WASHINGTON –Although an implantable device for detecting myocardial infarction missed the primary composite outcome endpoint in a controlled trial, a newly completed extended analysis associated the device with a higher positive predictive value and a lower false positive rate when compared to sham control, according to data presented at CRT 2019, sponsored by MedStar Heart & Vascular Institute.

Ted Bosworth/MDedge News

“Among high risk patients, this system may be beneficial in the identification of both symptomatic and asymptomatic coronary events,” reported C. Michael Gibson, MD, chief of clinical research in the cardiology division at Beth Israel Deaconess Hospital, Boston.

The implantable device (AngelMed Guardian System), which received Food and Drug Administration approval in April 2018, is designed to identify MI through detection of ST-segment elevations in the absence of an elevated heart rate. When the system detects an event during continuous monitoring, it sends a signal (internal vibration and auditory signal to an external monitor) designed to tell the patient to seek medical care.

The previously published multicenter and randomized ALERTS (AngelMed for Early Recognition and Treatment of STEMI) trial that tested this device was negative for primary composite endpoint of cardiac or unexplained death, new Q-wave MI, or presentation at the emergency department (ED) more than 2 hours after symptom onset (J Am Coll Cardiol. 2019 Feb 25. pii: S0735-1097[19]30237-2). In that trial 907 patients were fitted with the device and then randomized to having the device switched on or left off.

At 7 days, a primary endpoint was reached by 3.8% of those in the device-on group versus 4.9% of those in the device-off group, which was not significantly different.

Although the primary endpoint was not met, there were promising results. For example, in those who did have an occlusive event, patients in the device-on group had better preserved left ventricular function when evaluated after the event, a result consistent with earlier presentation in the ED and earlier treatment. In fact, 85% of patients with an MI in the device-on group presented to a hospital within 2 hours, compared with just 5% of those in the device-off control group during the initial study period.

More evidence of a potential clinical role for the device has now been generated in a new extended analysis. This analysis was made possible because patients in both of the randomized groups continue to wear the device, including those in the device-off group who had their devices activated after 6 months. There are now 3 more years of data of follow-up from those initially in the device-on group and those switched from the device-off group.

“So we started the clock over with a new statistical analysis plan and new endpoints,” Dr. Gibson explained. The FDA was consulted in selecting endpoints, particularly regarding evidence that the device did not increase false-positive ED visits.

There were numerous encouraging findings. One was that 42 silent MIs, which would otherwise have been missed, were detected over the extended follow-up. Another was that the annualized false-positive rate was lower in those with an activated device (0.164/year) when compared to the original device-off group (0.678/year; P less than .001). Lastly, the positive predictive value of an alarm during the extended follow-up was higher than that of symptoms alone among the original device-off group (25.8% vs. 18.2%).

The device was found safe. The rate of system-related complications was under 4%, which Dr. Gibson said is noninferior to that associated with pacemakers.

One of the potential explanations for the failure of the device to achieve the primary endpoint in the original trial was an unexpectedly low event rate, according to Dr. Gibson.

Even before this extended analysis, the FDA had accepted the potential benefits of this device as demonstrated in the approval last year. In the labeling, the device is called “a more accurate predictor of acute coronary syndrome events when compared to patient recognized symptoms alone and demonstrates a reduced rate over time of patient presentations without ACS events.”

“About 50% of patients wait more than 3 hours after the onset of symptoms before reaching an emergency room,” observed Dr. Gibson. Emphasizing the evidence that delay is an important predictor of adverse outcomes, he suggested the alarm device might be useful in accelerating care in some high risk groups.

WASHINGTON –Although an implantable device for detecting myocardial infarction missed the primary composite outcome endpoint in a controlled trial, a newly completed extended analysis associated the device with a higher positive predictive value and a lower false positive rate when compared to sham control, according to data presented at CRT 2019, sponsored by MedStar Heart & Vascular Institute.

Ted Bosworth/MDedge News

“Among high risk patients, this system may be beneficial in the identification of both symptomatic and asymptomatic coronary events,” reported C. Michael Gibson, MD, chief of clinical research in the cardiology division at Beth Israel Deaconess Hospital, Boston.

The implantable device (AngelMed Guardian System), which received Food and Drug Administration approval in April 2018, is designed to identify MI through detection of ST-segment elevations in the absence of an elevated heart rate. When the system detects an event during continuous monitoring, it sends a signal (internal vibration and auditory signal to an external monitor) designed to tell the patient to seek medical care.

The previously published multicenter and randomized ALERTS (AngelMed for Early Recognition and Treatment of STEMI) trial that tested this device was negative for primary composite endpoint of cardiac or unexplained death, new Q-wave MI, or presentation at the emergency department (ED) more than 2 hours after symptom onset (J Am Coll Cardiol. 2019 Feb 25. pii: S0735-1097[19]30237-2). In that trial 907 patients were fitted with the device and then randomized to having the device switched on or left off.

At 7 days, a primary endpoint was reached by 3.8% of those in the device-on group versus 4.9% of those in the device-off group, which was not significantly different.

Although the primary endpoint was not met, there were promising results. For example, in those who did have an occlusive event, patients in the device-on group had better preserved left ventricular function when evaluated after the event, a result consistent with earlier presentation in the ED and earlier treatment. In fact, 85% of patients with an MI in the device-on group presented to a hospital within 2 hours, compared with just 5% of those in the device-off control group during the initial study period.

More evidence of a potential clinical role for the device has now been generated in a new extended analysis. This analysis was made possible because patients in both of the randomized groups continue to wear the device, including those in the device-off group who had their devices activated after 6 months. There are now 3 more years of data of follow-up from those initially in the device-on group and those switched from the device-off group.

“So we started the clock over with a new statistical analysis plan and new endpoints,” Dr. Gibson explained. The FDA was consulted in selecting endpoints, particularly regarding evidence that the device did not increase false-positive ED visits.

There were numerous encouraging findings. One was that 42 silent MIs, which would otherwise have been missed, were detected over the extended follow-up. Another was that the annualized false-positive rate was lower in those with an activated device (0.164/year) when compared to the original device-off group (0.678/year; P less than .001). Lastly, the positive predictive value of an alarm during the extended follow-up was higher than that of symptoms alone among the original device-off group (25.8% vs. 18.2%).

The device was found safe. The rate of system-related complications was under 4%, which Dr. Gibson said is noninferior to that associated with pacemakers.

One of the potential explanations for the failure of the device to achieve the primary endpoint in the original trial was an unexpectedly low event rate, according to Dr. Gibson.

Even before this extended analysis, the FDA had accepted the potential benefits of this device as demonstrated in the approval last year. In the labeling, the device is called “a more accurate predictor of acute coronary syndrome events when compared to patient recognized symptoms alone and demonstrates a reduced rate over time of patient presentations without ACS events.”

“About 50% of patients wait more than 3 hours after the onset of symptoms before reaching an emergency room,” observed Dr. Gibson. Emphasizing the evidence that delay is an important predictor of adverse outcomes, he suggested the alarm device might be useful in accelerating care in some high risk groups.

WASHINGTON –Although an implantable device for detecting myocardial infarction missed the primary composite outcome endpoint in a controlled trial, a newly completed extended analysis associated the device with a higher positive predictive value and a lower false positive rate when compared to sham control, according to data presented at CRT 2019, sponsored by MedStar Heart & Vascular Institute.

Ted Bosworth/MDedge News

“Among high risk patients, this system may be beneficial in the identification of both symptomatic and asymptomatic coronary events,” reported C. Michael Gibson, MD, chief of clinical research in the cardiology division at Beth Israel Deaconess Hospital, Boston.

The implantable device (AngelMed Guardian System), which received Food and Drug Administration approval in April 2018, is designed to identify MI through detection of ST-segment elevations in the absence of an elevated heart rate. When the system detects an event during continuous monitoring, it sends a signal (internal vibration and auditory signal to an external monitor) designed to tell the patient to seek medical care.

The previously published multicenter and randomized ALERTS (AngelMed for Early Recognition and Treatment of STEMI) trial that tested this device was negative for primary composite endpoint of cardiac or unexplained death, new Q-wave MI, or presentation at the emergency department (ED) more than 2 hours after symptom onset (J Am Coll Cardiol. 2019 Feb 25. pii: S0735-1097[19]30237-2). In that trial 907 patients were fitted with the device and then randomized to having the device switched on or left off.

At 7 days, a primary endpoint was reached by 3.8% of those in the device-on group versus 4.9% of those in the device-off group, which was not significantly different.

Although the primary endpoint was not met, there were promising results. For example, in those who did have an occlusive event, patients in the device-on group had better preserved left ventricular function when evaluated after the event, a result consistent with earlier presentation in the ED and earlier treatment. In fact, 85% of patients with an MI in the device-on group presented to a hospital within 2 hours, compared with just 5% of those in the device-off control group during the initial study period.

More evidence of a potential clinical role for the device has now been generated in a new extended analysis. This analysis was made possible because patients in both of the randomized groups continue to wear the device, including those in the device-off group who had their devices activated after 6 months. There are now 3 more years of data of follow-up from those initially in the device-on group and those switched from the device-off group.

“So we started the clock over with a new statistical analysis plan and new endpoints,” Dr. Gibson explained. The FDA was consulted in selecting endpoints, particularly regarding evidence that the device did not increase false-positive ED visits.

There were numerous encouraging findings. One was that 42 silent MIs, which would otherwise have been missed, were detected over the extended follow-up. Another was that the annualized false-positive rate was lower in those with an activated device (0.164/year) when compared to the original device-off group (0.678/year; P less than .001). Lastly, the positive predictive value of an alarm during the extended follow-up was higher than that of symptoms alone among the original device-off group (25.8% vs. 18.2%).

The device was found safe. The rate of system-related complications was under 4%, which Dr. Gibson said is noninferior to that associated with pacemakers.

One of the potential explanations for the failure of the device to achieve the primary endpoint in the original trial was an unexpectedly low event rate, according to Dr. Gibson.

Even before this extended analysis, the FDA had accepted the potential benefits of this device as demonstrated in the approval last year. In the labeling, the device is called “a more accurate predictor of acute coronary syndrome events when compared to patient recognized symptoms alone and demonstrates a reduced rate over time of patient presentations without ACS events.”

“About 50% of patients wait more than 3 hours after the onset of symptoms before reaching an emergency room,” observed Dr. Gibson. Emphasizing the evidence that delay is an important predictor of adverse outcomes, he suggested the alarm device might be useful in accelerating care in some high risk groups.

GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.

Will Pass/MDedge News

A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.

Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.

“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.

The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.

Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.

Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.

“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”

Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.

Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.

“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”

Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.

“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.

Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”

The study was sponsored by NHS England. The investigators reported having no conflicts of interest.

SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.

GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.

Will Pass/MDedge News

A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.

Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.

“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.

The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.

Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.

Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.

“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”

Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.

Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.

“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”

Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.

“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.

Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”

The study was sponsored by NHS England. The investigators reported having no conflicts of interest.

SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.

GLASGOW – Whole genome sequencing (WGS) appears capable of replacing cytogenetic testing and next generation sequencing (NGS) for the detection of clinically relevant molecular abnormalities in hematological malignancies, according to investigators.

Will Pass/MDedge News

A comparison of WGS with fluorescence in situ hybridization (FISH) showed that WGS caught all the same significant structural variants, plus some abnormalities that FISH had not detected, reported lead author Shirley Henderson, PhD, lead for cancer molecular diagnostics at Genomics England in Oxford.

Although further validation is needed, these findings, reported at the annual meeting of the British Society for Haematology, support an ongoing effort to validate the clinical reliability of WGS, which is currently reserved for research purposes.

“It’s vitally important that the clinical community engage with this and understand both the power and the limitations of this technique and how this work is going to be interpreted for the benefit of patients,” said Adele Fielding, PhD, session chair from University College London’s Cancer Institute.

The investigators compared WGS with FISH for detection of clinically significant structural variants (SVs) and copy number variants (CNVs) in tumor samples from 34 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

The 252 standard of care FISH tests – conducted at three separate clinical diagnostic centers in the United Kingdom – included 138 SVs and 114 CNVs. WGS relied on a combination of bioinformatics and visual inspection of Circos plots. WGS confirmed all of the SVs detected by FISH with high confidence; WGS detected four additional SVs, also with high confidence, including an ETV6-RUNX1 fusion not detected by FISH because of probe limitations.

Results for CNVs were similar, with WGS detecting 78 out of 85 positive CNVs. Six of the missed positives were associated with low quality samples or low level mutations in the FISH test, suggesting that at least some positives may have been detected with better samples. Only one negative CNV from FISH was missed by WGS.

Overall, WGS had a false positive rate of less than 5% and a positive percentage agreement with FISH that exceeded 90%.

“Further work is required to fully validate all aspects of the WGS analysis pipeline,” Dr. Henderson said. “But these results indicate that WGS has the potential to reliably detect SVs and CNVs in these conditions while offering the advantage of detecting all SVs and CNVs present without the need for additional interrogation of the sample by multiple tests or probes.”

Dr. Henderson noted that there is really no “perfect method” for identifying structural and copy number variants at the present time.

Small variants are relatively easy to detect with techniques such as karyotyping and gene banding, but these tests have shortcomings, namely, that they require live cells and have “fairly high failure rates for various reasons,” Dr. Henderson said.

“FISH is an incredibly useful test and it has higher resolution than gene banding, but the problem with FISH is that you only find what you’re looking at,” Dr. Henderson said. “It’s not genome wide; it’s very targeted.”

Similarly, polymerase chain reaction (PCR), including next generation sequencing (NGS), can detect molecular abnormalities, but only those that are targeted, which may necessitate multiple tests, she said.

“If you start looking for all of the structural variants [with existing techniques], then you’re going to be doing an awful lot of tests,” Dr. Henderson said.

Another potential benefit of WGS is that it is “future resistant,” Dr. Henderson said. “As new biomarkers are discovered, you don’t have to redesign a new targeted test. It will also detect emerging biomarkers, such as mutational signatures and burden.”

The study was sponsored by NHS England. The investigators reported having no conflicts of interest.

SOURCE: Henderson S et al. BSH 2019, Abstract OR-002.

To the Editor:

Epidermolysis bullosa (EB) was first described in 1886, with the first classification scheme proposed in 1962 utilizing transmission electron microscopy (TEM) findings to delineate categories: epidermolytic (EB simplex [EBS]), lucidolytic (junctional EB), and dermolytic (dystrophic EB).¹ Localized EBS (EBS-loc) is an autosomal-dominant disorder caused by negative mutations in keratin-5 and keratin-14, proteins expressed in the intermediate filaments of basal keratinocytes, which result in fragility of the skin in response to minor trauma.² The incidence of EBS-loc is approximately 10 to 30 cases per million live births, with the age of presentation typically between the first and third decades of life.^3,4 Because EBS-loc is the most common and often mildest form of EB, not all patients present for medical evaluation and true prevalence may be underestimated.⁴ We report a case of EBS-loc.

A 26-year-old woman with no notable medical history presented to the dermatology clinic for evaluation of skin blisters that had been intermittently present since infancy. The blisters primarily occurred on the feet, but she did occasionally develop blisters on the hands, knees, and elbows and at sites of friction or trauma (eg, bra line, medial thighs) following exercise. The blisters were worsened by heat and tight-fitting shoes. Because of the painful nature of the blisters, she would lance them with a needle. On the medial thighs, she utilized nonstick and gauze bandage roll dressings to minimize friction. A review of systems was positive for hyperhidrosis. Her family history revealed multiple family members with blisters involving the feet and areas of friction or trauma for 4 generations with no known diagnosis.

Physical examination revealed multiple tense bullae and calluses scattered over the bilateral plantar and distal dorsal feet with a few healing, superficially eroded, erythematous papules and plaques on the bilateral medial thighs (Figure 1). A biopsy from an induced blister on the right dorsal second toe was performed and sent in glutaraldehyde to the Epidermolysis Bullosa Clinic at Stanford University (Redwood City, California) for electron microscopy, which revealed lysis within the basal keratinocytes through the tonofilaments with continuous and intact lamina densa and lamina lucida (Figure 2). In this clinical context with the relevant family history, the findings were consistent with the diagnosis of EBS-loc (formerly Weber-Cockayne syndrome).²

Light microscopy does not have a notable role in diagnosis of classic forms of inherited EB unless another autoimmune blistering disorder is suspected.^2,5 Both TEM and immunofluorescence mapping are used to diagnose EB.¹ DNA mutational analysis is not considered a first-line diagnostic test for EB given it is a costly labor-intensive technique with limited access at present, but it may be considered in settings of prenatal diagnosis or in vitro fertilization.¹ Biopsy of a freshly induced blister should be performed, as early reepithelialization of an existing blister makes it difficult to establish the level of cleavage.⁵ Applying firm pressure using a pencil eraser and rotating it on intact skin induces a subclinical blister. Two punch biopsies (4 mm) at the edge of the blister with one-third lesional and two-thirds perilesional skin should be obtained, with one biopsy sent for immunofluorescence mapping in Michel fixative and the other for TEM in glutaraldehyde.^3,5 Transmission electron microscopy of an induced blister in EBS-loc shows cleavage within the most inferior portion of the basilar keratinocyte.² Immunofluorescence mapping with anti–epidermal basement membrane monoclonal antibodies can distinguish between EB subtypes and assess expression of specific skin-associated proteins on both a qualitative or semiquantitative basis, providing insight on which structural protein is mutated.^1,5

No specific treatments are available for EBS-loc. Mainstays of treatment include prevention of mechanical trauma and secondary infection. Hyperhidrosis of thepalms and soles may be treated with topical aluminum chloride hexahydrate or injections of botulinum toxin type A.^2,6 Patients have normal life expectancy, though some cases may have complications with substantial morbidity.¹ Awareness of this disease, its clinical course, and therapeutic options will allow physicians to more appropriately counsel patients on the disease process.

Localized EBS may be more common than previously thought, as not all patients seek medical care. Given its impact on patient quality of life, it is important for clinicians to recognize EBS-loc. Although no specific treatments are available, wound care counseling and explanation of the genetics of the disease should be provided to patients.

