Pediatrics

NATIONAL HARBOR, MD—Serial EEG has been confirmed as an accurate biomarker for risk of epilepsy in infants with tuberous sclerosis complex (TSC). In a prospective observational study involving five centers, the positive predictive value of epileptiform discharges for subsequent epilepsy was 100%, according to data presented at the 2015 Child Neurology Society Annual Meeting.

“The average interval between the time that EEG demonstrated epileptiform activity and the onset of the first seizure is between two to three months,” reported E. Martina Bebin, MD, a pediatric neurologist at the University of Alabama, Birmingham. She suggested that this interval is important because it may allow clinicians to pursue strategies designed to prevent or at least delay seizure onset.

While EEG is currently recommended at the time of TSC diagnosis, these data support the ability of serial EEG to screen for impending epilepsy, Dr. Bebin said. She noted that a recommendation for serial EEG had been issued in Europe through a consensus statement. The work by Dr. Bebin and colleagues, which was characterized as the first multicenter prospective study to establish EEG as a biomarker for epilepsy in TSC, also was published online ahead of print September 25 in Pediatric Neurology.

Heightened Risk

Studies have shown that as much as 80% of patients with TSC eventually develop epilepsy, and onset within the first six months of life is common. In a retrospective series conducted in Europe cited by Dr. Bebin, the majority of patients diagnosed with TSC early in life developed seizures before age 6 months. Many seizures were observed after a period of latent epileptogenesis. Other data linking EEG abnormalities to increased risk of overt seizures led to the multicenter trial to evaluate whether EEG could serve as a biomarker for epilepsy risk.

The investigators enrolled seizure-free children younger than 7 months old with a clinical or genetic diagnosis of TSC. Children previously treated with vigabatrin or inhibitors of the mammalian target of rapamycin were not eligible. Prematurity after at least 32 weeks’ gestation was not an exclusion criterion if there were no complications involving major organs. In addition to the University of Alabama, participating centers included Boston Children’s Hospital, Cincinnati Children’s Hospital, University of California at Los Angeles, and the University of Texas Medical School at Houston.

After enrollment, physical and neurologic evaluations were accompanied by a baseline one-hour EEG. The intent was to monitor brain activity during periods of wakefulness and sleep. Subsequent patient evaluations and EEGs were performed every six weeks for the first six months, every three months for another six months, and then every six months thereafter. The researchers considered more frequent monitoring over the first six months, which is the most common period of epilepsy onset, but the time commitment for families was a concern.

Forty children were enrolled. Dr. Bebin presented interim data on 28 children who had been followed past 12 months of age. Of the remaining children, six children were younger than 12 months, three had not yet had their EEG data fully analyzed, and three were treated with antiepileptic therapies on the basis of seizure activity observed on EEG and therefore excluded from analysis.

Initial Seizures

Clinical seizures developed in 19 children (67.8%) after enrollment. The average age at the time of first seizure was 6.7 months, with a range of 2 months to 20 months. Epileptic spasms were the most common type of initial seizures observed, accounting for 52.6%. In most other cases, patients had focal seizures either alone (26.3%) or in conjunction with epileptic spasms (15.8%).

EEG abnormalities, primarily in the form of epileptiform discharges, preceded the onset of the first seizure in 14 (73.7%) of the 19 infants. These EEG abnormalities were first observed between 1.2 and 9.0 months of age. The median interval between the epileptiform discharges and the first clinical seizure was 1.9 months and the average was 2.8 months. In the remaining five infants (26.3%) of the 19 who developed seizures, no EEG abnormalities were detected. Again, this group also largely developed focal seizures and epileptic spasms, but the only generalized tonic-clonic seizure occurred in this group.

Nine infants remained seizure-free off therapy, and all nine had normal EEGs over the period of evaluation.

As no infant demonstrated abnormal EEG without subsequently developing epilepsy, the positive predictive value was 100%. The negative predictive value, based on the five infants who developed epilepsy without first demonstrating an EEG abnormality, was 64%. Dr. Bebin pointed out that it is possible that abnormal EEG activity was missed in at least some of these infants due to the interval between EEG evaluations. In these patients, seizures developed at between two weeks and two months after the last EEG.

Opportunity for Trials

There were several strengths to this study, including the fact that independent reviewers, blinded to patient characteristics other than age, evaluated each EEG. At enrollment of the infants, parents received education about seizure recognition to improve the accuracy of identifying the time of onset.

Of the nine patients who remained seizure-free, eight showed normal development. The exception was a child who showed early signs of autism. Of the three patients who were excluded from the interim analysis because they were treated with vigabatrin on the basis of EEG abnormalities, only one remained seizure-free, according to Dr. Bebin, who reported that continued follow-up on all 40 patients initially enrolled is planned.

While the study has immediate practical implications for monitoring infants with TSC, it also identifies an opportunity to pursue clinical trials testing disease-modifying antiepileptogenic treatment strategies prior to the onset of epilepsy. The identification of this reliable EEG biomarker is expected to facilitate larger studies of preventive epilepsy treatment strategies.

—Ted Bosworth

NATIONAL HARBOR, MD—Serial EEG has been confirmed as an accurate biomarker for risk of epilepsy in infants with tuberous sclerosis complex (TSC). In a prospective observational study involving five centers, the positive predictive value of epileptiform discharges for subsequent epilepsy was 100%, according to data presented at the 2015 Child Neurology Society Annual Meeting.

“The average interval between the time that EEG demonstrated epileptiform activity and the onset of the first seizure is between two to three months,” reported E. Martina Bebin, MD, a pediatric neurologist at the University of Alabama, Birmingham. She suggested that this interval is important because it may allow clinicians to pursue strategies designed to prevent or at least delay seizure onset.

While EEG is currently recommended at the time of TSC diagnosis, these data support the ability of serial EEG to screen for impending epilepsy, Dr. Bebin said. She noted that a recommendation for serial EEG had been issued in Europe through a consensus statement. The work by Dr. Bebin and colleagues, which was characterized as the first multicenter prospective study to establish EEG as a biomarker for epilepsy in TSC, also was published online ahead of print September 25 in Pediatric Neurology.

Heightened Risk

Studies have shown that as much as 80% of patients with TSC eventually develop epilepsy, and onset within the first six months of life is common. In a retrospective series conducted in Europe cited by Dr. Bebin, the majority of patients diagnosed with TSC early in life developed seizures before age 6 months. Many seizures were observed after a period of latent epileptogenesis. Other data linking EEG abnormalities to increased risk of overt seizures led to the multicenter trial to evaluate whether EEG could serve as a biomarker for epilepsy risk.

The investigators enrolled seizure-free children younger than 7 months old with a clinical or genetic diagnosis of TSC. Children previously treated with vigabatrin or inhibitors of the mammalian target of rapamycin were not eligible. Prematurity after at least 32 weeks’ gestation was not an exclusion criterion if there were no complications involving major organs. In addition to the University of Alabama, participating centers included Boston Children’s Hospital, Cincinnati Children’s Hospital, University of California at Los Angeles, and the University of Texas Medical School at Houston.

After enrollment, physical and neurologic evaluations were accompanied by a baseline one-hour EEG. The intent was to monitor brain activity during periods of wakefulness and sleep. Subsequent patient evaluations and EEGs were performed every six weeks for the first six months, every three months for another six months, and then every six months thereafter. The researchers considered more frequent monitoring over the first six months, which is the most common period of epilepsy onset, but the time commitment for families was a concern.

Forty children were enrolled. Dr. Bebin presented interim data on 28 children who had been followed past 12 months of age. Of the remaining children, six children were younger than 12 months, three had not yet had their EEG data fully analyzed, and three were treated with antiepileptic therapies on the basis of seizure activity observed on EEG and therefore excluded from analysis.

Initial Seizures

Clinical seizures developed in 19 children (67.8%) after enrollment. The average age at the time of first seizure was 6.7 months, with a range of 2 months to 20 months. Epileptic spasms were the most common type of initial seizures observed, accounting for 52.6%. In most other cases, patients had focal seizures either alone (26.3%) or in conjunction with epileptic spasms (15.8%).

EEG abnormalities, primarily in the form of epileptiform discharges, preceded the onset of the first seizure in 14 (73.7%) of the 19 infants. These EEG abnormalities were first observed between 1.2 and 9.0 months of age. The median interval between the epileptiform discharges and the first clinical seizure was 1.9 months and the average was 2.8 months. In the remaining five infants (26.3%) of the 19 who developed seizures, no EEG abnormalities were detected. Again, this group also largely developed focal seizures and epileptic spasms, but the only generalized tonic-clonic seizure occurred in this group.

Nine infants remained seizure-free off therapy, and all nine had normal EEGs over the period of evaluation.

As no infant demonstrated abnormal EEG without subsequently developing epilepsy, the positive predictive value was 100%. The negative predictive value, based on the five infants who developed epilepsy without first demonstrating an EEG abnormality, was 64%. Dr. Bebin pointed out that it is possible that abnormal EEG activity was missed in at least some of these infants due to the interval between EEG evaluations. In these patients, seizures developed at between two weeks and two months after the last EEG.

