My approach spans many options, and I look at all of those to make an appropriate decision for each patient.

Q: How do you determine what options would be best suited for the patient?

Dr. Estes: The first line of symptom treatment best suited for the patient is always NSAIDs, which are nonsteroidal anti-inflammatory drugs. These are an appropriate first start in managing the dysmenorrhea and pelvic pain that can be associated with endometriosis. If there are no contraindications, the next most common way to manage endometriosis symptoms is combined oral contraceptive pills, transdermal patches, or rings. A key principle, especially when selecting a pill, is to look at the type of estrogen and progestin you’re choosing. Some practitioners may see these pills as equals, but there are differences. I always select a 20-µm ethinyl estradiol pill for my endometriosis patients. Then, I select a progestin, such as norethindrone or levonorgestrel, which provide good suppressive treatment.

The preferred hormonal therapy for endometriosis symptoms not only should be easy for the patient to use but also accomplish management of the symptoms that they are coming in for. Hormonal therapies have a low side-effect profile, which allows the patient to feel well for a long time. We know that endometriosis is a chronic disease, so this is something that the patient is going to need to manage for a long time. I really like to help my patients because they have other things to do in life. They want to take care of their kids, or they’re in school, or have other goals. Patients want to feel well while doing all these activities of life, and so an individualized approach is important. Some of my patients love taking pills, and they are perfectly happy to do so. Other people would prefer a more long-acting treatment so that they do not have to deal with remembering to take a medication every day.

Q: Explain how you would apply the use of an intrauterine device (IUD) to manage endometriosis. 

Dr. Estes: I use many IUDs with progestin because evidence has shown them to be effective in managing endometriosis symptoms, specifically by decreasing dysmenorrhea. I will usually insert them during a patient’s surgery in the operating room. If I identify endometriosis and can place the IUD at the same time of the surgery, this see-and-treat philosophy maximizes the efficiency of patient care—and the patient avoids the discomfort of an in-office insertion. During the patient’s post-operative check, I evaluate how they feel and how the IUD is working for them. I think many patients are candidates for progestin IUDs, especially those who cannot take an estrogen-containing compound.

Q: Where do newly available therapies for endometriosis fit into your overall management approach?

Dr. Estes: Norethindrone 5 mg is an effective treatment for endometriosis and it is US Food and Drug Administration (FDA)‒approved for that cause. And then, the other medications that Penn State Hershey was part of the clinical trials for include Gonadotropin-releasing hormone (GnRH) antagonists such as elagolix. I saw the improvement in symptoms not only in the trial but also in continued follow-up of patients. GnRH antagonists are a group of medications that have a very good side-effect profile. Patients typically do not have significant side effects, however, hot flashes can me common. Hot flashes that can be ameliorated with some add back hormone therapy. The other drugs in the pipeline are relugolix and linzagolix. Relugolix is FDA approved for prostate cancer treatment. Endometriosis trials are expensive, and they are long and hard to do because of the pain factor—people do not want to stop their other medications to do the trial; however, the use of these medications will continue to be studied, and I look further to continuing to fine tune treatment options

Q: Is cost to the patient a consideration during management counseling, and should it be? 

Dr. Estes: Absolutely. It comes up in every conversation because endometriosis is a long-term disease process that needs to be managed throughout the life cycle of a woman; you cannot have something that is going to be so expensive that will have to be taken for years and years or is not going to be continued. Because cost is critical, I use Lupron Depot as well as letrozole, and goserelin implants are also approved for endometriosis treatment. I also occasionally use danazol, which is a very different mechanism of action in select patients, so multiple options are all present. We have streamlined our pre-approval process for the GnRH antagonists to make it fairly easy.

It used to be a little bit harder, but now, if a patient has found that other medications did not offer relief for her endometriosis, then GnRH antagonists are much easier to obtain.

Q: Is there anything else you’d like to add?

Dr. Estes: Our patient involvement in clinical trials is just so valuable for endometriosis disease research. So, anyone out there living with endometriosis who would like to help medical science—wherever you live, wherever you are—get involved because this can help not only you but also the next person who comes after you. We are currently participating in a study right now on quinagolide. It is a vaginal ring that is not hormonal.

Again, we want to keep all options open and see what works and does not work. Science is so fantastic, and it is one of those summary points to note that we always need more information in terms of endometriosis. We really are aspiring to develop and apply treatment options that are effective throughout the lifespan of those affected by endometriosis.

 Stephanie J. Estes, MD is a board certified Obstetrician/Gynecologist and Professor of Reproductive Endocrinology and Infertility at the Penn State Hershey Medical center in Hershey, Pennsylvania.  As a subspecialist, she has a focus on endometriosis and fibroid research and also advances the care of women through advanced reproductive surgery techniques and robotic surgery. 

Q: At what point do you consider medical therapies in your approach to a patient with endometriosis?

Dr. Estes: I consider medical therapies for every patient that I see. There are 3 categories that I think about:

• Are they a candidate for medical therapy?
• Are they a candidate for surgical therapy?
• Lastly, are they a candidate for fertility treatment?

The difference between the plans is if the patient desires fertility. Next, I consider the advantages and disadvantages of medical therapy. The pros of medical therapy are avoiding the risks of surgery, with known and unknown complications or adhesions. And the cons are side effects of medical therapy. Also, medical therapy does not address treating hydrosalpinges, endometriomas, or other deep infiltrating nodules and, clearly, it also inhibits fertility treatment. So, my overall process is looking at the patient’s goal of symptom management and how best to limit their number of surgical procedures. My approach spans many options, and I look at all of those to make an appropriate decision for each patient.

Q: How do you determine what options would be best suited for the patient?

Dr. Estes: The first line of symptom treatment best suited for the patient is always NSAIDs, which are nonsteroidal anti-inflammatory drugs. These are an appropriate first start in managing the dysmenorrhea and pelvic pain that can be associated with endometriosis. If there are no contraindications, the next most common way to manage endometriosis symptoms is combined oral contraceptive pills, transdermal patches, or rings. A key principle, especially when selecting a pill, is to look at the type of estrogen and progestin you’re choosing. Some practitioners may see these pills as equals, but there are differences. I always select a 20-µm ethinyl estradiol pill for my endometriosis patients. Then, I select a progestin, such as norethindrone or levonorgestrel, which provide good suppressive treatment.

The preferred hormonal therapy for endometriosis symptoms not only should be easy for the patient to use but also accomplish management of the symptoms that they are coming in for. Hormonal therapies have a low side-effect profile, which allows the patient to feel well for a long time. We know that endometriosis is a chronic disease, so this is something that the patient is going to need to manage for a long time. I really like to help my patients because they have other things to do in life. They want to take care of their kids, or they’re in school, or have other goals. Patients want to feel well while doing all these activities of life, and so an individualized approach is important. Some of my patients love taking pills, and they are perfectly happy to do so. Other people would prefer a more long-acting treatment so that they do not have to deal with remembering to take a medication every day.

Q: Explain how you would apply the use of an intrauterine device (IUD) to manage endometriosis. 

Dr. Estes: I use many IUDs with progestin because evidence has shown them to be effective in managing endometriosis symptoms, specifically by decreasing dysmenorrhea. I will usually insert them during a patient’s surgery in the operating room. If I identify endometriosis and can place the IUD at the same time of the surgery, this see-and-treat philosophy maximizes the efficiency of patient care—and the patient avoids the discomfort of an in-office insertion. During the patient’s post-operative check, I evaluate how they feel and how the IUD is working for them. I think many patients are candidates for progestin IUDs, especially those who cannot take an estrogen-containing compound.

Q: Where do newly available therapies for endometriosis fit into your overall management approach?

Dr. Estes: Norethindrone 5 mg is an effective treatment for endometriosis and it is US Food and Drug Administration (FDA)‒approved for that cause. And then, the other medications that Penn State Hershey was part of the clinical trials for include Gonadotropin-releasing hormone (GnRH) antagonists such as elagolix. I saw the improvement in symptoms not only in the trial but also in continued follow-up of patients. GnRH antagonists are a group of medications that have a very good side-effect profile. Patients typically do not have significant side effects, however, hot flashes can me common. Hot flashes that can be ameliorated with some add back hormone therapy. The other drugs in the pipeline are relugolix and linzagolix. Relugolix is FDA approved for prostate cancer treatment. Endometriosis trials are expensive, and they are long and hard to do because of the pain factor—people do not want to stop their other medications to do the trial; however, the use of these medications will continue to be studied, and I look further to continuing to fine tune treatment options

Q: Is cost to the patient a consideration during management counseling, and should it be? 

Dr. Estes: Absolutely. It comes up in every conversation because endometriosis is a long-term disease process that needs to be managed throughout the life cycle of a woman; you cannot have something that is going to be so expensive that will have to be taken for years and years or is not going to be continued. Because cost is critical, I use Lupron Depot as well as letrozole, and goserelin implants are also approved for endometriosis treatment. I also occasionally use danazol, which is a very different mechanism of action in select patients, so multiple options are all present. We have streamlined our pre-approval process for the GnRH antagonists to make it fairly easy.

It used to be a little bit harder, but now, if a patient has found that other medications did not offer relief for her endometriosis, then GnRH antagonists are much easier to obtain.

Q: Is there anything else you’d like to add?

Dr. Estes: Our patient involvement in clinical trials is just so valuable for endometriosis disease research. So, anyone out there living with endometriosis who would like to help medical science—wherever you live, wherever you are—get involved because this can help not only you but also the next person who comes after you. We are currently participating in a study right now on quinagolide. It is a vaginal ring that is not hormonal.

Again, we want to keep all options open and see what works and does not work. Science is so fantastic, and it is one of those summary points to note that we always need more information in terms of endometriosis. We really are aspiring to develop and apply treatment options that are effective throughout the lifespan of those affected by endometriosis.

Naila Makhani, MD completed medical school training at the University of British Columbia (Vancouver, Canada). This was followed by a residency in child neurology and fellowship in MS and other demyelinating diseases at the University of Toronto and The Hospital for Sick Children (Toronto, Canada). Concurrent with fellowship training, Dr. Makhani obtained a Masters’ degree in public health from Harvard University. Dr. Makhani is the Director of the Pediatric MS Program at Yale and the lead investigator of a multi-center international study examining outcomes following the radiologically isolated syndrome in children.

Q1. Could you please provide an overview of Radiologically Isolated Syndrome ?

A1. Radiologically Isolated Syndrome (RIS) was first described in adults in 2009. Since then it has also been increasingly recognized and diagnosed in children. RIS is diagnosed after an MRI of the brain that the patient has sought for reasons other than suspected multiple sclerosis-- for instance, for evaluation of head trauma or headache. However, unexpectedly or incidentally, the patient’s MRI shows the typical findings that we see in multiple sclerosis, even in the absence of any typical clinical symptoms. RIS is generally considered a rare syndrome.

Q2. You created Yale Medicine’s Pediatric Multiple Sclerosis program which advocates for the eradication of MS. What  criteria defines a rare disease? Does RIS meet these criteria? And if so, how?

A2. The criteria for a rare disease vary, depending on the reference. In the US, a rare disease is defined as a condition that affects fewer than 200,000 people, in total, across the country.  By contrast, in Europe, a disease is considered rare if it affects fewer than one in every 2,000 people within the country’s population.