To the Editor:

Epidermolysis bullosa (EB) was first described in 1886, with the first classification scheme proposed in 1962 utilizing transmission electron microscopy (TEM) findings to delineate categories: epidermolytic (EB simplex [EBS]), lucidolytic (junctional EB), and dermolytic (dystrophic EB).¹ Localized EBS (EBS-loc) is an autosomal-dominant disorder caused by negative mutations in keratin-5 and keratin-14, proteins expressed in the intermediate filaments of basal keratinocytes, which result in fragility of the skin in response to minor trauma.² The incidence of EBS-loc is approximately 10 to 30 cases per million live births, with the age of presentation typically between the first and third decades of life.^3,4 Because EBS-loc is the most common and often mildest form of EB, not all patients present for medical evaluation and true prevalence may be underestimated.⁴ We report a case of EBS-loc.

A 26-year-old woman with no notable medical history presented to the dermatology clinic for evaluation of skin blisters that had been intermittently present since infancy. The blisters primarily occurred on the feet, but she did occasionally develop blisters on the hands, knees, and elbows and at sites of friction or trauma (eg, bra line, medial thighs) following exercise. The blisters were worsened by heat and tight-fitting shoes. Because of the painful nature of the blisters, she would lance them with a needle. On the medial thighs, she utilized nonstick and gauze bandage roll dressings to minimize friction. A review of systems was positive for hyperhidrosis. Her family history revealed multiple family members with blisters involving the feet and areas of friction or trauma for 4 generations with no known diagnosis.

Physical examination revealed multiple tense bullae and calluses scattered over the bilateral plantar and distal dorsal feet with a few healing, superficially eroded, erythematous papules and plaques on the bilateral medial thighs (Figure 1). A biopsy from an induced blister on the right dorsal second toe was performed and sent in glutaraldehyde to the Epidermolysis Bullosa Clinic at Stanford University (Redwood City, California) for electron microscopy, which revealed lysis within the basal keratinocytes through the tonofilaments with continuous and intact lamina densa and lamina lucida (Figure 2). In this clinical context with the relevant family history, the findings were consistent with the diagnosis of EBS-loc (formerly Weber-Cockayne syndrome).²

Light microscopy does not have a notable role in diagnosis of classic forms of inherited EB unless another autoimmune blistering disorder is suspected.^2,5 Both TEM and immunofluorescence mapping are used to diagnose EB.¹ DNA mutational analysis is not considered a first-line diagnostic test for EB given it is a costly labor-intensive technique with limited access at present, but it may be considered in settings of prenatal diagnosis or in vitro fertilization.¹ Biopsy of a freshly induced blister should be performed, as early reepithelialization of an existing blister makes it difficult to establish the level of cleavage.⁵ Applying firm pressure using a pencil eraser and rotating it on intact skin induces a subclinical blister. Two punch biopsies (4 mm) at the edge of the blister with one-third lesional and two-thirds perilesional skin should be obtained, with one biopsy sent for immunofluorescence mapping in Michel fixative and the other for TEM in glutaraldehyde.^3,5 Transmission electron microscopy of an induced blister in EBS-loc shows cleavage within the most inferior portion of the basilar keratinocyte.² Immunofluorescence mapping with anti–epidermal basement membrane monoclonal antibodies can distinguish between EB subtypes and assess expression of specific skin-associated proteins on both a qualitative or semiquantitative basis, providing insight on which structural protein is mutated.^1,5

No specific treatments are available for EBS-loc. Mainstays of treatment include prevention of mechanical trauma and secondary infection. Hyperhidrosis of thepalms and soles may be treated with topical aluminum chloride hexahydrate or injections of botulinum toxin type A.^2,6 Patients have normal life expectancy, though some cases may have complications with substantial morbidity.¹ Awareness of this disease, its clinical course, and therapeutic options will allow physicians to more appropriately counsel patients on the disease process.

Localized EBS may be more common than previously thought, as not all patients seek medical care. Given its impact on patient quality of life, it is important for clinicians to recognize EBS-loc. Although no specific treatments are available, wound care counseling and explanation of the genetics of the disease should be provided to patients.

To the Editor:

Epidermolysis bullosa (EB) was first described in 1886, with the first classification scheme proposed in 1962 utilizing transmission electron microscopy (TEM) findings to delineate categories: epidermolytic (EB simplex [EBS]), lucidolytic (junctional EB), and dermolytic (dystrophic EB).¹ Localized EBS (EBS-loc) is an autosomal-dominant disorder caused by negative mutations in keratin-5 and keratin-14, proteins expressed in the intermediate filaments of basal keratinocytes, which result in fragility of the skin in response to minor trauma.² The incidence of EBS-loc is approximately 10 to 30 cases per million live births, with the age of presentation typically between the first and third decades of life.^3,4 Because EBS-loc is the most common and often mildest form of EB, not all patients present for medical evaluation and true prevalence may be underestimated.⁴ We report a case of EBS-loc.

A 26-year-old woman with no notable medical history presented to the dermatology clinic for evaluation of skin blisters that had been intermittently present since infancy. The blisters primarily occurred on the feet, but she did occasionally develop blisters on the hands, knees, and elbows and at sites of friction or trauma (eg, bra line, medial thighs) following exercise. The blisters were worsened by heat and tight-fitting shoes. Because of the painful nature of the blisters, she would lance them with a needle. On the medial thighs, she utilized nonstick and gauze bandage roll dressings to minimize friction. A review of systems was positive for hyperhidrosis. Her family history revealed multiple family members with blisters involving the feet and areas of friction or trauma for 4 generations with no known diagnosis.

Physical examination revealed multiple tense bullae and calluses scattered over the bilateral plantar and distal dorsal feet with a few healing, superficially eroded, erythematous papules and plaques on the bilateral medial thighs (Figure 1). A biopsy from an induced blister on the right dorsal second toe was performed and sent in glutaraldehyde to the Epidermolysis Bullosa Clinic at Stanford University (Redwood City, California) for electron microscopy, which revealed lysis within the basal keratinocytes through the tonofilaments with continuous and intact lamina densa and lamina lucida (Figure 2). In this clinical context with the relevant family history, the findings were consistent with the diagnosis of EBS-loc (formerly Weber-Cockayne syndrome).²

Light microscopy does not have a notable role in diagnosis of classic forms of inherited EB unless another autoimmune blistering disorder is suspected.^2,5 Both TEM and immunofluorescence mapping are used to diagnose EB.¹ DNA mutational analysis is not considered a first-line diagnostic test for EB given it is a costly labor-intensive technique with limited access at present, but it may be considered in settings of prenatal diagnosis or in vitro fertilization.¹ Biopsy of a freshly induced blister should be performed, as early reepithelialization of an existing blister makes it difficult to establish the level of cleavage.⁵ Applying firm pressure using a pencil eraser and rotating it on intact skin induces a subclinical blister. Two punch biopsies (4 mm) at the edge of the blister with one-third lesional and two-thirds perilesional skin should be obtained, with one biopsy sent for immunofluorescence mapping in Michel fixative and the other for TEM in glutaraldehyde.^3,5 Transmission electron microscopy of an induced blister in EBS-loc shows cleavage within the most inferior portion of the basilar keratinocyte.² Immunofluorescence mapping with anti–epidermal basement membrane monoclonal antibodies can distinguish between EB subtypes and assess expression of specific skin-associated proteins on both a qualitative or semiquantitative basis, providing insight on which structural protein is mutated.^1,5

No specific treatments are available for EBS-loc. Mainstays of treatment include prevention of mechanical trauma and secondary infection. Hyperhidrosis of thepalms and soles may be treated with topical aluminum chloride hexahydrate or injections of botulinum toxin type A.^2,6 Patients have normal life expectancy, though some cases may have complications with substantial morbidity.¹ Awareness of this disease, its clinical course, and therapeutic options will allow physicians to more appropriately counsel patients on the disease process.

Localized EBS may be more common than previously thought, as not all patients seek medical care. Given its impact on patient quality of life, it is important for clinicians to recognize EBS-loc. Although no specific treatments are available, wound care counseling and explanation of the genetics of the disease should be provided to patients.

WASHINGTON – One transcatheter device designed to prevent left ventricular outflow tract (LVOT) obstruction relevant to transcatheter mitral valve replacement (TMVR) and another designed to prevent coronary obstruction relevant to transcatheter aortic valve replacement (TAVR) performed well in feasibility studies, according to data presented in two separate late breaking clinical trial sessions at the CRT 2019, sponsored by MedStar Heart & Vascular Institute.

LVOT obstruction prevention

“The 30-day survival in subjects with an increased risk of LVOT obstruction was significantly better than that previously reported in registries,” said Jaffar M. Khan, BM BCh, of the National Heart, Lung, and Blood Institute, who addressing results with the LAMPOON device prior to TMVR,.

LAMPOON is an acronym for intentional Laceration of the Anterior Mitral valve leaflet to Prevent LVOT ObstructioN. Introduced percutaneously and guided to the valve with wires, it was designed to tear existing mitral valve leaflets to prevent them from causing life-threatening LVOT obstruction. It is used immediately prior to TMVR in patients at risk for this complication.

In a feasibility study, delivery, deployment, and retrieval of the device was achieved in all 30 patients. On the basis of the primary endpoint of LVOT gradients of less than 50 mm Hg and no emergency surgery, the procedural success was 73%. The 30-day survival was 93%.

Citing data from registries, Dr. Khan said that the expected survival in TMVR patients with LVOT obstruction caused by a native mitral valve leaflet has been less than 40%. With few existing options to prevent this complication, none of which are reliable, LAMPOON is poised to permit patients who are poor candidates or are contraindicated for TMVR to undergo this treatment, according to Dr. Khan.

“LAMPOON is feasible in all anatomies and calcium patterns,” said Dr. Khan, who noted that gradients of less than 30 mm Hg was achieved in 29 of the 30 patients. Although Dr. Khan acknowledged that this study was small and uncontrolled, and he further cautioned that current strategies for predicting mitral valve leaflet LVOT obstruction are “imprecise,” he believes larger studies of LAMPOON are warranted based on these results.
 

Coronary artery obstruction prevention

Dr. Khan also presented data on the BASILICA device from a second feasibility study. The device is employed immediately prior to TAVR in order to prevent large aortic valve leaflets, whether native or from an existing bioprosthetic valve, from producing coronary obstruction. BASILICA is an acronym for Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction.

This device is also introduced percutaneously and uses radiofrequency ablation to split leaflets that are considered to pose a risk for coronary obstruction. Even though Dr. Khan acknowledged that there is also a lack of precision for predicting which TAVR candidates require an intervention to prevent coronary obstruction, he cited mortality rates exceeding 40% when this complication occurs.

In the feasibility study, 30 patients, of whom 80% were female, were enrolled. In half of the cases, the target for BASILICA was a native valve. The remainder was treated for risk of coronary obstruction posed by a bioprosthetic valve. Multiple comorbidities, including a high proportion with prior stroke, made those selected for enrollment poor candidates for surgery.

The BASILICA intervention was successful in 28 of the 30 participants and in 35 of the 37 leaflets treated. At 30 days, there was one death and one disabling stroke. The overall success rate of the procedure was 93%, according to Dr. Khan.

“One hundred percent of patients were discharged from the cath lab without coronary obstruction despite the high baseline risk,” Dr. Khan said. Again, larger studies are needed to validate the safety and efficacy of this approach, but Dr. Khan believes the outcomes in this study warrant expanded clinical studies.

[email protected]

WASHINGTON – One transcatheter device designed to prevent left ventricular outflow tract (LVOT) obstruction relevant to transcatheter mitral valve replacement (TMVR) and another designed to prevent coronary obstruction relevant to transcatheter aortic valve replacement (TAVR) performed well in feasibility studies, according to data presented in two separate late breaking clinical trial sessions at the CRT 2019, sponsored by MedStar Heart & Vascular Institute.

LVOT obstruction prevention

“The 30-day survival in subjects with an increased risk of LVOT obstruction was significantly better than that previously reported in registries,” said Jaffar M. Khan, BM BCh, of the National Heart, Lung, and Blood Institute, who addressing results with the LAMPOON device prior to TMVR,.

LAMPOON is an acronym for intentional Laceration of the Anterior Mitral valve leaflet to Prevent LVOT ObstructioN. Introduced percutaneously and guided to the valve with wires, it was designed to tear existing mitral valve leaflets to prevent them from causing life-threatening LVOT obstruction. It is used immediately prior to TMVR in patients at risk for this complication.

In a feasibility study, delivery, deployment, and retrieval of the device was achieved in all 30 patients. On the basis of the primary endpoint of LVOT gradients of less than 50 mm Hg and no emergency surgery, the procedural success was 73%. The 30-day survival was 93%.

Citing data from registries, Dr. Khan said that the expected survival in TMVR patients with LVOT obstruction caused by a native mitral valve leaflet has been less than 40%. With few existing options to prevent this complication, none of which are reliable, LAMPOON is poised to permit patients who are poor candidates or are contraindicated for TMVR to undergo this treatment, according to Dr. Khan.

“LAMPOON is feasible in all anatomies and calcium patterns,” said Dr. Khan, who noted that gradients of less than 30 mm Hg was achieved in 29 of the 30 patients. Although Dr. Khan acknowledged that this study was small and uncontrolled, and he further cautioned that current strategies for predicting mitral valve leaflet LVOT obstruction are “imprecise,” he believes larger studies of LAMPOON are warranted based on these results.
 

Coronary artery obstruction prevention

Dr. Khan also presented data on the BASILICA device from a second feasibility study. The device is employed immediately prior to TAVR in order to prevent large aortic valve leaflets, whether native or from an existing bioprosthetic valve, from producing coronary obstruction. BASILICA is an acronym for Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction.

This device is also introduced percutaneously and uses radiofrequency ablation to split leaflets that are considered to pose a risk for coronary obstruction. Even though Dr. Khan acknowledged that there is also a lack of precision for predicting which TAVR candidates require an intervention to prevent coronary obstruction, he cited mortality rates exceeding 40% when this complication occurs.

In the feasibility study, 30 patients, of whom 80% were female, were enrolled. In half of the cases, the target for BASILICA was a native valve. The remainder was treated for risk of coronary obstruction posed by a bioprosthetic valve. Multiple comorbidities, including a high proportion with prior stroke, made those selected for enrollment poor candidates for surgery.

The BASILICA intervention was successful in 28 of the 30 participants and in 35 of the 37 leaflets treated. At 30 days, there was one death and one disabling stroke. The overall success rate of the procedure was 93%, according to Dr. Khan.

“One hundred percent of patients were discharged from the cath lab without coronary obstruction despite the high baseline risk,” Dr. Khan said. Again, larger studies are needed to validate the safety and efficacy of this approach, but Dr. Khan believes the outcomes in this study warrant expanded clinical studies.

[email protected]

WASHINGTON – One transcatheter device designed to prevent left ventricular outflow tract (LVOT) obstruction relevant to transcatheter mitral valve replacement (TMVR) and another designed to prevent coronary obstruction relevant to transcatheter aortic valve replacement (TAVR) performed well in feasibility studies, according to data presented in two separate late breaking clinical trial sessions at the CRT 2019, sponsored by MedStar Heart & Vascular Institute.

LVOT obstruction prevention

“The 30-day survival in subjects with an increased risk of LVOT obstruction was significantly better than that previously reported in registries,” said Jaffar M. Khan, BM BCh, of the National Heart, Lung, and Blood Institute, who addressing results with the LAMPOON device prior to TMVR,.

LAMPOON is an acronym for intentional Laceration of the Anterior Mitral valve leaflet to Prevent LVOT ObstructioN. Introduced percutaneously and guided to the valve with wires, it was designed to tear existing mitral valve leaflets to prevent them from causing life-threatening LVOT obstruction. It is used immediately prior to TMVR in patients at risk for this complication.

In a feasibility study, delivery, deployment, and retrieval of the device was achieved in all 30 patients. On the basis of the primary endpoint of LVOT gradients of less than 50 mm Hg and no emergency surgery, the procedural success was 73%. The 30-day survival was 93%.

Citing data from registries, Dr. Khan said that the expected survival in TMVR patients with LVOT obstruction caused by a native mitral valve leaflet has been less than 40%. With few existing options to prevent this complication, none of which are reliable, LAMPOON is poised to permit patients who are poor candidates or are contraindicated for TMVR to undergo this treatment, according to Dr. Khan.

“LAMPOON is feasible in all anatomies and calcium patterns,” said Dr. Khan, who noted that gradients of less than 30 mm Hg was achieved in 29 of the 30 patients. Although Dr. Khan acknowledged that this study was small and uncontrolled, and he further cautioned that current strategies for predicting mitral valve leaflet LVOT obstruction are “imprecise,” he believes larger studies of LAMPOON are warranted based on these results.
 

Coronary artery obstruction prevention

Dr. Khan also presented data on the BASILICA device from a second feasibility study. The device is employed immediately prior to TAVR in order to prevent large aortic valve leaflets, whether native or from an existing bioprosthetic valve, from producing coronary obstruction. BASILICA is an acronym for Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction.

This device is also introduced percutaneously and uses radiofrequency ablation to split leaflets that are considered to pose a risk for coronary obstruction. Even though Dr. Khan acknowledged that there is also a lack of precision for predicting which TAVR candidates require an intervention to prevent coronary obstruction, he cited mortality rates exceeding 40% when this complication occurs.

In the feasibility study, 30 patients, of whom 80% were female, were enrolled. In half of the cases, the target for BASILICA was a native valve. The remainder was treated for risk of coronary obstruction posed by a bioprosthetic valve. Multiple comorbidities, including a high proportion with prior stroke, made those selected for enrollment poor candidates for surgery.

The BASILICA intervention was successful in 28 of the 30 participants and in 35 of the 37 leaflets treated. At 30 days, there was one death and one disabling stroke. The overall success rate of the procedure was 93%, according to Dr. Khan.