Opportunity for Trials

There were several strengths to this study, including the fact that independent reviewers, blinded to patient characteristics other than age, evaluated each EEG. At enrollment of the infants, parents received education about seizure recognition to improve the accuracy of identifying the time of onset.

Of the nine patients who remained seizure-free, eight showed normal development. The exception was a child who showed early signs of autism. Of the three patients who were excluded from the interim analysis because they were treated with vigabatrin on the basis of EEG abnormalities, only one remained seizure-free, according to Dr. Bebin, who reported that continued follow-up on all 40 patients initially enrolled is planned.

While the study has immediate practical implications for monitoring infants with TSC, it also identifies an opportunity to pursue clinical trials testing disease-modifying antiepileptogenic treatment strategies prior to the onset of epilepsy. The identification of this reliable EEG biomarker is expected to facilitate larger studies of preventive epilepsy treatment strategies.

—Ted Bosworth

NATIONAL HARBOR, MD—Serial EEG has been confirmed as an accurate biomarker for risk of epilepsy in infants with tuberous sclerosis complex (TSC). In a prospective observational study involving five centers, the positive predictive value of epileptiform discharges for subsequent epilepsy was 100%, according to data presented at the 2015 Child Neurology Society Annual Meeting.

“The average interval between the time that EEG demonstrated epileptiform activity and the onset of the first seizure is between two to three months,” reported E. Martina Bebin, MD, a pediatric neurologist at the University of Alabama, Birmingham. She suggested that this interval is important because it may allow clinicians to pursue strategies designed to prevent or at least delay seizure onset.

While EEG is currently recommended at the time of TSC diagnosis, these data support the ability of serial EEG to screen for impending epilepsy, Dr. Bebin said. She noted that a recommendation for serial EEG had been issued in Europe through a consensus statement. The work by Dr. Bebin and colleagues, which was characterized as the first multicenter prospective study to establish EEG as a biomarker for epilepsy in TSC, also was published online ahead of print September 25 in Pediatric Neurology.

Heightened Risk

Studies have shown that as much as 80% of patients with TSC eventually develop epilepsy, and onset within the first six months of life is common. In a retrospective series conducted in Europe cited by Dr. Bebin, the majority of patients diagnosed with TSC early in life developed seizures before age 6 months. Many seizures were observed after a period of latent epileptogenesis. Other data linking EEG abnormalities to increased risk of overt seizures led to the multicenter trial to evaluate whether EEG could serve as a biomarker for epilepsy risk.

The investigators enrolled seizure-free children younger than 7 months old with a clinical or genetic diagnosis of TSC. Children previously treated with vigabatrin or inhibitors of the mammalian target of rapamycin were not eligible. Prematurity after at least 32 weeks’ gestation was not an exclusion criterion if there were no complications involving major organs. In addition to the University of Alabama, participating centers included Boston Children’s Hospital, Cincinnati Children’s Hospital, University of California at Los Angeles, and the University of Texas Medical School at Houston.

After enrollment, physical and neurologic evaluations were accompanied by a baseline one-hour EEG. The intent was to monitor brain activity during periods of wakefulness and sleep. Subsequent patient evaluations and EEGs were performed every six weeks for the first six months, every three months for another six months, and then every six months thereafter. The researchers considered more frequent monitoring over the first six months, which is the most common period of epilepsy onset, but the time commitment for families was a concern.

Forty children were enrolled. Dr. Bebin presented interim data on 28 children who had been followed past 12 months of age. Of the remaining children, six children were younger than 12 months, three had not yet had their EEG data fully analyzed, and three were treated with antiepileptic therapies on the basis of seizure activity observed on EEG and therefore excluded from analysis.

Initial Seizures

Clinical seizures developed in 19 children (67.8%) after enrollment. The average age at the time of first seizure was 6.7 months, with a range of 2 months to 20 months. Epileptic spasms were the most common type of initial seizures observed, accounting for 52.6%. In most other cases, patients had focal seizures either alone (26.3%) or in conjunction with epileptic spasms (15.8%).

EEG abnormalities, primarily in the form of epileptiform discharges, preceded the onset of the first seizure in 14 (73.7%) of the 19 infants. These EEG abnormalities were first observed between 1.2 and 9.0 months of age. The median interval between the epileptiform discharges and the first clinical seizure was 1.9 months and the average was 2.8 months. In the remaining five infants (26.3%) of the 19 who developed seizures, no EEG abnormalities were detected. Again, this group also largely developed focal seizures and epileptic spasms, but the only generalized tonic-clonic seizure occurred in this group.

Nine infants remained seizure-free off therapy, and all nine had normal EEGs over the period of evaluation.

As no infant demonstrated abnormal EEG without subsequently developing epilepsy, the positive predictive value was 100%. The negative predictive value, based on the five infants who developed epilepsy without first demonstrating an EEG abnormality, was 64%. Dr. Bebin pointed out that it is possible that abnormal EEG activity was missed in at least some of these infants due to the interval between EEG evaluations. In these patients, seizures developed at between two weeks and two months after the last EEG.

Opportunity for Trials

There were several strengths to this study, including the fact that independent reviewers, blinded to patient characteristics other than age, evaluated each EEG. At enrollment of the infants, parents received education about seizure recognition to improve the accuracy of identifying the time of onset.

Of the nine patients who remained seizure-free, eight showed normal development. The exception was a child who showed early signs of autism. Of the three patients who were excluded from the interim analysis because they were treated with vigabatrin on the basis of EEG abnormalities, only one remained seizure-free, according to Dr. Bebin, who reported that continued follow-up on all 40 patients initially enrolled is planned.

While the study has immediate practical implications for monitoring infants with TSC, it also identifies an opportunity to pursue clinical trials testing disease-modifying antiepileptogenic treatment strategies prior to the onset of epilepsy. The identification of this reliable EEG biomarker is expected to facilitate larger studies of preventive epilepsy treatment strategies.

—Ted Bosworth

NATIONAL HARBOR, MD—Clinicians often make “poor treatment choices” when presented with a patient with infantile spasms, said W. Donald Shields, MD, Past President of the Child Neurology Foundation and Emeritus Professor of Neurology and Pediatrics at the University of California, Los Angeles. “Some people think that the best way to go is to start with the dose low, but this is one where you make the diagnosis and you nuke it,” he said at the 2015 Child Neurology Society Annual Meeting. “You want to get to therapeutic levels as fast as you possibly can.”

Left untreated, infantile spasms can lead to serious outcomes, including an estimated infant mortality rate of between 5% and 6%. The most significant concern, however, is that infantile spasms are associated with autism and intellectual deficits that permanently affect quality of life. These outcomes are modifiable, said Dr. Shields.

In a 2004 study of long-term outcomes in cryptogenic infantile spasms, 100% of children seen within one month of parents’ recognition of the spasm developed IQs in the normal range, said Dr. Shields. When patients were treated later, less than 40% of them had good outcomes. Treatment is more likely to provide a sustained response if implemented within three weeks after the spasm, he explained.

“A huge challenge is that we have to get the child into effective treatment quickly,” said James Wheless, MD, Chief of Pediatric Neurology at the University of Tennessee Health Science Center, and Director of the Le Bonheur Comprehensive Epilepsy Program and the Neuroscience Institute at Le Bonheur Children’s Hospital in Memphis.

This goal is often difficult to achieve because of a lack of consensus on the best therapy, and treatment practices vary greatly by location, said Dr. Wheless. “Not all drugs are approved everywhere.” In Japan, only zonisamide is approved for the treatment of infantile spasms, while in the United States, vigabatrin and adrenocorticotropic hormone (ACTH) are the only agents with FDA approval.

Lack of Evidence-Based Medicine

These inconsistencies have contributed to a scarcity of data from evidence-based sources. “We have a lot of variation in treatment here, for different countries, which speaks to the fact that we need better data to review and [a better understanding] of the regulatory statutes that affect them,” said Dr. Wheless.

In recommendations published in 2006, the International League Against Epilepsy (ILAE) considered the data too limited to develop guidelines for infantile spasms, Dr. Wheless said. As late as 2013, “again, the data were not strong enough to make guidelines, so [the ILAE] made recommendations,” he observed. Level B evidence indicated that ACTH is preferable for short-term spasm control, and Level C evidence suggested that corticosteroids are probably effective for short-term spasm control. Updates to the recommendations in 2008 and 2013 indicated that vigabatrin is effective in the short term, especially in the treatment of tuberous sclerosis complex. “Treatment with ACTH or [an] oral steroid is better in the long term, especially in cases with no known etiology,” said Dr. Wheless.

Further review of the data revealed little evidence that one particular treatment was optimal, although high-dose ACTH was found to be more effective than prednisone. In the 2008 update, ACTH also was considered more effective than vigabatrin. The authors found that a high dose of prednisone was preferred to a low dose.

