Neurology

Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.

Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.

Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.

A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.

The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.

The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.

“Understanding these regional differences in the drugs most frequently involved in drug overdose deaths may help inform prevention and policy efforts,” the investigators wrote.

rfranki@mdedge.com

Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.

Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.

Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.

A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.

The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.

The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.

“Understanding these regional differences in the drugs most frequently involved in drug overdose deaths may help inform prevention and policy efforts,” the investigators wrote.

rfranki@mdedge.com

Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.

Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.

Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.

A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.

The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.

The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.

“Understanding these regional differences in the drugs most frequently involved in drug overdose deaths may help inform prevention and policy efforts,” the investigators wrote.

rfranki@mdedge.com

STOCKHOLM – The long-term prognosis of multiple sclerosis has improved markedly around the world,, according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”

At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.

The relative prevalence of mild disability has increased

About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”

The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.

The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.

Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.

Trend toward milder disability

The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.

In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.

International data show similar trends

Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.

More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.

In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.

In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.

Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.

The role of DMTs

The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.

Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.

Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.

Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.

Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.

egreb@mdedge.com

SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.

STOCKHOLM – The long-term prognosis of multiple sclerosis has improved markedly around the world,, according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”

At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.

The relative prevalence of mild disability has increased

About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”

The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.

The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.

Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.

Trend toward milder disability

The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.

In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.

International data show similar trends

Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.

More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.

In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.

In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.

Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.

The role of DMTs

The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.

Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.

Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.

Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.

Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.

egreb@mdedge.com

SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.

STOCKHOLM – The long-term prognosis of multiple sclerosis has improved markedly around the world,, according to an overview provided at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Data consistently indicate that the time that elapses before a patient requires a cane for ambulation has increased, and survival has likewise improved. “Some of the improvement can be attributed confidently to treatment effect,” said Ilya Kister, MD, associate professor of neurology at NYU Langone Health in New York. “We hope to see an even greater change with newer therapies.”

At the same time, neurologists appear to be diagnosing more cases of MS than they previously did, said Dr. Kister, which suggests that neurologists probably are diagnosing milder cases. The overall societal burden of MS remains high.

The relative prevalence of mild disability has increased

About 25 years have elapsed since the first disease-modifying treatment (DMT) for MS became available, and treatment has become widespread during that time. Dr. Kister and colleagues sought to determine whether the current clinical population of patients with MS, who for the most part receive DMTs, has less disability than do untreated patients or patients from natural history studies do. They identified the MS Severity Score (MSSS) as a measure with which to compare populations. The MSSS assigns a patient a ranking according to his or her level of disability, using a reference population of patients with the same disease duration for comparison. “MSSS can be conceptualized as rate of disability accumulation,” said Dr. Kister. “Lower MSSS corresponds to relatively slower disability accumulation, and higher MSSS to higher disability accumulation.”

The MSSS was developed using the Expanded Disability Status Scale (EDSS) score as a measure of disability. Because many neurologists do not routinely obtain EDSS scores for their patients, Dr. Kister and colleagues used the Patient-Determined Disease Steps (PDDS) to measure disability. As its name implies, the PDDS is a patient-reported outcome measure that mainly measures ambulation. It correlates strongly with EDSS, said Dr. Kister. He and colleagues used the PDDS to develop a reference table of MS disability, which they called the Patient-Derived MSSS.

The investigators examined a large sample of patients at NYU MS Center and Barnabas MS Center in Livingston, N.J. They grouped patients into sextiles according to their Patient-Derived MSSS. Dr. Kister and colleagues found that, rather than arriving at sextiles that contained equal numbers of patients, as would be expected if disability were distributed as in the reference population, they had significantly more patients in the two lowest sextiles and significantly fewer patients in the two highest sextiles. “This [result] suggests that the disability curve has indeed shifted toward the more benign end of the spectrum in the contemporary clinic population,” said Dr. Kister.

Other researchers have observed a similar phenomenon. George et al. published the results of a large, international collaboration in Neurology Genetics in 2016. After examining more than 7,000 patients, the investigators noted a similar overrepresentation of patients with milder severity scores and underrepresentation of patients with higher severity scores. These results support the hypothesis of a shift toward milder disability, said Dr. Kister.

Trend toward milder disability

The investigators next examined whether the rate of accumulation of disability among patients with MS had changed from year to year since DMTs were introduced. They conducted a univariate analysis of MSSS for 6,238 patients who were enrolled in the N.Y. State MS Consortium during 1996-2007. They found that patients who were enrolled in more recent years had significantly lower MSSS than patients who were enrolled in earlier years, regardless of disease duration. When Dr. Kister and colleagues replicated their analysis using EDSS, they found significantly lower levels of disability for patients enrolled in more recent years, except for patients with disease duration of 26-30 years. A multivariate analysis showed that the median MSSS of enrollees into the N.Y. State MS Consortium decreased from 5.04 in 1996 to 3.78 in 2006.

In a subsequent study, Dr. Kister and colleagues examined the age at which patients in the MSBase registry reached various disability milestones (e.g., EDSS of 6, which indicates the need of a cane to walk outdoors), according to their year of enrollment in the registry. They found a significant increase in age at milestone achievement with each subsequent calendar year. For example, for every consecutive year of enrollment, the age at which patients attained an EDSS of 6 increased by 0.38 years. These analyses were confirmed for the subgroups of patients diagnosed according to the Poser and McDonald criteria. The increase in age “is probably not just related to the shift in diagnostic criteria,” said Dr. Kister. When the researchers calculated the net average gains in years over the 13-year follow-up period, they found that patients who entered at the end of the enrollment period were 4.9 years older when they reached an EDSS of 6, compared with patients with an EDSS of 6 who entered at the beginning of the enrollment period.

International data show similar trends

Research conducted around the world shows similar trends, said Dr. Kister. In 2009, Veugelers et al. published the results of a study that included 1,752 patients with MS in Nova Scotia. Before the 1998 introduction of a drug insurance program that provides DMTs, the time to an EDSS of 6 was 14.4 years. After the introduction of this program, the time to EDSS of 6 was 18.6 years.

More recently, Capra et al. examined 1,324 patients with MS who attended an MS center in Brescia, Italy, during 1980-2010. They found that the age at which 50% of patients reached an EDSS of 6 was approximately 55 years in 1990. By 2010, the age at achieving this milestone had increased to approximately 63 years.

In a prospective study, Cree et al. examined the evolution of disability in 448 actively treated patients with relapsing-remitting MS and 69 patients with progressive MS. Approximately 45% of patients had no disability worsening during a 10-year follow-up period. Furthermore, a comparatively low 11% of patients had reached an EDSS of 6 at 10 years. The average disease duration of the cohort at that time was 17 years, said Dr. Kister. The results indicated that about 50% of patients would be expected to reach an EDSS of 6 after a disease duration of approximately 38 years, “which is much longer than in the natural history studies,” he added.

In 2019, Beiki et al. found that among patients with relapsing-remitting MS, the risk of reaching an EDSS of 6 decreased by 7% with each subsequent calendar year of diagnosis. The researchers did not observe a similar trend among patients with progressive MS. Their population-based, retrospective study included 7,331 patients in Sweden.

Two additional studies in Scandinavian populations add to the evidence of decreasing disability. In their examination of Swedish patients with MS who received a diagnosis of MS during 1968-2012, Burkill et al. found that the risk of death decreased over time. The hazard ratio of mortality for patients with MS, compared with a non-MS comparator group, decreased from 6.52 among those diagnosed during 1968-1980 to 2.08 for patients diagnosed during 2001-2012. The decrease in the risk of mortality was greater among patients with MS than in a matched comparator population. Similarly, in a nationwide, population-based study, Koch-Henriksen et al. found that all-cause excess mortality in Danish patients with MS decreased from 1950 through 1999.

The role of DMTs

The evidence suggests that DMTs are affecting the long-term progression of MS, said Dr. Kister. Palace et al. compared patients with MS in the UK who received treatment with interferon-beta with a modeled untreated cohort of patients in British Columbia. They found that treated patients reached an EDSS of 6 4 years later than did untreated patients.

Furthermore, an analysis by Brown et al. showed that the time to conversion to secondary progressive MS was longer among treated patients, compared with untreated patients. The risk of conversion was lower for patients treated with newer, more effective therapies (i.e., fingolimod, alemtuzumab, or natalizumab) than for those treated with glatiramer acetate or interferon beta.

Finally, Kingwell and colleagues examined the effect of treatment with interferon-beta on survival using an international cohort of approximately 6,000 patients with relapsing-remitting MS. They found that exposure to interferon-beta for more than 3 years was associated with a 32% reduction in the risk of mortality. They observed no similar risk reduction among patients exposed to interferon-beta for 6 months to 3 years.

Although these data are encouraging, other evidence indicates that the prevalence of MS in the United States has increased considerably in the past 40 years. Researchers estimate that 1 million Americans have MS, which “suggests that we are diagnosing many more mild cases,” said Dr. Kister. The burden of the disease remains high, he concluded.

Dr. Kister reported receiving consulting fees or research grants from Biogen, Roche, Genzyme and Genentech.

egreb@mdedge.com

SOURCE: Kister I et al. ECTRIMS 2019. Abstract 281754.

Average out-of-pocket costs for Medicare beneficiaries with Alzheimer’s disease were more than 2.7 times higher than for enrollees overall in 2016, according to the Kaiser Family Foundation.

Out-of-pocket spending for Alzheimer’s disease or other dementia was higher than any other chronic condition, averaging $14,913 in 2016 (the latest year for which data are available), compared with $5,460 for all beneficiaries in traditional Medicare, Kaiser investigators said in a recent report based on data for 5,369 respondents to the Medicare Current Beneficiary Survey.

Those totals were divided between services – including long-term care facilities, medical providers and supplies, and prescription drugs – and premiums for Medicare and other types of supplemental insurance. The premium associated with Alzheimer’s, $1,643, was the lowest of any major chronic condition, but the average cost for services, $13,269, was almost twice as high as the next most expensive condition, Parkinson’s disease, and more than four times higher than the overall Medicare average, Juliette Cubanski, PhD, and associates said.

Out-of-pocket costs are higher for patients with Alzheimer’s and Parkinson’s because “these beneficiaries are more likely to reside in a long-term care facility than those with other conditions,” they said. In 2016, out-of-pocket spending on long-term care facility services averaged over $27,000 for Medicare beneficiaries with Alzheimer’s and other dementia and over $28,000 for those with Parkinson’s disease. For all traditional Medicare beneficiaries, average out-of-pocket spending on such services was $1,014.

“The fact that traditional Medicare does not have an annual out-of-pocket limit and does not cover certain services that older adults are more likely to need may undermine the financial security that Medicare provides, especially for people with significant needs and limited incomes. Addressing these gaps would help to alleviate the financial burden of health care for people with Medicare, although doing so would also increase federal spending and taxes,” Dr. Cubanski and associates wrote.

rfranki@mdedge.com

Average out-of-pocket costs for Medicare beneficiaries with Alzheimer’s disease were more than 2.7 times higher than for enrollees overall in 2016, according to the Kaiser Family Foundation.

Out-of-pocket spending for Alzheimer’s disease or other dementia was higher than any other chronic condition, averaging $14,913 in 2016 (the latest year for which data are available), compared with $5,460 for all beneficiaries in traditional Medicare, Kaiser investigators said in a recent report based on data for 5,369 respondents to the Medicare Current Beneficiary Survey.

Those totals were divided between services – including long-term care facilities, medical providers and supplies, and prescription drugs – and premiums for Medicare and other types of supplemental insurance. The premium associated with Alzheimer’s, $1,643, was the lowest of any major chronic condition, but the average cost for services, $13,269, was almost twice as high as the next most expensive condition, Parkinson’s disease, and more than four times higher than the overall Medicare average, Juliette Cubanski, PhD, and associates said.