In the case of RIS, especially in children, we suspect that this is a rare condition, but we don't know for sure, as there have been very few population-based studies. There is one large study that was conducted in Europe that found one case of RIS among approximately 5,000 otherwise healthy children, who were between 7 and 14 years of age.  I think that's our best estimate of the overall prevalence of RIS in children. Using that finding, it likely would qualify as a rare condition, although, as I said, we really don't know for sure, as the prevalence may vary among different populations or age groups.

Q3. How do you investigate and manage RIS in children? What are some of the challenges?  

A3. For children with radiologically isolated syndrome, we usually undertake a comprehensive workup. This includes a detailed clinical neurological exam to ensure that there are no abnormalities that would, for instance, suggest a misdiagnosis of multiple sclerosis or an alternative diagnosis. In addition to the brain MRI, we usually obtain an MRI of the spinal cord to determine whether there is any spinal cord involvement. We also obtain blood tests. We often analyze spinal fluid as well, primarily to exclude other alternative processes that may explain the  MRI findings. A key challenge in this field is that there are currently no formal guidelines for the investigation and management of children with RIS. Collaborations within the pediatric MS community are needed to develop such consensus approaches to standardize care.

Q4. What are the most significant risk factors that indicate children with RIS could one day develop multiple sclerosis?

A4.This is an area of active research within our group. So far, we've found that approximately 42% of children with RIS develop multiple sclerosis in the future; on average, two years following their first abnormal MRI. Therefore, this is a high-risk group for developing  multiple sclerosis in the future. Thus far, we've determined that in children with RIS, it is the presence of abnormal spinal cord imaging and an abnormality in spinal fluid – namely, the presence of oligoclonal bands – that are likely the predictors of whether these children could develop MS in the future. a child’s possible development 

Q5. Based on your recent studies, are there data in children highlighting the potential for higher prevalence  in one population over another?

A5. Thus far, population-based studies assessing RIS, especially in children, have been rare and thus far have not identified particular subgroups with increased prevalence. We do know that the prevalence of multiple sclerosis varies across different age groups and across gender. Whether such associations are also present for RIS is an area of active research.

Naila Makhani, MD completed medical school training at the University of British Columbia (Vancouver, Canada). This was followed by a residency in child neurology and fellowship in MS and other demyelinating diseases at the University of Toronto and The Hospital for Sick Children (Toronto, Canada). Concurrent with fellowship training, Dr. Makhani obtained a Masters’ degree in public health from Harvard University. Dr. Makhani is the Director of the Pediatric MS Program at Yale and the lead investigator of a multi-center international study examining outcomes following the radiologically isolated syndrome in children.

Q1. Could you please provide an overview of Radiologically Isolated Syndrome ?

A1. Radiologically Isolated Syndrome (RIS) was first described in adults in 2009. Since then it has also been increasingly recognized and diagnosed in children. RIS is diagnosed after an MRI of the brain that the patient has sought for reasons other than suspected multiple sclerosis-- for instance, for evaluation of head trauma or headache. However, unexpectedly or incidentally, the patient’s MRI shows the typical findings that we see in multiple sclerosis, even in the absence of any typical clinical symptoms. RIS is generally considered a rare syndrome.

Q2. You created Yale Medicine’s Pediatric Multiple Sclerosis program which advocates for the eradication of MS. What  criteria defines a rare disease? Does RIS meet these criteria? And if so, how?

A2. The criteria for a rare disease vary, depending on the reference. In the US, a rare disease is defined as a condition that affects fewer than 200,000 people, in total, across the country.  By contrast, in Europe, a disease is considered rare if it affects fewer than one in every 2,000 people within the country’s population.

In the case of RIS, especially in children, we suspect that this is a rare condition, but we don't know for sure, as there have been very few population-based studies. There is one large study that was conducted in Europe that found one case of RIS among approximately 5,000 otherwise healthy children, who were between 7 and 14 years of age.  I think that's our best estimate of the overall prevalence of RIS in children. Using that finding, it likely would qualify as a rare condition, although, as I said, we really don't know for sure, as the prevalence may vary among different populations or age groups.

Q3. How do you investigate and manage RIS in children? What are some of the challenges?  

A3. For children with radiologically isolated syndrome, we usually undertake a comprehensive workup. This includes a detailed clinical neurological exam to ensure that there are no abnormalities that would, for instance, suggest a misdiagnosis of multiple sclerosis or an alternative diagnosis. In addition to the brain MRI, we usually obtain an MRI of the spinal cord to determine whether there is any spinal cord involvement. We also obtain blood tests. We often analyze spinal fluid as well, primarily to exclude other alternative processes that may explain the  MRI findings. A key challenge in this field is that there are currently no formal guidelines for the investigation and management of children with RIS. Collaborations within the pediatric MS community are needed to develop such consensus approaches to standardize care.

Q4. What are the most significant risk factors that indicate children with RIS could one day develop multiple sclerosis?

A4.This is an area of active research within our group. So far, we've found that approximately 42% of children with RIS develop multiple sclerosis in the future; on average, two years following their first abnormal MRI. Therefore, this is a high-risk group for developing  multiple sclerosis in the future. Thus far, we've determined that in children with RIS, it is the presence of abnormal spinal cord imaging and an abnormality in spinal fluid – namely, the presence of oligoclonal bands – that are likely the predictors of whether these children could develop MS in the future. a child’s possible development 

Q5. Based on your recent studies, are there data in children highlighting the potential for higher prevalence  in one population over another?

A5. Thus far, population-based studies assessing RIS, especially in children, have been rare and thus far have not identified particular subgroups with increased prevalence. We do know that the prevalence of multiple sclerosis varies across different age groups and across gender. Whether such associations are also present for RIS is an area of active research.

Naila Makhani, MD completed medical school training at the University of British Columbia (Vancouver, Canada). This was followed by a residency in child neurology and fellowship in MS and other demyelinating diseases at the University of Toronto and The Hospital for Sick Children (Toronto, Canada). Concurrent with fellowship training, Dr. Makhani obtained a Masters’ degree in public health from Harvard University. Dr. Makhani is the Director of the Pediatric MS Program at Yale and the lead investigator of a multi-center international study examining outcomes following the radiologically isolated syndrome in children.

Q1. Could you please provide an overview of Radiologically Isolated Syndrome ?

A1. Radiologically Isolated Syndrome (RIS) was first described in adults in 2009. Since then it has also been increasingly recognized and diagnosed in children. RIS is diagnosed after an MRI of the brain that the patient has sought for reasons other than suspected multiple sclerosis-- for instance, for evaluation of head trauma or headache. However, unexpectedly or incidentally, the patient’s MRI shows the typical findings that we see in multiple sclerosis, even in the absence of any typical clinical symptoms. RIS is generally considered a rare syndrome.

Q2. You created Yale Medicine’s Pediatric Multiple Sclerosis program which advocates for the eradication of MS. What  criteria defines a rare disease? Does RIS meet these criteria? And if so, how?

A2. The criteria for a rare disease vary, depending on the reference. In the US, a rare disease is defined as a condition that affects fewer than 200,000 people, in total, across the country.  By contrast, in Europe, a disease is considered rare if it affects fewer than one in every 2,000 people within the country’s population.

In the case of RIS, especially in children, we suspect that this is a rare condition, but we don't know for sure, as there have been very few population-based studies. There is one large study that was conducted in Europe that found one case of RIS among approximately 5,000 otherwise healthy children, who were between 7 and 14 years of age.  I think that's our best estimate of the overall prevalence of RIS in children. Using that finding, it likely would qualify as a rare condition, although, as I said, we really don't know for sure, as the prevalence may vary among different populations or age groups.

Q3. How do you investigate and manage RIS in children? What are some of the challenges?  

A3. For children with radiologically isolated syndrome, we usually undertake a comprehensive workup. This includes a detailed clinical neurological exam to ensure that there are no abnormalities that would, for instance, suggest a misdiagnosis of multiple sclerosis or an alternative diagnosis. In addition to the brain MRI, we usually obtain an MRI of the spinal cord to determine whether there is any spinal cord involvement. We also obtain blood tests. We often analyze spinal fluid as well, primarily to exclude other alternative processes that may explain the  MRI findings. A key challenge in this field is that there are currently no formal guidelines for the investigation and management of children with RIS. Collaborations within the pediatric MS community are needed to develop such consensus approaches to standardize care.

Q4. What are the most significant risk factors that indicate children with RIS could one day develop multiple sclerosis?

A4.This is an area of active research within our group. So far, we've found that approximately 42% of children with RIS develop multiple sclerosis in the future; on average, two years following their first abnormal MRI. Therefore, this is a high-risk group for developing  multiple sclerosis in the future. Thus far, we've determined that in children with RIS, it is the presence of abnormal spinal cord imaging and an abnormality in spinal fluid – namely, the presence of oligoclonal bands – that are likely the predictors of whether these children could develop MS in the future. a child’s possible development 

Q5. Based on your recent studies, are there data in children highlighting the potential for higher prevalence  in one population over another?

A5. Thus far, population-based studies assessing RIS, especially in children, have been rare and thus far have not identified particular subgroups with increased prevalence. We do know that the prevalence of multiple sclerosis varies across different age groups and across gender. Whether such associations are also present for RIS is an area of active research.

Naila Makhani, MD completed medical school training at the University of British Columbia (Vancouver, Canada). This was followed by a residency in child neurology and fellowship in MS and other demyelinating diseases at the University of Toronto and The Hospital for Sick Children (Toronto, Canada). Concurrent with fellowship training, Dr. Makhani obtained a Masters’ degree in public health from Harvard University. Dr. Makhani is the Director of the Pediatric MS Program at Yale and the lead investigator of a multi-center international study examining outcomes following the radiologically isolated syndrome in children.

Q1. Could you please provide an overview of Radiologically Isolated Syndrome ?

A1. Radiologically Isolated Syndrome (RIS) was first described in adults in 2009. Since then it has also been increasingly recognized and diagnosed in children. RIS is diagnosed after an MRI of the brain that the patient has sought for reasons other than suspected multiple sclerosis-- for instance, for evaluation of head trauma or headache. However, unexpectedly or incidentally, the patient’s MRI shows the typical findings that we see in multiple sclerosis, even in the absence of any typical clinical symptoms. RIS is generally considered a rare syndrome.

Q2. You created Yale Medicine’s Pediatric Multiple Sclerosis program which advocates for the eradication of MS. What  criteria defines a rare disease? Does RIS meet these criteria? And if so, how?

A2. The criteria for a rare disease vary, depending on the reference. In the US, a rare disease is defined as a condition that affects fewer than 200,000 people, in total, across the country.  By contrast, in Europe, a disease is considered rare if it affects fewer than one in every 2,000 people within the country’s population.

In the case of RIS, especially in children, we suspect that this is a rare condition, but we don't know for sure, as there have been very few population-based studies. There is one large study that was conducted in Europe that found one case of RIS among approximately 5,000 otherwise healthy children, who were between 7 and 14 years of age.  I think that's our best estimate of the overall prevalence of RIS in children. Using that finding, it likely would qualify as a rare condition, although, as I said, we really don't know for sure, as the prevalence may vary among different populations or age groups.

Q3. How do you investigate and manage RIS in children? What are some of the challenges?  