Goals of Therapy

Although neurologists have no clear guidelines on the best therapies for infantile spasms, clear indications about the best strategies have emerged. Neurologists should treat infantile spasms as an encephalopathic disorder that visually manifests on EEG, said Drs. Shields and Wheless. “We need to not only control the spasms, but we have to improve the EEG, because the EEG is the harbinger for the development of continuing problems,” added Dr. Wheless.

Regardless of the initial agent used, the goals of therapy for symptomatic infantile spasms are to treat early, to treat effectively with a known agent with demonstrated efficacy, and to try a second therapy if the first is not effective. “You really have to be using effective therapies,” Dr. Wheless said. Several studies indicate that high-dose protocols of drugs, including prednisone, vigabatrin, and particularly ACTH, produce better outcomes. “All ACTH studies showed a dose response,” said Dr. Wheless.

The American Academy of Neurology and Child Neurology Society reviewed 14 studies of ACTH therapy. Across those studies, high-dose ACTH treatment was associated with remission rates for infantile spasms estimated at 90% over two months. “High dose is where we get our bang for our buck,” said Dr. Wheless.

Clinical practice in the most recent studies has tended to proceed from high-dose oral prednisone to very-high-dose therapy, he continued. Outcome data from a study by Hussain et al showed that 63% of patients had a complete response to a very high dose (ie, 8 mg/kg/day and a maximum of 60 mg/day) of oral prednisolone for two weeks. Furthermore, 40% of nonresponders had a complete response to a subsequent two-week course of ACTH.

A similar study showed excellent responses to high-dose (ie, 40 mg/day) prednisolone with an increase to a very high dose (ie, 60 mg/day) if spasms continued, compared with moderate to high doses of synthetic ACTH. Response to very-high-dose prednisolone in this study was 58%. “It’s better than we used to see with 2 mg/kg/day, so very-high-dose prednisolone seems to be better than high-dose prednisolone, but it’s lower than what we’re used to seeing with high-dose ACTH,” said Dr. Wheless. He cited a need for a study comparing a very high dose of prednisolone with high-dose ACTH.

A dose comparison study by Elterman et al in 2010 supported the use of high-dose vigabatrin for infantile spasms. The study had a response rate of about 65%. Patients who did not respond had a much better response to high-dose synthetic ACTH than to high-dose prednisone as a second agent. “If vigabatrin doesn’t work, you might be better off going to a high-dose ACTH as a next step,” said Dr. Wheless.

—Linda Peckel

NATIONAL HARBOR, MD—Clinicians often make “poor treatment choices” when presented with a patient with infantile spasms, said W. Donald Shields, MD, Past President of the Child Neurology Foundation and Emeritus Professor of Neurology and Pediatrics at the University of California, Los Angeles. “Some people think that the best way to go is to start with the dose low, but this is one where you make the diagnosis and you nuke it,” he said at the 2015 Child Neurology Society Annual Meeting. “You want to get to therapeutic levels as fast as you possibly can.”

Left untreated, infantile spasms can lead to serious outcomes, including an estimated infant mortality rate of between 5% and 6%. The most significant concern, however, is that infantile spasms are associated with autism and intellectual deficits that permanently affect quality of life. These outcomes are modifiable, said Dr. Shields.

In a 2004 study of long-term outcomes in cryptogenic infantile spasms, 100% of children seen within one month of parents’ recognition of the spasm developed IQs in the normal range, said Dr. Shields. When patients were treated later, less than 40% of them had good outcomes. Treatment is more likely to provide a sustained response if implemented within three weeks after the spasm, he explained.

“A huge challenge is that we have to get the child into effective treatment quickly,” said James Wheless, MD, Chief of Pediatric Neurology at the University of Tennessee Health Science Center, and Director of the Le Bonheur Comprehensive Epilepsy Program and the Neuroscience Institute at Le Bonheur Children’s Hospital in Memphis.

This goal is often difficult to achieve because of a lack of consensus on the best therapy, and treatment practices vary greatly by location, said Dr. Wheless. “Not all drugs are approved everywhere.” In Japan, only zonisamide is approved for the treatment of infantile spasms, while in the United States, vigabatrin and adrenocorticotropic hormone (ACTH) are the only agents with FDA approval.

Lack of Evidence-Based Medicine

These inconsistencies have contributed to a scarcity of data from evidence-based sources. “We have a lot of variation in treatment here, for different countries, which speaks to the fact that we need better data to review and [a better understanding] of the regulatory statutes that affect them,” said Dr. Wheless.

In recommendations published in 2006, the International League Against Epilepsy (ILAE) considered the data too limited to develop guidelines for infantile spasms, Dr. Wheless said. As late as 2013, “again, the data were not strong enough to make guidelines, so [the ILAE] made recommendations,” he observed. Level B evidence indicated that ACTH is preferable for short-term spasm control, and Level C evidence suggested that corticosteroids are probably effective for short-term spasm control. Updates to the recommendations in 2008 and 2013 indicated that vigabatrin is effective in the short term, especially in the treatment of tuberous sclerosis complex. “Treatment with ACTH or [an] oral steroid is better in the long term, especially in cases with no known etiology,” said Dr. Wheless.

Further review of the data revealed little evidence that one particular treatment was optimal, although high-dose ACTH was found to be more effective than prednisone. In the 2008 update, ACTH also was considered more effective than vigabatrin. The authors found that a high dose of prednisone was preferred to a low dose.

Goals of Therapy

Although neurologists have no clear guidelines on the best therapies for infantile spasms, clear indications about the best strategies have emerged. Neurologists should treat infantile spasms as an encephalopathic disorder that visually manifests on EEG, said Drs. Shields and Wheless. “We need to not only control the spasms, but we have to improve the EEG, because the EEG is the harbinger for the development of continuing problems,” added Dr. Wheless.

Regardless of the initial agent used, the goals of therapy for symptomatic infantile spasms are to treat early, to treat effectively with a known agent with demonstrated efficacy, and to try a second therapy if the first is not effective. “You really have to be using effective therapies,” Dr. Wheless said. Several studies indicate that high-dose protocols of drugs, including prednisone, vigabatrin, and particularly ACTH, produce better outcomes. “All ACTH studies showed a dose response,” said Dr. Wheless.

The American Academy of Neurology and Child Neurology Society reviewed 14 studies of ACTH therapy. Across those studies, high-dose ACTH treatment was associated with remission rates for infantile spasms estimated at 90% over two months. “High dose is where we get our bang for our buck,” said Dr. Wheless.

Clinical practice in the most recent studies has tended to proceed from high-dose oral prednisone to very-high-dose therapy, he continued. Outcome data from a study by Hussain et al showed that 63% of patients had a complete response to a very high dose (ie, 8 mg/kg/day and a maximum of 60 mg/day) of oral prednisolone for two weeks. Furthermore, 40% of nonresponders had a complete response to a subsequent two-week course of ACTH.

A similar study showed excellent responses to high-dose (ie, 40 mg/day) prednisolone with an increase to a very high dose (ie, 60 mg/day) if spasms continued, compared with moderate to high doses of synthetic ACTH. Response to very-high-dose prednisolone in this study was 58%. “It’s better than we used to see with 2 mg/kg/day, so very-high-dose prednisolone seems to be better than high-dose prednisolone, but it’s lower than what we’re used to seeing with high-dose ACTH,” said Dr. Wheless. He cited a need for a study comparing a very high dose of prednisolone with high-dose ACTH.

A dose comparison study by Elterman et al in 2010 supported the use of high-dose vigabatrin for infantile spasms. The study had a response rate of about 65%. Patients who did not respond had a much better response to high-dose synthetic ACTH than to high-dose prednisone as a second agent. “If vigabatrin doesn’t work, you might be better off going to a high-dose ACTH as a next step,” said Dr. Wheless.

—Linda Peckel

NATIONAL HARBOR, MD—Clinicians often make “poor treatment choices” when presented with a patient with infantile spasms, said W. Donald Shields, MD, Past President of the Child Neurology Foundation and Emeritus Professor of Neurology and Pediatrics at the University of California, Los Angeles. “Some people think that the best way to go is to start with the dose low, but this is one where you make the diagnosis and you nuke it,” he said at the 2015 Child Neurology Society Annual Meeting. “You want to get to therapeutic levels as fast as you possibly can.”

Left untreated, infantile spasms can lead to serious outcomes, including an estimated infant mortality rate of between 5% and 6%. The most significant concern, however, is that infantile spasms are associated with autism and intellectual deficits that permanently affect quality of life. These outcomes are modifiable, said Dr. Shields.

In a 2004 study of long-term outcomes in cryptogenic infantile spasms, 100% of children seen within one month of parents’ recognition of the spasm developed IQs in the normal range, said Dr. Shields. When patients were treated later, less than 40% of them had good outcomes. Treatment is more likely to provide a sustained response if implemented within three weeks after the spasm, he explained.