Out-of-pocket costs are higher for patients with Alzheimer’s and Parkinson’s because “these beneficiaries are more likely to reside in a long-term care facility than those with other conditions,” they said. In 2016, out-of-pocket spending on long-term care facility services averaged over $27,000 for Medicare beneficiaries with Alzheimer’s and other dementia and over $28,000 for those with Parkinson’s disease. For all traditional Medicare beneficiaries, average out-of-pocket spending on such services was $1,014.

“The fact that traditional Medicare does not have an annual out-of-pocket limit and does not cover certain services that older adults are more likely to need may undermine the financial security that Medicare provides, especially for people with significant needs and limited incomes. Addressing these gaps would help to alleviate the financial burden of health care for people with Medicare, although doing so would also increase federal spending and taxes,” Dr. Cubanski and associates wrote.

rfranki@mdedge.com

Average out-of-pocket costs for Medicare beneficiaries with Alzheimer’s disease were more than 2.7 times higher than for enrollees overall in 2016, according to the Kaiser Family Foundation.

Out-of-pocket spending for Alzheimer’s disease or other dementia was higher than any other chronic condition, averaging $14,913 in 2016 (the latest year for which data are available), compared with $5,460 for all beneficiaries in traditional Medicare, Kaiser investigators said in a recent report based on data for 5,369 respondents to the Medicare Current Beneficiary Survey.

Those totals were divided between services – including long-term care facilities, medical providers and supplies, and prescription drugs – and premiums for Medicare and other types of supplemental insurance. The premium associated with Alzheimer’s, $1,643, was the lowest of any major chronic condition, but the average cost for services, $13,269, was almost twice as high as the next most expensive condition, Parkinson’s disease, and more than four times higher than the overall Medicare average, Juliette Cubanski, PhD, and associates said.

Out-of-pocket costs are higher for patients with Alzheimer’s and Parkinson’s because “these beneficiaries are more likely to reside in a long-term care facility than those with other conditions,” they said. In 2016, out-of-pocket spending on long-term care facility services averaged over $27,000 for Medicare beneficiaries with Alzheimer’s and other dementia and over $28,000 for those with Parkinson’s disease. For all traditional Medicare beneficiaries, average out-of-pocket spending on such services was $1,014.

“The fact that traditional Medicare does not have an annual out-of-pocket limit and does not cover certain services that older adults are more likely to need may undermine the financial security that Medicare provides, especially for people with significant needs and limited incomes. Addressing these gaps would help to alleviate the financial burden of health care for people with Medicare, although doing so would also increase federal spending and taxes,” Dr. Cubanski and associates wrote.

rfranki@mdedge.com

THE CASE

A 26-year-old Hispanic/African American woman presented to our clinic with a 2-month history of nausea and vomiting, along with dizziness. The nausea and vomiting persistently worsened, and she was only able to tolerate apples and berries. During this 2-month period, she lost 20 pounds and her symptoms progressed to include pruritus, ataxia, and mild hearing loss, with reoccurring episodes of falls.

THE DIAGNOSIS

On examination, she was found to be bradycardic with a heart rate of 47 beats/min, right- axis deviation, and inverted T waves in leads I, II, and augmented vector left. Her family history included the death of an aunt who was in her early 30s due to an unknown heart condition.

Echocardiogram identified mild mitral valve regurgitation with an ejection fraction of 55% to 60% (reference range: 55%-70%). Cardiology determined that her bradycardia was not the source of her symptoms. A neurologic exam identified 3+ hyperreflexia (indicating the reflex was increased), tandem gait instability, and left oculomotor dysfunction.

Brain magnetic resonance imaging (MRI) identified bilateral parietal white matter lesions where a demyelinating process could not be excluded (FIGURE 1A). The patient’s symptoms of nausea and vomiting continued, and she only tolerated peanuts and liquids. An MRI of the spine was negative.

Laboratory testing revealed that the patient was negative for human immunodeficiency virus (HIV), syphilis, Lyme disease, and lupus. Her thyroid-stimulating hormone level was 1.7 mIU/L (reference range: 0.4-4.2 mIU/L), and her vitamin B₁₂ level was 504 pg/mL (reference range: 160-950 pg/mL).

The patient’s lumbar puncture was negative for oligoclonal bands. The IgG synthesis rate/index cerebrospinal fluid (CSF) was –3.9, ruling out multiple sclerosis. Her CSF culture was negative, with a glucose level of 42 mg/dL (reference range: 70-110 mg/dL), colorless appearance, 1 white blood cell, and spinal albumin of 12.2 mg/dL (reference range: 8-42 mg/dL). The visual evoked potential was negative. The aquaporin-4 (AQP4) antibody was positive at 3.4 U/mL, and the myelin oligodendrocyte glycoprotein (MOG) antibody was positive.

Gastroenterology concluded a normal gastric accommodation and unremarkable computed tomography (CT) enterography. Moderate erosions were identified in the stomach with an erythematous gastropathy. The patient was placed on a proton pump inhibitor.

Continue to: Following the examination...

Following the examination and laboratory testing, the patient was admitted under our family medicine service for neuromyelitis optica (NMO) affecting the area postrema. NMO, also known as Devic’s disease, is an autoimmune disorder that affects the spinal cord and optic nerves. Autoantibodies against AQP4 are created in the periphery and are directed against astrocytes in the central nervous system. These antibodies bind to the foot processes of astrocytes, inducing complement-mediated cell damage and granulocyte infiltration.^1-5

Intravenous methylprednisolone was initiated at 250 mg every 6 hours for 3 days. A repeat brain MRI demonstrated nonspecific multiple scattered foci of hyperintense signal involving the subcortical supratentorial white matter without abnormal enhancement, most likely representing nonactive demyelinating plaques (FIGURES 1B and 1C).

Dx is revisited. Our patient was referred to an NMO clinic for evaluation. After further testing (including a repeat MRI based on the neurologist’s specifications, anti-aquaporin antibody testing, and MOG-antibody testing) and case discussion, it was determined that the patient had MOG-antibody disease. This disease, along with NMO, comprise a spectrum of disorders referred to as neuromyelitis optica spectrum disorder (NMOSD).

The patient was subsequently prescribed a rituximab infusion, 500 mg/50 mL, to treat the current attack. One infusion was to be completed weekly for 2 weeks with plans to repeat treatment every 6 months to prevent flares of NMO. During the first dose, the patient had a reaction to the treatment, which caused pruritus and chest tightness. She was able to complete the infusion after being treated with diphenhydramine.

Tx continued. In order to complete the second of 2 infusions of rituximab, the patient was pretreated with oral methylprednisolone the night before the infusion, along with diphenhydramine and acetaminophen on the day of treatment. Fortunately, the patient tolerated the infusion well with no adverse effects or reactions.

Continue to: DISCUSSION

DISCUSSION

Within the NMO spectrum, the MOG antibody is positive in up to 42% of AQP4-seronegative cases.⁶ MOG is a minor myelin component that is expressed exclusively in the central nervous system on the surface of myelin and oligodendrocyte processes. The role of this glycoprotein is not well understood but is hypothesized to function as a cell surface receptor or cell adhesion molecule.⁷

Among a cohort of 252 patients from the United Kingdom who tested positive for the MOG-IgG1 antibody, optic neuritis was seen in 55%, while 18% experienced transverse myelitis, and 15% had a history of area postrema syndrome. A brain MRI identified lesions in all areas of the brain including the brain stem, cerebellum, and cerebral hemispheres.⁸

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein Barr virus seropositivity, and tobacco abuse.

Differential diagnosis. Many diseases or conditions that are inflammatory, autoimmune, infectious, or neoplastic can involve the central nervous system and mimic the clinical and radiologic phenotypes of NMOSD-AQP4. They include lupus, SjÖgren’s syndrome, multiple sclerosis, sarcoidosis, acute disseminated encephalomyelitis, HIV, and vitamin B₁₂ deficiency.

Treatment. The standard treatment is intravenous methylprednisolone, 1 g/d for 3 to 5 days followed by a steroid taper. Therapeutic plasma exchange is recommended for refractory cases and in patients with spinal cord demyelination.^9-11 Rituximab is the first-line therapy for attack prevention^12-15 in NMOSD broadly and may be effective in MOG antibody disease, as well. In an open-label study of patients with NMOSD treated with rituximab, 64% were relapse free at follow-up, which ranged from 12 to 67 months.¹³ In a long-term study of patients treated with rituximab, 87% maintained a reduced relapse rate and 93% had improvement or stability over a 5-year follow-up.¹⁴

Continue to: Our patient

Our patient. After her diagnosis of NMOSD/MOG-antibody disease, our patient’s symptoms progressed to include vertigo, vestibular ataxia, pruritus, left foot drop, lower extremity numbness, and decreased hearing. After the second rituximab infusion her symptoms continued, but over time stabilized and have not worsened. She currently receives gabapentin 300 mg every 8 hours, as needed, for extremity numbness (which has been working well) along with sertraline 100 mg/d for depression.

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein-Barr virus seropositivity, and tobacco abuse.

Subsequent office visits have showed no further weight loss. Based on the current response to the rituximab, her prognosis is undetermined by Neurology as they continue to monitor for progression.

THE TAKEAWAY

Vestibular ataxia, foot drop, pruritus, vertigo, decreased hearing, numbness, and oculomotor dysfunction in the presence of nausea and vomiting should raise suspicion for NMOSD. The presence of AQP4 antibodies along with demyelinating central nervous system lesions, is highly indicative of NMO. The presence of MOG antibodies may indicate NMOSD/MOG-antibody disease. The initial treatment of NMOSD is intravenous methylprednisolone, which can be followed by treatment with rituximab to achieve remission.

CORRESPONDENCE
Daniel Murphy, MD, FAAFP, Department of Family and Community Medicine, Texas Tech University Health Science Center El Paso, 9849 Kenworthy Street, El Paso, Texas 79924; Daniel.murphy@ttuhsc.edu

THE CASE

A 26-year-old Hispanic/African American woman presented to our clinic with a 2-month history of nausea and vomiting, along with dizziness. The nausea and vomiting persistently worsened, and she was only able to tolerate apples and berries. During this 2-month period, she lost 20 pounds and her symptoms progressed to include pruritus, ataxia, and mild hearing loss, with reoccurring episodes of falls.

THE DIAGNOSIS

On examination, she was found to be bradycardic with a heart rate of 47 beats/min, right- axis deviation, and inverted T waves in leads I, II, and augmented vector left. Her family history included the death of an aunt who was in her early 30s due to an unknown heart condition.

Echocardiogram identified mild mitral valve regurgitation with an ejection fraction of 55% to 60% (reference range: 55%-70%). Cardiology determined that her bradycardia was not the source of her symptoms. A neurologic exam identified 3+ hyperreflexia (indicating the reflex was increased), tandem gait instability, and left oculomotor dysfunction.

Brain magnetic resonance imaging (MRI) identified bilateral parietal white matter lesions where a demyelinating process could not be excluded (FIGURE 1A). The patient’s symptoms of nausea and vomiting continued, and she only tolerated peanuts and liquids. An MRI of the spine was negative.

Laboratory testing revealed that the patient was negative for human immunodeficiency virus (HIV), syphilis, Lyme disease, and lupus. Her thyroid-stimulating hormone level was 1.7 mIU/L (reference range: 0.4-4.2 mIU/L), and her vitamin B₁₂ level was 504 pg/mL (reference range: 160-950 pg/mL).

The patient’s lumbar puncture was negative for oligoclonal bands. The IgG synthesis rate/index cerebrospinal fluid (CSF) was –3.9, ruling out multiple sclerosis. Her CSF culture was negative, with a glucose level of 42 mg/dL (reference range: 70-110 mg/dL), colorless appearance, 1 white blood cell, and spinal albumin of 12.2 mg/dL (reference range: 8-42 mg/dL). The visual evoked potential was negative. The aquaporin-4 (AQP4) antibody was positive at 3.4 U/mL, and the myelin oligodendrocyte glycoprotein (MOG) antibody was positive.

Gastroenterology concluded a normal gastric accommodation and unremarkable computed tomography (CT) enterography. Moderate erosions were identified in the stomach with an erythematous gastropathy. The patient was placed on a proton pump inhibitor.