A3. For children with radiologically isolated syndrome, we usually undertake a comprehensive workup. This includes a detailed clinical neurological exam to ensure that there are no abnormalities that would, for instance, suggest a misdiagnosis of multiple sclerosis or an alternative diagnosis. In addition to the brain MRI, we usually obtain an MRI of the spinal cord to determine whether there is any spinal cord involvement. We also obtain blood tests. We often analyze spinal fluid as well, primarily to exclude other alternative processes that may explain the  MRI findings. A key challenge in this field is that there are currently no formal guidelines for the investigation and management of children with RIS. Collaborations within the pediatric MS community are needed to develop such consensus approaches to standardize care.

Q4. What are the most significant risk factors that indicate children with RIS could one day develop multiple sclerosis?

A4.This is an area of active research within our group. So far, we've found that approximately 42% of children with RIS develop multiple sclerosis in the future; on average, two years following their first abnormal MRI. Therefore, this is a high-risk group for developing  multiple sclerosis in the future. Thus far, we've determined that in children with RIS, it is the presence of abnormal spinal cord imaging and an abnormality in spinal fluid – namely, the presence of oligoclonal bands – that are likely the predictors of whether these children could develop MS in the future. a child’s possible development 

Q5. Based on your recent studies, are there data in children highlighting the potential for higher prevalence  in one population over another?

A5. Thus far, population-based studies assessing RIS, especially in children, have been rare and thus far have not identified particular subgroups with increased prevalence. We do know that the prevalence of multiple sclerosis varies across different age groups and across gender. Whether such associations are also present for RIS is an area of active research.

Naila Makhani, MD completed medical school training at the University of British Columbia (Vancouver, Canada). This was followed by a residency in child neurology and fellowship in MS and other demyelinating diseases at the University of Toronto and The Hospital for Sick Children (Toronto, Canada). Concurrent with fellowship training, Dr. Makhani obtained a Masters’ degree in public health from Harvard University. Dr. Makhani is the Director of the Pediatric MS Program at Yale and the lead investigator of a multi-center international study examining outcomes following the radiologically isolated syndrome in children.

Q1. Could you please provide an overview of Radiologically Isolated Syndrome ?

A1. Radiologically Isolated Syndrome (RIS) was first described in adults in 2009. Since then it has also been increasingly recognized and diagnosed in children. RIS is diagnosed after an MRI of the brain that the patient has sought for reasons other than suspected multiple sclerosis-- for instance, for evaluation of head trauma or headache. However, unexpectedly or incidentally, the patient’s MRI shows the typical findings that we see in multiple sclerosis, even in the absence of any typical clinical symptoms. RIS is generally considered a rare syndrome.

Q2. You created Yale Medicine’s Pediatric Multiple Sclerosis program which advocates for the eradication of MS. What  criteria defines a rare disease? Does RIS meet these criteria? And if so, how?

A2. The criteria for a rare disease vary, depending on the reference. In the US, a rare disease is defined as a condition that affects fewer than 200,000 people, in total, across the country.  By contrast, in Europe, a disease is considered rare if it affects fewer than one in every 2,000 people within the country’s population.

In the case of RIS, especially in children, we suspect that this is a rare condition, but we don't know for sure, as there have been very few population-based studies. There is one large study that was conducted in Europe that found one case of RIS among approximately 5,000 otherwise healthy children, who were between 7 and 14 years of age.  I think that's our best estimate of the overall prevalence of RIS in children. Using that finding, it likely would qualify as a rare condition, although, as I said, we really don't know for sure, as the prevalence may vary among different populations or age groups.

Q3. How do you investigate and manage RIS in children? What are some of the challenges?  

A3. For children with radiologically isolated syndrome, we usually undertake a comprehensive workup. This includes a detailed clinical neurological exam to ensure that there are no abnormalities that would, for instance, suggest a misdiagnosis of multiple sclerosis or an alternative diagnosis. In addition to the brain MRI, we usually obtain an MRI of the spinal cord to determine whether there is any spinal cord involvement. We also obtain blood tests. We often analyze spinal fluid as well, primarily to exclude other alternative processes that may explain the  MRI findings. A key challenge in this field is that there are currently no formal guidelines for the investigation and management of children with RIS. Collaborations within the pediatric MS community are needed to develop such consensus approaches to standardize care.

Q4. What are the most significant risk factors that indicate children with RIS could one day develop multiple sclerosis?

A4.This is an area of active research within our group. So far, we've found that approximately 42% of children with RIS develop multiple sclerosis in the future; on average, two years following their first abnormal MRI. Therefore, this is a high-risk group for developing  multiple sclerosis in the future. Thus far, we've determined that in children with RIS, it is the presence of abnormal spinal cord imaging and an abnormality in spinal fluid – namely, the presence of oligoclonal bands – that are likely the predictors of whether these children could develop MS in the future. a child’s possible development 

Q5. Based on your recent studies, are there data in children highlighting the potential for higher prevalence  in one population over another?

A5. Thus far, population-based studies assessing RIS, especially in children, have been rare and thus far have not identified particular subgroups with increased prevalence. We do know that the prevalence of multiple sclerosis varies across different age groups and across gender. Whether such associations are also present for RIS is an area of active research.

Naila Makhani, MD completed medical school training at the University of British Columbia (Vancouver, Canada). This was followed by a residency in child neurology and fellowship in MS and other demyelinating diseases at the University of Toronto and The Hospital for Sick Children (Toronto, Canada). Concurrent with fellowship training, Dr. Makhani obtained a Masters’ degree in public health from Harvard University. Dr. Makhani is the Director of the Pediatric MS Program at Yale and the lead investigator of a multi-center international study examining outcomes following the radiologically isolated syndrome in children.

Q1. Could you please provide an overview of Radiologically Isolated Syndrome ?

A1. Radiologically Isolated Syndrome (RIS) was first described in adults in 2009. Since then it has also been increasingly recognized and diagnosed in children. RIS is diagnosed after an MRI of the brain that the patient has sought for reasons other than suspected multiple sclerosis-- for instance, for evaluation of head trauma or headache. However, unexpectedly or incidentally, the patient’s MRI shows the typical findings that we see in multiple sclerosis, even in the absence of any typical clinical symptoms. RIS is generally considered a rare syndrome.

Q2. You created Yale Medicine’s Pediatric Multiple Sclerosis program which advocates for the eradication of MS. What  criteria defines a rare disease? Does RIS meet these criteria? And if so, how?

A2. The criteria for a rare disease vary, depending on the reference. In the US, a rare disease is defined as a condition that affects fewer than 200,000 people, in total, across the country.  By contrast, in Europe, a disease is considered rare if it affects fewer than one in every 2,000 people within the country’s population.

In the case of RIS, especially in children, we suspect that this is a rare condition, but we don't know for sure, as there have been very few population-based studies. There is one large study that was conducted in Europe that found one case of RIS among approximately 5,000 otherwise healthy children, who were between 7 and 14 years of age.  I think that's our best estimate of the overall prevalence of RIS in children. Using that finding, it likely would qualify as a rare condition, although, as I said, we really don't know for sure, as the prevalence may vary among different populations or age groups.

Q3. How do you investigate and manage RIS in children? What are some of the challenges?  

A3. For children with radiologically isolated syndrome, we usually undertake a comprehensive workup. This includes a detailed clinical neurological exam to ensure that there are no abnormalities that would, for instance, suggest a misdiagnosis of multiple sclerosis or an alternative diagnosis. In addition to the brain MRI, we usually obtain an MRI of the spinal cord to determine whether there is any spinal cord involvement. We also obtain blood tests. We often analyze spinal fluid as well, primarily to exclude other alternative processes that may explain the  MRI findings. A key challenge in this field is that there are currently no formal guidelines for the investigation and management of children with RIS. Collaborations within the pediatric MS community are needed to develop such consensus approaches to standardize care.

Q4. What are the most significant risk factors that indicate children with RIS could one day develop multiple sclerosis?

A4.This is an area of active research within our group. So far, we've found that approximately 42% of children with RIS develop multiple sclerosis in the future; on average, two years following their first abnormal MRI. Therefore, this is a high-risk group for developing  multiple sclerosis in the future. Thus far, we've determined that in children with RIS, it is the presence of abnormal spinal cord imaging and an abnormality in spinal fluid – namely, the presence of oligoclonal bands – that are likely the predictors of whether these children could develop MS in the future. a child’s possible development 

Q5. Based on your recent studies, are there data in children highlighting the potential for higher prevalence  in one population over another?

A5. Thus far, population-based studies assessing RIS, especially in children, have been rare and thus far have not identified particular subgroups with increased prevalence. We do know that the prevalence of multiple sclerosis varies across different age groups and across gender. Whether such associations are also present for RIS is an area of active research.

James Nicholas Brenton, M.D., is the director of the University of Virginia’s Pediatric and Young Adult MS and Related Disorders Clinic. He is also associate professor of neurology and pediatrics for clinical research and performs collaborative clinical research within the field of pediatric MS. His research focuses on pediatric demyelinating disease and autoimmune epilepsies.

As the director of a clinic focusing on pediatric and young adults MS and related disorders, how do modifiable risk factors such as obesity, smoking, et cetera, increase the risk of MS in general?

Dr. Brenton: There are several risk factors for pediatric-onset MS. When I say pediatric-onset, I'm referring to patients with clinical onset of MS prior to the age of 18 years. Some MS risk factors are not considered “modifiable,” such as genetic risks. The greatest genetic risk for MS is related to specific haplotypes in the HLA-DRB1 gene. Another risk factor that is less amenable to modification is early exposure to certain viruses, like the Epstein-Barr virus (Makhani, et al 2016).

On the other hand, there are several potentially modifiable risk factors for MS. This includes smoking - either first or second-hand smoke. In the case of pediatric MS patients, it is most often related to second-hand (or passive) smoke exposure (Lavery, et al 2019). Another example of a modifiable MS risk factor is vitamin D deficiency. Vitamin D levels are influenced significantly by duration and intensity of direct exposure to sunlight, which depends (in part) on the geographic location of where you grow up. For example, those who live at higher latitudes (e.g. live further away from the equator) have less exposure to direct sunlight than a child who lives at lower latitudes (e.g. closer to the equator) (Banwell, et al  2011).

Obesity during childhood or adolescence is another modifiable risk factor for MS. Obesity’s risk for MS (like smoking) is dose-dependent – meaning, the more obese that you are, the higher your overall risk for future development of MS. In fact, the BMI in children with MS is markedly higher than their non-MS peers, and begins in early childhood, years before the clinical onset of the disease (Brenton, et al 2019).

There is mixed evidence regarding the impact of certain perinatal factors on future risk for MS. For example, some literature suggests that Caesarean delivery increases the risk of MS (Maghzi, et al 2012). Our research has found that infantile breastfeeding is associated with a lower future risk of pediatric-onset MS (Brenton, et al 2017).

Children are two to three times more likely to experience MS relapses compared with adults. How likely is it for the childhood obesity epidemic to lead to increased morbidity from MS or CIS, particularly in adolescent girls?

Dr. Brenton:  Obesity is a systemic disease that manifests as excessive or abnormal accumulation of body fat. We know that chronic obesity leads to higher overall morbidity, lower quality of life, and reduced life expectancy. There are several common co-morbidities associated with obesity - like cardiovascular disease, type II diabetes mellitus, hypertension, polycystic ovarian syndrome, dyslipidemia, infertility, and some cancers (Abdelaal, et al 2017). Certainly, all these implications for the general population would pertain to those with MS who exhibit chronic obesity.