“A huge challenge is that we have to get the child into effective treatment quickly,” said James Wheless, MD, Chief of Pediatric Neurology at the University of Tennessee Health Science Center, and Director of the Le Bonheur Comprehensive Epilepsy Program and the Neuroscience Institute at Le Bonheur Children’s Hospital in Memphis.

This goal is often difficult to achieve because of a lack of consensus on the best therapy, and treatment practices vary greatly by location, said Dr. Wheless. “Not all drugs are approved everywhere.” In Japan, only zonisamide is approved for the treatment of infantile spasms, while in the United States, vigabatrin and adrenocorticotropic hormone (ACTH) are the only agents with FDA approval.

Lack of Evidence-Based Medicine

These inconsistencies have contributed to a scarcity of data from evidence-based sources. “We have a lot of variation in treatment here, for different countries, which speaks to the fact that we need better data to review and [a better understanding] of the regulatory statutes that affect them,” said Dr. Wheless.

In recommendations published in 2006, the International League Against Epilepsy (ILAE) considered the data too limited to develop guidelines for infantile spasms, Dr. Wheless said. As late as 2013, “again, the data were not strong enough to make guidelines, so [the ILAE] made recommendations,” he observed. Level B evidence indicated that ACTH is preferable for short-term spasm control, and Level C evidence suggested that corticosteroids are probably effective for short-term spasm control. Updates to the recommendations in 2008 and 2013 indicated that vigabatrin is effective in the short term, especially in the treatment of tuberous sclerosis complex. “Treatment with ACTH or [an] oral steroid is better in the long term, especially in cases with no known etiology,” said Dr. Wheless.

Further review of the data revealed little evidence that one particular treatment was optimal, although high-dose ACTH was found to be more effective than prednisone. In the 2008 update, ACTH also was considered more effective than vigabatrin. The authors found that a high dose of prednisone was preferred to a low dose.

Goals of Therapy

Although neurologists have no clear guidelines on the best therapies for infantile spasms, clear indications about the best strategies have emerged. Neurologists should treat infantile spasms as an encephalopathic disorder that visually manifests on EEG, said Drs. Shields and Wheless. “We need to not only control the spasms, but we have to improve the EEG, because the EEG is the harbinger for the development of continuing problems,” added Dr. Wheless.

Regardless of the initial agent used, the goals of therapy for symptomatic infantile spasms are to treat early, to treat effectively with a known agent with demonstrated efficacy, and to try a second therapy if the first is not effective. “You really have to be using effective therapies,” Dr. Wheless said. Several studies indicate that high-dose protocols of drugs, including prednisone, vigabatrin, and particularly ACTH, produce better outcomes. “All ACTH studies showed a dose response,” said Dr. Wheless.

The American Academy of Neurology and Child Neurology Society reviewed 14 studies of ACTH therapy. Across those studies, high-dose ACTH treatment was associated with remission rates for infantile spasms estimated at 90% over two months. “High dose is where we get our bang for our buck,” said Dr. Wheless.

Clinical practice in the most recent studies has tended to proceed from high-dose oral prednisone to very-high-dose therapy, he continued. Outcome data from a study by Hussain et al showed that 63% of patients had a complete response to a very high dose (ie, 8 mg/kg/day and a maximum of 60 mg/day) of oral prednisolone for two weeks. Furthermore, 40% of nonresponders had a complete response to a subsequent two-week course of ACTH.

A similar study showed excellent responses to high-dose (ie, 40 mg/day) prednisolone with an increase to a very high dose (ie, 60 mg/day) if spasms continued, compared with moderate to high doses of synthetic ACTH. Response to very-high-dose prednisolone in this study was 58%. “It’s better than we used to see with 2 mg/kg/day, so very-high-dose prednisolone seems to be better than high-dose prednisolone, but it’s lower than what we’re used to seeing with high-dose ACTH,” said Dr. Wheless. He cited a need for a study comparing a very high dose of prednisolone with high-dose ACTH.

A dose comparison study by Elterman et al in 2010 supported the use of high-dose vigabatrin for infantile spasms. The study had a response rate of about 65%. Patients who did not respond had a much better response to high-dose synthetic ACTH than to high-dose prednisone as a second agent. “If vigabatrin doesn’t work, you might be better off going to a high-dose ACTH as a next step,” said Dr. Wheless.

—Linda Peckel

TALKING OUT CHILDHOOD OBESITY
Resnicow K, McMaster F, Bocian A, et al. Motivational interviewing and dietary counseling for obesity in primary care: an RCT. Pediatrics. 2015;135(4):649-657.

Counseling parents of overweight children using motivational interviewing from both health care providers and registered dietitians can significantly improve BMI, according to a study of 42 practices in the Pediatric Research in Office Settings Network of the American Academy of Pediatrics.

Researchers randomly assigned parents of overweight children, ages 2 through 8, to one of three groups: (1) usual care, (2) four provider-delivered motivational interviewing sessions over two years, or (3) four provider-delivered motivational interviewing sessions plus six sessions with a registered dietitian over two years. At study end, BMI percentile and change in BMI for the different groups were as follows:

COMMENTARY
The results of this study are exciting. Motivational interviewing is a technique in which the practitioner asks questions of a patient and allows the patient to discover his/her own conclusions about the topic. By so doing, the patient is more engaged in the discussion and is less resistant to input. This technique, with excellent evidence of effectiveness in the area of drug and alcohol abuse, has been shown to facilitate effective behavioral change in many areas and is recommended by the American Heart Association for behavioral change in adults.1,2 This is an exciting paper demonstrating evidence-based efficacy in addressing childhood obesity—a critical health issue—and is worth trying in the office. 

1. Rubak S, Sandbaek A, Lauritzen T, Christensen B. Motivational interviewing: a systematic review and meta-analysis. Br J Gen Pract. 2005;55(513):305-312.
2. Spring B, Ockene JK, Gidding SS, et al; American Heart Association Behavior Change Committee of the Council on Epidemiology and Prevention, Council on Lifestyle and Cardiometabolic Health, Council for High Blood Pressure Research, and Council on Cardiovascular and Stroke Nursing. Better population health through behavior change in adults: a call to action. Circulation. 2013;128(19):2169-2176. doi: 10.1161/01.cir.0000435173.25936.e1. 

Continue for long-acting reversible contraception among teens >>

LONG-ACTING REVERSIBLE CONTRACEPTION AMONG TEENS
Romero L, Pazol K, Warner L, et al. Vital signs: trends in use of long-acting reversible contraception among teens aged 15-19 years seeking contraceptive services – United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2015;64(13):363-369.

Efforts to improve teen access to long-acting reversible contraception (LARC) have increased use of these methods, according to a CDC review of services provided at Title X National Family Planning Program centers. The report found
• LARC rates among teen patients increased from 0.4% in 2005 to 7.2% in 2013.
• In 2013, 2.8% of those seeking contraception used IUDs and 4.3% used implants.
• Among Title X patients, 7.6% of 18- and 19-year-olds used LARC, compared with 6.5% of 15- to 17-year-olds.
• Rates of LARC were lowest in Mississippi (0.7%) and highest in Colorado (25.8%).

COMMENTARY
LARCs, which include IUD and implantable hormonal contraceptive devices, require no effort for adherence on the part of the user; once in place, they are effective without further action. Current CDC guidelines on contraceptive use clearly recommend LARC for teenagers based on the efficacy and safety.¹ LARCs are favored for teenagers because poor compliance has yielded suboptimal effectiveness of oral contraceptives and condoms in teenagers, who often forget to take their birth control pills or don’t use condoms when they should. Many clinicians have been slow to recommend LARCs in teenagers based on safety concerns related to adverse experience with IUDs 20 to 30 years ago. According to CDC guidelines, IUDs and implantable contraceptive devices now have robust safety data, and this article shows that they are being increasingly made available to teenagers who need them.

1. Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. US Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep. 2013;62(RR-05):1-60.

Continue to testing for celiac in pediatric rheumatology patients >>

TESTING FOR CELIAC IN PEDIATRIC RHEUMATOLOGY PATIENTS
Sherman Y, Karanicolas R, DiMarco B, et al. Unrecognized celiac disease in children presenting for rheumatology evaluation. Pediatrics. 2015; [Epub ahead of print].

Children presenting for rheumatology evaluation should be screened for celiac disease, according to a review of 2,125 pediatric patients who were screened for celiac as part of the standard initial serologic evaluation.

Researchers identified 36 new cases of celiac disease (2.0% prevalence rate). The most common presenting complaints among these patients were myalgia, arthralgia, and rash. Less frequent complaints included gastrointestinal complaints of abdominal pain, nausea, and diarrhea.

After initiating a gluten-free diet, all of the patients with celiac disease reported improvement or complete resolution of musculoskeletal symptoms.