Continue to: Following the examination...

Following the examination and laboratory testing, the patient was admitted under our family medicine service for neuromyelitis optica (NMO) affecting the area postrema. NMO, also known as Devic’s disease, is an autoimmune disorder that affects the spinal cord and optic nerves. Autoantibodies against AQP4 are created in the periphery and are directed against astrocytes in the central nervous system. These antibodies bind to the foot processes of astrocytes, inducing complement-mediated cell damage and granulocyte infiltration.^1-5

Intravenous methylprednisolone was initiated at 250 mg every 6 hours for 3 days. A repeat brain MRI demonstrated nonspecific multiple scattered foci of hyperintense signal involving the subcortical supratentorial white matter without abnormal enhancement, most likely representing nonactive demyelinating plaques (FIGURES 1B and 1C).

Dx is revisited. Our patient was referred to an NMO clinic for evaluation. After further testing (including a repeat MRI based on the neurologist’s specifications, anti-aquaporin antibody testing, and MOG-antibody testing) and case discussion, it was determined that the patient had MOG-antibody disease. This disease, along with NMO, comprise a spectrum of disorders referred to as neuromyelitis optica spectrum disorder (NMOSD).

The patient was subsequently prescribed a rituximab infusion, 500 mg/50 mL, to treat the current attack. One infusion was to be completed weekly for 2 weeks with plans to repeat treatment every 6 months to prevent flares of NMO. During the first dose, the patient had a reaction to the treatment, which caused pruritus and chest tightness. She was able to complete the infusion after being treated with diphenhydramine.

Tx continued. In order to complete the second of 2 infusions of rituximab, the patient was pretreated with oral methylprednisolone the night before the infusion, along with diphenhydramine and acetaminophen on the day of treatment. Fortunately, the patient tolerated the infusion well with no adverse effects or reactions.

Continue to: DISCUSSION

DISCUSSION

Within the NMO spectrum, the MOG antibody is positive in up to 42% of AQP4-seronegative cases.⁶ MOG is a minor myelin component that is expressed exclusively in the central nervous system on the surface of myelin and oligodendrocyte processes. The role of this glycoprotein is not well understood but is hypothesized to function as a cell surface receptor or cell adhesion molecule.⁷

Among a cohort of 252 patients from the United Kingdom who tested positive for the MOG-IgG1 antibody, optic neuritis was seen in 55%, while 18% experienced transverse myelitis, and 15% had a history of area postrema syndrome. A brain MRI identified lesions in all areas of the brain including the brain stem, cerebellum, and cerebral hemispheres.⁸

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein Barr virus seropositivity, and tobacco abuse.

Differential diagnosis. Many diseases or conditions that are inflammatory, autoimmune, infectious, or neoplastic can involve the central nervous system and mimic the clinical and radiologic phenotypes of NMOSD-AQP4. They include lupus, SjÖgren’s syndrome, multiple sclerosis, sarcoidosis, acute disseminated encephalomyelitis, HIV, and vitamin B₁₂ deficiency.

Treatment. The standard treatment is intravenous methylprednisolone, 1 g/d for 3 to 5 days followed by a steroid taper. Therapeutic plasma exchange is recommended for refractory cases and in patients with spinal cord demyelination.^9-11 Rituximab is the first-line therapy for attack prevention^12-15 in NMOSD broadly and may be effective in MOG antibody disease, as well. In an open-label study of patients with NMOSD treated with rituximab, 64% were relapse free at follow-up, which ranged from 12 to 67 months.¹³ In a long-term study of patients treated with rituximab, 87% maintained a reduced relapse rate and 93% had improvement or stability over a 5-year follow-up.¹⁴

Continue to: Our patient

Our patient. After her diagnosis of NMOSD/MOG-antibody disease, our patient’s symptoms progressed to include vertigo, vestibular ataxia, pruritus, left foot drop, lower extremity numbness, and decreased hearing. After the second rituximab infusion her symptoms continued, but over time stabilized and have not worsened. She currently receives gabapentin 300 mg every 8 hours, as needed, for extremity numbness (which has been working well) along with sertraline 100 mg/d for depression.

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein-Barr virus seropositivity, and tobacco abuse.

Subsequent office visits have showed no further weight loss. Based on the current response to the rituximab, her prognosis is undetermined by Neurology as they continue to monitor for progression.

THE TAKEAWAY

Vestibular ataxia, foot drop, pruritus, vertigo, decreased hearing, numbness, and oculomotor dysfunction in the presence of nausea and vomiting should raise suspicion for NMOSD. The presence of AQP4 antibodies along with demyelinating central nervous system lesions, is highly indicative of NMO. The presence of MOG antibodies may indicate NMOSD/MOG-antibody disease. The initial treatment of NMOSD is intravenous methylprednisolone, which can be followed by treatment with rituximab to achieve remission.

CORRESPONDENCE
Daniel Murphy, MD, FAAFP, Department of Family and Community Medicine, Texas Tech University Health Science Center El Paso, 9849 Kenworthy Street, El Paso, Texas 79924; Daniel.murphy@ttuhsc.edu

THE CASE

A 26-year-old Hispanic/African American woman presented to our clinic with a 2-month history of nausea and vomiting, along with dizziness. The nausea and vomiting persistently worsened, and she was only able to tolerate apples and berries. During this 2-month period, she lost 20 pounds and her symptoms progressed to include pruritus, ataxia, and mild hearing loss, with reoccurring episodes of falls.

THE DIAGNOSIS

On examination, she was found to be bradycardic with a heart rate of 47 beats/min, right- axis deviation, and inverted T waves in leads I, II, and augmented vector left. Her family history included the death of an aunt who was in her early 30s due to an unknown heart condition.

Echocardiogram identified mild mitral valve regurgitation with an ejection fraction of 55% to 60% (reference range: 55%-70%). Cardiology determined that her bradycardia was not the source of her symptoms. A neurologic exam identified 3+ hyperreflexia (indicating the reflex was increased), tandem gait instability, and left oculomotor dysfunction.

Brain magnetic resonance imaging (MRI) identified bilateral parietal white matter lesions where a demyelinating process could not be excluded (FIGURE 1A). The patient’s symptoms of nausea and vomiting continued, and she only tolerated peanuts and liquids. An MRI of the spine was negative.

Laboratory testing revealed that the patient was negative for human immunodeficiency virus (HIV), syphilis, Lyme disease, and lupus. Her thyroid-stimulating hormone level was 1.7 mIU/L (reference range: 0.4-4.2 mIU/L), and her vitamin B₁₂ level was 504 pg/mL (reference range: 160-950 pg/mL).

The patient’s lumbar puncture was negative for oligoclonal bands. The IgG synthesis rate/index cerebrospinal fluid (CSF) was –3.9, ruling out multiple sclerosis. Her CSF culture was negative, with a glucose level of 42 mg/dL (reference range: 70-110 mg/dL), colorless appearance, 1 white blood cell, and spinal albumin of 12.2 mg/dL (reference range: 8-42 mg/dL). The visual evoked potential was negative. The aquaporin-4 (AQP4) antibody was positive at 3.4 U/mL, and the myelin oligodendrocyte glycoprotein (MOG) antibody was positive.

Gastroenterology concluded a normal gastric accommodation and unremarkable computed tomography (CT) enterography. Moderate erosions were identified in the stomach with an erythematous gastropathy. The patient was placed on a proton pump inhibitor.

Continue to: Following the examination...

Following the examination and laboratory testing, the patient was admitted under our family medicine service for neuromyelitis optica (NMO) affecting the area postrema. NMO, also known as Devic’s disease, is an autoimmune disorder that affects the spinal cord and optic nerves. Autoantibodies against AQP4 are created in the periphery and are directed against astrocytes in the central nervous system. These antibodies bind to the foot processes of astrocytes, inducing complement-mediated cell damage and granulocyte infiltration.^1-5

Intravenous methylprednisolone was initiated at 250 mg every 6 hours for 3 days. A repeat brain MRI demonstrated nonspecific multiple scattered foci of hyperintense signal involving the subcortical supratentorial white matter without abnormal enhancement, most likely representing nonactive demyelinating plaques (FIGURES 1B and 1C).

Dx is revisited. Our patient was referred to an NMO clinic for evaluation. After further testing (including a repeat MRI based on the neurologist’s specifications, anti-aquaporin antibody testing, and MOG-antibody testing) and case discussion, it was determined that the patient had MOG-antibody disease. This disease, along with NMO, comprise a spectrum of disorders referred to as neuromyelitis optica spectrum disorder (NMOSD).

The patient was subsequently prescribed a rituximab infusion, 500 mg/50 mL, to treat the current attack. One infusion was to be completed weekly for 2 weeks with plans to repeat treatment every 6 months to prevent flares of NMO. During the first dose, the patient had a reaction to the treatment, which caused pruritus and chest tightness. She was able to complete the infusion after being treated with diphenhydramine.

Tx continued. In order to complete the second of 2 infusions of rituximab, the patient was pretreated with oral methylprednisolone the night before the infusion, along with diphenhydramine and acetaminophen on the day of treatment. Fortunately, the patient tolerated the infusion well with no adverse effects or reactions.

Continue to: DISCUSSION

DISCUSSION

Within the NMO spectrum, the MOG antibody is positive in up to 42% of AQP4-seronegative cases.⁶ MOG is a minor myelin component that is expressed exclusively in the central nervous system on the surface of myelin and oligodendrocyte processes. The role of this glycoprotein is not well understood but is hypothesized to function as a cell surface receptor or cell adhesion molecule.⁷

Among a cohort of 252 patients from the United Kingdom who tested positive for the MOG-IgG1 antibody, optic neuritis was seen in 55%, while 18% experienced transverse myelitis, and 15% had a history of area postrema syndrome. A brain MRI identified lesions in all areas of the brain including the brain stem, cerebellum, and cerebral hemispheres.⁸

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein Barr virus seropositivity, and tobacco abuse.

Differential diagnosis. Many diseases or conditions that are inflammatory, autoimmune, infectious, or neoplastic can involve the central nervous system and mimic the clinical and radiologic phenotypes of NMOSD-AQP4. They include lupus, SjÖgren’s syndrome, multiple sclerosis, sarcoidosis, acute disseminated encephalomyelitis, HIV, and vitamin B₁₂ deficiency.

Treatment. The standard treatment is intravenous methylprednisolone, 1 g/d for 3 to 5 days followed by a steroid taper. Therapeutic plasma exchange is recommended for refractory cases and in patients with spinal cord demyelination.^9-11 Rituximab is the first-line therapy for attack prevention^12-15 in NMOSD broadly and may be effective in MOG antibody disease, as well. In an open-label study of patients with NMOSD treated with rituximab, 64% were relapse free at follow-up, which ranged from 12 to 67 months.¹³ In a long-term study of patients treated with rituximab, 87% maintained a reduced relapse rate and 93% had improvement or stability over a 5-year follow-up.¹⁴

Continue to: Our patient

Our patient. After her diagnosis of NMOSD/MOG-antibody disease, our patient’s symptoms progressed to include vertigo, vestibular ataxia, pruritus, left foot drop, lower extremity numbness, and decreased hearing. After the second rituximab infusion her symptoms continued, but over time stabilized and have not worsened. She currently receives gabapentin 300 mg every 8 hours, as needed, for extremity numbness (which has been working well) along with sertraline 100 mg/d for depression.

Risk factors for NMOSD include female gender, Asian and African ethnicities, Epstein-Barr virus seropositivity, and tobacco abuse.

Subsequent office visits have showed no further weight loss. Based on the current response to the rituximab, her prognosis is undetermined by Neurology as they continue to monitor for progression.