“One hundred percent of patients were discharged from the cath lab without coronary obstruction despite the high baseline risk,” Dr. Khan said. Again, larger studies are needed to validate the safety and efficacy of this approach, but Dr. Khan believes the outcomes in this study warrant expanded clinical studies.

[email protected]

The FP was extremely concerned that this was a large melanoma due the lesion’s chaotic appearance, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the lesion was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was > 6 mm, and it was Enlarging by history.

With his dermatoscope attached to his smart phone, the FP looked at the lesion and took a photograph (Figure B). The image revealed a pigment network of the original nevus at 5:00 to 6:00 o’clock and extensions of the tumor due to in-transit metastases. Satellites were visible, especially in the top right and left corners. The FP noted the shiny white lines caused by collagen deposition found in growing tumors. (See “Dermoscopy in family medicine: A primer.”)

The FP knew that the mass needed to be biopsied, but because of its size, the best he could do would be to perform a partial biopsy. So on the day of presentation, the FP performed a 6-mm punch biopsy in the most raised area of the lesion to try and get sufficient depth and breadth for diagnosis and prognosis. (See the Watch & Learn video on “Punch biopsy.”)

The pathology report indicated that the lesion was a nodular melanoma with a Breslow depth of 5.5 mm. This melanoma arose in a nevus, which occurs in about 30% of melanomas. Most melanomas arise de novo.

The FP referred the patient to a surgical oncologist for an excision with 2 cm margins and a sentinel lymph node biopsy. The sentinel node was in the right axilla and was remarkably negative despite the local in-transit metastases/satellites. One year after the original diagnosis was made, there was no evidence of metastatic disease and no new melanomas. The patient follows up with the dermatologist for skin and lymph node surveillance every 3 months.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill;2019:1112-1123.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP was extremely concerned that this was a large melanoma due the lesion’s chaotic appearance, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the lesion was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was > 6 mm, and it was Enlarging by history.

With his dermatoscope attached to his smart phone, the FP looked at the lesion and took a photograph (Figure B). The image revealed a pigment network of the original nevus at 5:00 to 6:00 o’clock and extensions of the tumor due to in-transit metastases. Satellites were visible, especially in the top right and left corners. The FP noted the shiny white lines caused by collagen deposition found in growing tumors. (See “Dermoscopy in family medicine: A primer.”)

The FP knew that the mass needed to be biopsied, but because of its size, the best he could do would be to perform a partial biopsy. So on the day of presentation, the FP performed a 6-mm punch biopsy in the most raised area of the lesion to try and get sufficient depth and breadth for diagnosis and prognosis. (See the Watch & Learn video on “Punch biopsy.”)

The pathology report indicated that the lesion was a nodular melanoma with a Breslow depth of 5.5 mm. This melanoma arose in a nevus, which occurs in about 30% of melanomas. Most melanomas arise de novo.

The FP referred the patient to a surgical oncologist for an excision with 2 cm margins and a sentinel lymph node biopsy. The sentinel node was in the right axilla and was remarkably negative despite the local in-transit metastases/satellites. One year after the original diagnosis was made, there was no evidence of metastatic disease and no new melanomas. The patient follows up with the dermatologist for skin and lymph node surveillance every 3 months.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill;2019:1112-1123.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

The FP was extremely concerned that this was a large melanoma due the lesion’s chaotic appearance, with multiple colors and an irregular border. Going through the ABCDE criteria, he noted that the lesion was Asymmetric, the Border was irregular, the Colors were varied, the Diameter was > 6 mm, and it was Enlarging by history.

With his dermatoscope attached to his smart phone, the FP looked at the lesion and took a photograph (Figure B). The image revealed a pigment network of the original nevus at 5:00 to 6:00 o’clock and extensions of the tumor due to in-transit metastases. Satellites were visible, especially in the top right and left corners. The FP noted the shiny white lines caused by collagen deposition found in growing tumors. (See “Dermoscopy in family medicine: A primer.”)

The FP knew that the mass needed to be biopsied, but because of its size, the best he could do would be to perform a partial biopsy. So on the day of presentation, the FP performed a 6-mm punch biopsy in the most raised area of the lesion to try and get sufficient depth and breadth for diagnosis and prognosis. (See the Watch & Learn video on “Punch biopsy.”)

The pathology report indicated that the lesion was a nodular melanoma with a Breslow depth of 5.5 mm. This melanoma arose in a nevus, which occurs in about 30% of melanomas. Most melanomas arise de novo.

The FP referred the patient to a surgical oncologist for an excision with 2 cm margins and a sentinel lymph node biopsy. The sentinel node was in the right axilla and was remarkably negative despite the local in-transit metastases/satellites. One year after the original diagnosis was made, there was no evidence of metastatic disease and no new melanomas. The patient follows up with the dermatologist for skin and lymph node surveillance every 3 months.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Melanoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill;2019:1112-1123.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com

EVIDENCE SUMMARY

A 2017 meta-analysis of 16 RCTs examined the risk of cardiovascular events in 7540 adult patients taking PPIs for GERD (mean ages 45-55 years).¹ The primary outcome was cardiovascular events—including acute myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, and coronary artery stenosis—and cardiac disorders.

Analysis of pooled data found that PPI use was associated with a 70% increase in cardiovascular risk (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.13-2.56; number needed to harm [NNH] = 241) when compared with controls (placebo, H₂ blocker, or surgery). A subgroup analysis found that PPI use for longer than 8 weeks was associated with an even higher risk of adverse cardiovascular events (6 trials, 2296 patients; RR = 2.33; 95% CI, 1.33-4.08; NNH = 67) when compared with controls. The meta-analysis wasn’t limited by heterogeneity (I² = 0).

C difficile infection risk is higherfor PPI users

A 2016 meta-analysis of 23 observational studies (19 case-control, 4 retrospective cohort; 186,033 patients) examined the risk of hospital-acquired C difficile infections in adults prescribed PPI for any indication.² PPI exposure varied from use at time of diagnosis or hospitalization to any use within 90 days. Of the 23 studies, 16 reported sufficient data to calculate the mean age for the patients which was 69.9 years.

The risk of C difficile infection was found to be higher with PPI use than no use (pooled odds ratio [OR] = 1.81; 95% CI, 1.52-2.14). Although a significant association was found across a large group, the results were limited by considerable heterogeneity (I² = 82%).

Risk of community-acquired pneumonia also increases with PPI use

A 2015 systematic review and meta-analysis of 33 trials (18 case-control, 10 cohort, 4 RCTs, and 1 case-crossover study) examined the risk of CAP in adult patients prescribed PPI for any indication for durations ranging from less than 1 month to > 6 months.³ The systematic review was distilled to 26 studies because of overlapping study populations. These 26 studies included 226,769 cases of CAP among 6,351,656 patients. The primary outcome was development of CAP, the secondary outcome was hospitalization for CAP.

PPI use, compared with no use, was associated with an increased risk of developing CAP (pooled OR = 1.49; 95% CI, 1.16-1.92) and an increased risk of hospitalization for CAP (pooled OR = 1.61; 95% CI, 1.12-2.31).

Extrapolation from studies on all adults suggests a significant link between proton pump inhibitors and higher risk of cardiovascular events— especially with treatment > 8 weeks.

In a subgroup analysis for age, patients older than 65 years were also found to have an increased risk of developing CAP with PPI use (11 trials, total number of patients not provided; OR = 1.33; 95% CI, 1.13-1.58). Despite the significant associations of PPI use with risk revealed in the primary, secondary, and subgroup analyses, the results were limited by marked heterogeneity, with an I² > 99%.

Continue to: Hip and vertebral fracture risks associated with PPIs

A 2011 systematic review and meta-analysis investigated the risk of fracture in adult patients taking PPIs for any indication.⁴ The analysis included 10 observational studies (4 cohort, 6 case-control) with a total of 223,210 fracture cases. The authors examined the incidence of hip, vertebral, and wrist or forearm fractures.

No significant association was found between PPI use and wrist or forearm fracture (3 studies; pooled OR = 1.09; 95% CI, 0.95-1.24). A modest association was noted between PPI use and both hip fractures (9 trials; OR = 1.25; 95% CI, 1.14-1.37) and vertebral fractures (4 trials; OR = 1.5; 95% CI, 1.32-1.72).

Subgroup analysis didn’t reveal evidence of an effect of duration of PPI use on fracture. Investigators didn’t conduct subgroup analysis of different patient ages. Final results were limited by significant heterogeneity with an I² of 86%.

RECOMMENDATIONS

A 2015 American Geriatrics Society Beers Criteria update recommends limiting PPI use because of increased risk of C difficile infections and fractures. It also recommends against using PPIs for longer than 8 weeks except for high-risk patients (such as patients taking oral corticosteroids or chronic nonsteroidal anti-inflammatory drug users), patients with Barrett’s esophagitis, or patients who need maintenance after failure of a drug discontinuation trial or H₂ blockers (quality of evidence, high; SOR, strong).⁵

Editor’s takeaway: Despite limited evidence specific to patients over age 65, or perhaps because the majority of the studied populations were younger, increased caution should be exercised in the use of PPIs.

EVIDENCE SUMMARY

A 2017 meta-analysis of 16 RCTs examined the risk of cardiovascular events in 7540 adult patients taking PPIs for GERD (mean ages 45-55 years).¹ The primary outcome was cardiovascular events—including acute myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, and coronary artery stenosis—and cardiac disorders.

Analysis of pooled data found that PPI use was associated with a 70% increase in cardiovascular risk (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.13-2.56; number needed to harm [NNH] = 241) when compared with controls (placebo, H₂ blocker, or surgery). A subgroup analysis found that PPI use for longer than 8 weeks was associated with an even higher risk of adverse cardiovascular events (6 trials, 2296 patients; RR = 2.33; 95% CI, 1.33-4.08; NNH = 67) when compared with controls. The meta-analysis wasn’t limited by heterogeneity (I² = 0).

C difficile infection risk is higherfor PPI users

A 2016 meta-analysis of 23 observational studies (19 case-control, 4 retrospective cohort; 186,033 patients) examined the risk of hospital-acquired C difficile infections in adults prescribed PPI for any indication.² PPI exposure varied from use at time of diagnosis or hospitalization to any use within 90 days. Of the 23 studies, 16 reported sufficient data to calculate the mean age for the patients which was 69.9 years.

The risk of C difficile infection was found to be higher with PPI use than no use (pooled odds ratio [OR] = 1.81; 95% CI, 1.52-2.14). Although a significant association was found across a large group, the results were limited by considerable heterogeneity (I² = 82%).

Risk of community-acquired pneumonia also increases with PPI use

A 2015 systematic review and meta-analysis of 33 trials (18 case-control, 10 cohort, 4 RCTs, and 1 case-crossover study) examined the risk of CAP in adult patients prescribed PPI for any indication for durations ranging from less than 1 month to > 6 months.³ The systematic review was distilled to 26 studies because of overlapping study populations. These 26 studies included 226,769 cases of CAP among 6,351,656 patients. The primary outcome was development of CAP, the secondary outcome was hospitalization for CAP.

PPI use, compared with no use, was associated with an increased risk of developing CAP (pooled OR = 1.49; 95% CI, 1.16-1.92) and an increased risk of hospitalization for CAP (pooled OR = 1.61; 95% CI, 1.12-2.31).

Extrapolation from studies on all adults suggests a significant link between proton pump inhibitors and higher risk of cardiovascular events— especially with treatment > 8 weeks.

In a subgroup analysis for age, patients older than 65 years were also found to have an increased risk of developing CAP with PPI use (11 trials, total number of patients not provided; OR = 1.33; 95% CI, 1.13-1.58). Despite the significant associations of PPI use with risk revealed in the primary, secondary, and subgroup analyses, the results were limited by marked heterogeneity, with an I² > 99%.

Continue to: Hip and vertebral fracture risks associated with PPIs

A 2011 systematic review and meta-analysis investigated the risk of fracture in adult patients taking PPIs for any indication.⁴ The analysis included 10 observational studies (4 cohort, 6 case-control) with a total of 223,210 fracture cases. The authors examined the incidence of hip, vertebral, and wrist or forearm fractures.

No significant association was found between PPI use and wrist or forearm fracture (3 studies; pooled OR = 1.09; 95% CI, 0.95-1.24). A modest association was noted between PPI use and both hip fractures (9 trials; OR = 1.25; 95% CI, 1.14-1.37) and vertebral fractures (4 trials; OR = 1.5; 95% CI, 1.32-1.72).

Subgroup analysis didn’t reveal evidence of an effect of duration of PPI use on fracture. Investigators didn’t conduct subgroup analysis of different patient ages. Final results were limited by significant heterogeneity with an I² of 86%.

RECOMMENDATIONS

A 2015 American Geriatrics Society Beers Criteria update recommends limiting PPI use because of increased risk of C difficile infections and fractures. It also recommends against using PPIs for longer than 8 weeks except for high-risk patients (such as patients taking oral corticosteroids or chronic nonsteroidal anti-inflammatory drug users), patients with Barrett’s esophagitis, or patients who need maintenance after failure of a drug discontinuation trial or H₂ blockers (quality of evidence, high; SOR, strong).⁵

Editor’s takeaway: Despite limited evidence specific to patients over age 65, or perhaps because the majority of the studied populations were younger, increased caution should be exercised in the use of PPIs.

EVIDENCE SUMMARY

A 2017 meta-analysis of 16 RCTs examined the risk of cardiovascular events in 7540 adult patients taking PPIs for GERD (mean ages 45-55 years).¹ The primary outcome was cardiovascular events—including acute myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, and coronary artery stenosis—and cardiac disorders.

Analysis of pooled data found that PPI use was associated with a 70% increase in cardiovascular risk (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.13-2.56; number needed to harm [NNH] = 241) when compared with controls (placebo, H₂ blocker, or surgery). A subgroup analysis found that PPI use for longer than 8 weeks was associated with an even higher risk of adverse cardiovascular events (6 trials, 2296 patients; RR = 2.33; 95% CI, 1.33-4.08; NNH = 67) when compared with controls. The meta-analysis wasn’t limited by heterogeneity (I² = 0).

C difficile infection risk is higherfor PPI users

A 2016 meta-analysis of 23 observational studies (19 case-control, 4 retrospective cohort; 186,033 patients) examined the risk of hospital-acquired C difficile infections in adults prescribed PPI for any indication.² PPI exposure varied from use at time of diagnosis or hospitalization to any use within 90 days. Of the 23 studies, 16 reported sufficient data to calculate the mean age for the patients which was 69.9 years.

The risk of C difficile infection was found to be higher with PPI use than no use (pooled odds ratio [OR] = 1.81; 95% CI, 1.52-2.14). Although a significant association was found across a large group, the results were limited by considerable heterogeneity (I² = 82%).

Risk of community-acquired pneumonia also increases with PPI use

A 2015 systematic review and meta-analysis of 33 trials (18 case-control, 10 cohort, 4 RCTs, and 1 case-crossover study) examined the risk of CAP in adult patients prescribed PPI for any indication for durations ranging from less than 1 month to > 6 months.³ The systematic review was distilled to 26 studies because of overlapping study populations. These 26 studies included 226,769 cases of CAP among 6,351,656 patients. The primary outcome was development of CAP, the secondary outcome was hospitalization for CAP.

PPI use, compared with no use, was associated with an increased risk of developing CAP (pooled OR = 1.49; 95% CI, 1.16-1.92) and an increased risk of hospitalization for CAP (pooled OR = 1.61; 95% CI, 1.12-2.31).

Extrapolation from studies on all adults suggests a significant link between proton pump inhibitors and higher risk of cardiovascular events— especially with treatment > 8 weeks.

In a subgroup analysis for age, patients older than 65 years were also found to have an increased risk of developing CAP with PPI use (11 trials, total number of patients not provided; OR = 1.33; 95% CI, 1.13-1.58). Despite the significant associations of PPI use with risk revealed in the primary, secondary, and subgroup analyses, the results were limited by marked heterogeneity, with an I² > 99%.

Continue to: Hip and vertebral fracture risks associated with PPIs

A 2011 systematic review and meta-analysis investigated the risk of fracture in adult patients taking PPIs for any indication.⁴ The analysis included 10 observational studies (4 cohort, 6 case-control) with a total of 223,210 fracture cases. The authors examined the incidence of hip, vertebral, and wrist or forearm fractures.

No significant association was found between PPI use and wrist or forearm fracture (3 studies; pooled OR = 1.09; 95% CI, 0.95-1.24). A modest association was noted between PPI use and both hip fractures (9 trials; OR = 1.25; 95% CI, 1.14-1.37) and vertebral fractures (4 trials; OR = 1.5; 95% CI, 1.32-1.72).

Subgroup analysis didn’t reveal evidence of an effect of duration of PPI use on fracture. Investigators didn’t conduct subgroup analysis of different patient ages. Final results were limited by significant heterogeneity with an I² of 86%.

RECOMMENDATIONS

A 2015 American Geriatrics Society Beers Criteria update recommends limiting PPI use because of increased risk of C difficile infections and fractures. It also recommends against using PPIs for longer than 8 weeks except for high-risk patients (such as patients taking oral corticosteroids or chronic nonsteroidal anti-inflammatory drug users), patients with Barrett’s esophagitis, or patients who need maintenance after failure of a drug discontinuation trial or H₂ blockers (quality of evidence, high; SOR, strong).⁵

Editor’s takeaway: Despite limited evidence specific to patients over age 65, or perhaps because the majority of the studied populations were younger, increased caution should be exercised in the use of PPIs.

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

CASE

A 19-year-old college football player presents to your outpatient family practice clinic after suffering a right ankle injury during a football game over the weekend. He reports having his right ankle planted on the turf with his foot externally rotated when an opponent fell onto his posterior right lower extremity. He reports having felt immediate pain in the area of the right ankle and requiring assistance off of the field, as he had difficulty walking. The patient was taken to the emergency department where x-rays of the right foot and ankle did not show any signs of acute fracture or dislocation. The patient was diagnosed with a lateral ankle sprain, placed in a pneumatic ankle walking brace, and given crutches.