COMMENTARY
Celiac disease has a prevalence of 0.5% to 1% in the US and can present with a range of symptoms that include diarrhea, abdominal discomfort, and weight loss. In addition to these typical symptoms, celiac disease can cause a wide range of systemic symptoms, including osteopenia, abnormal liver function tests, anemia, neurologic symptoms, and general malaise and fatigue.¹ This study suggests that celiac testing be considered in children presenting with rheumatologic symptoms, including myalgia, arthralgia, and rash.

1. Presutti RJ, Cangemi JR, Cassidy HD, et al. Celiac disease. Am Fam Physician. 2007;76(12):1795-1802, 1809-1810.

Continue for educating parents about antibiotic use >>

EDUCATING PARENTS ABOUT ANTIBIOTIC USE
Vaz LE, Kleinman KP, Lakoma MD, et al. Prevalence of parental misconceptions about antibiotic use. Pediatrics. 2015;136:221-231.

Misperceptions about antibiotic use persist and continue to be more prevalent among parents of Medicaid-insured children, according to a study of 1,500 Massachusetts parents.

Investigators examined antibiotic-related knowledge and attitudes among both Medicaid-insured and private-insured parents and found
• Fewer Medicaid parents answered questions correctly, except for one regarding bronchitis.
• Medicaid patients were more likely to request unnecessary antibiotics.
• More parents in 2013 understood that green nasal discharge did not require antibiotics than in 2000.
• Medicaid-insured parents were younger, less likely to be white, and had less education than those commercially insured.

COMMENTARY
Decreasing the unnecessary use of antibiotics for viral infections is an important component of decreasing the development of antibiotic-resistant organisms. An important driver of clinician use of antibiotics is patients’ expectations for antibiotics. This study shows that much work remains to be done in changing patient expectations, which is not surprising to any practicing clinician. This study also suggests that the expectation for antibiotics is greater among those individuals with Medicaid insurance, which suggests that an opportunity exists for Medicaid insurance plans to do targeted patient education on this issue—which should improve patient outcomes, decrease cost from use of unneeded antibiotics, and decrease the development of antibiotic-resistant organisms.

Continue for newborn pulmonary hypertension and maternal antidepressant use >>

NEWBORN PULMONARY HYPERTENSION AND MATERNAL ANTIDEPRESSANT USE
Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151.

Taking antidepressants during late pregnancy may increase the risk for persistent pulmonary hypertension of the newborn (PPHN), according to a nested cohort study of more than 3.7 million pregnant women in the 2000-2010 Medicaid Analytic eXtract.

Investigators compared offspring of mothers who used selective serotonin reuptake inhibitors (SSRIs) or non-SSRI monotherapy in the last 90 days of pregnancy to those who did not and found 3.4% of women filled at least one prescription for antidepressants late in pregnancy, primarily SSRIs.

Rates and odds ratios (ORs) of PPHN stratified by use and type of antidepressant were as follows:

The study authors note the absolute risk is small, and the increased risk is more modest than previous studies found.

COMMENTARY
Depression affects more than 12% of pregnancies and has important consequences, including increased risk for suicide, preterm birth, poor fetal growth, and impaired fetal and infant development.¹ PPHN is a serious condition that can require intubation and can be fatal in 10% to 20% of cases. This study adds to the conflicting data suggesting that SSRI use in pregnancy can lead to an increase in this rare condition. The decision to use an antidepressant during pregnancy is a difficult one, because depression has serious consequences but so, potentially, does treatment. The treatment of depression during pregnancy requires thoughtful, informed discussion between patient and provider. 

1. Stewart DE. Clinical practice. Depression during pregnancy. N Engl J Med. 2011;365(17):1605-1611. doi:10.1056/NEJMcp1102730.

Continue for new infant vaccine treats 6 diseases >>

NEW INFANT VACCINE TREATS 6 DISEASES
Marshall GS, Adams GL, Leonardi ML, et al. Immunogenicity, safety, and tolerability of a hexavalent vaccine in infants. Pediatrics. 2015:136(2):323-332.

The safety and immunogenicity of DTaP5-IPV-Hib-HepB fully liquid investigational hexavalent vaccine are comparable with the analogous licensed component vaccines and provide a new combination vaccine option aligned with the recommended US infant immunization schedule, according to a phase III study of 1,465 participants. Overall, 981 healthy infants were vaccinated in group 1 with the hexavalent vaccine and 484 in group 2 with the analogous licensed component vaccines.

The study found
• Immune responses in group 1 to all antigens contained in the vaccine one month after dose 3 were essentially noninferior to those in group 2.
• Adverse event rates after any dose were similar in both groups.

COMMENTARY
Vaccine administration has led to many diseases, including Haemophilus influenzae type b, polio, and measles, becoming quite rare. As we have recently seen with the resurgence of measles, continued vigilance and high immunization rates are important in ensuring that these diseases remain rare. The development of a hexavalent vaccine is another step in making immunization easier for clinicians to administer and for patients to accept.

Continue for treating infants with bronchiolitis >>

TREATING INFANTS WITH BRONCHIOLITIS
Silver AH, Esteban-Cruciani N, Azzarone G, et al. 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial. Pediatrics. 2015;136:1036-1043.

Infants hospitalized with bronchiolitis saw no difference in length of stay or seven-day readmission rates when treated with nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS), according to a randomized, controlled study of 227 infants who were younger than 12 months when admitted. Patients received either 4 mL nebulized 3% HS (113 infants) or 4 mL 0.9% NS (114 infants) every four hours from enrollment until hospital discharge. Researchers found
• Median length of stay of HS and NS groups was 2.1 days vs 2.1 days, respectively.
• Seven-day readmission rates for HS and NS groups were 4.3% vs 3.1%, respectively.
• Clinical worsening events were similar between groups.

COMMENTARY
Bronchiolitis, the most common lower respiratory tract infection in infants, is usually due to a viral infection, most often respiratory syncytial virus, and can cause disease that ranges in severity from mild to life-threatening. Infants with bronchiolitis typically present with rhinitis, tachypnea, wheezing, and cough, and occasionally crackles and use of accessory muscles. While many medications are used, supportive care and monitoring are the mainstays of therapy. Maintaining pulse above 90% is important, using supplemental oxygen when needed to achieve this. Alpha-adrenergic and beta-adrenergic bronchodilators are often used; though the evidence suggests that they are not usually helpful, they can be tried and continued if they appear to help. Systemic steroids are often used, but they too lack evidence of efficacy.¹ This study shows that hypertonic saline can now join the list of interventions used with evidence of a lack of efficacy.

1. Diagnosis and management of bronchiolitis. Subcommittee on diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. doi:10.1542/peds.2006-2223.

Continue for azithromycin and preschool children >>

AZITHROMYCIN AND PRESCHOOL CHILDREN: CAN ANTIBIOTICS LESSEN ONSET OF SEVERE LRTIs?
Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034-2044.

The use of azithromycin early during an apparent respiratory tract illness (RTI) reduced the likelihood of severe lower RTI (LRTI) among young children with a history of recurrent severe LRTI, compared with placebo, according to a study of 607 children ages 12 to 71 months. Participants were randomized in a 1:1 ratio to receive either azithromycin (12 mg/kg/d for 5 d) or matching placebo at the start of an RTI. Researchers found
• A total of 937 treated RTIs were experienced by 443 children, including 92 severe LRTIs (azithromycin group, 35; placebo group, 57).
• Azithromycin significantly reduced the risk for progression to severe LRTI relative to placebo (HR, 0.64).
• Induction of azithromycin-resistant organisms and adverse events were infrequent.

COMMENTARY
Recurrent episodes of severe wheezing with RTI are an important and common occurrence, affecting up to 15% to 20% of children prior to age 6.¹ LRTI was defined in this study as RTI that required the use of additional rescue medication. The current approach to RTI is to try to minimize the use of antibiotics unless an infection is clearly bacterial in origin, and to treat severe LRTI when it occurs. The results of this trial suggest that in children at high risk for severe LRTI, identified by their episodes of recurrent wheezing, early treatment of RTI with azithromycin may decrease the development of severe LRTI by more than 35%—an important result. It is important to recognize that this study does not suggest treating all RTIs with antibiotics, but rather that the use of a macrolide antibiotic may be considered, perhaps, in the select group of children similar to those studied, with a history of recurrent wheezing with previous RTIs.

1. Ly NP, Gold DR, Weiss ST, Celedón JC. Recurrent wheeze in early childhood and asthma among children at risk for atopy. Pediatrics. 2006;117(6):e1132-e1138.

TALKING OUT CHILDHOOD OBESITY
Resnicow K, McMaster F, Bocian A, et al. Motivational interviewing and dietary counseling for obesity in primary care: an RCT. Pediatrics. 2015;135(4):649-657.

Counseling parents of overweight children using motivational interviewing from both health care providers and registered dietitians can significantly improve BMI, according to a study of 42 practices in the Pediatric Research in Office Settings Network of the American Academy of Pediatrics.