THE TAKEAWAY

Vestibular ataxia, foot drop, pruritus, vertigo, decreased hearing, numbness, and oculomotor dysfunction in the presence of nausea and vomiting should raise suspicion for NMOSD. The presence of AQP4 antibodies along with demyelinating central nervous system lesions, is highly indicative of NMO. The presence of MOG antibodies may indicate NMOSD/MOG-antibody disease. The initial treatment of NMOSD is intravenous methylprednisolone, which can be followed by treatment with rituximab to achieve remission.

CORRESPONDENCE
Daniel Murphy, MD, FAAFP, Department of Family and Community Medicine, Texas Tech University Health Science Center El Paso, 9849 Kenworthy Street, El Paso, Texas 79924; Daniel.murphy@ttuhsc.edu

The presence of insomnia symptoms increases the likelihood of cardiovascular or cerebrovascular disease during approximately 10 years of follow-up, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.

Karen Winton/iStockphoto

“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.

To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.

For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.

The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.

More than 16% had any insomnia symptom

Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.

After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.

In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”

Opportunity for intervention

Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”

The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.

The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.

This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.

jremaly@mdedge.com

SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.

The presence of insomnia symptoms increases the likelihood of cardiovascular or cerebrovascular disease during approximately 10 years of follow-up, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.

Karen Winton/iStockphoto

“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.

To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.

For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.

The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.

More than 16% had any insomnia symptom

Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.

After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.

In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”

Opportunity for intervention

Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”

The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.

The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.

This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.

jremaly@mdedge.com

SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.

The presence of insomnia symptoms increases the likelihood of cardiovascular or cerebrovascular disease during approximately 10 years of follow-up, according to a large cohort study of adults in China. A greater number of insomnia symptoms is associated with increased risk, and this relationship is more evident in younger adults and in adults without hypertension at baseline, researchers reported Nov. 6 in Neurology.

Karen Winton/iStockphoto

“These results suggest that, if we can target people who are having trouble sleeping with behavioral therapies, it’s possible that we could reduce the number of cases of stroke, heart attack, and other diseases later down the line,” study author Liming Li, MD, professor of epidemiology at Peking University, Beijing, said in a news release.

To clarify the relationships between individual insomnia symptoms, cardiocerebral vascular diseases, and potential effect modifiers, Dr. Li and colleagues analyzed data from the China Kadoorie Biobank Study. For this study, more than 500,000 adults in China aged 30-79 years completed a baseline survey during 2004-2008. The present analysis included data from 487,200 participants who did not have a history of stroke, coronary heart disease, or cancer at baseline.

For the baseline survey, participants answered questions about whether specific insomnia symptoms occurred at least 3 days per week during the past month. The symptoms included difficulty initiating or maintaining sleep (that is, sleep onset latency of 30 minutes or more after going to bed or waking up in the middle of the night); waking too early and being unable to fall back asleep; and trouble functioning during the day because of bad sleep.

The researchers assessed the incidence of cardiocerebral vascular diseases through 2016 by examining disease registries, national health insurance claims databases, and local records. Investigators identified participants with any cardiocerebral vascular disease and assessed the incidence of ischemic heart disease, acute myocardial infarction, hemorrhagic stroke, and ischemic stroke. The researchers followed each participant until the diagnosis of a cardiocerebral vascular disease outcome, death from any cause, loss to follow-up, or Dec. 31, 2016. The researchers used Cox proportional hazard models to estimate hazard ratios for the association between each insomnia symptom and cardiocerebral vascular disease outcomes. They adjusted the models for established and potential confounding factors, including age, income, smoking status, diet, and physical activity.

More than 16% had any insomnia symptom

Of the 487,200 participants, 11.3% had difficulty initiating or maintaining sleep, 10.4% had early morning awakening, and 2.2% had daytime dysfunction attributed to poor sleep. Compared with participants without insomnia symptoms, participants with insomnia symptoms tended to be older and were more likely to be female, not married, and from a rural area. In addition, those with insomnia symptoms were more likely have depression or anxiety symptoms, lower education level, lower household income, and lower body mass index. They also were more likely to have a history of diabetes mellitus. During a median follow-up of 9.6 years, 130,032 cases of cardiocerebral vascular disease occurred, including 40,348 cases of ischemic heart disease and 45,316 cases of stroke.

After adjustment for potential confounders, each insomnia symptom was associated with greater risk of cardiocerebral vascular disease. For difficulty initiating or maintaining sleep, the hazard ratio was 1.09. For early-morning awakening, the HR was 1.07. For daytime dysfunction, the HR was 1.13. Each insomnia symptom was associated with increased risk of ischemic heart disease and ischemic stroke, whereas only difficulty initiating or maintaining sleep was associated with increased risk of acute MI.

In all, 16.4% of participants reported any insomnia symptom; 10% had one symptom, 5.2% had two symptoms, and 1.2% had three symptoms. “Compared with those without any insomnia symptoms, participants with one, two, or three symptoms had a 7%, 10%, or 18% higher risk of total [cardiocerebral vascular disease] incidence, respectively,” the authors wrote. “Our study is the first large-scale cohort study that identified positive dose-response relationships between the number of insomnia symptoms and risks of [cardiocerebral vascular diseases, ischemic heart disease] and stroke incidence.”

Opportunity for intervention

Compared with clinical diagnostic criteria for insomnia, “individual insomnia symptoms are better defined and more feasible to assess with questionnaires in large-scale population studies and clinical practice,” Dr. Li and colleagues wrote. “Moreover, it is reasonable that insomnia symptoms are more modifiable and precisely targetable through behavioral therapies before developing into clinically significant insomnia disorder. Therefore, future clinical trials or community-based intervention studies should be conducted to test whether lifestyle or sleep hygiene interventions for insomnia symptoms can reduce subsequent [cardiocerebral vascular disease] risks.”

The results suggest that efforts aimed at early detection and intervention should include a focus on younger adults and people who do not have high blood pressure, Dr. Li said.

The self-reported insomnia symptoms used in this study have not been fully validated, the investigators noted. The researchers also lacked information about potential confounders, such as shift work and obstructive sleep apnea, that are risk factors for coronary heart disease or stroke and may interfere with insomnia symptoms. In addition, the study did not capture changes in insomnia symptoms over time.

This study was supported by the National Key Research and Development Program of China, the Chinese Ministry of Science and Technology, and the National Natural Science Foundation of China. The China Kadoorie Biobank surveys were supported by grants from the Kadoorie Charitable Foundation and the U.K. Wellcome Trust. The authors had no relevant disclosures.

jremaly@mdedge.com

SOURCE: Zheng B et al. Neurology. 2019 Nov 6. doi: 10.1212/WNL.0000000000008581.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Background: Identifying paroxysmal atrial fibrillation (AFib) as the etiology of a transient ischemic attack (TIA) or stroke has implications for treatment as well as secondary prevention. Currently, there is not a universal, practical way to help determine which patients would benefit from prolonged cardiac monitoring to establish the diagnosis of AFib.

Dr. Phillips is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine at Harvard Medical School.

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

aotto@mdedge.com

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

aotto@mdedge.com

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

aotto@mdedge.com

Migraine is the second leading cause of years of life lived with a disability globally.¹ It affects people of all ages, but particularly during the years associated with the highest productivity in terms of work and family life.

Migraine is a genetic neurologic disease that can be influenced or triggered by environmental factors. However, triggers do not cause migraine. For example, stress does not cause migraine, but it can exacerbate it.

Primary care physicians can help patients reduce the likelihood of a migraine attack, the severity of symptoms, or both by offering lifestyle counseling centered around the mnemonic SEEDS: sleep, exercise, eat, diary, and stress. In this article, each factor is discussed individually for its current support in the literature along with best-practice recommendations.

S IS FOR SLEEP

Before optimizing sleep hygiene, screen for sleep apnea, especially in those who have chronic daily headache upon awakening. An excellent tool is the STOP-Bang screening questionnaire⁵ (www.stopbang.ca/osa/screening.php). Patients respond “yes” or “no” to the following questions:

• Snoring: Do you snore loudly (louder than talking or loud enough to be heard through closed doors)?
• Tired: Do you often feel tired, fatigued, or sleepy during the daytime?
• Observed: Has anyone observed you stop breathing during your sleep?
• Pressure: Do you have or are you being treated for high blood pressure?
• Body mass index greater than 35 kg/m²?
• Age over 50?
• Neck circumference larger than 40 cm (females) or  42 cm (males)?
• Gender—male?

Each “yes” answer is scored as 1 point. A score less than 3 indicates low risk of obstructive sleep apnea; 3 to 4 indicates moderate risk; and 5 or more indicates high risk. Optimization of sleep apnea with continuous positive airway pressure therapy can improve sleep apnea headache.⁶ The improved sleep from reduced arousals may also mitigate migraine symptoms.

Behavioral modification for sleep hygiene can convert chronic migraine to episodic migraine.⁷ One such program is stimulus control therapy, which focuses on using cues to initiate sleep (Table 1). Patients are encouraged to keep the bedroom quiet, dark, and cool, and to go to sleep at the same time every night. Importantly, the bed should be associated only with sleep. If patients are unable to fall asleep within 20 to 30 minutes, they should leave the room so they do not associate the bed with frustration and anxiety. Use of phones, tablets, and television in the bedroom is discouraged as these devices may make it more difficult to fall asleep.⁸

The next option is sleep restriction, which is useful for comorbid insomnia. Patients keep a sleep diary to better understand their sleep-wake cycle. The goal is 90% sleep efficiency, meaning that 90% of the time in bed (TIB) is spent asleep. For example, if the patient is in bed 8 hours but asleep only 4 hours, sleep efficiency is 50%. The goal is to reduce TIB to match the time asleep and to agree on a prescribed daily wake-up time. When the patient is consistently sleeping 90% of the TIB, add 30-minute increments until he or she is appropriately sleeping 7 to 8 hours at night.⁹ Naps are not recommended.

Let patients know that their migraine may worsen until a new routine sleep pattern emerges. This method is not recommended for patients with untreated sleep apnea.

E IS FOR EXERCISE

Exercise is broadly recommended for a healthy lifestyle; some evidence suggests that it can also be useful in the management of migraine.¹⁰ Low levels of physical activity and a sedentary lifestyle are associated with migraine.¹¹ It is unclear if patients with migraine are less likely to exercise because they want to avoid triggering a migraine or if a sedentary lifestyle increases their risk.

Exercise has been studied for its prophylactic benefits in migraine, and one hypothesis relates to beta-endorphins. Levels of beta-endorphins are reduced in the cerebrospinal fluid of patients with migraine.¹² Exercise programs may increase levels while reducing headache frequency and duration.¹³ One study showed that pain thresholds do not change with exercise programs, suggesting that it is avoidance behavior that is positively altered rather than the underlying pain pathways.¹⁴

A systematic review and meta-analysis based on 5 randomized controlled trials and 1 nonrandomized controlled clinical trial showed that exercise reduced monthly migraine days by only 0.6 (± 0.3) days, but the data also suggested that as the exercise intensity increased, so did the positive effects.¹⁰

Some data suggest that exercise may also reduce migraine duration and severity as well as the need for abortive medication.¹⁰ Two studies in this systematic review^15,16 showed that exercise benefits were equivalent to those of migraine preventives such as amitriptyline and topiramate; the combination of amitriptyline and exercise was more beneficial than exercise alone. Multiple types of exercise were beneficial, including walking, jogging, cross-training, and cycling when done for least 6 weeks and for 30 to 50 minutes 3 to 5 times a week.

These findings are in line with the current recommendations for general health from the American College of Sports Medicine, ie, moderate to vigorous cardio­respiratory exercise for 30 to 60 minutes 3 to 5 times a week (or 150 minutes per week). The daily exercise can be continuous or done in intervals of less than 20 minutes. For those with a sedentary lifestyle, as is seen in a significant proportion of the migraine population, light to moderate exercise for less than 20 minutes is still beneficial.¹⁷

Based on this evidence, the best current recommendation for patients with migraine is to engage in graded moderate cardiorespiratory exercise, although any exercise is better than none. If a patient is sedentary or has poor exercise tolerance, or both, exercising once a week for shorter time periods may be a manageable place to start.