A high ankle sprain, or distal tibiofibular syndesmotic injury, can be an elusive diagnosis and is often mistaken for the more common lateral ankle sprain. Syndesmotic injuries have been documented to occur in approximately 1% to 10% of all ankle sprains.^1-3 The highest number of these injuries occurs between the ages of 18 and 34 years, and they are more frequently seen in athletes than in nonathletes, particularly those who play collision sports, such as football, ice hockey, rugby, wrestling, and lacrosse.^1-9 In one study by Hunt et al,¹⁰ syndesmotic injuries accounted for 24.6% of all ankle injuries in National Collegiate Athletic Association (NCAA) football players. Incidence continues to grow as recognition of high ankle sprains increases among medical professionals.^1,5 Identification of syndesmotic injury is critical, as lack of detection can lead to extensive time missed from athletic participation and chronic ankle dysfunction, including pain and instability.^2,4,6,11

Back to basics: A brief anatomy review

Stability in the distal tibiofibular joint is maintained by the syndesmotic ligaments, which include the anterior inferior tibiofibular ligament (AITFL), the posterior inferior tibiofibular ligament (PITFL), the transverse ligament, and the interosseous ligament.^3-6,8 This complex of ligaments stabilizes the fibula within the incisura of the tibia and maintains a stable ankle mortise.^1,4,5,11 The deep portion of the deltoid ligament also adds stability to the syndesmosis and may be disrupted by a syndesmotic injury.^2,5-7,11

Mechanisms of injury: From most common to less likely

The distal tibiofibular syndesmosis is disrupted when an injury forces apart the distal tibiofibular joint. The most commonly reported means of injury is external rotation with hyper-dorsiflexion of the ankle.^1-3,5,6,11 With excessive external rotation of the forefoot, the talus is forced against the medial aspect of the fibula, resulting in separation of the distal tibia and fibula and injury to the syndesmotic ligaments.^2,3,5,6 Injuries associated with external rotation are commonly seen in sports that immobilize the ankle within a rigid boot, such as skiing and ice hockey.^1,2,5 Some authors have suggested that a planovalgus foot alignment may place athletes at inherent risk for an external rotation ankle injury.^5,6

Trauma causing ankle syndesmotic injuries may be associated with Weber B or Weber C distal fibula fractures or a Maisonneuve fracture.

Syndesmotic injury may also occur with hyper-dorsiflexion, as the anterior, widest portion of the talus rotates into the ankle mortise, wedging the tibia and fibula apart.^2,3,5 There have also been reports of syndesmotic injuries associated with internal rotation, plantar flexion, inversion, and eversion.^3,5,11 Therefore, physicians should maintain a high index of suspicion for injury to the distal tibiofibular joint, regardless of the mechanism of injury.

Presentation and evaluation

Observation of the patient and visualization of the affected ankle can provide many clues. Many patients will have difficulty walking after suffering a syndesmotic injury and may require the use of an assistive device.⁵ The inability to bear weight after an ankle injury points to a more severe diagnosis, such as an ankle fracture or syndesmotic injury, as opposed to a simple lateral ankle sprain. Patients may report anterior ankle pain, a sensation of instability with weight bearing on the affected ankle, or have persistent symptoms despite a course of conservative treatment. Also, they can have a variable amount of edema and ecchymosis associated with their injury; a minimal extent of swelling or ecchymosis does not exclude syndesmotic injury.³

A large percentage of patients will present with a concomitant sprain of the lateral ligaments associated with lateral swelling and bruising. One study found that 91% of syndesmotic injuries involved at least 1 of the lateral collateral ligaments (anterior talofibular ligament [ATFL], calcaneofibular ligament [CFL], or posterior talofibular ligament [PTFL]).¹² Patients may have pain or a sensation of instability when pushing off with the toes,⁵ and patients with syndesmotic injuries often have tenderness to palpation over the distal anterolateral ankle or syndesmotic ligaments.⁷

Continue to: A thorough examination...

A thorough examination of the ankle, including palpation of common fracture sites, is important. Employ the Ottawa Ankle Rules (see http://www.theottawarules.ca/ankle_rules) to investigate for: tenderness to palpation over the posterior 6 cm of the posterior aspects of the distal medial and lateral malleoli; tenderness over the navicular; tenderness over the base of the fifth metatarsal; and/or the inability to bear weight on the affected lower extremity immediately after injury or upon evaluation in the physician’s office. Any of these findings should raise concern for a possible fracture (see “Adult foot fractures: A guide”) and require an x-ray(s) for further evaluation.¹³

Perform range-of-motion and strength testing with regard to ankle dorsiflexion, plantar flexion, abduction, adduction, inversion, and eversion. Palpate the ATFL, CFL, and PTFL for tenderness, as these structures may be involved to varying degrees in lateral ankle sprains. An anterior drawer test (see https://www.youtube.com/watch?v=vAcBEYZKcto) may be positive with injury to the ATFL. This test is performed by stabilizing the distal tibia with one hand and using the other hand to grasp the posterior aspect of the calcaneus and apply an anterior force. The test is positive if the talus translates forward, which correlates with laxity or rupture of the ATFL.¹³ The examiner should also palpate the Achilles tendon, peroneal tendons just posterior to the lateral malleolus, and the tibialis posterior tendon just posterior to the medial malleolus to inspect for tenderness or defects that may be signs of injury to these tendons.

An associated Weber B or C fracture? Trauma causing ankle syndesmosis injuries may be associated with Weber B or Weber C distal fibula fractures.⁷ Weber B fractures occur in the distal fibula at the level of the ankle joint (see FIGURE 1). These types of fractures are typically associated with external rotation injuries and are usually not associated with disruption of the interosseous membrane.

Weber C fractures are distal fibular fractures occurring above the level of the ankle joint. These fractures are also typically associated with external ankle rotation injuries and include disruption of the syndesmosis and deltoid ligament.¹⁴

Also pay special attention to the proximal fibula, as syndesmotic injuries are commonly associated with a Maisonneuve fracture, which is a proximal fibula fracture associated with external rotation forces of the ankle (see FIGURE 1).^{1,2,4,11,14,15} Further workup should occur in any patient with the possibility of a Weber- or Maisonneuve-type fracture.

Continue to: Multiple tests...

Multiple tests are available to investigate the possibility of a syndesmotic injury and to assess return-to-sport readiness, including the External Rotation Test, the Squeeze Test, the Crossed-Leg Test, the Dorsiflexion Compression Test, the Cotton Test, the Stabilization Test, the Fibular Translation Test, and the Single Leg Hop Test (see TABLE^{1-3,5,6,16,17}). The External Rotation Test is noted by some authors to have the highest interobserver reliability, and is our preferred test.² The Squeeze Test also has moderate interobserver reliability.² There is a significant degree of variation among the sensitivity and specificity of these diagnostic tests, and no single test is sufficiently reliable or accurate to diagnose a syndesmotic ankle injury. Therefore, it is recommended to use multiple physical exam maneuvers, the history and mechanism of injury, and findings on imaging studies in conjunction to make the diagnosis of a syndesmotic injury.^1,16

Imaging: Which modes and when?

The initial workup should include ankle x-rays when evaluating for the possibility of a distal tibiofibular syndesmosis injury. While the Ottawa Ankle Rules are helpful in providing guidance with regard to x-rays, suspicion of a syndesmotic injury mandates x-rays to determine the stability of the joint and rule out fracture. The European Society of Sports Traumatology, Knee Surgery and Arthroscopy–European Foot and Ankle Associates (ESSKA-AFAS) recommend, at a minimum, obtaining anteroposterior (AP)- and mortise-view ankle x-rays to investigate the tibiofibular clear space, medial clear space, and tibiofibular overlap.⁷ Most physicians also include a lateral ankle x-ray.

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

If possible, images should be performed while the patient is bearing weight to further evaluate stability. Radiographic findings that support the diagnosis of syndesmotic injury include a tibiofibular clear space > 6 mm on AP view, medial clear space > 4 mm on mortise view, or tibiofibular overlap < 6 mm on AP view or < 1 mm on mortise view (see FIGURES 2 and 3).^1,3,5,8 Additionally, if you suspect a proximal fibular fracture, obtain an x-ray series of the proximal tibia and fibula to investigate the possibility of a Maisonneuve injury.^1,2,4,11

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

The External Rotation Test is noted by some authors to have the highest interobserver reliability.

If you continue to suspect a syndesmotic injury despite normal x-rays, obtain stress x-rays, in addition to the AP and mortise views, to ensure stability. These x-rays include AP and mortise ankle views with manual external rotation of the ankle joint, which may demonstrate abnormalities not seen on standard x-rays. Bilateral imaging can also be useful to further assess when mild abnormalities vs symmetric anatomic variants are in question.^1,7

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

If there is concern for an unstable injury, refer the patient to a foot and ankle surgeon, who may pursue magnetic resonance imaging (MRI) or standing computed tomography (CT).^1,2,5,7 MRI is the recommended choice for further evaluation of a syndesmotic injury, as it is proven to be accurate in evaluating the integrity of the syndesmotic ligaments (see FIGURES 4 and 5).¹⁸ MRI has demonstrated 100% sensitivity for detecting AITFL and PITFL injuries, as well as 93% and 100% specificity for AITFL and PITFL tears, respectively.⁸ A weight-bearing CT scan, particularly axial views, can also be a useful adjunct, as it is more sensitive than standard x-rays for assessing for mild diastasis. Although CT can provide an assessment of bony structures, it is not able to evaluate soft tissue structures, limiting its utility in evaluation of syndesmotic injuries.^1,7

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

Continue to: Although not the standard of care...

Although not the standard of care, ultrasonography (US) is gaining traction as a means of investigating the integrity of the syndesmotic ligaments. US is inexpensive, readily available in many clinics, allows for dynamic testing, and avoids radiation exposure.⁷ However, US requires a skilled sonographer with experience in the ankle joint for an accurate diagnosis. If the workup with advanced imaging is inconclusive, but a high degree of suspicion remains for an unstable syndesmotic injury, consider arthroscopy to directly visualize and assess the syndesmotic structures.^1,2,5,7,8

Grading the severity of the injury and pursuing appropriate Tx

Typically, the severity of a syndesmotic injury is classified as fitting into 1 of 3 categories: Grade I and II injuries are the most common, each accounting for 40% of syndesmotic injuries, while 20% of high ankle sprains are classified as Grade III.¹²

No single test is sufficiently reliable or accurate to diagnose a syndesmotic ankle injury.

A Grade I injury consists of a stable syndesmotic joint without abnormal radiographic findings. There may be associated tenderness to palpation over the distal tibiofibular joint, and provocative testing may be subtle or normal. These injuries are often minor and able to be treated conservatively.

A Grade II injury is associated with a partial syndesmotic disruption, typically with partial tearing of the AITFL and interosseous ligament. These injuries may be stable or accompanied by mild instability, and provocative testing is usually positive. X-rays are typically normal with Grade II injuries, but may display subtle radiographic findings suggestive of a syndesmotic injury. Treatment of Grade II injuries is somewhat controversial and should be an individualized decision based upon the patient’s age, activity level, clinical exam, and imaging findings. Therefore, treatment of Grade II syndesmotic injuries may include a trial of conservative management or surgical intervention.

A Grade III injury represents inherent instability of the distal tibiofibular joint with complete disruption of all syndesmotic ligaments, with or without involvement of the deltoid ligament. X-rays will be positive in Grade III syndesmotic injuries because of the complete disruption of syndesmotic ligaments. All Grade III injuries require surgical intervention with a syndesmotic screw or other stabilization procedure.^1,6-8,15

Continue to: A 3-stage rehabilitation protocol

When conservative management is deemed appropriate for a stable syndesmotic sprain, a 3-stage rehabilitation protocol is typically utilized.

The acute phase focuses on protection, pain control, and decreasing inflammation. The patient’s ankle is often immobilized in a cast or controlled ankle movement (CAM) boot. The patient is typically allowed to bear weight in the immobilizer during this phase as long as he/she is pain-free. If pain is present with weight bearing despite immobilization, non-weight bearing is recommended. The patient is instructed to elevate the lower extremity, take anti-inflammatory medication, and ice the affected ankle. Additionally, physical therapy modalities may be utilized to help with edema and pain. Joint immobilization is typically employed for 1 to 3 weeks post-injury. In the acute phase, the patient may also work with a physical therapist or athletic trainer on passive range of motion (ROM), progressing to active ROM as tolerated.^1,5,7,8,19

The patient can transition from the CAM boot to a lace-up ankle brace when he/she is able to bear full weight and can navigate stairs without pain, which typically occurs around 3 to 6 weeks post-injury.^1,5,7 A pneumatic walking brace may also be used as a transition device to provide added stabilization.

In the sub-acute phase, rehabilitation may progress to increase ankle mobility, strengthening, neuromuscular control, and to allow the patient to perform activities of daily living.^5-7

The advanced training phase includes continued neuromuscular control, increased strengthening, plyometrics, agility, and sports-specific drills.⁵ Athletes are allowed to return to full participation when they have regained full ROM, are able to perform sport-specific agility drills without pain or instability, and have near-normal strength.^5-7 Some authors also advocate that a Single Leg Hop Test should be included in the physical exam, and that it should be pain free prior to allowing an athlete to return to competition.²⁰ Both progression in physical rehabilitation and return to sport should be individualized based upon injury severity, patient functionality, and physical exam findings.

Continue to: Outcomes forecast

Outcomes forecast: Variable

The resolution of symptoms and return to competition after a syndesmotic injury is variable. In one cohort study of cadets (N = 614) at the United States Military Academy, the average time lost from a syndesmotic ankle sprain was 9.82 days (range 3-21 days).⁹ In a retrospective review of National Hockey League players, average time to return to competition after a syndesmotic ankle injury sprain (n = 14) was 45 days (range 6-137 days) vs 1.4 days (range 0-6 days) for lateral ankle sprains (n = 5).²¹ In another study, National Football League players with syndesmotic sprains (n = 36) had a mean time loss from play of 15.4 days (± 11.1 days) vs 6.5 days (± 6.5 days) of time loss from play in those with lateral ankle sprains (n = 53).²²

Although CT can provide an assessment of bony structures, it is not able to evaluate soft tissue structures, limiting its utility in evaluation of syndesmotic injuries.

Although there is a fair amount of variability among studies, most authors agree that the average athlete can expect to return to sport 4 to 8 weeks post-injury with conservative management.¹⁹ At least 1 study suggests that the average time to return to sport in patients with Grade III syndesmotic injuries who undergo surgical treatment with a syndesmotic screw is 41 days (range 32-48).²³ The differences in return to sport may be related to severity of injury and/or type of activity.

Persistent symptoms are relatively common after conservative management of syndesmotic injuries. One case series found that 36% of patients treated conservatively had complaints of persistent mild-to-moderate ankle stiffness, 23% had mild-to-moderate pain, and 18% had mild-to-moderate ankle swelling.²⁴ Despite these symptoms, 86% of the patients rated their ankle function as good after conservative treatment.²⁴ In patients with persistent symptoms, other possible etiologies should be considered including neurologic injury, complex regional pain syndrome, osteochondral defect, loose body, or other sources that may be contributing to pain, swelling, or delayed recovery.

At least 1 randomized controlled trial (RCT) investigated the utility of platelet rich plasma (PRP) injections around the injured AITFL in the setting of an acute syndesmotic injury. The study showed promising results, including quicker return to play, restabilization of the syndesmotic joint, and less residual pain;²⁵ however, the study population was relatively small (N = 16), and the authors believed that more research is required on the benefits of PRP therapy in syndesmotic injuries before recommendations can be made.

An ounce of preventionis worth a pound of cure

Although injury is not always avoidable, there are measures that can help prevent ankle sprains and facilitate return to play after injury. As previously mentioned, athletes should be able to demonstrate the ability to run, cut, jump, and perform sport-specific activities without limitations prior to being allowed to return to sport after injury.^5-7,26 Additionally, issues with biomechanics and functional deficits should be analyzed and addressed. By targeting specific strength deficits, focusing on proprioceptive awareness, and working on neuromuscular control, injury rates and recurrent injuries can be minimized. One RCT showed a 35% reduction in the recurrence rate of lateral ankle sprains with the use of an unsupervised home-based proprioceptive training program.²⁷

Continue to: Strength training...

Although not the standard of care, ultrasonography is gaining traction as a means of investigating the integrity of the syndesmotic ligaments.

Strength training, proprioceptive and neuromuscular control activities, and low-risk activities such as jogging, biking, and swimming do not necessarily require the use of prophylactic bracing. However, because syndesmotic injuries are associated with recurrent ankle injuries, prophylactic bracing should be used during high-risk activities that involve agility maneuvers and jumping. Substantial evidence demonstrates that the use of ankle taping or ankle bracing decreases the incidence of ankle injuries, particularly in those who have had previous ankle injuries.²⁶ In one study (N = 450), only 3% of athletes with a history of prior ankle injuries suffered a recurrent ankle sprain when using an ankle orthosis compared with a 17% injury rate in the control group.²⁸

More recently, 2 separate studies by McGuine et al demonstrated that the use of lace-up ankle braces led to a reduction in the incidence of acute ankle injuries by 61% among 2081 high-school football players, and resulted in a significant reduction in acute ankle injuries in a study of 1460 male and female high-school basketball players, compared with the control groups.^29,30

CASE

Ten days after injuring himself, the patient returns for a follow-up exam. Despite using the walking brace and crutches, he is still having significant difficulty bearing weight. He reports a sensation of instability in the right ankle. On exam, you note visible edema of the right ankle and ecchymosis over the lateral ankle, as well as moderate tenderness to palpation over the area of the ATFL and deltoid ligament. Tenderness over the medial malleolus, lateral malleolus, fifth metatarsal, and navicular is absent. Pain is reproducible with external rotation, and a Squeeze Test is positive. There is no tenderness over the proximal tibia or fibula. The patient is neurovascularly intact.

You order stress x-rays, which show widening of the medial clear space. The patient is placed in a CAM boot, instructed to continue non–weight-bearing on the ankle, and referred to a local foot and ankle surgeon for consideration of surgical fixation.