Researchers randomly assigned parents of overweight children, ages 2 through 8, to one of three groups: (1) usual care, (2) four provider-delivered motivational interviewing sessions over two years, or (3) four provider-delivered motivational interviewing sessions plus six sessions with a registered dietitian over two years. At study end, BMI percentile and change in BMI for the different groups were as follows:

COMMENTARY
The results of this study are exciting. Motivational interviewing is a technique in which the practitioner asks questions of a patient and allows the patient to discover his/her own conclusions about the topic. By so doing, the patient is more engaged in the discussion and is less resistant to input. This technique, with excellent evidence of effectiveness in the area of drug and alcohol abuse, has been shown to facilitate effective behavioral change in many areas and is recommended by the American Heart Association for behavioral change in adults.1,2 This is an exciting paper demonstrating evidence-based efficacy in addressing childhood obesity—a critical health issue—and is worth trying in the office. 

1. Rubak S, Sandbaek A, Lauritzen T, Christensen B. Motivational interviewing: a systematic review and meta-analysis. Br J Gen Pract. 2005;55(513):305-312.
2. Spring B, Ockene JK, Gidding SS, et al; American Heart Association Behavior Change Committee of the Council on Epidemiology and Prevention, Council on Lifestyle and Cardiometabolic Health, Council for High Blood Pressure Research, and Council on Cardiovascular and Stroke Nursing. Better population health through behavior change in adults: a call to action. Circulation. 2013;128(19):2169-2176. doi: 10.1161/01.cir.0000435173.25936.e1. 

Continue for long-acting reversible contraception among teens >>

LONG-ACTING REVERSIBLE CONTRACEPTION AMONG TEENS
Romero L, Pazol K, Warner L, et al. Vital signs: trends in use of long-acting reversible contraception among teens aged 15-19 years seeking contraceptive services – United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2015;64(13):363-369.

Efforts to improve teen access to long-acting reversible contraception (LARC) have increased use of these methods, according to a CDC review of services provided at Title X National Family Planning Program centers. The report found
• LARC rates among teen patients increased from 0.4% in 2005 to 7.2% in 2013.
• In 2013, 2.8% of those seeking contraception used IUDs and 4.3% used implants.
• Among Title X patients, 7.6% of 18- and 19-year-olds used LARC, compared with 6.5% of 15- to 17-year-olds.
• Rates of LARC were lowest in Mississippi (0.7%) and highest in Colorado (25.8%).

COMMENTARY
LARCs, which include IUD and implantable hormonal contraceptive devices, require no effort for adherence on the part of the user; once in place, they are effective without further action. Current CDC guidelines on contraceptive use clearly recommend LARC for teenagers based on the efficacy and safety.¹ LARCs are favored for teenagers because poor compliance has yielded suboptimal effectiveness of oral contraceptives and condoms in teenagers, who often forget to take their birth control pills or don’t use condoms when they should. Many clinicians have been slow to recommend LARCs in teenagers based on safety concerns related to adverse experience with IUDs 20 to 30 years ago. According to CDC guidelines, IUDs and implantable contraceptive devices now have robust safety data, and this article shows that they are being increasingly made available to teenagers who need them.

1. Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. US Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep. 2013;62(RR-05):1-60.

Continue to testing for celiac in pediatric rheumatology patients >>

TESTING FOR CELIAC IN PEDIATRIC RHEUMATOLOGY PATIENTS
Sherman Y, Karanicolas R, DiMarco B, et al. Unrecognized celiac disease in children presenting for rheumatology evaluation. Pediatrics. 2015; [Epub ahead of print].

Children presenting for rheumatology evaluation should be screened for celiac disease, according to a review of 2,125 pediatric patients who were screened for celiac as part of the standard initial serologic evaluation.

Researchers identified 36 new cases of celiac disease (2.0% prevalence rate). The most common presenting complaints among these patients were myalgia, arthralgia, and rash. Less frequent complaints included gastrointestinal complaints of abdominal pain, nausea, and diarrhea.

After initiating a gluten-free diet, all of the patients with celiac disease reported improvement or complete resolution of musculoskeletal symptoms.

COMMENTARY
Celiac disease has a prevalence of 0.5% to 1% in the US and can present with a range of symptoms that include diarrhea, abdominal discomfort, and weight loss. In addition to these typical symptoms, celiac disease can cause a wide range of systemic symptoms, including osteopenia, abnormal liver function tests, anemia, neurologic symptoms, and general malaise and fatigue.¹ This study suggests that celiac testing be considered in children presenting with rheumatologic symptoms, including myalgia, arthralgia, and rash.

1. Presutti RJ, Cangemi JR, Cassidy HD, et al. Celiac disease. Am Fam Physician. 2007;76(12):1795-1802, 1809-1810.

Continue for educating parents about antibiotic use >>

EDUCATING PARENTS ABOUT ANTIBIOTIC USE
Vaz LE, Kleinman KP, Lakoma MD, et al. Prevalence of parental misconceptions about antibiotic use. Pediatrics. 2015;136:221-231.

Misperceptions about antibiotic use persist and continue to be more prevalent among parents of Medicaid-insured children, according to a study of 1,500 Massachusetts parents.

Investigators examined antibiotic-related knowledge and attitudes among both Medicaid-insured and private-insured parents and found
• Fewer Medicaid parents answered questions correctly, except for one regarding bronchitis.
• Medicaid patients were more likely to request unnecessary antibiotics.
• More parents in 2013 understood that green nasal discharge did not require antibiotics than in 2000.
• Medicaid-insured parents were younger, less likely to be white, and had less education than those commercially insured.

COMMENTARY
Decreasing the unnecessary use of antibiotics for viral infections is an important component of decreasing the development of antibiotic-resistant organisms. An important driver of clinician use of antibiotics is patients’ expectations for antibiotics. This study shows that much work remains to be done in changing patient expectations, which is not surprising to any practicing clinician. This study also suggests that the expectation for antibiotics is greater among those individuals with Medicaid insurance, which suggests that an opportunity exists for Medicaid insurance plans to do targeted patient education on this issue—which should improve patient outcomes, decrease cost from use of unneeded antibiotics, and decrease the development of antibiotic-resistant organisms.

Continue for newborn pulmonary hypertension and maternal antidepressant use >>

NEWBORN PULMONARY HYPERTENSION AND MATERNAL ANTIDEPRESSANT USE
Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151.

Taking antidepressants during late pregnancy may increase the risk for persistent pulmonary hypertension of the newborn (PPHN), according to a nested cohort study of more than 3.7 million pregnant women in the 2000-2010 Medicaid Analytic eXtract.

Investigators compared offspring of mothers who used selective serotonin reuptake inhibitors (SSRIs) or non-SSRI monotherapy in the last 90 days of pregnancy to those who did not and found 3.4% of women filled at least one prescription for antidepressants late in pregnancy, primarily SSRIs.

Rates and odds ratios (ORs) of PPHN stratified by use and type of antidepressant were as follows:

The study authors note the absolute risk is small, and the increased risk is more modest than previous studies found.

COMMENTARY
Depression affects more than 12% of pregnancies and has important consequences, including increased risk for suicide, preterm birth, poor fetal growth, and impaired fetal and infant development.¹ PPHN is a serious condition that can require intubation and can be fatal in 10% to 20% of cases. This study adds to the conflicting data suggesting that SSRI use in pregnancy can lead to an increase in this rare condition. The decision to use an antidepressant during pregnancy is a difficult one, because depression has serious consequences but so, potentially, does treatment. The treatment of depression during pregnancy requires thoughtful, informed discussion between patient and provider. 

1. Stewart DE. Clinical practice. Depression during pregnancy. N Engl J Med. 2011;365(17):1605-1611. doi:10.1056/NEJMcp1102730.

Continue for new infant vaccine treats 6 diseases >>

NEW INFANT VACCINE TREATS 6 DISEASES
Marshall GS, Adams GL, Leonardi ML, et al. Immunogenicity, safety, and tolerability of a hexavalent vaccine in infants. Pediatrics. 2015:136(2):323-332.

The safety and immunogenicity of DTaP5-IPV-Hib-HepB fully liquid investigational hexavalent vaccine are comparable with the analogous licensed component vaccines and provide a new combination vaccine option aligned with the recommended US infant immunization schedule, according to a phase III study of 1,465 participants. Overall, 981 healthy infants were vaccinated in group 1 with the hexavalent vaccine and 484 in group 2 with the analogous licensed component vaccines.

The study found
• Immune responses in group 1 to all antigens contained in the vaccine one month after dose 3 were essentially noninferior to those in group 2.
• Adverse event rates after any dose were similar in both groups.

COMMENTARY
Vaccine administration has led to many diseases, including Haemophilus influenzae type b, polio, and measles, becoming quite rare. As we have recently seen with the resurgence of measles, continued vigilance and high immunization rates are important in ensuring that these diseases remain rare. The development of a hexavalent vaccine is another step in making immunization easier for clinicians to administer and for patients to accept.

Continue for treating infants with bronchiolitis >>

TREATING INFANTS WITH BRONCHIOLITIS
Silver AH, Esteban-Cruciani N, Azzarone G, et al. 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial. Pediatrics. 2015;136:1036-1043.