Some patients may identify exercise as a trigger or exacerbating factor in migraine. These patients may need appropriate prophylactic and abortive therapies before starting an exercise regimen.

THE SECOND E IS FOR EAT (FOOD AND DRINK)

Many patients believe that some foods trigger migraine attacks, but further study is needed. The most consistent food triggers appear to be red wine and caffeine (withdrawal).^18,19 Interestingly, patients with migraine report low levels of alcohol consumption,²⁰ but it is unclear if that is because alcohol has a protective effect or if patients avoid it.

Some patients may crave certain foods in the prodromal phase of an attack, eat the food, experience the attack, and falsely conclude that the food caused the attack.²¹ Premonitory symptoms include fatigue, cognitive changes, homeostatic changes, sensory hyperresponsiveness, and food cravings.²¹ It is difficult to distinguish between premonitory phase food cravings and true triggers because premonitory symptoms can precede headache by 48 to 72 hours, and the timing for a trigger to be considered causal is not known.²²

Chocolate is often thought to be a migraine trigger, but the evidence argues against this and even suggests that sweet cravings are a part of the premonitory phase.²³ Monosodium glutamate is often identified as a trigger as well, but the literature is inconsistent and does not support a causal relationship.²⁴ Identifying true food triggers in migraine is difficult, and patients with migraine may have poor quality diets, with some foods acting as true triggers for certain patients.²⁵ These possibilities have led to the development of many “migraine diets,” including elimination diets.

Elimination diets

Elimination diets involve avoiding specific food items over a period of time and then adding them back in one at a time to gauge whether they cause a reaction in the body. A number of these diets have been studied for their effects on headache and migraine:

Gluten-free diets restrict foods that contain wheat, rye, and barley. A systematic review of gluten-free diets in patients with celiac disease found that headache or migraine frequency decreased by 51.6% to 100% based on multiple cohort studies (N = 42,388).²⁶ There are no studies on the use of a gluten-free diet for migraine in patients without celiac disease.

Immunoglobulin G-elimination diets restrict foods that serve as antigens for IgG. However, data supporting these diets are inconsistent. Two small randomized controlled trials found that the diets improved migraine symptoms, but a larger study found no improvement in the number of migraine days at 12 weeks, although there was an initially significant effect at 4 weeks.^27–29

Antihistamine diets restrict foods that have high levels of histamines, including fermented dairy, vegetables, soy products,  wine, beer, alcohol, and those that cause histamine release regardless of IgE testing results. A prospective single-arm study of antihistamine diets in patients with chronic headache reported symptom improvement, which could be applied to certain comorbidities such as  mast cell activation syndrome.³⁰ Another prospective nonrandomized controlled study eliminated foods based on positive IgE skin-prick testing for allergy in patients with recurrent migraine and found that it reduced headache frequency.³¹

Tyramine-free diets are often recommended due to the presumption that tyramine-containing foods (eg, aged cheese, cured or smoked meats and fish, and beer) are triggers. However, multiple studies have reviewed this theory with inconsistent results,³² and the only study of a tyramine-free diet was negative.³³ In addition, commonly purported high-tyramine foods have lower tyramine levels than previously thought.³⁴

Low-fat diets in migraine are supported by 2 small randomized controlled trials and a prospective study showing a decrease in symptom severity; the results for frequency are inconsistent.^35–37

Low-glycemic index diets are supported in migraine by 1 randomized controlled trial that showed improvement in migraine frequency in a diet group and in a control group of patients who took a standard migraine-preventive medication to manage their symptoms.³⁸

Other migraine diets

Diets high in certain foods or ingredient ratios, as opposed to elimination diets, have also been studied in patients with migraine. One promising diet containing high levels of omega-3 fatty acids and low levels of omega-6 fatty acids was shown in a systematic review to reduce the duration of migraine but not the frequency or severity.³⁹ A more recent randomized controlled trial of this diet in chronic migraine also showed that it decreased migraine frequency.⁴⁰

The ketogenic diet (high fat, low carbohydrate) had promising results in a randomized controlled trial in overweight women with migraine and in a prospective study.^41,42 However, a prospective study of the Atkins diet in teenagers with chronic daily headaches showed no benefit.⁴³ The ketogenic diet is difficult to follow and may work in part due to weight loss alone, although ketogenesis itself may also play a role.^41,44

Sodium levels have been shown to be higher in the cerebrospinal fluid of patients with migraine than in controls, particularly during an attack.⁴⁵ For a prehypertensive population or an elderly population, a low-sodium diet may be beneficial based on 2 prospective trials.^46,47 However, a younger female population without hypertension and low-to-normal body mass index had a reduced probability of migraine while consuming a high-sodium diet.⁴⁸

Counseling about sodium intake should be tailored to specific patient populations. For example, a diet low in sodium may be appropriate for patients with vascular risk factors such as hypertension, whereas a high-sodium diet may be appropriate in patients with comorbidities like postural tachycardia syndrome or in those with a propensity for low blood pressure or low body mass index.

Encourage routine meals and hydration

The standard advice for patients with migraine is to consume regular meals. Headaches have been associated with fasting, and those with migraine are predisposed to attacks in the setting of fasting.^49,50 Migraine is more common when meals are skipped, particularly breakfast.⁵¹

It is unclear how fasting lowers the migraine threshold. Nutritional studies show that skipping meals, particularly breakfast, increases low-grade inflammation and impairs  glucose metabolism by affecting insulin and fat oxidation metabolism.⁵² However, hypoglycemia itself is not a consistent cause of headache or migraine attacks.⁵³ As described above, a randomized controlled trial of a low-glycemic index diet actually decreased migraine frequency and severity.³⁸ Skipping meals also reduces energy and is associated with reduced physical activity, perhaps leading to multiple compounding triggers that further lower the migraine threshold.^54,55

When counseling patients about the need to eat breakfast, consider what they normally consume (eg, is breakfast just a cup of coffee?). Replacing simple carbohydrates with protein, fats, and fiber may be beneficial for general health, but the effects on migraine are not known, nor is the optimal composition of breakfast foods.⁵⁵

The optimal timing of breakfast relative to awakening is also unclear, but in general, it should be eaten within 30 to 60 minutes of rising. Also consider patients’ work hours—delayed-phase or shift workers have altered sleep cycles.

Recommendations vary in regard to hydration. Headache is associated with fluid restriction and dehydration,^56,57 but only a few studies suggest that rehydration and increased hydration status can improve migraine.⁵⁸ In fact, a single post hoc analysis of a metoclopramide study showed that intravenous fluid alone for patients with migraine in the emergency room did not improve pain outcomes.⁵⁹

The amount of water patients should drink daily in the setting of migraine is also unknown, but a study showed benefit with 4 L, which equates to a daily intake of 16 eight-ounce glasses.⁶⁰ One review on general health that could be extrapolated given the low risk of the intervention indicated that 1.8 L daily (7 to 8 eight-ounce glasses) promoted a euhydration status in most people, although many factors contribute to hydration status.⁶¹

Caffeine intake is also a major consideration. Caffeine is a nonspecific adenosine receptor antagonist that modulates adenosine receptors like the pronociceptive 2A receptor, leading to changes integral to the neuropathophysiology of migraine.⁶² Caffeine has analgesic properties at doses greater than 65 to 200 mg and augments the effects of analgesics such as acetaminophen and aspirin. Chronic caffeine use can lead to withdrawal symptoms when intake is stopped abruptly; this is thought to be due to upregulation of adenosine receptors, but the effect varies based on genetic predisposition.¹⁹

The risk of chronic daily headache may relate to high use of caffeine preceding the onset of chronification, and caffeine abstinence may improve response to acute migraine treatment.^19,63 There is a dose-dependent risk of headache.^64,65 Current recommendations suggest limiting caffeine consumption to less than 200 mg per day or stopping caffeine consumption altogether based on the quantity required for caffeine-withdrawal headache.⁶⁶ Varying  the caffeine dose from day to day may also trigger headache due to the high sensitivity to caffeine withdrawal.

While many diets have shown potential benefit in patients with migraine, more studies are needed before any one “migraine diet” can be recommended. Caution should be taken, as there is risk of adverse effects from nutrient deficiencies or excess levels, especially if the patient is not under the care of a healthcare professional who is familiar with the diet.

Whether it is beneficial to avoid specific food triggers at this time is unclear and still controversial even within the migraine community because some of these foods may be misattributed as triggers instead of premonitory cravings driven by the hypothalamus. It is important to counsel patients with migraine to eat a healthy diet with consistent meals, to maintain adequate hydration, and to keep their caffeine intake low or at least consistent, although these teachings are predominantly based on limited studies with extrapolation from nutrition research.

D IS FOR DIARY

A headache diary is a recommended part of headache management and may enhance the accuracy of diagnosis and assist in treatment modifications. Paper and electronic diaries have been used. Electronic diaries may be more accurate for real-time use, but patients may be more likely to complete a paper one.⁶⁷ Patients prefer electronic diaries over long paper forms,⁶⁸ but a practical issue to consider is easy electronic access.

Patients can start keeping a headache diary before the initial consultation to assist with diagnosis, or early in their management. A first-appointment diary mailed with instructions is a feasible option.⁶⁹ These types of diaries ask detailed questions to help diagnose all major primary headache types including menstrual migraine and to identify concomitant medication-overuse headache. Physicians and patients generally report improved communication with use of a diary.⁷⁰

Some providers distinguish between a headache diary and a calendar. In standard practice, a headache diary is the general term referring to both, but the literature differentiates between the two. Both should at least include headache frequency, with possible inclusion of other factors such as headache duration, headache intensity, analgesic use, headache impact on function, and absenteeism. Potential triggers including menses can also be tracked. The calendar version can fit on a single page and can be used for simple tracking of headache frequency and analgesia use.

One of the simplest calendars to use is the “stoplight” calendar. Red days are when a patient is completely debilitated in bed. On a yellow day, function at work, school, or daily activities is significantly reduced by migraine, but the patient is not bedbound. A green day is when headache is present but function is not affected. No color is placed if the patient is 100% headache-free.

Acute treatment use can be written in or, to improve compliance, a checkmark can be placed on days of treatment. Patients who are tracking menses circle the days of menstruation. The calendar-diary should be brought to every appointment to track treatment response and medication use.

THE SECOND S IS FOR STRESS

Behavioral management such as cognitive behavioral therapy in migraine has been shown to decrease catastrophizing, migraine disability, and headache severity and frequency.⁷⁴ Both depression and anxiety can improve along with migraine.⁷⁵ Cognitive behavioral therapy can be provided in individualized sessions or group sessions, either in person or online.^74,76,77 The effects become more prominent about 5 weeks into treatment.⁷⁸

Biofeedback, which uses behavioral techniques paired with physiologic autonomic measures, has been extensively studied, and shows benefit in migraine, including in meta-analysis.⁷⁹ The types of biofeedback measurements used include electromyography, electroencephalography, temperature, sweat sensors, heart rate, blood volume pulse feedback, and respiration bands. While biofeedback is generally done under the guidance of a therapist, it can still be useful with minimal therapist contact and supplemental audio.⁸⁰

Mindfulness, or the awareness of thoughts, feelings, and sensations in the present moment without judgment, is a behavioral technique that can be done alone or paired with another technique. It is often taught through a mindfulness-based stress-reduction  program, which relies on a standardized approach. A meta-analysis showed that mindfulness improves pain intensity, headache frequency, disability, self-efficacy, and quality of life.⁸¹ It may work by encouraging pain acceptance.⁸²

Relaxation techniques are also employed in migraine management, either alone or in conjunction with techniques mentioned  above, such as mindfulness. They include progressive muscle relaxation and deep breathing. Relaxation has been shown to be effective when done by professional trainers as well as lay trainers in both individual and group settings.^83,84

In patients with intractable headache, more-intensive inpatient and outpatient programs have been tried. Inpatient admissions with multidisciplinary programs that include a focus on behavioral techniques often paired with lifestyle education and sometimes pharmacologic management can be beneficial.^85,86 These programs have also been successfully conducted as multiple outpatient sessions.^86–88

Stress management is an important aspect of migraine management. These treatments often involve homework and require active participation.