CORRESPONDENCE
John T. Nickless, MD, Division of Primary Care Sports Medicine, Department of Orthopedic Surgery, Rush University Medical Center, 1611 W. Harrison Street, Suite 200, Chicago, IL, 60612; [email protected].

CASE

A 19-year-old college football player presents to your outpatient family practice clinic after suffering a right ankle injury during a football game over the weekend. He reports having his right ankle planted on the turf with his foot externally rotated when an opponent fell onto his posterior right lower extremity. He reports having felt immediate pain in the area of the right ankle and requiring assistance off of the field, as he had difficulty walking. The patient was taken to the emergency department where x-rays of the right foot and ankle did not show any signs of acute fracture or dislocation. The patient was diagnosed with a lateral ankle sprain, placed in a pneumatic ankle walking brace, and given crutches.

A high ankle sprain, or distal tibiofibular syndesmotic injury, can be an elusive diagnosis and is often mistaken for the more common lateral ankle sprain. Syndesmotic injuries have been documented to occur in approximately 1% to 10% of all ankle sprains.^1-3 The highest number of these injuries occurs between the ages of 18 and 34 years, and they are more frequently seen in athletes than in nonathletes, particularly those who play collision sports, such as football, ice hockey, rugby, wrestling, and lacrosse.^1-9 In one study by Hunt et al,¹⁰ syndesmotic injuries accounted for 24.6% of all ankle injuries in National Collegiate Athletic Association (NCAA) football players. Incidence continues to grow as recognition of high ankle sprains increases among medical professionals.^1,5 Identification of syndesmotic injury is critical, as lack of detection can lead to extensive time missed from athletic participation and chronic ankle dysfunction, including pain and instability.^2,4,6,11

Back to basics: A brief anatomy review

Stability in the distal tibiofibular joint is maintained by the syndesmotic ligaments, which include the anterior inferior tibiofibular ligament (AITFL), the posterior inferior tibiofibular ligament (PITFL), the transverse ligament, and the interosseous ligament.^3-6,8 This complex of ligaments stabilizes the fibula within the incisura of the tibia and maintains a stable ankle mortise.^1,4,5,11 The deep portion of the deltoid ligament also adds stability to the syndesmosis and may be disrupted by a syndesmotic injury.^2,5-7,11

Mechanisms of injury: From most common to less likely

The distal tibiofibular syndesmosis is disrupted when an injury forces apart the distal tibiofibular joint. The most commonly reported means of injury is external rotation with hyper-dorsiflexion of the ankle.^1-3,5,6,11 With excessive external rotation of the forefoot, the talus is forced against the medial aspect of the fibula, resulting in separation of the distal tibia and fibula and injury to the syndesmotic ligaments.^2,3,5,6 Injuries associated with external rotation are commonly seen in sports that immobilize the ankle within a rigid boot, such as skiing and ice hockey.^1,2,5 Some authors have suggested that a planovalgus foot alignment may place athletes at inherent risk for an external rotation ankle injury.^5,6

Trauma causing ankle syndesmotic injuries may be associated with Weber B or Weber C distal fibula fractures or a Maisonneuve fracture.

Syndesmotic injury may also occur with hyper-dorsiflexion, as the anterior, widest portion of the talus rotates into the ankle mortise, wedging the tibia and fibula apart.^2,3,5 There have also been reports of syndesmotic injuries associated with internal rotation, plantar flexion, inversion, and eversion.^3,5,11 Therefore, physicians should maintain a high index of suspicion for injury to the distal tibiofibular joint, regardless of the mechanism of injury.

Presentation and evaluation

Observation of the patient and visualization of the affected ankle can provide many clues. Many patients will have difficulty walking after suffering a syndesmotic injury and may require the use of an assistive device.⁵ The inability to bear weight after an ankle injury points to a more severe diagnosis, such as an ankle fracture or syndesmotic injury, as opposed to a simple lateral ankle sprain. Patients may report anterior ankle pain, a sensation of instability with weight bearing on the affected ankle, or have persistent symptoms despite a course of conservative treatment. Also, they can have a variable amount of edema and ecchymosis associated with their injury; a minimal extent of swelling or ecchymosis does not exclude syndesmotic injury.³

A large percentage of patients will present with a concomitant sprain of the lateral ligaments associated with lateral swelling and bruising. One study found that 91% of syndesmotic injuries involved at least 1 of the lateral collateral ligaments (anterior talofibular ligament [ATFL], calcaneofibular ligament [CFL], or posterior talofibular ligament [PTFL]).¹² Patients may have pain or a sensation of instability when pushing off with the toes,⁵ and patients with syndesmotic injuries often have tenderness to palpation over the distal anterolateral ankle or syndesmotic ligaments.⁷

Continue to: A thorough examination...

A thorough examination of the ankle, including palpation of common fracture sites, is important. Employ the Ottawa Ankle Rules (see http://www.theottawarules.ca/ankle_rules) to investigate for: tenderness to palpation over the posterior 6 cm of the posterior aspects of the distal medial and lateral malleoli; tenderness over the navicular; tenderness over the base of the fifth metatarsal; and/or the inability to bear weight on the affected lower extremity immediately after injury or upon evaluation in the physician’s office. Any of these findings should raise concern for a possible fracture (see “Adult foot fractures: A guide”) and require an x-ray(s) for further evaluation.¹³

Perform range-of-motion and strength testing with regard to ankle dorsiflexion, plantar flexion, abduction, adduction, inversion, and eversion. Palpate the ATFL, CFL, and PTFL for tenderness, as these structures may be involved to varying degrees in lateral ankle sprains. An anterior drawer test (see https://www.youtube.com/watch?v=vAcBEYZKcto) may be positive with injury to the ATFL. This test is performed by stabilizing the distal tibia with one hand and using the other hand to grasp the posterior aspect of the calcaneus and apply an anterior force. The test is positive if the talus translates forward, which correlates with laxity or rupture of the ATFL.¹³ The examiner should also palpate the Achilles tendon, peroneal tendons just posterior to the lateral malleolus, and the tibialis posterior tendon just posterior to the medial malleolus to inspect for tenderness or defects that may be signs of injury to these tendons.

An associated Weber B or C fracture? Trauma causing ankle syndesmosis injuries may be associated with Weber B or Weber C distal fibula fractures.⁷ Weber B fractures occur in the distal fibula at the level of the ankle joint (see FIGURE 1). These types of fractures are typically associated with external rotation injuries and are usually not associated with disruption of the interosseous membrane.

Weber C fractures are distal fibular fractures occurring above the level of the ankle joint. These fractures are also typically associated with external ankle rotation injuries and include disruption of the syndesmosis and deltoid ligament.¹⁴

Also pay special attention to the proximal fibula, as syndesmotic injuries are commonly associated with a Maisonneuve fracture, which is a proximal fibula fracture associated with external rotation forces of the ankle (see FIGURE 1).^{1,2,4,11,14,15} Further workup should occur in any patient with the possibility of a Weber- or Maisonneuve-type fracture.

Continue to: Multiple tests...

Multiple tests are available to investigate the possibility of a syndesmotic injury and to assess return-to-sport readiness, including the External Rotation Test, the Squeeze Test, the Crossed-Leg Test, the Dorsiflexion Compression Test, the Cotton Test, the Stabilization Test, the Fibular Translation Test, and the Single Leg Hop Test (see TABLE^{1-3,5,6,16,17}). The External Rotation Test is noted by some authors to have the highest interobserver reliability, and is our preferred test.² The Squeeze Test also has moderate interobserver reliability.² There is a significant degree of variation among the sensitivity and specificity of these diagnostic tests, and no single test is sufficiently reliable or accurate to diagnose a syndesmotic ankle injury. Therefore, it is recommended to use multiple physical exam maneuvers, the history and mechanism of injury, and findings on imaging studies in conjunction to make the diagnosis of a syndesmotic injury.^1,16

Imaging: Which modes and when?

The initial workup should include ankle x-rays when evaluating for the possibility of a distal tibiofibular syndesmosis injury. While the Ottawa Ankle Rules are helpful in providing guidance with regard to x-rays, suspicion of a syndesmotic injury mandates x-rays to determine the stability of the joint and rule out fracture. The European Society of Sports Traumatology, Knee Surgery and Arthroscopy–European Foot and Ankle Associates (ESSKA-AFAS) recommend, at a minimum, obtaining anteroposterior (AP)- and mortise-view ankle x-rays to investigate the tibiofibular clear space, medial clear space, and tibiofibular overlap.⁷ Most physicians also include a lateral ankle x-ray.

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

If possible, images should be performed while the patient is bearing weight to further evaluate stability. Radiographic findings that support the diagnosis of syndesmotic injury include a tibiofibular clear space > 6 mm on AP view, medial clear space > 4 mm on mortise view, or tibiofibular overlap < 6 mm on AP view or < 1 mm on mortise view (see FIGURES 2 and 3).^1,3,5,8 Additionally, if you suspect a proximal fibular fracture, obtain an x-ray series of the proximal tibia and fibula to investigate the possibility of a Maisonneuve injury.^1,2,4,11

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

The External Rotation Test is noted by some authors to have the highest interobserver reliability.

If you continue to suspect a syndesmotic injury despite normal x-rays, obtain stress x-rays, in addition to the AP and mortise views, to ensure stability. These x-rays include AP and mortise ankle views with manual external rotation of the ankle joint, which may demonstrate abnormalities not seen on standard x-rays. Bilateral imaging can also be useful to further assess when mild abnormalities vs symmetric anatomic variants are in question.^1,7

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

If there is concern for an unstable injury, refer the patient to a foot and ankle surgeon, who may pursue magnetic resonance imaging (MRI) or standing computed tomography (CT).^1,2,5,7 MRI is the recommended choice for further evaluation of a syndesmotic injury, as it is proven to be accurate in evaluating the integrity of the syndesmotic ligaments (see FIGURES 4 and 5).¹⁸ MRI has demonstrated 100% sensitivity for detecting AITFL and PITFL injuries, as well as 93% and 100% specificity for AITFL and PITFL tears, respectively.⁸ A weight-bearing CT scan, particularly axial views, can also be a useful adjunct, as it is more sensitive than standard x-rays for assessing for mild diastasis. Although CT can provide an assessment of bony structures, it is not able to evaluate soft tissue structures, limiting its utility in evaluation of syndesmotic injuries.^1,7

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

Continue to: Although not the standard of care...

Although not the standard of care, ultrasonography (US) is gaining traction as a means of investigating the integrity of the syndesmotic ligaments. US is inexpensive, readily available in many clinics, allows for dynamic testing, and avoids radiation exposure.⁷ However, US requires a skilled sonographer with experience in the ankle joint for an accurate diagnosis. If the workup with advanced imaging is inconclusive, but a high degree of suspicion remains for an unstable syndesmotic injury, consider arthroscopy to directly visualize and assess the syndesmotic structures.^1,2,5,7,8

Grading the severity of the injury and pursuing appropriate Tx

Typically, the severity of a syndesmotic injury is classified as fitting into 1 of 3 categories: Grade I and II injuries are the most common, each accounting for 40% of syndesmotic injuries, while 20% of high ankle sprains are classified as Grade III.¹²

No single test is sufficiently reliable or accurate to diagnose a syndesmotic ankle injury.

A Grade I injury consists of a stable syndesmotic joint without abnormal radiographic findings. There may be associated tenderness to palpation over the distal tibiofibular joint, and provocative testing may be subtle or normal. These injuries are often minor and able to be treated conservatively.

A Grade II injury is associated with a partial syndesmotic disruption, typically with partial tearing of the AITFL and interosseous ligament. These injuries may be stable or accompanied by mild instability, and provocative testing is usually positive. X-rays are typically normal with Grade II injuries, but may display subtle radiographic findings suggestive of a syndesmotic injury. Treatment of Grade II injuries is somewhat controversial and should be an individualized decision based upon the patient’s age, activity level, clinical exam, and imaging findings. Therefore, treatment of Grade II syndesmotic injuries may include a trial of conservative management or surgical intervention.

A Grade III injury represents inherent instability of the distal tibiofibular joint with complete disruption of all syndesmotic ligaments, with or without involvement of the deltoid ligament. X-rays will be positive in Grade III syndesmotic injuries because of the complete disruption of syndesmotic ligaments. All Grade III injuries require surgical intervention with a syndesmotic screw or other stabilization procedure.^1,6-8,15

Continue to: A 3-stage rehabilitation protocol

When conservative management is deemed appropriate for a stable syndesmotic sprain, a 3-stage rehabilitation protocol is typically utilized.

The acute phase focuses on protection, pain control, and decreasing inflammation. The patient’s ankle is often immobilized in a cast or controlled ankle movement (CAM) boot. The patient is typically allowed to bear weight in the immobilizer during this phase as long as he/she is pain-free. If pain is present with weight bearing despite immobilization, non-weight bearing is recommended. The patient is instructed to elevate the lower extremity, take anti-inflammatory medication, and ice the affected ankle. Additionally, physical therapy modalities may be utilized to help with edema and pain. Joint immobilization is typically employed for 1 to 3 weeks post-injury. In the acute phase, the patient may also work with a physical therapist or athletic trainer on passive range of motion (ROM), progressing to active ROM as tolerated.^1,5,7,8,19

The patient can transition from the CAM boot to a lace-up ankle brace when he/she is able to bear full weight and can navigate stairs without pain, which typically occurs around 3 to 6 weeks post-injury.^1,5,7 A pneumatic walking brace may also be used as a transition device to provide added stabilization.

In the sub-acute phase, rehabilitation may progress to increase ankle mobility, strengthening, neuromuscular control, and to allow the patient to perform activities of daily living.^5-7

The advanced training phase includes continued neuromuscular control, increased strengthening, plyometrics, agility, and sports-specific drills.⁵ Athletes are allowed to return to full participation when they have regained full ROM, are able to perform sport-specific agility drills without pain or instability, and have near-normal strength.^5-7 Some authors also advocate that a Single Leg Hop Test should be included in the physical exam, and that it should be pain free prior to allowing an athlete to return to competition.²⁰ Both progression in physical rehabilitation and return to sport should be individualized based upon injury severity, patient functionality, and physical exam findings.

Continue to: Outcomes forecast

Outcomes forecast: Variable

The resolution of symptoms and return to competition after a syndesmotic injury is variable. In one cohort study of cadets (N = 614) at the United States Military Academy, the average time lost from a syndesmotic ankle sprain was 9.82 days (range 3-21 days).⁹ In a retrospective review of National Hockey League players, average time to return to competition after a syndesmotic ankle injury sprain (n = 14) was 45 days (range 6-137 days) vs 1.4 days (range 0-6 days) for lateral ankle sprains (n = 5).²¹ In another study, National Football League players with syndesmotic sprains (n = 36) had a mean time loss from play of 15.4 days (± 11.1 days) vs 6.5 days (± 6.5 days) of time loss from play in those with lateral ankle sprains (n = 53).²²

Although CT can provide an assessment of bony structures, it is not able to evaluate soft tissue structures, limiting its utility in evaluation of syndesmotic injuries.

Although there is a fair amount of variability among studies, most authors agree that the average athlete can expect to return to sport 4 to 8 weeks post-injury with conservative management.¹⁹ At least 1 study suggests that the average time to return to sport in patients with Grade III syndesmotic injuries who undergo surgical treatment with a syndesmotic screw is 41 days (range 32-48).²³ The differences in return to sport may be related to severity of injury and/or type of activity.

Persistent symptoms are relatively common after conservative management of syndesmotic injuries. One case series found that 36% of patients treated conservatively had complaints of persistent mild-to-moderate ankle stiffness, 23% had mild-to-moderate pain, and 18% had mild-to-moderate ankle swelling.²⁴ Despite these symptoms, 86% of the patients rated their ankle function as good after conservative treatment.²⁴ In patients with persistent symptoms, other possible etiologies should be considered including neurologic injury, complex regional pain syndrome, osteochondral defect, loose body, or other sources that may be contributing to pain, swelling, or delayed recovery.

At least 1 randomized controlled trial (RCT) investigated the utility of platelet rich plasma (PRP) injections around the injured AITFL in the setting of an acute syndesmotic injury. The study showed promising results, including quicker return to play, restabilization of the syndesmotic joint, and less residual pain;²⁵ however, the study population was relatively small (N = 16), and the authors believed that more research is required on the benefits of PRP therapy in syndesmotic injuries before recommendations can be made.

An ounce of preventionis worth a pound of cure

Although injury is not always avoidable, there are measures that can help prevent ankle sprains and facilitate return to play after injury. As previously mentioned, athletes should be able to demonstrate the ability to run, cut, jump, and perform sport-specific activities without limitations prior to being allowed to return to sport after injury.^5-7,26 Additionally, issues with biomechanics and functional deficits should be analyzed and addressed. By targeting specific strength deficits, focusing on proprioceptive awareness, and working on neuromuscular control, injury rates and recurrent injuries can be minimized. One RCT showed a 35% reduction in the recurrence rate of lateral ankle sprains with the use of an unsupervised home-based proprioceptive training program.²⁷

Continue to: Strength training...

Although not the standard of care, ultrasonography is gaining traction as a means of investigating the integrity of the syndesmotic ligaments.

Strength training, proprioceptive and neuromuscular control activities, and low-risk activities such as jogging, biking, and swimming do not necessarily require the use of prophylactic bracing. However, because syndesmotic injuries are associated with recurrent ankle injuries, prophylactic bracing should be used during high-risk activities that involve agility maneuvers and jumping. Substantial evidence demonstrates that the use of ankle taping or ankle bracing decreases the incidence of ankle injuries, particularly in those who have had previous ankle injuries.²⁶ In one study (N = 450), only 3% of athletes with a history of prior ankle injuries suffered a recurrent ankle sprain when using an ankle orthosis compared with a 17% injury rate in the control group.²⁸

More recently, 2 separate studies by McGuine et al demonstrated that the use of lace-up ankle braces led to a reduction in the incidence of acute ankle injuries by 61% among 2081 high-school football players, and resulted in a significant reduction in acute ankle injuries in a study of 1460 male and female high-school basketball players, compared with the control groups.^29,30

CASE

Ten days after injuring himself, the patient returns for a follow-up exam. Despite using the walking brace and crutches, he is still having significant difficulty bearing weight. He reports a sensation of instability in the right ankle. On exam, you note visible edema of the right ankle and ecchymosis over the lateral ankle, as well as moderate tenderness to palpation over the area of the ATFL and deltoid ligament. Tenderness over the medial malleolus, lateral malleolus, fifth metatarsal, and navicular is absent. Pain is reproducible with external rotation, and a Squeeze Test is positive. There is no tenderness over the proximal tibia or fibula. The patient is neurovascularly intact.