While we have fairly good evidence that obesity is a causal risk factor for the development of MS, there actually is a paucity of literature that has studied the impact of persistent obesity on an already established MS disease state. Several recent studies show that obesity is associated with a pro-inflammatory state in the blood and cerebrospinal fluid of MS patients (Stampanoni, et al 2019). There are other studies that shown a direct association between MS-related neurologic disability and obesity – such that those with a greater waist circumference exhibit higher rates of neurologic disability (Fitzgerald, et al 2019).

Recent studies have assessed whether SNAP factors are associated with health outcomes. How does a modifiable SNAP risk score in people with multiple sclerosis impacts the likelihood of disability worsening??

Dr. Brenton: SNAP factors may not be as well known to some people in this field. SNAP factors refer to smoking (“S”), poor nutrition (“N”), alcohol consumption (“A”) and insufficient physical activity (“P”). These four factors appear to be the most preventable causes of morbidity within the general population. SNAP factors are common in people with MS. The most common SNAP factors in MS patients are poor nutrition and insufficient physical activity. Cross-sectionally, these factors appear to be associated with worsening neurologic disability (Marck, et al 2019).

There is data suggesting that SNAP factors, particularly those that increase over time, can associate with worsening disability when followed over several years. Importantly, your baseline SNAP score does not appear to predict your future level of disability (Marck, et al 2019). Collective SNAP scores have not yet been well-studied in pediatric MS patients, but are important to study - particularly given that children with MS reach maximum neurologic disability at a younger age than adult-onset MS patients (Renoux, et al 2007).

What are some of the best practices MS health care providers can engage in to promote exercise and rehabilitative protocols to significantly impact the physical and cognitive performance of MS patients?

Dr. Brenton: Even though pediatric MS patients exhibit relatively low levels of physical neurologic disability early in their disease, the physical activity levels of youth with MS are quite low. These patients engage in less moderate and vigorous physical activity when you compare them to their non-MS peers (Grover, et al 2016), but we still don't fully understand why this is the case. In fact, it may be related to several different factors - including pain, fatigue, sleep quality, MS disease activity, and psychological factors (such as depression, social anxiety, and perceptions of self-efficacy). In order to truly provide patient-specific interventions that positively impact physical activity we need to better understand what factors to study and how these factors play into the individual patient. For example, if high levels of fatigue are inhibiting a patient from being physically active, the provider should explore sources of fatigue: “how are sleep patterns?”, “are they napping throughout the day?”, “does the fatigue occur only after a period of physical activity, or is it persistent despite how active they are?” These are examples of questions that may lead a neurologist to different approaches for managing reduced physical activity.

Generally speaking however, pediatric and adult MS providers would ideally provide healthy nutrition guidance and counseling to all patients, regardless of their weight. Though there is no particular proven “MS diet,” in general, we recommend a balanced diet that is lower in saturated fats and processed sugars and higher in fruits and vegetables. In the case of a pediatric MS patient, it's important to have the family on board with consuming a healthier diet, as parental involvement increases the likelihood of healthy behavioral changes in the child.

It is important to ask patients targeted questions about their physical activity and assist with goal setting toward achievable targets. If the patient is receptive, a provider can advise on the use of digital interventions, like apps or internet-based social groups that incorporate education, accountability, and self-monitoring. What we do not know yet, but hope to know soon, is if physical activity and/or reducing obesity/improving diet can serve as a modifier of disease in kids and adults with MS. My current research is focused on studying the role of obesity and diet on the clinical course of children with MS. Many others are studying the role of physical activity on the disease course of children with MS. Suffice to say, there is much more to learn on the role of diet, body composition, and physical activity in youth with MS.

James Nicholas Brenton, M.D., is the director of the University of Virginia’s Pediatric and Young Adult MS and Related Disorders Clinic. He is also associate professor of neurology and pediatrics for clinical research and performs collaborative clinical research within the field of pediatric MS. His research focuses on pediatric demyelinating disease and autoimmune epilepsies.

As the director of a clinic focusing on pediatric and young adults MS and related disorders, how do modifiable risk factors such as obesity, smoking, et cetera, increase the risk of MS in general?

Dr. Brenton: There are several risk factors for pediatric-onset MS. When I say pediatric-onset, I'm referring to patients with clinical onset of MS prior to the age of 18 years. Some MS risk factors are not considered “modifiable,” such as genetic risks. The greatest genetic risk for MS is related to specific haplotypes in the HLA-DRB1 gene. Another risk factor that is less amenable to modification is early exposure to certain viruses, like the Epstein-Barr virus (Makhani, et al 2016).

On the other hand, there are several potentially modifiable risk factors for MS. This includes smoking - either first or second-hand smoke. In the case of pediatric MS patients, it is most often related to second-hand (or passive) smoke exposure (Lavery, et al 2019). Another example of a modifiable MS risk factor is vitamin D deficiency. Vitamin D levels are influenced significantly by duration and intensity of direct exposure to sunlight, which depends (in part) on the geographic location of where you grow up. For example, those who live at higher latitudes (e.g. live further away from the equator) have less exposure to direct sunlight than a child who lives at lower latitudes (e.g. closer to the equator) (Banwell, et al  2011).

Obesity during childhood or adolescence is another modifiable risk factor for MS. Obesity’s risk for MS (like smoking) is dose-dependent – meaning, the more obese that you are, the higher your overall risk for future development of MS. In fact, the BMI in children with MS is markedly higher than their non-MS peers, and begins in early childhood, years before the clinical onset of the disease (Brenton, et al 2019).

There is mixed evidence regarding the impact of certain perinatal factors on future risk for MS. For example, some literature suggests that Caesarean delivery increases the risk of MS (Maghzi, et al 2012). Our research has found that infantile breastfeeding is associated with a lower future risk of pediatric-onset MS (Brenton, et al 2017).

Children are two to three times more likely to experience MS relapses compared with adults. How likely is it for the childhood obesity epidemic to lead to increased morbidity from MS or CIS, particularly in adolescent girls?

Dr. Brenton:  Obesity is a systemic disease that manifests as excessive or abnormal accumulation of body fat. We know that chronic obesity leads to higher overall morbidity, lower quality of life, and reduced life expectancy. There are several common co-morbidities associated with obesity - like cardiovascular disease, type II diabetes mellitus, hypertension, polycystic ovarian syndrome, dyslipidemia, infertility, and some cancers (Abdelaal, et al 2017). Certainly, all these implications for the general population would pertain to those with MS who exhibit chronic obesity.

While we have fairly good evidence that obesity is a causal risk factor for the development of MS, there actually is a paucity of literature that has studied the impact of persistent obesity on an already established MS disease state. Several recent studies show that obesity is associated with a pro-inflammatory state in the blood and cerebrospinal fluid of MS patients (Stampanoni, et al 2019). There are other studies that shown a direct association between MS-related neurologic disability and obesity – such that those with a greater waist circumference exhibit higher rates of neurologic disability (Fitzgerald, et al 2019).

Recent studies have assessed whether SNAP factors are associated with health outcomes. How does a modifiable SNAP risk score in people with multiple sclerosis impacts the likelihood of disability worsening??

Dr. Brenton: SNAP factors may not be as well known to some people in this field. SNAP factors refer to smoking (“S”), poor nutrition (“N”), alcohol consumption (“A”) and insufficient physical activity (“P”). These four factors appear to be the most preventable causes of morbidity within the general population. SNAP factors are common in people with MS. The most common SNAP factors in MS patients are poor nutrition and insufficient physical activity. Cross-sectionally, these factors appear to be associated with worsening neurologic disability (Marck, et al 2019).

There is data suggesting that SNAP factors, particularly those that increase over time, can associate with worsening disability when followed over several years. Importantly, your baseline SNAP score does not appear to predict your future level of disability (Marck, et al 2019). Collective SNAP scores have not yet been well-studied in pediatric MS patients, but are important to study - particularly given that children with MS reach maximum neurologic disability at a younger age than adult-onset MS patients (Renoux, et al 2007).

What are some of the best practices MS health care providers can engage in to promote exercise and rehabilitative protocols to significantly impact the physical and cognitive performance of MS patients?

Dr. Brenton: Even though pediatric MS patients exhibit relatively low levels of physical neurologic disability early in their disease, the physical activity levels of youth with MS are quite low. These patients engage in less moderate and vigorous physical activity when you compare them to their non-MS peers (Grover, et al 2016), but we still don't fully understand why this is the case. In fact, it may be related to several different factors - including pain, fatigue, sleep quality, MS disease activity, and psychological factors (such as depression, social anxiety, and perceptions of self-efficacy). In order to truly provide patient-specific interventions that positively impact physical activity we need to better understand what factors to study and how these factors play into the individual patient. For example, if high levels of fatigue are inhibiting a patient from being physically active, the provider should explore sources of fatigue: “how are sleep patterns?”, “are they napping throughout the day?”, “does the fatigue occur only after a period of physical activity, or is it persistent despite how active they are?” These are examples of questions that may lead a neurologist to different approaches for managing reduced physical activity.

Generally speaking however, pediatric and adult MS providers would ideally provide healthy nutrition guidance and counseling to all patients, regardless of their weight. Though there is no particular proven “MS diet,” in general, we recommend a balanced diet that is lower in saturated fats and processed sugars and higher in fruits and vegetables. In the case of a pediatric MS patient, it's important to have the family on board with consuming a healthier diet, as parental involvement increases the likelihood of healthy behavioral changes in the child.

It is important to ask patients targeted questions about their physical activity and assist with goal setting toward achievable targets. If the patient is receptive, a provider can advise on the use of digital interventions, like apps or internet-based social groups that incorporate education, accountability, and self-monitoring. What we do not know yet, but hope to know soon, is if physical activity and/or reducing obesity/improving diet can serve as a modifier of disease in kids and adults with MS. My current research is focused on studying the role of obesity and diet on the clinical course of children with MS. Many others are studying the role of physical activity on the disease course of children with MS. Suffice to say, there is much more to learn on the role of diet, body composition, and physical activity in youth with MS.

James Nicholas Brenton, M.D., is the director of the University of Virginia’s Pediatric and Young Adult MS and Related Disorders Clinic. He is also associate professor of neurology and pediatrics for clinical research and performs collaborative clinical research within the field of pediatric MS. His research focuses on pediatric demyelinating disease and autoimmune epilepsies.

As the director of a clinic focusing on pediatric and young adults MS and related disorders, how do modifiable risk factors such as obesity, smoking, et cetera, increase the risk of MS in general?

Dr. Brenton: There are several risk factors for pediatric-onset MS. When I say pediatric-onset, I'm referring to patients with clinical onset of MS prior to the age of 18 years. Some MS risk factors are not considered “modifiable,” such as genetic risks. The greatest genetic risk for MS is related to specific haplotypes in the HLA-DRB1 gene. Another risk factor that is less amenable to modification is early exposure to certain viruses, like the Epstein-Barr virus (Makhani, et al 2016).