Infants hospitalized with bronchiolitis saw no difference in length of stay or seven-day readmission rates when treated with nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS), according to a randomized, controlled study of 227 infants who were younger than 12 months when admitted. Patients received either 4 mL nebulized 3% HS (113 infants) or 4 mL 0.9% NS (114 infants) every four hours from enrollment until hospital discharge. Researchers found
• Median length of stay of HS and NS groups was 2.1 days vs 2.1 days, respectively.
• Seven-day readmission rates for HS and NS groups were 4.3% vs 3.1%, respectively.
• Clinical worsening events were similar between groups.

COMMENTARY
Bronchiolitis, the most common lower respiratory tract infection in infants, is usually due to a viral infection, most often respiratory syncytial virus, and can cause disease that ranges in severity from mild to life-threatening. Infants with bronchiolitis typically present with rhinitis, tachypnea, wheezing, and cough, and occasionally crackles and use of accessory muscles. While many medications are used, supportive care and monitoring are the mainstays of therapy. Maintaining pulse above 90% is important, using supplemental oxygen when needed to achieve this. Alpha-adrenergic and beta-adrenergic bronchodilators are often used; though the evidence suggests that they are not usually helpful, they can be tried and continued if they appear to help. Systemic steroids are often used, but they too lack evidence of efficacy.¹ This study shows that hypertonic saline can now join the list of interventions used with evidence of a lack of efficacy.

1. Diagnosis and management of bronchiolitis. Subcommittee on diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. doi:10.1542/peds.2006-2223.

Continue for azithromycin and preschool children >>

AZITHROMYCIN AND PRESCHOOL CHILDREN: CAN ANTIBIOTICS LESSEN ONSET OF SEVERE LRTIs?
Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034-2044.

The use of azithromycin early during an apparent respiratory tract illness (RTI) reduced the likelihood of severe lower RTI (LRTI) among young children with a history of recurrent severe LRTI, compared with placebo, according to a study of 607 children ages 12 to 71 months. Participants were randomized in a 1:1 ratio to receive either azithromycin (12 mg/kg/d for 5 d) or matching placebo at the start of an RTI. Researchers found
• A total of 937 treated RTIs were experienced by 443 children, including 92 severe LRTIs (azithromycin group, 35; placebo group, 57).
• Azithromycin significantly reduced the risk for progression to severe LRTI relative to placebo (HR, 0.64).
• Induction of azithromycin-resistant organisms and adverse events were infrequent.

COMMENTARY
Recurrent episodes of severe wheezing with RTI are an important and common occurrence, affecting up to 15% to 20% of children prior to age 6.¹ LRTI was defined in this study as RTI that required the use of additional rescue medication. The current approach to RTI is to try to minimize the use of antibiotics unless an infection is clearly bacterial in origin, and to treat severe LRTI when it occurs. The results of this trial suggest that in children at high risk for severe LRTI, identified by their episodes of recurrent wheezing, early treatment of RTI with azithromycin may decrease the development of severe LRTI by more than 35%—an important result. It is important to recognize that this study does not suggest treating all RTIs with antibiotics, but rather that the use of a macrolide antibiotic may be considered, perhaps, in the select group of children similar to those studied, with a history of recurrent wheezing with previous RTIs.

1. Ly NP, Gold DR, Weiss ST, Celedón JC. Recurrent wheeze in early childhood and asthma among children at risk for atopy. Pediatrics. 2006;117(6):e1132-e1138.

TALKING OUT CHILDHOOD OBESITY
Resnicow K, McMaster F, Bocian A, et al. Motivational interviewing and dietary counseling for obesity in primary care: an RCT. Pediatrics. 2015;135(4):649-657.

Counseling parents of overweight children using motivational interviewing from both health care providers and registered dietitians can significantly improve BMI, according to a study of 42 practices in the Pediatric Research in Office Settings Network of the American Academy of Pediatrics.

Researchers randomly assigned parents of overweight children, ages 2 through 8, to one of three groups: (1) usual care, (2) four provider-delivered motivational interviewing sessions over two years, or (3) four provider-delivered motivational interviewing sessions plus six sessions with a registered dietitian over two years. At study end, BMI percentile and change in BMI for the different groups were as follows:

COMMENTARY
The results of this study are exciting. Motivational interviewing is a technique in which the practitioner asks questions of a patient and allows the patient to discover his/her own conclusions about the topic. By so doing, the patient is more engaged in the discussion and is less resistant to input. This technique, with excellent evidence of effectiveness in the area of drug and alcohol abuse, has been shown to facilitate effective behavioral change in many areas and is recommended by the American Heart Association for behavioral change in adults.1,2 This is an exciting paper demonstrating evidence-based efficacy in addressing childhood obesity—a critical health issue—and is worth trying in the office. 

1. Rubak S, Sandbaek A, Lauritzen T, Christensen B. Motivational interviewing: a systematic review and meta-analysis. Br J Gen Pract. 2005;55(513):305-312.
2. Spring B, Ockene JK, Gidding SS, et al; American Heart Association Behavior Change Committee of the Council on Epidemiology and Prevention, Council on Lifestyle and Cardiometabolic Health, Council for High Blood Pressure Research, and Council on Cardiovascular and Stroke Nursing. Better population health through behavior change in adults: a call to action. Circulation. 2013;128(19):2169-2176. doi: 10.1161/01.cir.0000435173.25936.e1. 

Continue for long-acting reversible contraception among teens >>

LONG-ACTING REVERSIBLE CONTRACEPTION AMONG TEENS
Romero L, Pazol K, Warner L, et al. Vital signs: trends in use of long-acting reversible contraception among teens aged 15-19 years seeking contraceptive services – United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2015;64(13):363-369.

Efforts to improve teen access to long-acting reversible contraception (LARC) have increased use of these methods, according to a CDC review of services provided at Title X National Family Planning Program centers. The report found
• LARC rates among teen patients increased from 0.4% in 2005 to 7.2% in 2013.
• In 2013, 2.8% of those seeking contraception used IUDs and 4.3% used implants.
• Among Title X patients, 7.6% of 18- and 19-year-olds used LARC, compared with 6.5% of 15- to 17-year-olds.
• Rates of LARC were lowest in Mississippi (0.7%) and highest in Colorado (25.8%).

COMMENTARY
LARCs, which include IUD and implantable hormonal contraceptive devices, require no effort for adherence on the part of the user; once in place, they are effective without further action. Current CDC guidelines on contraceptive use clearly recommend LARC for teenagers based on the efficacy and safety.¹ LARCs are favored for teenagers because poor compliance has yielded suboptimal effectiveness of oral contraceptives and condoms in teenagers, who often forget to take their birth control pills or don’t use condoms when they should. Many clinicians have been slow to recommend LARCs in teenagers based on safety concerns related to adverse experience with IUDs 20 to 30 years ago. According to CDC guidelines, IUDs and implantable contraceptive devices now have robust safety data, and this article shows that they are being increasingly made available to teenagers who need them.

1. Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. US Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep. 2013;62(RR-05):1-60.

Continue to testing for celiac in pediatric rheumatology patients >>

TESTING FOR CELIAC IN PEDIATRIC RHEUMATOLOGY PATIENTS
Sherman Y, Karanicolas R, DiMarco B, et al. Unrecognized celiac disease in children presenting for rheumatology evaluation. Pediatrics. 2015; [Epub ahead of print].

Children presenting for rheumatology evaluation should be screened for celiac disease, according to a review of 2,125 pediatric patients who were screened for celiac as part of the standard initial serologic evaluation.

Researchers identified 36 new cases of celiac disease (2.0% prevalence rate). The most common presenting complaints among these patients were myalgia, arthralgia, and rash. Less frequent complaints included gastrointestinal complaints of abdominal pain, nausea, and diarrhea.

After initiating a gluten-free diet, all of the patients with celiac disease reported improvement or complete resolution of musculoskeletal symptoms.

COMMENTARY
Celiac disease has a prevalence of 0.5% to 1% in the US and can present with a range of symptoms that include diarrhea, abdominal discomfort, and weight loss. In addition to these typical symptoms, celiac disease can cause a wide range of systemic symptoms, including osteopenia, abnormal liver function tests, anemia, neurologic symptoms, and general malaise and fatigue.¹ This study suggests that celiac testing be considered in children presenting with rheumatologic symptoms, including myalgia, arthralgia, and rash.

1. Presutti RJ, Cangemi JR, Cassidy HD, et al. Celiac disease. Am Fam Physician. 2007;76(12):1795-1802, 1809-1810.

Continue for educating parents about antibiotic use >>

EDUCATING PARENTS ABOUT ANTIBIOTIC USE
Vaz LE, Kleinman KP, Lakoma MD, et al. Prevalence of parental misconceptions about antibiotic use. Pediatrics. 2015;136:221-231.

Misperceptions about antibiotic use persist and continue to be more prevalent among parents of Medicaid-insured children, according to a study of 1,500 Massachusetts parents.