You order stress x-rays, which show widening of the medial clear space. The patient is placed in a CAM boot, instructed to continue non–weight-bearing on the ankle, and referred to a local foot and ankle surgeon for consideration of surgical fixation.

CORRESPONDENCE
John T. Nickless, MD, Division of Primary Care Sports Medicine, Department of Orthopedic Surgery, Rush University Medical Center, 1611 W. Harrison Street, Suite 200, Chicago, IL, 60612; [email protected].

CASE

A 19-year-old college football player presents to your outpatient family practice clinic after suffering a right ankle injury during a football game over the weekend. He reports having his right ankle planted on the turf with his foot externally rotated when an opponent fell onto his posterior right lower extremity. He reports having felt immediate pain in the area of the right ankle and requiring assistance off of the field, as he had difficulty walking. The patient was taken to the emergency department where x-rays of the right foot and ankle did not show any signs of acute fracture or dislocation. The patient was diagnosed with a lateral ankle sprain, placed in a pneumatic ankle walking brace, and given crutches.

A high ankle sprain, or distal tibiofibular syndesmotic injury, can be an elusive diagnosis and is often mistaken for the more common lateral ankle sprain. Syndesmotic injuries have been documented to occur in approximately 1% to 10% of all ankle sprains.^1-3 The highest number of these injuries occurs between the ages of 18 and 34 years, and they are more frequently seen in athletes than in nonathletes, particularly those who play collision sports, such as football, ice hockey, rugby, wrestling, and lacrosse.^1-9 In one study by Hunt et al,¹⁰ syndesmotic injuries accounted for 24.6% of all ankle injuries in National Collegiate Athletic Association (NCAA) football players. Incidence continues to grow as recognition of high ankle sprains increases among medical professionals.^1,5 Identification of syndesmotic injury is critical, as lack of detection can lead to extensive time missed from athletic participation and chronic ankle dysfunction, including pain and instability.^2,4,6,11

Back to basics: A brief anatomy review

Stability in the distal tibiofibular joint is maintained by the syndesmotic ligaments, which include the anterior inferior tibiofibular ligament (AITFL), the posterior inferior tibiofibular ligament (PITFL), the transverse ligament, and the interosseous ligament.^3-6,8 This complex of ligaments stabilizes the fibula within the incisura of the tibia and maintains a stable ankle mortise.^1,4,5,11 The deep portion of the deltoid ligament also adds stability to the syndesmosis and may be disrupted by a syndesmotic injury.^2,5-7,11

Mechanisms of injury: From most common to less likely

The distal tibiofibular syndesmosis is disrupted when an injury forces apart the distal tibiofibular joint. The most commonly reported means of injury is external rotation with hyper-dorsiflexion of the ankle.^1-3,5,6,11 With excessive external rotation of the forefoot, the talus is forced against the medial aspect of the fibula, resulting in separation of the distal tibia and fibula and injury to the syndesmotic ligaments.^2,3,5,6 Injuries associated with external rotation are commonly seen in sports that immobilize the ankle within a rigid boot, such as skiing and ice hockey.^1,2,5 Some authors have suggested that a planovalgus foot alignment may place athletes at inherent risk for an external rotation ankle injury.^5,6

Trauma causing ankle syndesmotic injuries may be associated with Weber B or Weber C distal fibula fractures or a Maisonneuve fracture.

Syndesmotic injury may also occur with hyper-dorsiflexion, as the anterior, widest portion of the talus rotates into the ankle mortise, wedging the tibia and fibula apart.^2,3,5 There have also been reports of syndesmotic injuries associated with internal rotation, plantar flexion, inversion, and eversion.^3,5,11 Therefore, physicians should maintain a high index of suspicion for injury to the distal tibiofibular joint, regardless of the mechanism of injury.

Presentation and evaluation

Observation of the patient and visualization of the affected ankle can provide many clues. Many patients will have difficulty walking after suffering a syndesmotic injury and may require the use of an assistive device.⁵ The inability to bear weight after an ankle injury points to a more severe diagnosis, such as an ankle fracture or syndesmotic injury, as opposed to a simple lateral ankle sprain. Patients may report anterior ankle pain, a sensation of instability with weight bearing on the affected ankle, or have persistent symptoms despite a course of conservative treatment. Also, they can have a variable amount of edema and ecchymosis associated with their injury; a minimal extent of swelling or ecchymosis does not exclude syndesmotic injury.³

A large percentage of patients will present with a concomitant sprain of the lateral ligaments associated with lateral swelling and bruising. One study found that 91% of syndesmotic injuries involved at least 1 of the lateral collateral ligaments (anterior talofibular ligament [ATFL], calcaneofibular ligament [CFL], or posterior talofibular ligament [PTFL]).¹² Patients may have pain or a sensation of instability when pushing off with the toes,⁵ and patients with syndesmotic injuries often have tenderness to palpation over the distal anterolateral ankle or syndesmotic ligaments.⁷

Continue to: A thorough examination...

A thorough examination of the ankle, including palpation of common fracture sites, is important. Employ the Ottawa Ankle Rules (see http://www.theottawarules.ca/ankle_rules) to investigate for: tenderness to palpation over the posterior 6 cm of the posterior aspects of the distal medial and lateral malleoli; tenderness over the navicular; tenderness over the base of the fifth metatarsal; and/or the inability to bear weight on the affected lower extremity immediately after injury or upon evaluation in the physician’s office. Any of these findings should raise concern for a possible fracture (see “Adult foot fractures: A guide”) and require an x-ray(s) for further evaluation.¹³

Perform range-of-motion and strength testing with regard to ankle dorsiflexion, plantar flexion, abduction, adduction, inversion, and eversion. Palpate the ATFL, CFL, and PTFL for tenderness, as these structures may be involved to varying degrees in lateral ankle sprains. An anterior drawer test (see https://www.youtube.com/watch?v=vAcBEYZKcto) may be positive with injury to the ATFL. This test is performed by stabilizing the distal tibia with one hand and using the other hand to grasp the posterior aspect of the calcaneus and apply an anterior force. The test is positive if the talus translates forward, which correlates with laxity or rupture of the ATFL.¹³ The examiner should also palpate the Achilles tendon, peroneal tendons just posterior to the lateral malleolus, and the tibialis posterior tendon just posterior to the medial malleolus to inspect for tenderness or defects that may be signs of injury to these tendons.

An associated Weber B or C fracture? Trauma causing ankle syndesmosis injuries may be associated with Weber B or Weber C distal fibula fractures.⁷ Weber B fractures occur in the distal fibula at the level of the ankle joint (see FIGURE 1). These types of fractures are typically associated with external rotation injuries and are usually not associated with disruption of the interosseous membrane.

Weber C fractures are distal fibular fractures occurring above the level of the ankle joint. These fractures are also typically associated with external ankle rotation injuries and include disruption of the syndesmosis and deltoid ligament.¹⁴

Also pay special attention to the proximal fibula, as syndesmotic injuries are commonly associated with a Maisonneuve fracture, which is a proximal fibula fracture associated with external rotation forces of the ankle (see FIGURE 1).^{1,2,4,11,14,15} Further workup should occur in any patient with the possibility of a Weber- or Maisonneuve-type fracture.

Continue to: Multiple tests...

Multiple tests are available to investigate the possibility of a syndesmotic injury and to assess return-to-sport readiness, including the External Rotation Test, the Squeeze Test, the Crossed-Leg Test, the Dorsiflexion Compression Test, the Cotton Test, the Stabilization Test, the Fibular Translation Test, and the Single Leg Hop Test (see TABLE^{1-3,5,6,16,17}). The External Rotation Test is noted by some authors to have the highest interobserver reliability, and is our preferred test.² The Squeeze Test also has moderate interobserver reliability.² There is a significant degree of variation among the sensitivity and specificity of these diagnostic tests, and no single test is sufficiently reliable or accurate to diagnose a syndesmotic ankle injury. Therefore, it is recommended to use multiple physical exam maneuvers, the history and mechanism of injury, and findings on imaging studies in conjunction to make the diagnosis of a syndesmotic injury.^1,16

Imaging: Which modes and when?

The initial workup should include ankle x-rays when evaluating for the possibility of a distal tibiofibular syndesmosis injury. While the Ottawa Ankle Rules are helpful in providing guidance with regard to x-rays, suspicion of a syndesmotic injury mandates x-rays to determine the stability of the joint and rule out fracture. The European Society of Sports Traumatology, Knee Surgery and Arthroscopy–European Foot and Ankle Associates (ESSKA-AFAS) recommend, at a minimum, obtaining anteroposterior (AP)- and mortise-view ankle x-rays to investigate the tibiofibular clear space, medial clear space, and tibiofibular overlap.⁷ Most physicians also include a lateral ankle x-ray.

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

If possible, images should be performed while the patient is bearing weight to further evaluate stability. Radiographic findings that support the diagnosis of syndesmotic injury include a tibiofibular clear space > 6 mm on AP view, medial clear space > 4 mm on mortise view, or tibiofibular overlap < 6 mm on AP view or < 1 mm on mortise view (see FIGURES 2 and 3).^1,3,5,8 Additionally, if you suspect a proximal fibular fracture, obtain an x-ray series of the proximal tibia and fibula to investigate the possibility of a Maisonneuve injury.^1,2,4,11

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

The External Rotation Test is noted by some authors to have the highest interobserver reliability.

If you continue to suspect a syndesmotic injury despite normal x-rays, obtain stress x-rays, in addition to the AP and mortise views, to ensure stability. These x-rays include AP and mortise ankle views with manual external rotation of the ankle joint, which may demonstrate abnormalities not seen on standard x-rays. Bilateral imaging can also be useful to further assess when mild abnormalities vs symmetric anatomic variants are in question.^1,7

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

If there is concern for an unstable injury, refer the patient to a foot and ankle surgeon, who may pursue magnetic resonance imaging (MRI) or standing computed tomography (CT).^1,2,5,7 MRI is the recommended choice for further evaluation of a syndesmotic injury, as it is proven to be accurate in evaluating the integrity of the syndesmotic ligaments (see FIGURES 4 and 5).¹⁸ MRI has demonstrated 100% sensitivity for detecting AITFL and PITFL injuries, as well as 93% and 100% specificity for AITFL and PITFL tears, respectively.⁸ A weight-bearing CT scan, particularly axial views, can also be a useful adjunct, as it is more sensitive than standard x-rays for assessing for mild diastasis. Although CT can provide an assessment of bony structures, it is not able to evaluate soft tissue structures, limiting its utility in evaluation of syndesmotic injuries.^1,7

COURTESY OF: MIDWEST ORTHOPEDICS AT RUSH, RUSH

Continue to: Although not the standard of care...

Although not the standard of care, ultrasonography (US) is gaining traction as a means of investigating the integrity of the syndesmotic ligaments. US is inexpensive, readily available in many clinics, allows for dynamic testing, and avoids radiation exposure.⁷ However, US requires a skilled sonographer with experience in the ankle joint for an accurate diagnosis. If the workup with advanced imaging is inconclusive, but a high degree of suspicion remains for an unstable syndesmotic injury, consider arthroscopy to directly visualize and assess the syndesmotic structures.^1,2,5,7,8

Grading the severity of the injury and pursuing appropriate Tx

Typically, the severity of a syndesmotic injury is classified as fitting into 1 of 3 categories: Grade I and II injuries are the most common, each accounting for 40% of syndesmotic injuries, while 20% of high ankle sprains are classified as Grade III.¹²

No single test is sufficiently reliable or accurate to diagnose a syndesmotic ankle injury.

A Grade I injury consists of a stable syndesmotic joint without abnormal radiographic findings. There may be associated tenderness to palpation over the distal tibiofibular joint, and provocative testing may be subtle or normal. These injuries are often minor and able to be treated conservatively.

A Grade II injury is associated with a partial syndesmotic disruption, typically with partial tearing of the AITFL and interosseous ligament. These injuries may be stable or accompanied by mild instability, and provocative testing is usually positive. X-rays are typically normal with Grade II injuries, but may display subtle radiographic findings suggestive of a syndesmotic injury. Treatment of Grade II injuries is somewhat controversial and should be an individualized decision based upon the patient’s age, activity level, clinical exam, and imaging findings. Therefore, treatment of Grade II syndesmotic injuries may include a trial of conservative management or surgical intervention.

A Grade III injury represents inherent instability of the distal tibiofibular joint with complete disruption of all syndesmotic ligaments, with or without involvement of the deltoid ligament. X-rays will be positive in Grade III syndesmotic injuries because of the complete disruption of syndesmotic ligaments. All Grade III injuries require surgical intervention with a syndesmotic screw or other stabilization procedure.^1,6-8,15

Continue to: A 3-stage rehabilitation protocol

When conservative management is deemed appropriate for a stable syndesmotic sprain, a 3-stage rehabilitation protocol is typically utilized.

The acute phase focuses on protection, pain control, and decreasing inflammation. The patient’s ankle is often immobilized in a cast or controlled ankle movement (CAM) boot. The patient is typically allowed to bear weight in the immobilizer during this phase as long as he/she is pain-free. If pain is present with weight bearing despite immobilization, non-weight bearing is recommended. The patient is instructed to elevate the lower extremity, take anti-inflammatory medication, and ice the affected ankle. Additionally, physical therapy modalities may be utilized to help with edema and pain. Joint immobilization is typically employed for 1 to 3 weeks post-injury. In the acute phase, the patient may also work with a physical therapist or athletic trainer on passive range of motion (ROM), progressing to active ROM as tolerated.^1,5,7,8,19

The patient can transition from the CAM boot to a lace-up ankle brace when he/she is able to bear full weight and can navigate stairs without pain, which typically occurs around 3 to 6 weeks post-injury.^1,5,7 A pneumatic walking brace may also be used as a transition device to provide added stabilization.

In the sub-acute phase, rehabilitation may progress to increase ankle mobility, strengthening, neuromuscular control, and to allow the patient to perform activities of daily living.^5-7

The advanced training phase includes continued neuromuscular control, increased strengthening, plyometrics, agility, and sports-specific drills.⁵ Athletes are allowed to return to full participation when they have regained full ROM, are able to perform sport-specific agility drills without pain or instability, and have near-normal strength.^5-7 Some authors also advocate that a Single Leg Hop Test should be included in the physical exam, and that it should be pain free prior to allowing an athlete to return to competition.²⁰ Both progression in physical rehabilitation and return to sport should be individualized based upon injury severity, patient functionality, and physical exam findings.

Continue to: Outcomes forecast

Outcomes forecast: Variable

The resolution of symptoms and return to competition after a syndesmotic injury is variable. In one cohort study of cadets (N = 614) at the United States Military Academy, the average time lost from a syndesmotic ankle sprain was 9.82 days (range 3-21 days).⁹ In a retrospective review of National Hockey League players, average time to return to competition after a syndesmotic ankle injury sprain (n = 14) was 45 days (range 6-137 days) vs 1.4 days (range 0-6 days) for lateral ankle sprains (n = 5).²¹ In another study, National Football League players with syndesmotic sprains (n = 36) had a mean time loss from play of 15.4 days (± 11.1 days) vs 6.5 days (± 6.5 days) of time loss from play in those with lateral ankle sprains (n = 53).²²

Although CT can provide an assessment of bony structures, it is not able to evaluate soft tissue structures, limiting its utility in evaluation of syndesmotic injuries.

Although there is a fair amount of variability among studies, most authors agree that the average athlete can expect to return to sport 4 to 8 weeks post-injury with conservative management.¹⁹ At least 1 study suggests that the average time to return to sport in patients with Grade III syndesmotic injuries who undergo surgical treatment with a syndesmotic screw is 41 days (range 32-48).²³ The differences in return to sport may be related to severity of injury and/or type of activity.

Persistent symptoms are relatively common after conservative management of syndesmotic injuries. One case series found that 36% of patients treated conservatively had complaints of persistent mild-to-moderate ankle stiffness, 23% had mild-to-moderate pain, and 18% had mild-to-moderate ankle swelling.²⁴ Despite these symptoms, 86% of the patients rated their ankle function as good after conservative treatment.²⁴ In patients with persistent symptoms, other possible etiologies should be considered including neurologic injury, complex regional pain syndrome, osteochondral defect, loose body, or other sources that may be contributing to pain, swelling, or delayed recovery.

At least 1 randomized controlled trial (RCT) investigated the utility of platelet rich plasma (PRP) injections around the injured AITFL in the setting of an acute syndesmotic injury. The study showed promising results, including quicker return to play, restabilization of the syndesmotic joint, and less residual pain;²⁵ however, the study population was relatively small (N = 16), and the authors believed that more research is required on the benefits of PRP therapy in syndesmotic injuries before recommendations can be made.

An ounce of preventionis worth a pound of cure

Although injury is not always avoidable, there are measures that can help prevent ankle sprains and facilitate return to play after injury. As previously mentioned, athletes should be able to demonstrate the ability to run, cut, jump, and perform sport-specific activities without limitations prior to being allowed to return to sport after injury.^5-7,26 Additionally, issues with biomechanics and functional deficits should be analyzed and addressed. By targeting specific strength deficits, focusing on proprioceptive awareness, and working on neuromuscular control, injury rates and recurrent injuries can be minimized. One RCT showed a 35% reduction in the recurrence rate of lateral ankle sprains with the use of an unsupervised home-based proprioceptive training program.²⁷

Continue to: Strength training...