On the other hand, there are several potentially modifiable risk factors for MS. This includes smoking - either first or second-hand smoke. In the case of pediatric MS patients, it is most often related to second-hand (or passive) smoke exposure (Lavery, et al 2019). Another example of a modifiable MS risk factor is vitamin D deficiency. Vitamin D levels are influenced significantly by duration and intensity of direct exposure to sunlight, which depends (in part) on the geographic location of where you grow up. For example, those who live at higher latitudes (e.g. live further away from the equator) have less exposure to direct sunlight than a child who lives at lower latitudes (e.g. closer to the equator) (Banwell, et al  2011).

Obesity during childhood or adolescence is another modifiable risk factor for MS. Obesity’s risk for MS (like smoking) is dose-dependent – meaning, the more obese that you are, the higher your overall risk for future development of MS. In fact, the BMI in children with MS is markedly higher than their non-MS peers, and begins in early childhood, years before the clinical onset of the disease (Brenton, et al 2019).

There is mixed evidence regarding the impact of certain perinatal factors on future risk for MS. For example, some literature suggests that Caesarean delivery increases the risk of MS (Maghzi, et al 2012). Our research has found that infantile breastfeeding is associated with a lower future risk of pediatric-onset MS (Brenton, et al 2017).

Children are two to three times more likely to experience MS relapses compared with adults. How likely is it for the childhood obesity epidemic to lead to increased morbidity from MS or CIS, particularly in adolescent girls?

Dr. Brenton:  Obesity is a systemic disease that manifests as excessive or abnormal accumulation of body fat. We know that chronic obesity leads to higher overall morbidity, lower quality of life, and reduced life expectancy. There are several common co-morbidities associated with obesity - like cardiovascular disease, type II diabetes mellitus, hypertension, polycystic ovarian syndrome, dyslipidemia, infertility, and some cancers (Abdelaal, et al 2017). Certainly, all these implications for the general population would pertain to those with MS who exhibit chronic obesity.

While we have fairly good evidence that obesity is a causal risk factor for the development of MS, there actually is a paucity of literature that has studied the impact of persistent obesity on an already established MS disease state. Several recent studies show that obesity is associated with a pro-inflammatory state in the blood and cerebrospinal fluid of MS patients (Stampanoni, et al 2019). There are other studies that shown a direct association between MS-related neurologic disability and obesity – such that those with a greater waist circumference exhibit higher rates of neurologic disability (Fitzgerald, et al 2019).

Recent studies have assessed whether SNAP factors are associated with health outcomes. How does a modifiable SNAP risk score in people with multiple sclerosis impacts the likelihood of disability worsening??

Dr. Brenton: SNAP factors may not be as well known to some people in this field. SNAP factors refer to smoking (“S”), poor nutrition (“N”), alcohol consumption (“A”) and insufficient physical activity (“P”). These four factors appear to be the most preventable causes of morbidity within the general population. SNAP factors are common in people with MS. The most common SNAP factors in MS patients are poor nutrition and insufficient physical activity. Cross-sectionally, these factors appear to be associated with worsening neurologic disability (Marck, et al 2019).

There is data suggesting that SNAP factors, particularly those that increase over time, can associate with worsening disability when followed over several years. Importantly, your baseline SNAP score does not appear to predict your future level of disability (Marck, et al 2019). Collective SNAP scores have not yet been well-studied in pediatric MS patients, but are important to study - particularly given that children with MS reach maximum neurologic disability at a younger age than adult-onset MS patients (Renoux, et al 2007).

What are some of the best practices MS health care providers can engage in to promote exercise and rehabilitative protocols to significantly impact the physical and cognitive performance of MS patients?

Dr. Brenton: Even though pediatric MS patients exhibit relatively low levels of physical neurologic disability early in their disease, the physical activity levels of youth with MS are quite low. These patients engage in less moderate and vigorous physical activity when you compare them to their non-MS peers (Grover, et al 2016), but we still don't fully understand why this is the case. In fact, it may be related to several different factors - including pain, fatigue, sleep quality, MS disease activity, and psychological factors (such as depression, social anxiety, and perceptions of self-efficacy). In order to truly provide patient-specific interventions that positively impact physical activity we need to better understand what factors to study and how these factors play into the individual patient. For example, if high levels of fatigue are inhibiting a patient from being physically active, the provider should explore sources of fatigue: “how are sleep patterns?”, “are they napping throughout the day?”, “does the fatigue occur only after a period of physical activity, or is it persistent despite how active they are?” These are examples of questions that may lead a neurologist to different approaches for managing reduced physical activity.

Generally speaking however, pediatric and adult MS providers would ideally provide healthy nutrition guidance and counseling to all patients, regardless of their weight. Though there is no particular proven “MS diet,” in general, we recommend a balanced diet that is lower in saturated fats and processed sugars and higher in fruits and vegetables. In the case of a pediatric MS patient, it's important to have the family on board with consuming a healthier diet, as parental involvement increases the likelihood of healthy behavioral changes in the child.

It is important to ask patients targeted questions about their physical activity and assist with goal setting toward achievable targets. If the patient is receptive, a provider can advise on the use of digital interventions, like apps or internet-based social groups that incorporate education, accountability, and self-monitoring. What we do not know yet, but hope to know soon, is if physical activity and/or reducing obesity/improving diet can serve as a modifier of disease in kids and adults with MS. My current research is focused on studying the role of obesity and diet on the clinical course of children with MS. Many others are studying the role of physical activity on the disease course of children with MS. Suffice to say, there is much more to learn on the role of diet, body composition, and physical activity in youth with MS.

Andrea Rapkin, MD, is Board Certified by the American College of Obstetricians and Gynecologists (of which she is also a fellow). After obtaining her MD, she completed her residency in OBGYN at UCLA then joined the faculty at UCLA and is a Professor of Obstetrics and Gynecology. She was one of the first Obstetrician-Gynecologists to adapt the multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain.

You are the founder and director of a clinic focused on a multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain. How did you identify such a clinic as a therapeutic need for patients? 

Dr. Rapkin: The short answer is that a significant proportion of women were not experiencing pain relief or had incomplete relief with traditional medical or surgical therapy. At the time, we also identified various red flags for traditional treatment failures. These red flags included the following: pain of greater than 6 months duration, pain out of proportion to pathology found on examination, multiple visceral and somatic complaints, and psychosocial abnormalities. We now understand more about the neurobiology underpinning these red flags.  

With the widespread availability of laparoscopy in the late 70s and early 80s, many studies investigated the relationship between endometriosis lesions and pain. The general consensus is that there is no relationship between the location or severity of the endometriosis lesions or the disease stage (American Society for Reproductive Medicine staging) with type of symptoms, symptom severity, treatment response, recurrence, or even prognosis. In fact, pain recurrence after adequate surgical treatment is unrelated to the presence of endometriosis lesions found at the time of repeat laparoscopy. This lack of association between pain and presence of visible disease was supported by a recent New England Journal of Medicine article by Zondervan and colleagues demonstrating that up to 30% of women with chronic pelvic pain, present after excision of endometriotic lesions, become unresponsive to conventional treatment.

The neurobiological responses in an individual with chronic pain are more complicated than those seen in the setting of acute pain. Chronic pain may be triggered or maintained by an inflammatory process such as endometriosis but, over time, altered neural processing and psychosocial maladaptation can occur. The altered processing consists of both peripheral and central sensitization which change the way sensory information from the pelvic viscera and surrounding somatic structures in the periphery is transmitted and interpreted in the central nervous system (spinal cord and brain). Visceral pelvic pain can emanate from the uterus, ovaries and fallopian tubes, the urinary bladder, and the bowel, while the somatic sources include the surrounding abdominal wall, low back and pelvic floor muscles, and fascia, and bones. Signal amplification or peripheral sensitization in the pelvic region in women with endometriosis starts with localized inflammation, neovascularization, invasion and innervation of endometriotic implants. As the pelvic organs share thoracolumbar and sacral autonomic neural pathways, inflammation or dysfunction in one organ or tissue, such as the uterus, over time can sensitize or lead to dysfunction in other pelvic organs, such as the bladder or bowel (called viscero-visceral cross sensitization). Finally, somatic structures sharing intervention with the pelvic viscera, such as the fascia and muscles of the lower abdomen, pelvic floor lower back also become sources of pain because of a process called viscero-somatic sensitization. Women who have endometriosis are therefore more likely to experience IBS, bladder pain syndrome/interstitial cystitis and vulvodynia, and up to 80% of individuals can develop myofascial pain related to trigger points and muscle dysfunction. Up to 50% of women with bladder pain have endometriosis. Those with endometriosis or bladder pain are 2.5 times more likely to also have IBS. 

Over time, other visceral and somatic structures innervated by higher levels of the spinal cord can be affected, leading to more widespread pain. Central sensitization manifests as an amplification of pain in the spinal cord and brain. The presence of more than two chronic “unexplained” pain conditions, such as chronic pelvic pain, vulvodynia, myofascial pain, headache, etc suggest the presence of central sensitization. Anxiety, depression, and maladaptive coping strategies often ensue. Functional MRI studies have documented altered central processing in the brain in many chronic pain states including endometriosis. Interdisciplinary therapy including physical therapy, mental health, and pain management/anesthesiology is more effective compared with medical and or surgical therapy alone for endometriosis-related pain in the setting of peripheral and central sensitization.

What should clinicians look for, or what stands out to them, to confirm the endometriosis diagnosis when pain is the presenting symptom?

Dr. Rapkin: There are no pathognomonic symptoms or biomarkers for endometriosis; however, the following historical features have been shown to be linked with a greater likelihood of finding endometriosis:

• persistent dysmenorrhea (menstrual pain) despite NSAID and hormonal treatment
• cyclical pain that is premenstrual and menstrual that progresses to chronic pain or is accompanied by abnormal or heavy menstrual bleeding
• deep dyspareunia
• dyschezia (pain with bowel movements), and sometimes bloating.

An individual with menstrual pain since menarche can have up to a 5% increased risk of endometriosis. Endometriosis in a first-degree relative elevates the risk for endometriosis by 7% to 10%.

Given the complexity of chronic pain, it is important not to assume endometriosis is the only source of pain. All the pelvic visceral and somatic structures should be evaluated. A thorough history addresses all the patient’s symptoms, including vaginal, gastrointestinal and genitourinary. Aggravating factors such as menstrual cycle, bowel and bladder functioning, physical activity, sexual intercourse and stress should be queried. In addition, assessment of mood, anxiety or depression, sleep disturbance and effect of pain on daily functioning are relevant as is history of abuse or trauma (physical, sexual or emotional). This history can be lengthy, so a detailed pain questionnaire is helpful. (See the pelvicpain.org website for a user-friendly pain questionnaire).

With the previously mentioned risk factors in mind, and after a thorough history has been obtained, a pain-localizing exam should be conducted including the abdominal wall, pelvic floor, and then the bimanual and rectovaginal exams for the abdominal wall myofascial/neuropathic pain assessment for which Carnett’s test can be very useful—tender points on the abdominal wall are palpitated and the patient is asked to give a numerical rating of the pain (1-10/10) and marked with a pen. The patient is then asked to either perform a bilateral straight leg raise or an abdominal crunch, and the areas are re-palpitated. If the marked areas are more painful to palpation during the abdominal crunch or the bilateral straight leg raise, it suggests an abdominal wall pain (myofascial or neuropathic) or component of the pain. Similarly, pelvic floor muscles should be assessed after the abdominal wall exam is completed. This is best accomplished with a unit-digital exam with palpation of pelvic muscles for tenderness and hypertonia on exam. These myofascial findings are often present in the setting of endometriosis, but they can be primary-unrelated to presence or absence of endometriosis.