LIFESTYLE FOR ALL

All patients with migraine should initiate lifestyle modifications (see Advice to patients with migraine: SEEDS for success). Modifications with the highest level of evidence, specifically behavioral techniques, have had the most reproducible results. A headache diary is an essential tool to identify patterns and needs for optimization of acute or preventive treatment regimens. The strongest evidence is for the behavioral management techniques for stress reduction.

Migraine is the second leading cause of years of life lived with a disability globally.¹ It affects people of all ages, but particularly during the years associated with the highest productivity in terms of work and family life.

Migraine is a genetic neurologic disease that can be influenced or triggered by environmental factors. However, triggers do not cause migraine. For example, stress does not cause migraine, but it can exacerbate it.

Primary care physicians can help patients reduce the likelihood of a migraine attack, the severity of symptoms, or both by offering lifestyle counseling centered around the mnemonic SEEDS: sleep, exercise, eat, diary, and stress. In this article, each factor is discussed individually for its current support in the literature along with best-practice recommendations.

S IS FOR SLEEP

Before optimizing sleep hygiene, screen for sleep apnea, especially in those who have chronic daily headache upon awakening. An excellent tool is the STOP-Bang screening questionnaire⁵ (www.stopbang.ca/osa/screening.php). Patients respond “yes” or “no” to the following questions:

• Snoring: Do you snore loudly (louder than talking or loud enough to be heard through closed doors)?
• Tired: Do you often feel tired, fatigued, or sleepy during the daytime?
• Observed: Has anyone observed you stop breathing during your sleep?
• Pressure: Do you have or are you being treated for high blood pressure?
• Body mass index greater than 35 kg/m²?
• Age over 50?
• Neck circumference larger than 40 cm (females) or  42 cm (males)?
• Gender—male?

Each “yes” answer is scored as 1 point. A score less than 3 indicates low risk of obstructive sleep apnea; 3 to 4 indicates moderate risk; and 5 or more indicates high risk. Optimization of sleep apnea with continuous positive airway pressure therapy can improve sleep apnea headache.⁶ The improved sleep from reduced arousals may also mitigate migraine symptoms.

Behavioral modification for sleep hygiene can convert chronic migraine to episodic migraine.⁷ One such program is stimulus control therapy, which focuses on using cues to initiate sleep (Table 1). Patients are encouraged to keep the bedroom quiet, dark, and cool, and to go to sleep at the same time every night. Importantly, the bed should be associated only with sleep. If patients are unable to fall asleep within 20 to 30 minutes, they should leave the room so they do not associate the bed with frustration and anxiety. Use of phones, tablets, and television in the bedroom is discouraged as these devices may make it more difficult to fall asleep.⁸

The next option is sleep restriction, which is useful for comorbid insomnia. Patients keep a sleep diary to better understand their sleep-wake cycle. The goal is 90% sleep efficiency, meaning that 90% of the time in bed (TIB) is spent asleep. For example, if the patient is in bed 8 hours but asleep only 4 hours, sleep efficiency is 50%. The goal is to reduce TIB to match the time asleep and to agree on a prescribed daily wake-up time. When the patient is consistently sleeping 90% of the TIB, add 30-minute increments until he or she is appropriately sleeping 7 to 8 hours at night.⁹ Naps are not recommended.

Let patients know that their migraine may worsen until a new routine sleep pattern emerges. This method is not recommended for patients with untreated sleep apnea.

E IS FOR EXERCISE

Exercise is broadly recommended for a healthy lifestyle; some evidence suggests that it can also be useful in the management of migraine.¹⁰ Low levels of physical activity and a sedentary lifestyle are associated with migraine.¹¹ It is unclear if patients with migraine are less likely to exercise because they want to avoid triggering a migraine or if a sedentary lifestyle increases their risk.

Exercise has been studied for its prophylactic benefits in migraine, and one hypothesis relates to beta-endorphins. Levels of beta-endorphins are reduced in the cerebrospinal fluid of patients with migraine.¹² Exercise programs may increase levels while reducing headache frequency and duration.¹³ One study showed that pain thresholds do not change with exercise programs, suggesting that it is avoidance behavior that is positively altered rather than the underlying pain pathways.¹⁴

A systematic review and meta-analysis based on 5 randomized controlled trials and 1 nonrandomized controlled clinical trial showed that exercise reduced monthly migraine days by only 0.6 (± 0.3) days, but the data also suggested that as the exercise intensity increased, so did the positive effects.¹⁰

Some data suggest that exercise may also reduce migraine duration and severity as well as the need for abortive medication.¹⁰ Two studies in this systematic review^15,16 showed that exercise benefits were equivalent to those of migraine preventives such as amitriptyline and topiramate; the combination of amitriptyline and exercise was more beneficial than exercise alone. Multiple types of exercise were beneficial, including walking, jogging, cross-training, and cycling when done for least 6 weeks and for 30 to 50 minutes 3 to 5 times a week.

These findings are in line with the current recommendations for general health from the American College of Sports Medicine, ie, moderate to vigorous cardio­respiratory exercise for 30 to 60 minutes 3 to 5 times a week (or 150 minutes per week). The daily exercise can be continuous or done in intervals of less than 20 minutes. For those with a sedentary lifestyle, as is seen in a significant proportion of the migraine population, light to moderate exercise for less than 20 minutes is still beneficial.¹⁷

Based on this evidence, the best current recommendation for patients with migraine is to engage in graded moderate cardiorespiratory exercise, although any exercise is better than none. If a patient is sedentary or has poor exercise tolerance, or both, exercising once a week for shorter time periods may be a manageable place to start.

Some patients may identify exercise as a trigger or exacerbating factor in migraine. These patients may need appropriate prophylactic and abortive therapies before starting an exercise regimen.

THE SECOND E IS FOR EAT (FOOD AND DRINK)

Many patients believe that some foods trigger migraine attacks, but further study is needed. The most consistent food triggers appear to be red wine and caffeine (withdrawal).^18,19 Interestingly, patients with migraine report low levels of alcohol consumption,²⁰ but it is unclear if that is because alcohol has a protective effect or if patients avoid it.

Some patients may crave certain foods in the prodromal phase of an attack, eat the food, experience the attack, and falsely conclude that the food caused the attack.²¹ Premonitory symptoms include fatigue, cognitive changes, homeostatic changes, sensory hyperresponsiveness, and food cravings.²¹ It is difficult to distinguish between premonitory phase food cravings and true triggers because premonitory symptoms can precede headache by 48 to 72 hours, and the timing for a trigger to be considered causal is not known.²²

Chocolate is often thought to be a migraine trigger, but the evidence argues against this and even suggests that sweet cravings are a part of the premonitory phase.²³ Monosodium glutamate is often identified as a trigger as well, but the literature is inconsistent and does not support a causal relationship.²⁴ Identifying true food triggers in migraine is difficult, and patients with migraine may have poor quality diets, with some foods acting as true triggers for certain patients.²⁵ These possibilities have led to the development of many “migraine diets,” including elimination diets.

Elimination diets

Elimination diets involve avoiding specific food items over a period of time and then adding them back in one at a time to gauge whether they cause a reaction in the body. A number of these diets have been studied for their effects on headache and migraine:

Gluten-free diets restrict foods that contain wheat, rye, and barley. A systematic review of gluten-free diets in patients with celiac disease found that headache or migraine frequency decreased by 51.6% to 100% based on multiple cohort studies (N = 42,388).²⁶ There are no studies on the use of a gluten-free diet for migraine in patients without celiac disease.

Immunoglobulin G-elimination diets restrict foods that serve as antigens for IgG. However, data supporting these diets are inconsistent. Two small randomized controlled trials found that the diets improved migraine symptoms, but a larger study found no improvement in the number of migraine days at 12 weeks, although there was an initially significant effect at 4 weeks.^27–29

Antihistamine diets restrict foods that have high levels of histamines, including fermented dairy, vegetables, soy products,  wine, beer, alcohol, and those that cause histamine release regardless of IgE testing results. A prospective single-arm study of antihistamine diets in patients with chronic headache reported symptom improvement, which could be applied to certain comorbidities such as  mast cell activation syndrome.³⁰ Another prospective nonrandomized controlled study eliminated foods based on positive IgE skin-prick testing for allergy in patients with recurrent migraine and found that it reduced headache frequency.³¹

Tyramine-free diets are often recommended due to the presumption that tyramine-containing foods (eg, aged cheese, cured or smoked meats and fish, and beer) are triggers. However, multiple studies have reviewed this theory with inconsistent results,³² and the only study of a tyramine-free diet was negative.³³ In addition, commonly purported high-tyramine foods have lower tyramine levels than previously thought.³⁴

Low-fat diets in migraine are supported by 2 small randomized controlled trials and a prospective study showing a decrease in symptom severity; the results for frequency are inconsistent.^35–37

Low-glycemic index diets are supported in migraine by 1 randomized controlled trial that showed improvement in migraine frequency in a diet group and in a control group of patients who took a standard migraine-preventive medication to manage their symptoms.³⁸

Other migraine diets

Diets high in certain foods or ingredient ratios, as opposed to elimination diets, have also been studied in patients with migraine. One promising diet containing high levels of omega-3 fatty acids and low levels of omega-6 fatty acids was shown in a systematic review to reduce the duration of migraine but not the frequency or severity.³⁹ A more recent randomized controlled trial of this diet in chronic migraine also showed that it decreased migraine frequency.⁴⁰

The ketogenic diet (high fat, low carbohydrate) had promising results in a randomized controlled trial in overweight women with migraine and in a prospective study.^41,42 However, a prospective study of the Atkins diet in teenagers with chronic daily headaches showed no benefit.⁴³ The ketogenic diet is difficult to follow and may work in part due to weight loss alone, although ketogenesis itself may also play a role.^41,44

Sodium levels have been shown to be higher in the cerebrospinal fluid of patients with migraine than in controls, particularly during an attack.⁴⁵ For a prehypertensive population or an elderly population, a low-sodium diet may be beneficial based on 2 prospective trials.^46,47 However, a younger female population without hypertension and low-to-normal body mass index had a reduced probability of migraine while consuming a high-sodium diet.⁴⁸

Counseling about sodium intake should be tailored to specific patient populations. For example, a diet low in sodium may be appropriate for patients with vascular risk factors such as hypertension, whereas a high-sodium diet may be appropriate in patients with comorbidities like postural tachycardia syndrome or in those with a propensity for low blood pressure or low body mass index.

Encourage routine meals and hydration

The standard advice for patients with migraine is to consume regular meals. Headaches have been associated with fasting, and those with migraine are predisposed to attacks in the setting of fasting.^49,50 Migraine is more common when meals are skipped, particularly breakfast.⁵¹

It is unclear how fasting lowers the migraine threshold. Nutritional studies show that skipping meals, particularly breakfast, increases low-grade inflammation and impairs  glucose metabolism by affecting insulin and fat oxidation metabolism.⁵² However, hypoglycemia itself is not a consistent cause of headache or migraine attacks.⁵³ As described above, a randomized controlled trial of a low-glycemic index diet actually decreased migraine frequency and severity.³⁸ Skipping meals also reduces energy and is associated with reduced physical activity, perhaps leading to multiple compounding triggers that further lower the migraine threshold.^54,55

When counseling patients about the need to eat breakfast, consider what they normally consume (eg, is breakfast just a cup of coffee?). Replacing simple carbohydrates with protein, fats, and fiber may be beneficial for general health, but the effects on migraine are not known, nor is the optimal composition of breakfast foods.⁵⁵

The optimal timing of breakfast relative to awakening is also unclear, but in general, it should be eaten within 30 to 60 minutes of rising. Also consider patients’ work hours—delayed-phase or shift workers have altered sleep cycles.