Although not the standard of care, ultrasonography is gaining traction as a means of investigating the integrity of the syndesmotic ligaments.

Strength training, proprioceptive and neuromuscular control activities, and low-risk activities such as jogging, biking, and swimming do not necessarily require the use of prophylactic bracing. However, because syndesmotic injuries are associated with recurrent ankle injuries, prophylactic bracing should be used during high-risk activities that involve agility maneuvers and jumping. Substantial evidence demonstrates that the use of ankle taping or ankle bracing decreases the incidence of ankle injuries, particularly in those who have had previous ankle injuries.²⁶ In one study (N = 450), only 3% of athletes with a history of prior ankle injuries suffered a recurrent ankle sprain when using an ankle orthosis compared with a 17% injury rate in the control group.²⁸

More recently, 2 separate studies by McGuine et al demonstrated that the use of lace-up ankle braces led to a reduction in the incidence of acute ankle injuries by 61% among 2081 high-school football players, and resulted in a significant reduction in acute ankle injuries in a study of 1460 male and female high-school basketball players, compared with the control groups.^29,30

CASE

Ten days after injuring himself, the patient returns for a follow-up exam. Despite using the walking brace and crutches, he is still having significant difficulty bearing weight. He reports a sensation of instability in the right ankle. On exam, you note visible edema of the right ankle and ecchymosis over the lateral ankle, as well as moderate tenderness to palpation over the area of the ATFL and deltoid ligament. Tenderness over the medial malleolus, lateral malleolus, fifth metatarsal, and navicular is absent. Pain is reproducible with external rotation, and a Squeeze Test is positive. There is no tenderness over the proximal tibia or fibula. The patient is neurovascularly intact.

You order stress x-rays, which show widening of the medial clear space. The patient is placed in a CAM boot, instructed to continue non–weight-bearing on the ankle, and referred to a local foot and ankle surgeon for consideration of surgical fixation.

CORRESPONDENCE
John T. Nickless, MD, Division of Primary Care Sports Medicine, Department of Orthopedic Surgery, Rush University Medical Center, 1611 W. Harrison Street, Suite 200, Chicago, IL, 60612; [email protected].

Early childhood caries (ECCs) are a preventable public health challenge. Breastfeeding may provide early protection from ECCs. In addition, oral hygiene that begins in infancy, regular dental care visits, and a healthy diet can minimize ECC risk.

In this article we review the critical role of the family physician (FP) in reducing ECCs by promoting breastfeeding and infant oral health and addressing dental health concerns.

How ECCs develop

ECCs represent decayed, missing, or filled areas in the primary dentition of the tooth surface. The bacteria that cause them (most often Streptococcus mutans¹) strongly adhere to teeth and produce acids as waste products of fermentable carbohydrate metabolism that demineralize tooth enamel and progress into the dentin. Weakened enamel and dentin can result in cavitation (ie, a dental cavity). Left untreated, caries can extend to the pulp and destroy the entire tooth. ECCs are a risk factor not only for dental caries in primary teeth, but in permanent dentition as well.

ECCs are the most common chronic disease affecting young children.¹ Dental disease may begin soon after tooth eruption with detrimental effects on oral development. Almost half of children have dental caries by 5 years of age.²

ECCs represent a complex and multifactorial disease that is impacted by biomedical factors and unmet social needs. Children who are most at risk include those with low socioeconomic status, a high-sugar diet, exposure to household smoke, and limited dental care access.³ In addition, women with low education, poor oral health, and/or a lack of fluoride exposure are more likely to have children with ECCs.³ This is partly because of vertical transmission of cariogenic bacteria from caregiver to child. Horizontal transmission in daycare settings can also occur. Paternal and child oral health have not been linked.

Support breastfeeding; keep oral microbiome changes in mind

The American Academy of Pediatrics (AAP) recommends exclusive breastfeeding for the first 6 months of life, a combination of breastfeeding and complementary foods until 12 months of age, and continued breastfeeding for as long as mutually desired by mother and baby.⁴ The World Health Organization (WHO) recommends continued breastfeeding until 2 years of age or beyond.⁵ In fact, the WHO global nutrition targets for 2025 include increasing the rate of exclusive breastfeeding in the first 6 months of life to at least 50%.⁶

Early childhood caries are the most common chronic disease affecting young children.

In addition to maternal, financial, and societal benefits, human milk offers nutritional and other health-related advantages for children that optimize growth and development into adulthood.⁴ Breastfed infants may benefit from reduction in infections and diseases, including asthma, diabetes mellitus, childhood cancer, and obesity.⁷ Improved neurocognitive development, intelligence, and education attainment in adulthood have also been described.⁸ And the rich microbiome of human milk helps to establish oral and intestinal floras⁹ and may mediate protection from ECCs.³

Continue to: However, as a child's oral microbiome changes...

However, as a child’s oral microbiome changes with the emergence of primary teeth and exposure to more and varied bacteria and dietary sugars, the natural sugars in human milk may become the substrate for cariogenic bacteria.³ ECCs can develop and progress rapidly. Importantly, both the practice of breastfeeding and ECC risk are modified by socioeconomic status, maternal oral health and education, and exposure to household smoking.^3,7 Understanding these relationships may help you better target risk assessment and counseling efforts.

What the research tells us about breastfeeding and ECCs

Breastfeeding is hypothesized to be one of many factors that influence ECC development. However, studies on this association have had conflicting results and have not adequately controlled for major confounders, such as dietary composition, maternal and infant oral hygiene, and maternal oral health status.

So here is what we know.

Breastfeeding during the first year. In one meta-analysis involving children who breastfed for up to 12 months, those who breastfed longer within the 12-month period had a reduced risk of ECCs compared with those who breastfed for a shorter period of time,³ which implies that breast milk may be protective in the first year of life.³

Further, a 2014 study with about 500 participants found that children were more likely to have caries by 5 years of age if they breastfed for <6 months than if they breastfed for at least 6 months.¹⁰

Continue to: After the first year

After the first year. A Canadian study found an increased risk of ECCs associated with breastfeeding for longer periods of time. The study of healthy urban children reported that breastfeeding for >24 months was associated with a 2- to 3-fold increased odds of ECCs compared with shorter breastfeeding duration.¹¹

No relationship? Lastly, a US study using National Health and Nutrition Examination Survey data found there was no evidence to suggest that breastfeeding duration was an independent risk factor for ECCs.¹²

A possible explanation for a link

An initial protective effect of breastfeeding against ECCs may be related to breast milk’s immunomodulatory factors and rich microbiome. Breast milk contains Lactobacilli and substances, including human casein and secretory IgA, that inhibit growth and attachment of bacteria,⁹ particularly the caries pathogen S mutans. Early defense against ECCs may be mediated through the establishment of a healthy oral and gut microbiome that results from exposure to breastfeeding and contact with skin, gut, and breast milk microbiomes. Later on, the child’s oral microbiome changes with the emergence of teeth and the introduction of complementary foods andother drinks.

A look at the role vitamin D plays

Vitamin D status may influence childhood dental health.¹³ Low maternal vitamin D levels have been associated with ECCs,¹⁴ and mothers with higher prenatal vitamin D intakes were more likely to report that their children were caries-free compared with women who had lower vitamin D intake.¹⁵ Additionally, children with severe ECCs were found to have lower vitamin D levels than cavity-free children.¹⁶ Unfortunately, only a minority of infants who are predominantly breastfed for > 6 months receive vitamin D supplementation.¹⁷

Other factors at work: Carbohydrate exposure, nocturnal feedings

Exposure to carbohydrates—the essential substrate for cariogenic bacteria—is a key factor in ECC development. Refined sugars contribute considerably to tooth decay. Frequency of feeding and feeding practices, such as prolonged nocturnal feeding (either breast or bottle) may increase ECC risk.³ Further, a major determinant of ECC risk is colonization of the infant’s mouth by cariogenic bacteria. Finally, ECC risk depends on socioeconomic status, oral hygiene, exposure to fluoride, and the mother’s oral health, education, and smoking status.³ Even birth order plays a role, with those born first having lower risk than subsequent children.¹⁸

Continue to: Breastfeeding and another area of oral health...

Breastfeeding and another area of oral health: Malocclusion

In addition to its relationship with ECCs, breastfeeding promotes adequate development of craniofacial structures (comprising the tongue, facial muscles, and jaw), which are important for smiling, emotion, and social contact. Breastfeeding may prevent the development of malocclusion (ie, a misalignment of the teeth) in primary dentition, which is a risk factor for malocclusion in adulthood.⁷ Although previous studies had conflicting results, a large prospective study found that breastfeeding significantly reduced the risk of moderate and severe malocclusion; however, this effect was nullified by nonnutritive sucking and pacifier use.¹⁹

Oral health recommendations: The FP’s role

ECCs are theoretically preventable. To optimize the benefits of breastfeeding and minimize ECC risk, parents should follow recommendations for their children regarding proper oral hygiene, appropriate fluoride exposure, regular dental visits, and a healthy diet.¹

Be sure to advise parents to:

• avoid saliva-sharing behaviors (eg, sharing utensils with their children or cleaning a pacifier with their mouth), as these may increase early colonization of S mutans in infants;
• seek regular preventive dental care and attend to caries—both for their children and themselves; and
• use antimicrobial oral care products including xylitol-containing chewing gum to lower levels of cariogenic microorganisms in themselves and, in turn, reduce mother–child vertical transmission of S mutans.¹

In addition, make sure your prenatal counseling includes a discussion of the importance of good maternal oral health and diet—including an adequate vitamin D intake—to prevent ECCs in their children.

It’s never too early to start

Providing guidance on children’s oral health can start with the first well-infant visit. FPs should perform an oral health risk assessment by 6 months of age (see the AAP’s Oral Health Risk Assessment Tool at https://www.aap.org/en-us/Documents/oralhealth_RiskAssessmentTool.pdf) and evaluate fluoride exposure. Advise parents to establish a dental home by the time the child is 12 months of age; to clean their children’s mouths after feedings (before teeth arrive) with a clean, wet, soft washcloth; and to brush their children’s teeth, once they erupt, twice daily using a soft toothbrush (TABLE 1²⁰).

Continue to: Talk to parents about...

Talk to parents about how to provide optimal exposure to fluoride, which is known to be safe and effective for the prevention of ECCs.¹ Use of fluoridated toothpaste in small amounts provides the benefits of fluoride without increasing the risk of fluorosis, especially for children at risk for caries (see TABLE 2²¹).

The rich microbiome of human milk helps to establish oral and intestinal floras and may mediate protection from early childhood caries.

The US Preventive Services Task Force recommends that primary care practitioners apply fluoride varnish biannually for at least 2 years to the primary teeth of all children up to 5 years of age (Grade B evidence).²² This is particularly important for high-risk children, such as those with low-income or minority status. However, practitioners should also take into account that high cumulative fluoride intake can lead to dental fluorosis.¹ Finally, tell parents to avoid giving their children sugar-containing snacks and drinks to reduce ECC risk.

CORRESPONDENCE
Peter D. Wong, MD, 303-89 Humber College Boulevard, Toronto, Ontario, Canada M9V 4B8; [email protected].

Early childhood caries (ECCs) are a preventable public health challenge. Breastfeeding may provide early protection from ECCs. In addition, oral hygiene that begins in infancy, regular dental care visits, and a healthy diet can minimize ECC risk.

In this article we review the critical role of the family physician (FP) in reducing ECCs by promoting breastfeeding and infant oral health and addressing dental health concerns.

How ECCs develop

ECCs represent decayed, missing, or filled areas in the primary dentition of the tooth surface. The bacteria that cause them (most often Streptococcus mutans¹) strongly adhere to teeth and produce acids as waste products of fermentable carbohydrate metabolism that demineralize tooth enamel and progress into the dentin. Weakened enamel and dentin can result in cavitation (ie, a dental cavity). Left untreated, caries can extend to the pulp and destroy the entire tooth. ECCs are a risk factor not only for dental caries in primary teeth, but in permanent dentition as well.

ECCs are the most common chronic disease affecting young children.¹ Dental disease may begin soon after tooth eruption with detrimental effects on oral development. Almost half of children have dental caries by 5 years of age.²

ECCs represent a complex and multifactorial disease that is impacted by biomedical factors and unmet social needs. Children who are most at risk include those with low socioeconomic status, a high-sugar diet, exposure to household smoke, and limited dental care access.³ In addition, women with low education, poor oral health, and/or a lack of fluoride exposure are more likely to have children with ECCs.³ This is partly because of vertical transmission of cariogenic bacteria from caregiver to child. Horizontal transmission in daycare settings can also occur. Paternal and child oral health have not been linked.

Support breastfeeding; keep oral microbiome changes in mind

The American Academy of Pediatrics (AAP) recommends exclusive breastfeeding for the first 6 months of life, a combination of breastfeeding and complementary foods until 12 months of age, and continued breastfeeding for as long as mutually desired by mother and baby.⁴ The World Health Organization (WHO) recommends continued breastfeeding until 2 years of age or beyond.⁵ In fact, the WHO global nutrition targets for 2025 include increasing the rate of exclusive breastfeeding in the first 6 months of life to at least 50%.⁶

Early childhood caries are the most common chronic disease affecting young children.

In addition to maternal, financial, and societal benefits, human milk offers nutritional and other health-related advantages for children that optimize growth and development into adulthood.⁴ Breastfed infants may benefit from reduction in infections and diseases, including asthma, diabetes mellitus, childhood cancer, and obesity.⁷ Improved neurocognitive development, intelligence, and education attainment in adulthood have also been described.⁸ And the rich microbiome of human milk helps to establish oral and intestinal floras⁹ and may mediate protection from ECCs.³

Continue to: However, as a child's oral microbiome changes...

However, as a child’s oral microbiome changes with the emergence of primary teeth and exposure to more and varied bacteria and dietary sugars, the natural sugars in human milk may become the substrate for cariogenic bacteria.³ ECCs can develop and progress rapidly. Importantly, both the practice of breastfeeding and ECC risk are modified by socioeconomic status, maternal oral health and education, and exposure to household smoking.^3,7 Understanding these relationships may help you better target risk assessment and counseling efforts.

What the research tells us about breastfeeding and ECCs

Breastfeeding is hypothesized to be one of many factors that influence ECC development. However, studies on this association have had conflicting results and have not adequately controlled for major confounders, such as dietary composition, maternal and infant oral hygiene, and maternal oral health status.

So here is what we know.

Breastfeeding during the first year. In one meta-analysis involving children who breastfed for up to 12 months, those who breastfed longer within the 12-month period had a reduced risk of ECCs compared with those who breastfed for a shorter period of time,³ which implies that breast milk may be protective in the first year of life.³

Further, a 2014 study with about 500 participants found that children were more likely to have caries by 5 years of age if they breastfed for <6 months than if they breastfed for at least 6 months.¹⁰

Continue to: After the first year

After the first year. A Canadian study found an increased risk of ECCs associated with breastfeeding for longer periods of time. The study of healthy urban children reported that breastfeeding for >24 months was associated with a 2- to 3-fold increased odds of ECCs compared with shorter breastfeeding duration.¹¹

No relationship? Lastly, a US study using National Health and Nutrition Examination Survey data found there was no evidence to suggest that breastfeeding duration was an independent risk factor for ECCs.¹²

A possible explanation for a link

An initial protective effect of breastfeeding against ECCs may be related to breast milk’s immunomodulatory factors and rich microbiome. Breast milk contains Lactobacilli and substances, including human casein and secretory IgA, that inhibit growth and attachment of bacteria,⁹ particularly the caries pathogen S mutans. Early defense against ECCs may be mediated through the establishment of a healthy oral and gut microbiome that results from exposure to breastfeeding and contact with skin, gut, and breast milk microbiomes. Later on, the child’s oral microbiome changes with the emergence of teeth and the introduction of complementary foods andother drinks.

A look at the role vitamin D plays

Vitamin D status may influence childhood dental health.¹³ Low maternal vitamin D levels have been associated with ECCs,¹⁴ and mothers with higher prenatal vitamin D intakes were more likely to report that their children were caries-free compared with women who had lower vitamin D intake.¹⁵ Additionally, children with severe ECCs were found to have lower vitamin D levels than cavity-free children.¹⁶ Unfortunately, only a minority of infants who are predominantly breastfed for > 6 months receive vitamin D supplementation.¹⁷

Other factors at work: Carbohydrate exposure, nocturnal feedings

Exposure to carbohydrates—the essential substrate for cariogenic bacteria—is a key factor in ECC development. Refined sugars contribute considerably to tooth decay. Frequency of feeding and feeding practices, such as prolonged nocturnal feeding (either breast or bottle) may increase ECC risk.³ Further, a major determinant of ECC risk is colonization of the infant’s mouth by cariogenic bacteria. Finally, ECC risk depends on socioeconomic status, oral hygiene, exposure to fluoride, and the mother’s oral health, education, and smoking status.³ Even birth order plays a role, with those born first having lower risk than subsequent children.¹⁸

Continue to: Breastfeeding and another area of oral health...

Breastfeeding and another area of oral health: Malocclusion

In addition to its relationship with ECCs, breastfeeding promotes adequate development of craniofacial structures (comprising the tongue, facial muscles, and jaw), which are important for smiling, emotion, and social contact. Breastfeeding may prevent the development of malocclusion (ie, a misalignment of the teeth) in primary dentition, which is a risk factor for malocclusion in adulthood.⁷ Although previous studies had conflicting results, a large prospective study found that breastfeeding significantly reduced the risk of moderate and severe malocclusion; however, this effect was nullified by nonnutritive sucking and pacifier use.¹⁹

Oral health recommendations: The FP’s role

ECCs are theoretically preventable. To optimize the benefits of breastfeeding and minimize ECC risk, parents should follow recommendations for their children regarding proper oral hygiene, appropriate fluoride exposure, regular dental visits, and a healthy diet.¹

Be sure to advise parents to:

• avoid saliva-sharing behaviors (eg, sharing utensils with their children or cleaning a pacifier with their mouth), as these may increase early colonization of S mutans in infants;
• seek regular preventive dental care and attend to caries—both for their children and themselves; and
• use antimicrobial oral care products including xylitol-containing chewing gum to lower levels of cariogenic microorganisms in themselves and, in turn, reduce mother–child vertical transmission of S mutans.¹

In addition, make sure your prenatal counseling includes a discussion of the importance of good maternal oral health and diet—including an adequate vitamin D intake—to prevent ECCs in their children.