What are your focused disciplines for approaching endometriosis-associated pain? How do you recommend these clinicians or specialists come together to effectively manage a patient’s conditions? 

Dr. Rapkin: The gynecologist or primary care provider can address the chronic inflammatory, estrogen-dependent aspect of endometriosis. Begin with nonsteroidal, anti-inflammatory medication and combined estrogen-progestin or high-dose progestin-alone hormonal therapy to lower estrogenic stimulation of lesions and decidualize those progestin-sensitive lesions. For menstrual cycle related pain (luteal periovulatory or menstrual phase) cyclical exacerbation of other chronic pain conditions, early intervention is recommended. Adequately dosed preemptive nonsteroidal inflammatory agents and, if not tolerated or effective, begin combined hormonal contraceptives or intrauterine or higher dose progestins menstrual suppression, with either continuous monophasic hormonal contraceptives or progestins, is very important for pain that is cyclical or exacerbated in a cyclical fashion. Progestins can be administered orally, such as norethindrone acetate; intramuscularly or subdermally (depot medroxyprogesterone acetate or etonogestrel implant); or intrauterine (which does not lower estrogen levels but can be therapeutic for suppression of menses and local treatment of endometriosis). Failure of hormonal therapy and management of other co-occurring pain conditions warrants trial of a second-line medical therapy such as gonadotropin-releasing hormone antagonist or agonist or surgery for definitive diagnosis and surgical ablation or excision of endometriosis lesions.

I would suggest that gynecologists who treat women with endometriosis and chronic pain try to build a team in their geographic area. Relevant specialists for an interdisciplinary approach include:

• Pelvic floor physical therapist to evaluate and address myofascial dysfunction and pain and voiding abnormalities, such as urinary urgency or frequency and constipation
• Gastroenterologist for evaluation and treatment of irritable bowel or functional abdominal pain and bloating syndrome or inflammatory bowel disease. Urologist or urogynecologist to assess and treat bladder pain syndrome/interstitial cystitis
• Primary care evaluation for diffuse myofascial pain, fibromyalgia, arthralgias, and other inflammatory conditions, and for management of headache and migraine. Rheumatology and neurology specialists may be needed
• Mental health providers for treatment of anxiety, depression, or PTSD and to address stress management, coping skills and provide cognitive behavioral therapy
• Interventional pain management specialist such as physical medicine and rehabilitation (PM and R), pain anesthiologist, neurologist or interventional radiologist to provide relevant nerve blocks, trigger point injections, or botulinum toxin injection.
• Gynecologists experienced in the management of chronic pelvic pain also provide nerve blocks, trigger point and botulinum toxin injections.

Andrea Rapkin, MD, is Board Certified by the American College of Obstetricians and Gynecologists (of which she is also a fellow). After obtaining her MD, she completed her residency in OBGYN at UCLA then joined the faculty at UCLA and is a Professor of Obstetrics and Gynecology. She was one of the first Obstetrician-Gynecologists to adapt the multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain.

You are the founder and director of a clinic focused on a multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain. How did you identify such a clinic as a therapeutic need for patients? 

Dr. Rapkin: The short answer is that a significant proportion of women were not experiencing pain relief or had incomplete relief with traditional medical or surgical therapy. At the time, we also identified various red flags for traditional treatment failures. These red flags included the following: pain of greater than 6 months duration, pain out of proportion to pathology found on examination, multiple visceral and somatic complaints, and psychosocial abnormalities. We now understand more about the neurobiology underpinning these red flags.  

With the widespread availability of laparoscopy in the late 70s and early 80s, many studies investigated the relationship between endometriosis lesions and pain. The general consensus is that there is no relationship between the location or severity of the endometriosis lesions or the disease stage (American Society for Reproductive Medicine staging) with type of symptoms, symptom severity, treatment response, recurrence, or even prognosis. In fact, pain recurrence after adequate surgical treatment is unrelated to the presence of endometriosis lesions found at the time of repeat laparoscopy. This lack of association between pain and presence of visible disease was supported by a recent New England Journal of Medicine article by Zondervan and colleagues demonstrating that up to 30% of women with chronic pelvic pain, present after excision of endometriotic lesions, become unresponsive to conventional treatment.

The neurobiological responses in an individual with chronic pain are more complicated than those seen in the setting of acute pain. Chronic pain may be triggered or maintained by an inflammatory process such as endometriosis but, over time, altered neural processing and psychosocial maladaptation can occur. The altered processing consists of both peripheral and central sensitization which change the way sensory information from the pelvic viscera and surrounding somatic structures in the periphery is transmitted and interpreted in the central nervous system (spinal cord and brain). Visceral pelvic pain can emanate from the uterus, ovaries and fallopian tubes, the urinary bladder, and the bowel, while the somatic sources include the surrounding abdominal wall, low back and pelvic floor muscles, and fascia, and bones. Signal amplification or peripheral sensitization in the pelvic region in women with endometriosis starts with localized inflammation, neovascularization, invasion and innervation of endometriotic implants. As the pelvic organs share thoracolumbar and sacral autonomic neural pathways, inflammation or dysfunction in one organ or tissue, such as the uterus, over time can sensitize or lead to dysfunction in other pelvic organs, such as the bladder or bowel (called viscero-visceral cross sensitization). Finally, somatic structures sharing intervention with the pelvic viscera, such as the fascia and muscles of the lower abdomen, pelvic floor lower back also become sources of pain because of a process called viscero-somatic sensitization. Women who have endometriosis are therefore more likely to experience IBS, bladder pain syndrome/interstitial cystitis and vulvodynia, and up to 80% of individuals can develop myofascial pain related to trigger points and muscle dysfunction. Up to 50% of women with bladder pain have endometriosis. Those with endometriosis or bladder pain are 2.5 times more likely to also have IBS. 

Over time, other visceral and somatic structures innervated by higher levels of the spinal cord can be affected, leading to more widespread pain. Central sensitization manifests as an amplification of pain in the spinal cord and brain. The presence of more than two chronic “unexplained” pain conditions, such as chronic pelvic pain, vulvodynia, myofascial pain, headache, etc suggest the presence of central sensitization. Anxiety, depression, and maladaptive coping strategies often ensue. Functional MRI studies have documented altered central processing in the brain in many chronic pain states including endometriosis. Interdisciplinary therapy including physical therapy, mental health, and pain management/anesthesiology is more effective compared with medical and or surgical therapy alone for endometriosis-related pain in the setting of peripheral and central sensitization.

What should clinicians look for, or what stands out to them, to confirm the endometriosis diagnosis when pain is the presenting symptom?

Dr. Rapkin: There are no pathognomonic symptoms or biomarkers for endometriosis; however, the following historical features have been shown to be linked with a greater likelihood of finding endometriosis:

• persistent dysmenorrhea (menstrual pain) despite NSAID and hormonal treatment
• cyclical pain that is premenstrual and menstrual that progresses to chronic pain or is accompanied by abnormal or heavy menstrual bleeding
• deep dyspareunia
• dyschezia (pain with bowel movements), and sometimes bloating.

An individual with menstrual pain since menarche can have up to a 5% increased risk of endometriosis. Endometriosis in a first-degree relative elevates the risk for endometriosis by 7% to 10%.

Given the complexity of chronic pain, it is important not to assume endometriosis is the only source of pain. All the pelvic visceral and somatic structures should be evaluated. A thorough history addresses all the patient’s symptoms, including vaginal, gastrointestinal and genitourinary. Aggravating factors such as menstrual cycle, bowel and bladder functioning, physical activity, sexual intercourse and stress should be queried. In addition, assessment of mood, anxiety or depression, sleep disturbance and effect of pain on daily functioning are relevant as is history of abuse or trauma (physical, sexual or emotional). This history can be lengthy, so a detailed pain questionnaire is helpful. (See the pelvicpain.org website for a user-friendly pain questionnaire).

With the previously mentioned risk factors in mind, and after a thorough history has been obtained, a pain-localizing exam should be conducted including the abdominal wall, pelvic floor, and then the bimanual and rectovaginal exams for the abdominal wall myofascial/neuropathic pain assessment for which Carnett’s test can be very useful—tender points on the abdominal wall are palpitated and the patient is asked to give a numerical rating of the pain (1-10/10) and marked with a pen. The patient is then asked to either perform a bilateral straight leg raise or an abdominal crunch, and the areas are re-palpitated. If the marked areas are more painful to palpation during the abdominal crunch or the bilateral straight leg raise, it suggests an abdominal wall pain (myofascial or neuropathic) or component of the pain. Similarly, pelvic floor muscles should be assessed after the abdominal wall exam is completed. This is best accomplished with a unit-digital exam with palpation of pelvic muscles for tenderness and hypertonia on exam. These myofascial findings are often present in the setting of endometriosis, but they can be primary-unrelated to presence or absence of endometriosis.

What are your focused disciplines for approaching endometriosis-associated pain? How do you recommend these clinicians or specialists come together to effectively manage a patient’s conditions? 

Dr. Rapkin: The gynecologist or primary care provider can address the chronic inflammatory, estrogen-dependent aspect of endometriosis. Begin with nonsteroidal, anti-inflammatory medication and combined estrogen-progestin or high-dose progestin-alone hormonal therapy to lower estrogenic stimulation of lesions and decidualize those progestin-sensitive lesions. For menstrual cycle related pain (luteal periovulatory or menstrual phase) cyclical exacerbation of other chronic pain conditions, early intervention is recommended. Adequately dosed preemptive nonsteroidal inflammatory agents and, if not tolerated or effective, begin combined hormonal contraceptives or intrauterine or higher dose progestins menstrual suppression, with either continuous monophasic hormonal contraceptives or progestins, is very important for pain that is cyclical or exacerbated in a cyclical fashion. Progestins can be administered orally, such as norethindrone acetate; intramuscularly or subdermally (depot medroxyprogesterone acetate or etonogestrel implant); or intrauterine (which does not lower estrogen levels but can be therapeutic for suppression of menses and local treatment of endometriosis). Failure of hormonal therapy and management of other co-occurring pain conditions warrants trial of a second-line medical therapy such as gonadotropin-releasing hormone antagonist or agonist or surgery for definitive diagnosis and surgical ablation or excision of endometriosis lesions.

I would suggest that gynecologists who treat women with endometriosis and chronic pain try to build a team in their geographic area. Relevant specialists for an interdisciplinary approach include:

• Pelvic floor physical therapist to evaluate and address myofascial dysfunction and pain and voiding abnormalities, such as urinary urgency or frequency and constipation
• Gastroenterologist for evaluation and treatment of irritable bowel or functional abdominal pain and bloating syndrome or inflammatory bowel disease. Urologist or urogynecologist to assess and treat bladder pain syndrome/interstitial cystitis
• Primary care evaluation for diffuse myofascial pain, fibromyalgia, arthralgias, and other inflammatory conditions, and for management of headache and migraine. Rheumatology and neurology specialists may be needed
• Mental health providers for treatment of anxiety, depression, or PTSD and to address stress management, coping skills and provide cognitive behavioral therapy
• Interventional pain management specialist such as physical medicine and rehabilitation (PM and R), pain anesthiologist, neurologist or interventional radiologist to provide relevant nerve blocks, trigger point injections, or botulinum toxin injection.
• Gynecologists experienced in the management of chronic pelvic pain also provide nerve blocks, trigger point and botulinum toxin injections.