Recommendations vary in regard to hydration. Headache is associated with fluid restriction and dehydration,^56,57 but only a few studies suggest that rehydration and increased hydration status can improve migraine.⁵⁸ In fact, a single post hoc analysis of a metoclopramide study showed that intravenous fluid alone for patients with migraine in the emergency room did not improve pain outcomes.⁵⁹

The amount of water patients should drink daily in the setting of migraine is also unknown, but a study showed benefit with 4 L, which equates to a daily intake of 16 eight-ounce glasses.⁶⁰ One review on general health that could be extrapolated given the low risk of the intervention indicated that 1.8 L daily (7 to 8 eight-ounce glasses) promoted a euhydration status in most people, although many factors contribute to hydration status.⁶¹

Caffeine intake is also a major consideration. Caffeine is a nonspecific adenosine receptor antagonist that modulates adenosine receptors like the pronociceptive 2A receptor, leading to changes integral to the neuropathophysiology of migraine.⁶² Caffeine has analgesic properties at doses greater than 65 to 200 mg and augments the effects of analgesics such as acetaminophen and aspirin. Chronic caffeine use can lead to withdrawal symptoms when intake is stopped abruptly; this is thought to be due to upregulation of adenosine receptors, but the effect varies based on genetic predisposition.¹⁹

The risk of chronic daily headache may relate to high use of caffeine preceding the onset of chronification, and caffeine abstinence may improve response to acute migraine treatment.^19,63 There is a dose-dependent risk of headache.^64,65 Current recommendations suggest limiting caffeine consumption to less than 200 mg per day or stopping caffeine consumption altogether based on the quantity required for caffeine-withdrawal headache.⁶⁶ Varying  the caffeine dose from day to day may also trigger headache due to the high sensitivity to caffeine withdrawal.

While many diets have shown potential benefit in patients with migraine, more studies are needed before any one “migraine diet” can be recommended. Caution should be taken, as there is risk of adverse effects from nutrient deficiencies or excess levels, especially if the patient is not under the care of a healthcare professional who is familiar with the diet.

Whether it is beneficial to avoid specific food triggers at this time is unclear and still controversial even within the migraine community because some of these foods may be misattributed as triggers instead of premonitory cravings driven by the hypothalamus. It is important to counsel patients with migraine to eat a healthy diet with consistent meals, to maintain adequate hydration, and to keep their caffeine intake low or at least consistent, although these teachings are predominantly based on limited studies with extrapolation from nutrition research.

D IS FOR DIARY

A headache diary is a recommended part of headache management and may enhance the accuracy of diagnosis and assist in treatment modifications. Paper and electronic diaries have been used. Electronic diaries may be more accurate for real-time use, but patients may be more likely to complete a paper one.⁶⁷ Patients prefer electronic diaries over long paper forms,⁶⁸ but a practical issue to consider is easy electronic access.

Patients can start keeping a headache diary before the initial consultation to assist with diagnosis, or early in their management. A first-appointment diary mailed with instructions is a feasible option.⁶⁹ These types of diaries ask detailed questions to help diagnose all major primary headache types including menstrual migraine and to identify concomitant medication-overuse headache. Physicians and patients generally report improved communication with use of a diary.⁷⁰

Some providers distinguish between a headache diary and a calendar. In standard practice, a headache diary is the general term referring to both, but the literature differentiates between the two. Both should at least include headache frequency, with possible inclusion of other factors such as headache duration, headache intensity, analgesic use, headache impact on function, and absenteeism. Potential triggers including menses can also be tracked. The calendar version can fit on a single page and can be used for simple tracking of headache frequency and analgesia use.

One of the simplest calendars to use is the “stoplight” calendar. Red days are when a patient is completely debilitated in bed. On a yellow day, function at work, school, or daily activities is significantly reduced by migraine, but the patient is not bedbound. A green day is when headache is present but function is not affected. No color is placed if the patient is 100% headache-free.

Acute treatment use can be written in or, to improve compliance, a checkmark can be placed on days of treatment. Patients who are tracking menses circle the days of menstruation. The calendar-diary should be brought to every appointment to track treatment response and medication use.

THE SECOND S IS FOR STRESS

Behavioral management such as cognitive behavioral therapy in migraine has been shown to decrease catastrophizing, migraine disability, and headache severity and frequency.⁷⁴ Both depression and anxiety can improve along with migraine.⁷⁵ Cognitive behavioral therapy can be provided in individualized sessions or group sessions, either in person or online.^74,76,77 The effects become more prominent about 5 weeks into treatment.⁷⁸

Biofeedback, which uses behavioral techniques paired with physiologic autonomic measures, has been extensively studied, and shows benefit in migraine, including in meta-analysis.⁷⁹ The types of biofeedback measurements used include electromyography, electroencephalography, temperature, sweat sensors, heart rate, blood volume pulse feedback, and respiration bands. While biofeedback is generally done under the guidance of a therapist, it can still be useful with minimal therapist contact and supplemental audio.⁸⁰

Mindfulness, or the awareness of thoughts, feelings, and sensations in the present moment without judgment, is a behavioral technique that can be done alone or paired with another technique. It is often taught through a mindfulness-based stress-reduction  program, which relies on a standardized approach. A meta-analysis showed that mindfulness improves pain intensity, headache frequency, disability, self-efficacy, and quality of life.⁸¹ It may work by encouraging pain acceptance.⁸²

Relaxation techniques are also employed in migraine management, either alone or in conjunction with techniques mentioned  above, such as mindfulness. They include progressive muscle relaxation and deep breathing. Relaxation has been shown to be effective when done by professional trainers as well as lay trainers in both individual and group settings.^83,84

In patients with intractable headache, more-intensive inpatient and outpatient programs have been tried. Inpatient admissions with multidisciplinary programs that include a focus on behavioral techniques often paired with lifestyle education and sometimes pharmacologic management can be beneficial.^85,86 These programs have also been successfully conducted as multiple outpatient sessions.^86–88

Stress management is an important aspect of migraine management. These treatments often involve homework and require active participation.

LIFESTYLE FOR ALL

All patients with migraine should initiate lifestyle modifications (see Advice to patients with migraine: SEEDS for success). Modifications with the highest level of evidence, specifically behavioral techniques, have had the most reproducible results. A headache diary is an essential tool to identify patterns and needs for optimization of acute or preventive treatment regimens. The strongest evidence is for the behavioral management techniques for stress reduction.

Migraine is the second leading cause of years of life lived with a disability globally.¹ It affects people of all ages, but particularly during the years associated with the highest productivity in terms of work and family life.

Migraine is a genetic neurologic disease that can be influenced or triggered by environmental factors. However, triggers do not cause migraine. For example, stress does not cause migraine, but it can exacerbate it.

Primary care physicians can help patients reduce the likelihood of a migraine attack, the severity of symptoms, or both by offering lifestyle counseling centered around the mnemonic SEEDS: sleep, exercise, eat, diary, and stress. In this article, each factor is discussed individually for its current support in the literature along with best-practice recommendations.

S IS FOR SLEEP

Before optimizing sleep hygiene, screen for sleep apnea, especially in those who have chronic daily headache upon awakening. An excellent tool is the STOP-Bang screening questionnaire⁵ (www.stopbang.ca/osa/screening.php). Patients respond “yes” or “no” to the following questions:

• Snoring: Do you snore loudly (louder than talking or loud enough to be heard through closed doors)?
• Tired: Do you often feel tired, fatigued, or sleepy during the daytime?
• Observed: Has anyone observed you stop breathing during your sleep?
• Pressure: Do you have or are you being treated for high blood pressure?
• Body mass index greater than 35 kg/m²?
• Age over 50?
• Neck circumference larger than 40 cm (females) or  42 cm (males)?
• Gender—male?

Each “yes” answer is scored as 1 point. A score less than 3 indicates low risk of obstructive sleep apnea; 3 to 4 indicates moderate risk; and 5 or more indicates high risk. Optimization of sleep apnea with continuous positive airway pressure therapy can improve sleep apnea headache.⁶ The improved sleep from reduced arousals may also mitigate migraine symptoms.

Behavioral modification for sleep hygiene can convert chronic migraine to episodic migraine.⁷ One such program is stimulus control therapy, which focuses on using cues to initiate sleep (Table 1). Patients are encouraged to keep the bedroom quiet, dark, and cool, and to go to sleep at the same time every night. Importantly, the bed should be associated only with sleep. If patients are unable to fall asleep within 20 to 30 minutes, they should leave the room so they do not associate the bed with frustration and anxiety. Use of phones, tablets, and television in the bedroom is discouraged as these devices may make it more difficult to fall asleep.⁸

The next option is sleep restriction, which is useful for comorbid insomnia. Patients keep a sleep diary to better understand their sleep-wake cycle. The goal is 90% sleep efficiency, meaning that 90% of the time in bed (TIB) is spent asleep. For example, if the patient is in bed 8 hours but asleep only 4 hours, sleep efficiency is 50%. The goal is to reduce TIB to match the time asleep and to agree on a prescribed daily wake-up time. When the patient is consistently sleeping 90% of the TIB, add 30-minute increments until he or she is appropriately sleeping 7 to 8 hours at night.⁹ Naps are not recommended.

Let patients know that their migraine may worsen until a new routine sleep pattern emerges. This method is not recommended for patients with untreated sleep apnea.

E IS FOR EXERCISE

Exercise is broadly recommended for a healthy lifestyle; some evidence suggests that it can also be useful in the management of migraine.¹⁰ Low levels of physical activity and a sedentary lifestyle are associated with migraine.¹¹ It is unclear if patients with migraine are less likely to exercise because they want to avoid triggering a migraine or if a sedentary lifestyle increases their risk.

Exercise has been studied for its prophylactic benefits in migraine, and one hypothesis relates to beta-endorphins. Levels of beta-endorphins are reduced in the cerebrospinal fluid of patients with migraine.¹² Exercise programs may increase levels while reducing headache frequency and duration.¹³ One study showed that pain thresholds do not change with exercise programs, suggesting that it is avoidance behavior that is positively altered rather than the underlying pain pathways.¹⁴

A systematic review and meta-analysis based on 5 randomized controlled trials and 1 nonrandomized controlled clinical trial showed that exercise reduced monthly migraine days by only 0.6 (± 0.3) days, but the data also suggested that as the exercise intensity increased, so did the positive effects.¹⁰

Some data suggest that exercise may also reduce migraine duration and severity as well as the need for abortive medication.¹⁰ Two studies in this systematic review^15,16 showed that exercise benefits were equivalent to those of migraine preventives such as amitriptyline and topiramate; the combination of amitriptyline and exercise was more beneficial than exercise alone. Multiple types of exercise were beneficial, including walking, jogging, cross-training, and cycling when done for least 6 weeks and for 30 to 50 minutes 3 to 5 times a week.

These findings are in line with the current recommendations for general health from the American College of Sports Medicine, ie, moderate to vigorous cardio­respiratory exercise for 30 to 60 minutes 3 to 5 times a week (or 150 minutes per week). The daily exercise can be continuous or done in intervals of less than 20 minutes. For those with a sedentary lifestyle, as is seen in a significant proportion of the migraine population, light to moderate exercise for less than 20 minutes is still beneficial.¹⁷

Based on this evidence, the best current recommendation for patients with migraine is to engage in graded moderate cardiorespiratory exercise, although any exercise is better than none. If a patient is sedentary or has poor exercise tolerance, or both, exercising once a week for shorter time periods may be a manageable place to start.

Some patients may identify exercise as a trigger or exacerbating factor in migraine. These patients may need appropriate prophylactic and abortive therapies before starting an exercise regimen.

THE SECOND E IS FOR EAT (FOOD AND DRINK)

Many patients believe that some foods trigger migraine attacks, but further study is needed. The most consistent food triggers appear to be red wine and caffeine (withdrawal).^18,19 Interestingly, patients with migraine report low levels of alcohol consumption,²⁰ but it is unclear if that is because alcohol has a protective effect or if patients avoid it.