It’s never too early to start

Providing guidance on children’s oral health can start with the first well-infant visit. FPs should perform an oral health risk assessment by 6 months of age (see the AAP’s Oral Health Risk Assessment Tool at https://www.aap.org/en-us/Documents/oralhealth_RiskAssessmentTool.pdf) and evaluate fluoride exposure. Advise parents to establish a dental home by the time the child is 12 months of age; to clean their children’s mouths after feedings (before teeth arrive) with a clean, wet, soft washcloth; and to brush their children’s teeth, once they erupt, twice daily using a soft toothbrush (TABLE 1²⁰).

Continue to: Talk to parents about...

Talk to parents about how to provide optimal exposure to fluoride, which is known to be safe and effective for the prevention of ECCs.¹ Use of fluoridated toothpaste in small amounts provides the benefits of fluoride without increasing the risk of fluorosis, especially for children at risk for caries (see TABLE 2²¹).

The rich microbiome of human milk helps to establish oral and intestinal floras and may mediate protection from early childhood caries.

The US Preventive Services Task Force recommends that primary care practitioners apply fluoride varnish biannually for at least 2 years to the primary teeth of all children up to 5 years of age (Grade B evidence).²² This is particularly important for high-risk children, such as those with low-income or minority status. However, practitioners should also take into account that high cumulative fluoride intake can lead to dental fluorosis.¹ Finally, tell parents to avoid giving their children sugar-containing snacks and drinks to reduce ECC risk.

CORRESPONDENCE
Peter D. Wong, MD, 303-89 Humber College Boulevard, Toronto, Ontario, Canada M9V 4B8; [email protected].

Early childhood caries (ECCs) are a preventable public health challenge. Breastfeeding may provide early protection from ECCs. In addition, oral hygiene that begins in infancy, regular dental care visits, and a healthy diet can minimize ECC risk.

In this article we review the critical role of the family physician (FP) in reducing ECCs by promoting breastfeeding and infant oral health and addressing dental health concerns.

How ECCs develop

ECCs represent decayed, missing, or filled areas in the primary dentition of the tooth surface. The bacteria that cause them (most often Streptococcus mutans¹) strongly adhere to teeth and produce acids as waste products of fermentable carbohydrate metabolism that demineralize tooth enamel and progress into the dentin. Weakened enamel and dentin can result in cavitation (ie, a dental cavity). Left untreated, caries can extend to the pulp and destroy the entire tooth. ECCs are a risk factor not only for dental caries in primary teeth, but in permanent dentition as well.

ECCs are the most common chronic disease affecting young children.¹ Dental disease may begin soon after tooth eruption with detrimental effects on oral development. Almost half of children have dental caries by 5 years of age.²

ECCs represent a complex and multifactorial disease that is impacted by biomedical factors and unmet social needs. Children who are most at risk include those with low socioeconomic status, a high-sugar diet, exposure to household smoke, and limited dental care access.³ In addition, women with low education, poor oral health, and/or a lack of fluoride exposure are more likely to have children with ECCs.³ This is partly because of vertical transmission of cariogenic bacteria from caregiver to child. Horizontal transmission in daycare settings can also occur. Paternal and child oral health have not been linked.

Support breastfeeding; keep oral microbiome changes in mind

The American Academy of Pediatrics (AAP) recommends exclusive breastfeeding for the first 6 months of life, a combination of breastfeeding and complementary foods until 12 months of age, and continued breastfeeding for as long as mutually desired by mother and baby.⁴ The World Health Organization (WHO) recommends continued breastfeeding until 2 years of age or beyond.⁵ In fact, the WHO global nutrition targets for 2025 include increasing the rate of exclusive breastfeeding in the first 6 months of life to at least 50%.⁶

Early childhood caries are the most common chronic disease affecting young children.

In addition to maternal, financial, and societal benefits, human milk offers nutritional and other health-related advantages for children that optimize growth and development into adulthood.⁴ Breastfed infants may benefit from reduction in infections and diseases, including asthma, diabetes mellitus, childhood cancer, and obesity.⁷ Improved neurocognitive development, intelligence, and education attainment in adulthood have also been described.⁸ And the rich microbiome of human milk helps to establish oral and intestinal floras⁹ and may mediate protection from ECCs.³

Continue to: However, as a child's oral microbiome changes...

However, as a child’s oral microbiome changes with the emergence of primary teeth and exposure to more and varied bacteria and dietary sugars, the natural sugars in human milk may become the substrate for cariogenic bacteria.³ ECCs can develop and progress rapidly. Importantly, both the practice of breastfeeding and ECC risk are modified by socioeconomic status, maternal oral health and education, and exposure to household smoking.^3,7 Understanding these relationships may help you better target risk assessment and counseling efforts.

What the research tells us about breastfeeding and ECCs

Breastfeeding is hypothesized to be one of many factors that influence ECC development. However, studies on this association have had conflicting results and have not adequately controlled for major confounders, such as dietary composition, maternal and infant oral hygiene, and maternal oral health status.

So here is what we know.

Breastfeeding during the first year. In one meta-analysis involving children who breastfed for up to 12 months, those who breastfed longer within the 12-month period had a reduced risk of ECCs compared with those who breastfed for a shorter period of time,³ which implies that breast milk may be protective in the first year of life.³

Further, a 2014 study with about 500 participants found that children were more likely to have caries by 5 years of age if they breastfed for <6 months than if they breastfed for at least 6 months.¹⁰

Continue to: After the first year

After the first year. A Canadian study found an increased risk of ECCs associated with breastfeeding for longer periods of time. The study of healthy urban children reported that breastfeeding for >24 months was associated with a 2- to 3-fold increased odds of ECCs compared with shorter breastfeeding duration.¹¹

No relationship? Lastly, a US study using National Health and Nutrition Examination Survey data found there was no evidence to suggest that breastfeeding duration was an independent risk factor for ECCs.¹²

A possible explanation for a link

An initial protective effect of breastfeeding against ECCs may be related to breast milk’s immunomodulatory factors and rich microbiome. Breast milk contains Lactobacilli and substances, including human casein and secretory IgA, that inhibit growth and attachment of bacteria,⁹ particularly the caries pathogen S mutans. Early defense against ECCs may be mediated through the establishment of a healthy oral and gut microbiome that results from exposure to breastfeeding and contact with skin, gut, and breast milk microbiomes. Later on, the child’s oral microbiome changes with the emergence of teeth and the introduction of complementary foods andother drinks.

A look at the role vitamin D plays

Vitamin D status may influence childhood dental health.¹³ Low maternal vitamin D levels have been associated with ECCs,¹⁴ and mothers with higher prenatal vitamin D intakes were more likely to report that their children were caries-free compared with women who had lower vitamin D intake.¹⁵ Additionally, children with severe ECCs were found to have lower vitamin D levels than cavity-free children.¹⁶ Unfortunately, only a minority of infants who are predominantly breastfed for > 6 months receive vitamin D supplementation.¹⁷

Other factors at work: Carbohydrate exposure, nocturnal feedings

Exposure to carbohydrates—the essential substrate for cariogenic bacteria—is a key factor in ECC development. Refined sugars contribute considerably to tooth decay. Frequency of feeding and feeding practices, such as prolonged nocturnal feeding (either breast or bottle) may increase ECC risk.³ Further, a major determinant of ECC risk is colonization of the infant’s mouth by cariogenic bacteria. Finally, ECC risk depends on socioeconomic status, oral hygiene, exposure to fluoride, and the mother’s oral health, education, and smoking status.³ Even birth order plays a role, with those born first having lower risk than subsequent children.¹⁸

Continue to: Breastfeeding and another area of oral health...

Breastfeeding and another area of oral health: Malocclusion

In addition to its relationship with ECCs, breastfeeding promotes adequate development of craniofacial structures (comprising the tongue, facial muscles, and jaw), which are important for smiling, emotion, and social contact. Breastfeeding may prevent the development of malocclusion (ie, a misalignment of the teeth) in primary dentition, which is a risk factor for malocclusion in adulthood.⁷ Although previous studies had conflicting results, a large prospective study found that breastfeeding significantly reduced the risk of moderate and severe malocclusion; however, this effect was nullified by nonnutritive sucking and pacifier use.¹⁹

Oral health recommendations: The FP’s role

ECCs are theoretically preventable. To optimize the benefits of breastfeeding and minimize ECC risk, parents should follow recommendations for their children regarding proper oral hygiene, appropriate fluoride exposure, regular dental visits, and a healthy diet.¹

Be sure to advise parents to:

• avoid saliva-sharing behaviors (eg, sharing utensils with their children or cleaning a pacifier with their mouth), as these may increase early colonization of S mutans in infants;
• seek regular preventive dental care and attend to caries—both for their children and themselves; and
• use antimicrobial oral care products including xylitol-containing chewing gum to lower levels of cariogenic microorganisms in themselves and, in turn, reduce mother–child vertical transmission of S mutans.¹

In addition, make sure your prenatal counseling includes a discussion of the importance of good maternal oral health and diet—including an adequate vitamin D intake—to prevent ECCs in their children.

It’s never too early to start

Providing guidance on children’s oral health can start with the first well-infant visit. FPs should perform an oral health risk assessment by 6 months of age (see the AAP’s Oral Health Risk Assessment Tool at https://www.aap.org/en-us/Documents/oralhealth_RiskAssessmentTool.pdf) and evaluate fluoride exposure. Advise parents to establish a dental home by the time the child is 12 months of age; to clean their children’s mouths after feedings (before teeth arrive) with a clean, wet, soft washcloth; and to brush their children’s teeth, once they erupt, twice daily using a soft toothbrush (TABLE 1²⁰).

Continue to: Talk to parents about...

Talk to parents about how to provide optimal exposure to fluoride, which is known to be safe and effective for the prevention of ECCs.¹ Use of fluoridated toothpaste in small amounts provides the benefits of fluoride without increasing the risk of fluorosis, especially for children at risk for caries (see TABLE 2²¹).

The rich microbiome of human milk helps to establish oral and intestinal floras and may mediate protection from early childhood caries.

The US Preventive Services Task Force recommends that primary care practitioners apply fluoride varnish biannually for at least 2 years to the primary teeth of all children up to 5 years of age (Grade B evidence).²² This is particularly important for high-risk children, such as those with low-income or minority status. However, practitioners should also take into account that high cumulative fluoride intake can lead to dental fluorosis.¹ Finally, tell parents to avoid giving their children sugar-containing snacks and drinks to reduce ECC risk.

CORRESPONDENCE
Peter D. Wong, MD, 303-89 Humber College Boulevard, Toronto, Ontario, Canada M9V 4B8; [email protected].

Acetylsalicylic acid has been around for nearly 200 years. It traces its history back to a French chemist (Charles Frederic Gerhardt) and 2 German chemists (Felix Hoffmann and Arthur Eichengrün) who worked at Bayer, the company that launched the pain reliever under the name “aspirin” in 1899. It is now one of the most commonly used medications in the world.

No wonder our patients are confused!

With aspirin's anti-inflammatory properties in mind, researchers conducted randomized trials for secondary prevention of heart attacks in the 1970s; low-dose aspirin was proven effective in reducing risk for a second myocardial infarction. These trials led to speculation that aspirin might be effective for primary prevention as well. Indeed, in the 1980s the large Physicians' Health Study found aspirin reduced the incidence of first heart attack in healthy physicians by 44%.¹ Unfortunately, there was no reduction in mortality from heart disease and it was only effective for those older than 50.

The downside of aspirin was a slight increase in the incidence of hemorrhagic stroke and bleeding requiring transfusion. Nonetheless, many healthy adults started taking daily aspirin hoping to prevent a heart attack.

In this issue of JFP, Smith and colleagues summarize the 2016 recommendations of the US Preventive Services Task Force (USPSTF) regarding aspirin for primary prevention, as well as the 4 large aspirin prevention trials published in 2018 subsequent to the USPSTF recommendations. The USPSTF recommended aspirin for adults ages 50 to 59 with a 10-year cardiovascular risk of at least 10% (B recommendation). For those ages 60-69, the USPSTF recommendation for aspirin as primary prevention has a “C” rating, meaning that patient preference is important to consider in balancing benefit and harms. For those 70 and older, the USPSTF gave aspirin an “I” (insufficient evidence) rating because of increased risk for bleeding. It is important to note that the positive B recommendation for those ages 50-59 is based not only on cardiovascular risk reduction but also on a slight risk reduction for colon cancer for those taking aspirin for at least 10 years.

The 4 new, large randomized trials published in 2018, however, cast doubt on the USPSTF recommendations because the results of these trials were negative for the most part. The bottom line is that daily aspirin for prevention is definitely not for everyone and perhaps not for anyone except those who have established vascular disease or are at high risk for vascular disease and low risk for bleeding.

No wonder patients are confused!
Smith recommends that, before prescribing aspirin to healthy adults for prevention, we assess each individual’s personal cardiovascular and bleeding risk using an online decision tool called Aspirin-Guide (www.aspiringuide.com). I agree.

Acetylsalicylic acid has been around for nearly 200 years. It traces its history back to a French chemist (Charles Frederic Gerhardt) and 2 German chemists (Felix Hoffmann and Arthur Eichengrün) who worked at Bayer, the company that launched the pain reliever under the name “aspirin” in 1899. It is now one of the most commonly used medications in the world.

No wonder our patients are confused!

With aspirin's anti-inflammatory properties in mind, researchers conducted randomized trials for secondary prevention of heart attacks in the 1970s; low-dose aspirin was proven effective in reducing risk for a second myocardial infarction. These trials led to speculation that aspirin might be effective for primary prevention as well. Indeed, in the 1980s the large Physicians' Health Study found aspirin reduced the incidence of first heart attack in healthy physicians by 44%.¹ Unfortunately, there was no reduction in mortality from heart disease and it was only effective for those older than 50.

The downside of aspirin was a slight increase in the incidence of hemorrhagic stroke and bleeding requiring transfusion. Nonetheless, many healthy adults started taking daily aspirin hoping to prevent a heart attack.

In this issue of JFP, Smith and colleagues summarize the 2016 recommendations of the US Preventive Services Task Force (USPSTF) regarding aspirin for primary prevention, as well as the 4 large aspirin prevention trials published in 2018 subsequent to the USPSTF recommendations. The USPSTF recommended aspirin for adults ages 50 to 59 with a 10-year cardiovascular risk of at least 10% (B recommendation). For those ages 60-69, the USPSTF recommendation for aspirin as primary prevention has a “C” rating, meaning that patient preference is important to consider in balancing benefit and harms. For those 70 and older, the USPSTF gave aspirin an “I” (insufficient evidence) rating because of increased risk for bleeding. It is important to note that the positive B recommendation for those ages 50-59 is based not only on cardiovascular risk reduction but also on a slight risk reduction for colon cancer for those taking aspirin for at least 10 years.

The 4 new, large randomized trials published in 2018, however, cast doubt on the USPSTF recommendations because the results of these trials were negative for the most part. The bottom line is that daily aspirin for prevention is definitely not for everyone and perhaps not for anyone except those who have established vascular disease or are at high risk for vascular disease and low risk for bleeding.

No wonder patients are confused!
Smith recommends that, before prescribing aspirin to healthy adults for prevention, we assess each individual’s personal cardiovascular and bleeding risk using an online decision tool called Aspirin-Guide (www.aspiringuide.com). I agree.

Acetylsalicylic acid has been around for nearly 200 years. It traces its history back to a French chemist (Charles Frederic Gerhardt) and 2 German chemists (Felix Hoffmann and Arthur Eichengrün) who worked at Bayer, the company that launched the pain reliever under the name “aspirin” in 1899. It is now one of the most commonly used medications in the world.

No wonder our patients are confused!

With aspirin's anti-inflammatory properties in mind, researchers conducted randomized trials for secondary prevention of heart attacks in the 1970s; low-dose aspirin was proven effective in reducing risk for a second myocardial infarction. These trials led to speculation that aspirin might be effective for primary prevention as well. Indeed, in the 1980s the large Physicians' Health Study found aspirin reduced the incidence of first heart attack in healthy physicians by 44%.¹ Unfortunately, there was no reduction in mortality from heart disease and it was only effective for those older than 50.

The downside of aspirin was a slight increase in the incidence of hemorrhagic stroke and bleeding requiring transfusion. Nonetheless, many healthy adults started taking daily aspirin hoping to prevent a heart attack.

In this issue of JFP, Smith and colleagues summarize the 2016 recommendations of the US Preventive Services Task Force (USPSTF) regarding aspirin for primary prevention, as well as the 4 large aspirin prevention trials published in 2018 subsequent to the USPSTF recommendations. The USPSTF recommended aspirin for adults ages 50 to 59 with a 10-year cardiovascular risk of at least 10% (B recommendation). For those ages 60-69, the USPSTF recommendation for aspirin as primary prevention has a “C” rating, meaning that patient preference is important to consider in balancing benefit and harms. For those 70 and older, the USPSTF gave aspirin an “I” (insufficient evidence) rating because of increased risk for bleeding. It is important to note that the positive B recommendation for those ages 50-59 is based not only on cardiovascular risk reduction but also on a slight risk reduction for colon cancer for those taking aspirin for at least 10 years.

The 4 new, large randomized trials published in 2018, however, cast doubt on the USPSTF recommendations because the results of these trials were negative for the most part. The bottom line is that daily aspirin for prevention is definitely not for everyone and perhaps not for anyone except those who have established vascular disease or are at high risk for vascular disease and low risk for bleeding.

No wonder patients are confused!
Smith recommends that, before prescribing aspirin to healthy adults for prevention, we assess each individual’s personal cardiovascular and bleeding risk using an online decision tool called Aspirin-Guide (www.aspiringuide.com). I agree.