Andrea Rapkin, MD, is Board Certified by the American College of Obstetricians and Gynecologists (of which she is also a fellow). After obtaining her MD, she completed her residency in OBGYN at UCLA then joined the faculty at UCLA and is a Professor of Obstetrics and Gynecology. She was one of the first Obstetrician-Gynecologists to adapt the multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain.

You are the founder and director of a clinic focused on a multidisciplinary pain management approach to the evaluation and treatment of women with pelvic and vulvar pain. How did you identify such a clinic as a therapeutic need for patients? 

Dr. Rapkin: The short answer is that a significant proportion of women were not experiencing pain relief or had incomplete relief with traditional medical or surgical therapy. At the time, we also identified various red flags for traditional treatment failures. These red flags included the following: pain of greater than 6 months duration, pain out of proportion to pathology found on examination, multiple visceral and somatic complaints, and psychosocial abnormalities. We now understand more about the neurobiology underpinning these red flags.  

With the widespread availability of laparoscopy in the late 70s and early 80s, many studies investigated the relationship between endometriosis lesions and pain. The general consensus is that there is no relationship between the location or severity of the endometriosis lesions or the disease stage (American Society for Reproductive Medicine staging) with type of symptoms, symptom severity, treatment response, recurrence, or even prognosis. In fact, pain recurrence after adequate surgical treatment is unrelated to the presence of endometriosis lesions found at the time of repeat laparoscopy. This lack of association between pain and presence of visible disease was supported by a recent New England Journal of Medicine article by Zondervan and colleagues demonstrating that up to 30% of women with chronic pelvic pain, present after excision of endometriotic lesions, become unresponsive to conventional treatment.

The neurobiological responses in an individual with chronic pain are more complicated than those seen in the setting of acute pain. Chronic pain may be triggered or maintained by an inflammatory process such as endometriosis but, over time, altered neural processing and psychosocial maladaptation can occur. The altered processing consists of both peripheral and central sensitization which change the way sensory information from the pelvic viscera and surrounding somatic structures in the periphery is transmitted and interpreted in the central nervous system (spinal cord and brain). Visceral pelvic pain can emanate from the uterus, ovaries and fallopian tubes, the urinary bladder, and the bowel, while the somatic sources include the surrounding abdominal wall, low back and pelvic floor muscles, and fascia, and bones. Signal amplification or peripheral sensitization in the pelvic region in women with endometriosis starts with localized inflammation, neovascularization, invasion and innervation of endometriotic implants. As the pelvic organs share thoracolumbar and sacral autonomic neural pathways, inflammation or dysfunction in one organ or tissue, such as the uterus, over time can sensitize or lead to dysfunction in other pelvic organs, such as the bladder or bowel (called viscero-visceral cross sensitization). Finally, somatic structures sharing intervention with the pelvic viscera, such as the fascia and muscles of the lower abdomen, pelvic floor lower back also become sources of pain because of a process called viscero-somatic sensitization. Women who have endometriosis are therefore more likely to experience IBS, bladder pain syndrome/interstitial cystitis and vulvodynia, and up to 80% of individuals can develop myofascial pain related to trigger points and muscle dysfunction. Up to 50% of women with bladder pain have endometriosis. Those with endometriosis or bladder pain are 2.5 times more likely to also have IBS. 

Over time, other visceral and somatic structures innervated by higher levels of the spinal cord can be affected, leading to more widespread pain. Central sensitization manifests as an amplification of pain in the spinal cord and brain. The presence of more than two chronic “unexplained” pain conditions, such as chronic pelvic pain, vulvodynia, myofascial pain, headache, etc suggest the presence of central sensitization. Anxiety, depression, and maladaptive coping strategies often ensue. Functional MRI studies have documented altered central processing in the brain in many chronic pain states including endometriosis. Interdisciplinary therapy including physical therapy, mental health, and pain management/anesthesiology is more effective compared with medical and or surgical therapy alone for endometriosis-related pain in the setting of peripheral and central sensitization.

What should clinicians look for, or what stands out to them, to confirm the endometriosis diagnosis when pain is the presenting symptom?

Dr. Rapkin: There are no pathognomonic symptoms or biomarkers for endometriosis; however, the following historical features have been shown to be linked with a greater likelihood of finding endometriosis:

• persistent dysmenorrhea (menstrual pain) despite NSAID and hormonal treatment
• cyclical pain that is premenstrual and menstrual that progresses to chronic pain or is accompanied by abnormal or heavy menstrual bleeding
• deep dyspareunia
• dyschezia (pain with bowel movements), and sometimes bloating.

An individual with menstrual pain since menarche can have up to a 5% increased risk of endometriosis. Endometriosis in a first-degree relative elevates the risk for endometriosis by 7% to 10%.

Given the complexity of chronic pain, it is important not to assume endometriosis is the only source of pain. All the pelvic visceral and somatic structures should be evaluated. A thorough history addresses all the patient’s symptoms, including vaginal, gastrointestinal and genitourinary. Aggravating factors such as menstrual cycle, bowel and bladder functioning, physical activity, sexual intercourse and stress should be queried. In addition, assessment of mood, anxiety or depression, sleep disturbance and effect of pain on daily functioning are relevant as is history of abuse or trauma (physical, sexual or emotional). This history can be lengthy, so a detailed pain questionnaire is helpful. (See the pelvicpain.org website for a user-friendly pain questionnaire).

With the previously mentioned risk factors in mind, and after a thorough history has been obtained, a pain-localizing exam should be conducted including the abdominal wall, pelvic floor, and then the bimanual and rectovaginal exams for the abdominal wall myofascial/neuropathic pain assessment for which Carnett’s test can be very useful—tender points on the abdominal wall are palpitated and the patient is asked to give a numerical rating of the pain (1-10/10) and marked with a pen. The patient is then asked to either perform a bilateral straight leg raise or an abdominal crunch, and the areas are re-palpitated. If the marked areas are more painful to palpation during the abdominal crunch or the bilateral straight leg raise, it suggests an abdominal wall pain (myofascial or neuropathic) or component of the pain. Similarly, pelvic floor muscles should be assessed after the abdominal wall exam is completed. This is best accomplished with a unit-digital exam with palpation of pelvic muscles for tenderness and hypertonia on exam. These myofascial findings are often present in the setting of endometriosis, but they can be primary-unrelated to presence or absence of endometriosis.

What are your focused disciplines for approaching endometriosis-associated pain? How do you recommend these clinicians or specialists come together to effectively manage a patient’s conditions? 

Dr. Rapkin: The gynecologist or primary care provider can address the chronic inflammatory, estrogen-dependent aspect of endometriosis. Begin with nonsteroidal, anti-inflammatory medication and combined estrogen-progestin or high-dose progestin-alone hormonal therapy to lower estrogenic stimulation of lesions and decidualize those progestin-sensitive lesions. For menstrual cycle related pain (luteal periovulatory or menstrual phase) cyclical exacerbation of other chronic pain conditions, early intervention is recommended. Adequately dosed preemptive nonsteroidal inflammatory agents and, if not tolerated or effective, begin combined hormonal contraceptives or intrauterine or higher dose progestins menstrual suppression, with either continuous monophasic hormonal contraceptives or progestins, is very important for pain that is cyclical or exacerbated in a cyclical fashion. Progestins can be administered orally, such as norethindrone acetate; intramuscularly or subdermally (depot medroxyprogesterone acetate or etonogestrel implant); or intrauterine (which does not lower estrogen levels but can be therapeutic for suppression of menses and local treatment of endometriosis). Failure of hormonal therapy and management of other co-occurring pain conditions warrants trial of a second-line medical therapy such as gonadotropin-releasing hormone antagonist or agonist or surgery for definitive diagnosis and surgical ablation or excision of endometriosis lesions.

I would suggest that gynecologists who treat women with endometriosis and chronic pain try to build a team in their geographic area. Relevant specialists for an interdisciplinary approach include:

• Pelvic floor physical therapist to evaluate and address myofascial dysfunction and pain and voiding abnormalities, such as urinary urgency or frequency and constipation
• Gastroenterologist for evaluation and treatment of irritable bowel or functional abdominal pain and bloating syndrome or inflammatory bowel disease. Urologist or urogynecologist to assess and treat bladder pain syndrome/interstitial cystitis
• Primary care evaluation for diffuse myofascial pain, fibromyalgia, arthralgias, and other inflammatory conditions, and for management of headache and migraine. Rheumatology and neurology specialists may be needed
• Mental health providers for treatment of anxiety, depression, or PTSD and to address stress management, coping skills and provide cognitive behavioral therapy
• Interventional pain management specialist such as physical medicine and rehabilitation (PM and R), pain anesthiologist, neurologist or interventional radiologist to provide relevant nerve blocks, trigger point injections, or botulinum toxin injection.
• Gynecologists experienced in the management of chronic pelvic pain also provide nerve blocks, trigger point and botulinum toxin injections.

Vikram Bhise, MD, Is an Associate Professor at Rutgers – Robert Wood Johnson Medical School.  He specializes in Epilepsy and Pediatric Neuroimmunology, and runs the pediatric demyelinating diseases program, evaluating children with multiple sclerosis, autoimmune encephalopathy, and related diseases.  He trained in Pediatrics and Pediatric Neurology, at Maimonides Medical Center and Montefiore Medical Center, respectively.  He subsequently received additional training in Clinical Neurophysiology with a focus on Epilepsy at SUNY Downstate Medical Center, and in Pediatric Multiple Sclerosis at SUNY Stony Brook Medical Center. Dr. Bhise conducts clinical research focused on biomarkers and quality of life in pediatric multiple sclerosis, as well as studies in epilepsy and neurogenetics. 

Q1. As a specialist who focuses on neuroimmunology, what forms of measurement do you use to make an evaluation or diagnosis for children with multiple sclerosis?

A1. There's a lot that goes into evaluating or diagnosing children with MS. Usually we start off with the story that the family brings to us. We look at what the child is experiencing and what the parents are seeing. Then we do a dedicated examination trying to substantiate the findings that they're describing and look for others they may not even be aware of. If they are having some blurred vision in their eye, can we tell if there's some abnormalities there that are correlating with what they see?

We try to get a good sense of the time-course of things, observing whether this is the first time something's happened or if this has this been going on for a while. Have there been multiple things going on, multiple episodes? We're primarily looking for events called relapses, which are neurologic attacks that are not quick. They don’t last for seconds or hours; they can last for days to weeks, sometimes even months. Individuals will have episodes that tend to get worse and then tend to get better. This is the type of description we’re looking to come from the families.

Once that assessment is complete, we've found that the MRI is one of the best tools in helping us confirm the diagnosis. It's not just diagnostic but the MRI also  has some prognostic potential and we're looking specifically for patterns in the MRIs. For children, that pattern can be a little bit more challenging. Their patterns can often overlap with patterns of other inflammatory diseases of the brain like ADEM for example and make it much more difficult for us to characterize someone as truly having MS.