Some patients may crave certain foods in the prodromal phase of an attack, eat the food, experience the attack, and falsely conclude that the food caused the attack.²¹ Premonitory symptoms include fatigue, cognitive changes, homeostatic changes, sensory hyperresponsiveness, and food cravings.²¹ It is difficult to distinguish between premonitory phase food cravings and true triggers because premonitory symptoms can precede headache by 48 to 72 hours, and the timing for a trigger to be considered causal is not known.²²

Chocolate is often thought to be a migraine trigger, but the evidence argues against this and even suggests that sweet cravings are a part of the premonitory phase.²³ Monosodium glutamate is often identified as a trigger as well, but the literature is inconsistent and does not support a causal relationship.²⁴ Identifying true food triggers in migraine is difficult, and patients with migraine may have poor quality diets, with some foods acting as true triggers for certain patients.²⁵ These possibilities have led to the development of many “migraine diets,” including elimination diets.

Elimination diets

Elimination diets involve avoiding specific food items over a period of time and then adding them back in one at a time to gauge whether they cause a reaction in the body. A number of these diets have been studied for their effects on headache and migraine:

Gluten-free diets restrict foods that contain wheat, rye, and barley. A systematic review of gluten-free diets in patients with celiac disease found that headache or migraine frequency decreased by 51.6% to 100% based on multiple cohort studies (N = 42,388).²⁶ There are no studies on the use of a gluten-free diet for migraine in patients without celiac disease.

Immunoglobulin G-elimination diets restrict foods that serve as antigens for IgG. However, data supporting these diets are inconsistent. Two small randomized controlled trials found that the diets improved migraine symptoms, but a larger study found no improvement in the number of migraine days at 12 weeks, although there was an initially significant effect at 4 weeks.^27–29

Antihistamine diets restrict foods that have high levels of histamines, including fermented dairy, vegetables, soy products,  wine, beer, alcohol, and those that cause histamine release regardless of IgE testing results. A prospective single-arm study of antihistamine diets in patients with chronic headache reported symptom improvement, which could be applied to certain comorbidities such as  mast cell activation syndrome.³⁰ Another prospective nonrandomized controlled study eliminated foods based on positive IgE skin-prick testing for allergy in patients with recurrent migraine and found that it reduced headache frequency.³¹

Tyramine-free diets are often recommended due to the presumption that tyramine-containing foods (eg, aged cheese, cured or smoked meats and fish, and beer) are triggers. However, multiple studies have reviewed this theory with inconsistent results,³² and the only study of a tyramine-free diet was negative.³³ In addition, commonly purported high-tyramine foods have lower tyramine levels than previously thought.³⁴

Low-fat diets in migraine are supported by 2 small randomized controlled trials and a prospective study showing a decrease in symptom severity; the results for frequency are inconsistent.^35–37

Low-glycemic index diets are supported in migraine by 1 randomized controlled trial that showed improvement in migraine frequency in a diet group and in a control group of patients who took a standard migraine-preventive medication to manage their symptoms.³⁸

Other migraine diets

Diets high in certain foods or ingredient ratios, as opposed to elimination diets, have also been studied in patients with migraine. One promising diet containing high levels of omega-3 fatty acids and low levels of omega-6 fatty acids was shown in a systematic review to reduce the duration of migraine but not the frequency or severity.³⁹ A more recent randomized controlled trial of this diet in chronic migraine also showed that it decreased migraine frequency.⁴⁰

The ketogenic diet (high fat, low carbohydrate) had promising results in a randomized controlled trial in overweight women with migraine and in a prospective study.^41,42 However, a prospective study of the Atkins diet in teenagers with chronic daily headaches showed no benefit.⁴³ The ketogenic diet is difficult to follow and may work in part due to weight loss alone, although ketogenesis itself may also play a role.^41,44

Sodium levels have been shown to be higher in the cerebrospinal fluid of patients with migraine than in controls, particularly during an attack.⁴⁵ For a prehypertensive population or an elderly population, a low-sodium diet may be beneficial based on 2 prospective trials.^46,47 However, a younger female population without hypertension and low-to-normal body mass index had a reduced probability of migraine while consuming a high-sodium diet.⁴⁸

Counseling about sodium intake should be tailored to specific patient populations. For example, a diet low in sodium may be appropriate for patients with vascular risk factors such as hypertension, whereas a high-sodium diet may be appropriate in patients with comorbidities like postural tachycardia syndrome or in those with a propensity for low blood pressure or low body mass index.

Encourage routine meals and hydration

The standard advice for patients with migraine is to consume regular meals. Headaches have been associated with fasting, and those with migraine are predisposed to attacks in the setting of fasting.^49,50 Migraine is more common when meals are skipped, particularly breakfast.⁵¹

It is unclear how fasting lowers the migraine threshold. Nutritional studies show that skipping meals, particularly breakfast, increases low-grade inflammation and impairs  glucose metabolism by affecting insulin and fat oxidation metabolism.⁵² However, hypoglycemia itself is not a consistent cause of headache or migraine attacks.⁵³ As described above, a randomized controlled trial of a low-glycemic index diet actually decreased migraine frequency and severity.³⁸ Skipping meals also reduces energy and is associated with reduced physical activity, perhaps leading to multiple compounding triggers that further lower the migraine threshold.^54,55

When counseling patients about the need to eat breakfast, consider what they normally consume (eg, is breakfast just a cup of coffee?). Replacing simple carbohydrates with protein, fats, and fiber may be beneficial for general health, but the effects on migraine are not known, nor is the optimal composition of breakfast foods.⁵⁵

The optimal timing of breakfast relative to awakening is also unclear, but in general, it should be eaten within 30 to 60 minutes of rising. Also consider patients’ work hours—delayed-phase or shift workers have altered sleep cycles.

Recommendations vary in regard to hydration. Headache is associated with fluid restriction and dehydration,^56,57 but only a few studies suggest that rehydration and increased hydration status can improve migraine.⁵⁸ In fact, a single post hoc analysis of a metoclopramide study showed that intravenous fluid alone for patients with migraine in the emergency room did not improve pain outcomes.⁵⁹

The amount of water patients should drink daily in the setting of migraine is also unknown, but a study showed benefit with 4 L, which equates to a daily intake of 16 eight-ounce glasses.⁶⁰ One review on general health that could be extrapolated given the low risk of the intervention indicated that 1.8 L daily (7 to 8 eight-ounce glasses) promoted a euhydration status in most people, although many factors contribute to hydration status.⁶¹

Caffeine intake is also a major consideration. Caffeine is a nonspecific adenosine receptor antagonist that modulates adenosine receptors like the pronociceptive 2A receptor, leading to changes integral to the neuropathophysiology of migraine.⁶² Caffeine has analgesic properties at doses greater than 65 to 200 mg and augments the effects of analgesics such as acetaminophen and aspirin. Chronic caffeine use can lead to withdrawal symptoms when intake is stopped abruptly; this is thought to be due to upregulation of adenosine receptors, but the effect varies based on genetic predisposition.¹⁹

The risk of chronic daily headache may relate to high use of caffeine preceding the onset of chronification, and caffeine abstinence may improve response to acute migraine treatment.^19,63 There is a dose-dependent risk of headache.^64,65 Current recommendations suggest limiting caffeine consumption to less than 200 mg per day or stopping caffeine consumption altogether based on the quantity required for caffeine-withdrawal headache.⁶⁶ Varying  the caffeine dose from day to day may also trigger headache due to the high sensitivity to caffeine withdrawal.

While many diets have shown potential benefit in patients with migraine, more studies are needed before any one “migraine diet” can be recommended. Caution should be taken, as there is risk of adverse effects from nutrient deficiencies or excess levels, especially if the patient is not under the care of a healthcare professional who is familiar with the diet.

Whether it is beneficial to avoid specific food triggers at this time is unclear and still controversial even within the migraine community because some of these foods may be misattributed as triggers instead of premonitory cravings driven by the hypothalamus. It is important to counsel patients with migraine to eat a healthy diet with consistent meals, to maintain adequate hydration, and to keep their caffeine intake low or at least consistent, although these teachings are predominantly based on limited studies with extrapolation from nutrition research.

D IS FOR DIARY

A headache diary is a recommended part of headache management and may enhance the accuracy of diagnosis and assist in treatment modifications. Paper and electronic diaries have been used. Electronic diaries may be more accurate for real-time use, but patients may be more likely to complete a paper one.⁶⁷ Patients prefer electronic diaries over long paper forms,⁶⁸ but a practical issue to consider is easy electronic access.

Patients can start keeping a headache diary before the initial consultation to assist with diagnosis, or early in their management. A first-appointment diary mailed with instructions is a feasible option.⁶⁹ These types of diaries ask detailed questions to help diagnose all major primary headache types including menstrual migraine and to identify concomitant medication-overuse headache. Physicians and patients generally report improved communication with use of a diary.⁷⁰

Some providers distinguish between a headache diary and a calendar. In standard practice, a headache diary is the general term referring to both, but the literature differentiates between the two. Both should at least include headache frequency, with possible inclusion of other factors such as headache duration, headache intensity, analgesic use, headache impact on function, and absenteeism. Potential triggers including menses can also be tracked. The calendar version can fit on a single page and can be used for simple tracking of headache frequency and analgesia use.

One of the simplest calendars to use is the “stoplight” calendar. Red days are when a patient is completely debilitated in bed. On a yellow day, function at work, school, or daily activities is significantly reduced by migraine, but the patient is not bedbound. A green day is when headache is present but function is not affected. No color is placed if the patient is 100% headache-free.

Acute treatment use can be written in or, to improve compliance, a checkmark can be placed on days of treatment. Patients who are tracking menses circle the days of menstruation. The calendar-diary should be brought to every appointment to track treatment response and medication use.

THE SECOND S IS FOR STRESS

Behavioral management such as cognitive behavioral therapy in migraine has been shown to decrease catastrophizing, migraine disability, and headache severity and frequency.⁷⁴ Both depression and anxiety can improve along with migraine.⁷⁵ Cognitive behavioral therapy can be provided in individualized sessions or group sessions, either in person or online.^74,76,77 The effects become more prominent about 5 weeks into treatment.⁷⁸

Biofeedback, which uses behavioral techniques paired with physiologic autonomic measures, has been extensively studied, and shows benefit in migraine, including in meta-analysis.⁷⁹ The types of biofeedback measurements used include electromyography, electroencephalography, temperature, sweat sensors, heart rate, blood volume pulse feedback, and respiration bands. While biofeedback is generally done under the guidance of a therapist, it can still be useful with minimal therapist contact and supplemental audio.⁸⁰

Mindfulness, or the awareness of thoughts, feelings, and sensations in the present moment without judgment, is a behavioral technique that can be done alone or paired with another technique. It is often taught through a mindfulness-based stress-reduction  program, which relies on a standardized approach. A meta-analysis showed that mindfulness improves pain intensity, headache frequency, disability, self-efficacy, and quality of life.⁸¹ It may work by encouraging pain acceptance.⁸²

Relaxation techniques are also employed in migraine management, either alone or in conjunction with techniques mentioned  above, such as mindfulness. They include progressive muscle relaxation and deep breathing. Relaxation has been shown to be effective when done by professional trainers as well as lay trainers in both individual and group settings.^83,84

In patients with intractable headache, more-intensive inpatient and outpatient programs have been tried. Inpatient admissions with multidisciplinary programs that include a focus on behavioral techniques often paired with lifestyle education and sometimes pharmacologic management can be beneficial.^85,86 These programs have also been successfully conducted as multiple outpatient sessions.^86–88

Stress management is an important aspect of migraine management. These treatments often involve homework and require active participation.

LIFESTYLE FOR ALL

All patients with migraine should initiate lifestyle modifications (see Advice to patients with migraine: SEEDS for success). Modifications with the highest level of evidence, specifically behavioral techniques, have had the most reproducible results. A headache diary is an essential tool to identify patterns and needs for optimization of acute or preventive treatment regimens. The strongest evidence is for the behavioral management techniques for stress reduction.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.