There are also some other diseases which have been discovered in the past decade or elaborated upon like neuromyelitis optica and MOG antibody disorder, which can look exactly like MS in the early stages. Sometimes,  that's just not all the information we need. Sometimes it's more difficult to make those distinctions and in these cases, we will look at a spinal tap, a lumbar puncture, and for specific studies from those procedures to help us get a better understanding. There may be other ancillary tests that we use, such as evoked potentials, for example.

Evoked potential testing has kind of fallen to the wayside over the past decade because of the MRI studies becoming a much more useful tool, but we may still use the visual evoked potential to see if there are subtle lesions that can't be seen on the MRI. Other methods might include optical coherence tomography, which is another test looking at the eye that gives you a specific look at the retinal nerve fiber layer, which gets thinned after attacks on the eye on the optic nerve.

We may do neuropsychological testing, which is a battery of tests looking at different cognitive domains and trying to get a sense of a person's cognitive profile to see if that matches what we would expect in somebody with MS. This test could be more challenging for a teen and a child, particularly a younger child. When it comes to pediatric neuropsychology, it's a little bit harder sometimes to get good data, particularly from younger kids.

In addition, we have a battery of tests that we do on the serum. Some disorders, like NMO and MOG, have antibodies that help us identify them. We don't have a specific test that says, yes, you have MS and no, you don't have MS. It's really the combination of all the tools.

We do these tests often to look for things that mimic MS. We look for other neuroinflammatory or neurobiological diseases that can look a lot like MS and fool us. Most of the time they don't look exactly like MS, but every now and then you get a case that's virtually indistinguishable. There are other tools which may be in less use, but we put the combination of all these things together to help us make the most informed judgment.

The goal is to be able to have honest discussions with families that these tools are just tools that we're trying to play catch up with a disease and try to make a decision as fast as possible to prevent someone from going untreated.

Q2.  How does a diagnosis of multiple sclerosis affect the overall quality of life for a child/teen, and how does it affect their overall psychosocial health? Education?  Transition needs? Etc.

A2. It can be quite profound, just hearing the diagnosis can be truly life changing for most folks. It would really depend on the family the first time that we meet them. If they have no suspicion that this is what's going on, that can be a shock. Other families may be more aware of what’s going on. Perhaps another physician has already suggested it, or they came from the ER which had already done some of the baseline tests like the MRI, and they had some kind of  suspicion. Maybe they googled it and they saw something to be worried about, so they may be prepared. But even then,  once you confirm the diagnosis, it's really like the sky falling at that point.

Past the diagnosis stage, there's really an adjustment phase that we see, and we've been doing some work in this. We started doing some work looking at quality of life. We've interviewed a large  number of families and asked them some key questions such as, “What's important to you?” It is key for them to tell us rather than us telling them. By doing this, we’re finding out things that may not have been on the forefront of our minds, although it was certainly in the forefront of their minds,  so it's a good learning opportunity.

These may be things that we've seen in other quality of life studies in other diseases, but you also have to consider each disease unique and make sure you're looking at this from the perspective of the people that are really being affected. One of the great examples was that the teens really cared more about visible symptoms. For example, an adult with MS may have fatigue, severe fatigue. They may be unable to perform well in their job and that could be a game changer for them. Yet if they had a mild limp, they'd say, yeah, it's kind of embarrassing but I can keep going forward. I can hang in there and my colleagues at work might even support me; but for a teenager, they may care less about the fatigue and way more about having this limp that all their peers can now notice. The symptoms that are important to them can be totally different depending on the age group.

What we found is that teenagers look at things quite differently in trying to optimize their outcomes, and we don't just want them to be medically well. We want them to succeed in school, we want them to succeed in getting into college, or going into the workforce. So, we asked a lot about what it takes to get you there. We asked a lot of the young adults who had pediatric onset MS if they were  successful? And if you were, what got you there; and the ones who hadn't reached that yet we asked-- what do you need?

When it came to transition needs, by far, we’ve found almost complete silence on the teenager’s part, which was a little surprising for us. We thought that there would be a little bit of discussion. They didn’t understand what a 504 is. We don't expect the average individual to know, but we thought that they might understand what the tools were, yet they really had no language for discussing that with us. We realized that the start of our transition talks had to be focused on the things that we use for that language.

For example, if I wanted to get a ding in my car fixed. I had to spend 20 minutes explaining to the dealership what I wanted. It was a regular car dealership, so it was integrated. But I had to find the right words to say. I want “auto body.” If I said vehicle repair, they said, oh, you want your car tires replaced? No, no, no. so, it’s very important to speak the right language just to get the process started. Those are some of the things that we found.

Q3. In what ways do environmental and genetic risk factors influence therapeutic decisions in pediatric patients with MS? 

A3. They really play a big role in terms of the risk. We find that the more risk factors you have, likely we're dealing with a more severe disease. It doesn't necessarily always work that way, but you may be prepared to use a more potent therapy for individuals that are hitting more of the categories of concern.

But in addition to just the main disease modifying medications and MS, we look at vitamin D. And the data is yet to come out on that. There are some big studies that are trying to confirm or refute if vitamin D really has a therapeutic role, but we find that our teens and our kids have lower than average low vitamin D levels. We know that kids have low vitamin D levels nationwide in this country, but our patients are even lower than that. And that's one thing that we try to supplement and hope that by supplementing it, that it's going to be helpful. Maybe it's not as potent to therapy as the main medications, but we're hoping that's something to add on.

Q4. Overall, what are some advances, trends or recent studies regarding therapies that might support positive outcomes in children with MS? 

A4  Interestingly, we just don't have a lot of that research in kids. There's been tons and tons of great research in adults. Like many other fields, you take what you learn from that and you apply it to the teens and kids. But we've learned time and time again they're not just little adults. They're truly a separate group, and we must consider them as such, and we really need those studies in kids.

The first study that came out confirmed that fingolimod was a good and effective therapy in children. But does that mean that you're only limited to using the only FDA approved option, or do you really want to try to offer families the litany of choices that you do for an adult with MS? When I meet families for the first time, we’re spending a good hour just talking about the different treatment choices with them and looking at the risks, the benefits, why one option might be chosen over another,  how it's going to affect their lifestyle, and how it might fit into their life.

We want to still be able to make those decisions. I think we can make a more informed decision with fingolimod, but we don't want to just jump to conclusions with all those other therapies. We're a little bit behind the mark when it comes to therapies with kids, and we really need all those studies. They are active, and they are being done now; we're really waiting for those results to come out. That's going to be a huge change. Basically, that's the real trend. We're now going to see those studies in adults being replicated in kids one by one. Every time a new therapy comes out for adults, it must be validated in children as well.

Part of the regulations now do stipulate that these studies must be done. If you do a study in the adult population, you must see if you can do it in the pediatric population. You can't just say, hey, you know we're done. That's really what we're looking for in terms of getting the big therapeutic outcomes.

Vikram Bhise, MD, Is an Associate Professor at Rutgers – Robert Wood Johnson Medical School.  He specializes in Epilepsy and Pediatric Neuroimmunology, and runs the pediatric demyelinating diseases program, evaluating children with multiple sclerosis, autoimmune encephalopathy, and related diseases.  He trained in Pediatrics and Pediatric Neurology, at Maimonides Medical Center and Montefiore Medical Center, respectively.  He subsequently received additional training in Clinical Neurophysiology with a focus on Epilepsy at SUNY Downstate Medical Center, and in Pediatric Multiple Sclerosis at SUNY Stony Brook Medical Center. Dr. Bhise conducts clinical research focused on biomarkers and quality of life in pediatric multiple sclerosis, as well as studies in epilepsy and neurogenetics. 

Q1. As a specialist who focuses on neuroimmunology, what forms of measurement do you use to make an evaluation or diagnosis for children with multiple sclerosis?

A1. There's a lot that goes into evaluating or diagnosing children with MS. Usually we start off with the story that the family brings to us. We look at what the child is experiencing and what the parents are seeing. Then we do a dedicated examination trying to substantiate the findings that they're describing and look for others they may not even be aware of. If they are having some blurred vision in their eye, can we tell if there's some abnormalities there that are correlating with what they see?

We try to get a good sense of the time-course of things, observing whether this is the first time something's happened or if this has this been going on for a while. Have there been multiple things going on, multiple episodes? We're primarily looking for events called relapses, which are neurologic attacks that are not quick. They don’t last for seconds or hours; they can last for days to weeks, sometimes even months. Individuals will have episodes that tend to get worse and then tend to get better. This is the type of description we’re looking to come from the families.

Once that assessment is complete, we've found that the MRI is one of the best tools in helping us confirm the diagnosis. It's not just diagnostic but the MRI also  has some prognostic potential and we're looking specifically for patterns in the MRIs. For children, that pattern can be a little bit more challenging. Their patterns can often overlap with patterns of other inflammatory diseases of the brain like ADEM for example and make it much more difficult for us to characterize someone as truly having MS.

There are also some other diseases which have been discovered in the past decade or elaborated upon like neuromyelitis optica and MOG antibody disorder, which can look exactly like MS in the early stages. Sometimes,  that's just not all the information we need. Sometimes it's more difficult to make those distinctions and in these cases, we will look at a spinal tap, a lumbar puncture, and for specific studies from those procedures to help us get a better understanding. There may be other ancillary tests that we use, such as evoked potentials, for example.

Evoked potential testing has kind of fallen to the wayside over the past decade because of the MRI studies becoming a much more useful tool, but we may still use the visual evoked potential to see if there are subtle lesions that can't be seen on the MRI. Other methods might include optical coherence tomography, which is another test looking at the eye that gives you a specific look at the retinal nerve fiber layer, which gets thinned after attacks on the eye on the optic nerve.

We may do neuropsychological testing, which is a battery of tests looking at different cognitive domains and trying to get a sense of a person's cognitive profile to see if that matches what we would expect in somebody with MS. This test could be more challenging for a teen and a child, particularly a younger child. When it comes to pediatric neuropsychology, it's a little bit harder sometimes to get good data, particularly from younger kids.

In addition, we have a battery of tests that we do on the serum. Some disorders, like NMO and MOG, have antibodies that help us identify them. We don't have a specific test that says, yes, you have MS and no, you don't have MS. It's really the combination of all the tools.

We do these tests often to look for things that mimic MS. We look for other neuroinflammatory or neurobiological diseases that can look a lot like MS and fool us. Most of the time they don't look exactly like MS, but every now and then you get a case that's virtually indistinguishable. There are other tools which may be in less use, but we put the combination of all these things together to help us make the most informed judgment.

The goal is to be able to have honest discussions with families that these tools are just tools that we're trying to play catch up with a disease and try to make a decision as fast as possible to prevent someone from going untreated.

Q2.  How does a diagnosis of multiple sclerosis affect the overall quality of life for a child/teen, and how does it affect their overall psychosocial health? Education?  Transition needs? Etc.

A2. It can be quite profound, just hearing the diagnosis can be truly life changing for most folks. It would really depend on the family the first time that we meet them. If they have no suspicion that this is what's going on, that can be a shock. Other families may be more aware of what’s going on. Perhaps another physician has already suggested it, or they came from the ER which had already done some of the baseline tests like the MRI, and they had some kind of  suspicion. Maybe they googled it and they saw something to be worried about, so they may be prepared. But even then,  once you confirm the diagnosis, it's really like the sky falling at that point.