Investigators examined antibiotic-related knowledge and attitudes among both Medicaid-insured and private-insured parents and found
• Fewer Medicaid parents answered questions correctly, except for one regarding bronchitis.
• Medicaid patients were more likely to request unnecessary antibiotics.
• More parents in 2013 understood that green nasal discharge did not require antibiotics than in 2000.
• Medicaid-insured parents were younger, less likely to be white, and had less education than those commercially insured.

COMMENTARY
Decreasing the unnecessary use of antibiotics for viral infections is an important component of decreasing the development of antibiotic-resistant organisms. An important driver of clinician use of antibiotics is patients’ expectations for antibiotics. This study shows that much work remains to be done in changing patient expectations, which is not surprising to any practicing clinician. This study also suggests that the expectation for antibiotics is greater among those individuals with Medicaid insurance, which suggests that an opportunity exists for Medicaid insurance plans to do targeted patient education on this issue—which should improve patient outcomes, decrease cost from use of unneeded antibiotics, and decrease the development of antibiotic-resistant organisms.

Continue for newborn pulmonary hypertension and maternal antidepressant use >>

NEWBORN PULMONARY HYPERTENSION AND MATERNAL ANTIDEPRESSANT USE
Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151.

Taking antidepressants during late pregnancy may increase the risk for persistent pulmonary hypertension of the newborn (PPHN), according to a nested cohort study of more than 3.7 million pregnant women in the 2000-2010 Medicaid Analytic eXtract.

Investigators compared offspring of mothers who used selective serotonin reuptake inhibitors (SSRIs) or non-SSRI monotherapy in the last 90 days of pregnancy to those who did not and found 3.4% of women filled at least one prescription for antidepressants late in pregnancy, primarily SSRIs.

Rates and odds ratios (ORs) of PPHN stratified by use and type of antidepressant were as follows:

The study authors note the absolute risk is small, and the increased risk is more modest than previous studies found.

COMMENTARY
Depression affects more than 12% of pregnancies and has important consequences, including increased risk for suicide, preterm birth, poor fetal growth, and impaired fetal and infant development.¹ PPHN is a serious condition that can require intubation and can be fatal in 10% to 20% of cases. This study adds to the conflicting data suggesting that SSRI use in pregnancy can lead to an increase in this rare condition. The decision to use an antidepressant during pregnancy is a difficult one, because depression has serious consequences but so, potentially, does treatment. The treatment of depression during pregnancy requires thoughtful, informed discussion between patient and provider. 

1. Stewart DE. Clinical practice. Depression during pregnancy. N Engl J Med. 2011;365(17):1605-1611. doi:10.1056/NEJMcp1102730.

Continue for new infant vaccine treats 6 diseases >>

NEW INFANT VACCINE TREATS 6 DISEASES
Marshall GS, Adams GL, Leonardi ML, et al. Immunogenicity, safety, and tolerability of a hexavalent vaccine in infants. Pediatrics. 2015:136(2):323-332.

The safety and immunogenicity of DTaP5-IPV-Hib-HepB fully liquid investigational hexavalent vaccine are comparable with the analogous licensed component vaccines and provide a new combination vaccine option aligned with the recommended US infant immunization schedule, according to a phase III study of 1,465 participants. Overall, 981 healthy infants were vaccinated in group 1 with the hexavalent vaccine and 484 in group 2 with the analogous licensed component vaccines.

The study found
• Immune responses in group 1 to all antigens contained in the vaccine one month after dose 3 were essentially noninferior to those in group 2.
• Adverse event rates after any dose were similar in both groups.

COMMENTARY
Vaccine administration has led to many diseases, including Haemophilus influenzae type b, polio, and measles, becoming quite rare. As we have recently seen with the resurgence of measles, continued vigilance and high immunization rates are important in ensuring that these diseases remain rare. The development of a hexavalent vaccine is another step in making immunization easier for clinicians to administer and for patients to accept.

Continue for treating infants with bronchiolitis >>

TREATING INFANTS WITH BRONCHIOLITIS
Silver AH, Esteban-Cruciani N, Azzarone G, et al. 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial. Pediatrics. 2015;136:1036-1043.

Infants hospitalized with bronchiolitis saw no difference in length of stay or seven-day readmission rates when treated with nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS), according to a randomized, controlled study of 227 infants who were younger than 12 months when admitted. Patients received either 4 mL nebulized 3% HS (113 infants) or 4 mL 0.9% NS (114 infants) every four hours from enrollment until hospital discharge. Researchers found
• Median length of stay of HS and NS groups was 2.1 days vs 2.1 days, respectively.
• Seven-day readmission rates for HS and NS groups were 4.3% vs 3.1%, respectively.
• Clinical worsening events were similar between groups.

COMMENTARY
Bronchiolitis, the most common lower respiratory tract infection in infants, is usually due to a viral infection, most often respiratory syncytial virus, and can cause disease that ranges in severity from mild to life-threatening. Infants with bronchiolitis typically present with rhinitis, tachypnea, wheezing, and cough, and occasionally crackles and use of accessory muscles. While many medications are used, supportive care and monitoring are the mainstays of therapy. Maintaining pulse above 90% is important, using supplemental oxygen when needed to achieve this. Alpha-adrenergic and beta-adrenergic bronchodilators are often used; though the evidence suggests that they are not usually helpful, they can be tried and continued if they appear to help. Systemic steroids are often used, but they too lack evidence of efficacy.¹ This study shows that hypertonic saline can now join the list of interventions used with evidence of a lack of efficacy.

1. Diagnosis and management of bronchiolitis. Subcommittee on diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. doi:10.1542/peds.2006-2223.

Continue for azithromycin and preschool children >>

AZITHROMYCIN AND PRESCHOOL CHILDREN: CAN ANTIBIOTICS LESSEN ONSET OF SEVERE LRTIs?
Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034-2044.

The use of azithromycin early during an apparent respiratory tract illness (RTI) reduced the likelihood of severe lower RTI (LRTI) among young children with a history of recurrent severe LRTI, compared with placebo, according to a study of 607 children ages 12 to 71 months. Participants were randomized in a 1:1 ratio to receive either azithromycin (12 mg/kg/d for 5 d) or matching placebo at the start of an RTI. Researchers found
• A total of 937 treated RTIs were experienced by 443 children, including 92 severe LRTIs (azithromycin group, 35; placebo group, 57).
• Azithromycin significantly reduced the risk for progression to severe LRTI relative to placebo (HR, 0.64).
• Induction of azithromycin-resistant organisms and adverse events were infrequent.

COMMENTARY
Recurrent episodes of severe wheezing with RTI are an important and common occurrence, affecting up to 15% to 20% of children prior to age 6.¹ LRTI was defined in this study as RTI that required the use of additional rescue medication. The current approach to RTI is to try to minimize the use of antibiotics unless an infection is clearly bacterial in origin, and to treat severe LRTI when it occurs. The results of this trial suggest that in children at high risk for severe LRTI, identified by their episodes of recurrent wheezing, early treatment of RTI with azithromycin may decrease the development of severe LRTI by more than 35%—an important result. It is important to recognize that this study does not suggest treating all RTIs with antibiotics, but rather that the use of a macrolide antibiotic may be considered, perhaps, in the select group of children similar to those studied, with a history of recurrent wheezing with previous RTIs.

1. Ly NP, Gold DR, Weiss ST, Celedón JC. Recurrent wheeze in early childhood and asthma among children at risk for atopy. Pediatrics. 2006;117(6):e1132-e1138.

 A bone island is a focus of normal cortical bone located within the medullary cavity. The vast majority of bone islands are small, measuring from 1 mm to 2 cm in size. They are found more frequently in adults than in children. The lesion can be virtually diagnosed on the basis of its characteristic clinical and imaging features. Differential diagnosis may be difficult when the lesion manifests itself uncharacteristically by being symptomatic, very large, and hot on bone scan.^1-4

The term giant bone island has been used to describe a large lesion1 that measures more than 2 cm in any dimension.⁵ Giant bone islands have been described only in adults,^1,5-15 and the longest bone island length reported is 10.5 cm.¹⁰ They are usually symptomatic and associated with increased radionuclide uptake on bone scintigraphy.¹⁴

The history and the clinical and imaging presentation of an even longer, symptomatic, and scintigraphically hot lesion in the tibial diaphysis of a 10-year-old boy is reported. The lesion further exhibited several atypical imaging features necessitating an open biopsy, which confirmed the diagnosis of a giant bone island. The pertinent differential diagnosis and the clinical and radiographic findings after 15-year follow-up are also presented and discussed. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 10-year-old boy was admitted for surgical repair of an inguinal hernia. Physical examination revealed a painless but tender anterior bowing of the right tibial diaphysis. The patient was a healthy-appearing white male with normal vital signs, gait, and posture. His parents noticed a slight protuberance of the tibia at age 2.5 years. No medical advice was asked for the bone swelling after that time. After recovery from the inguinal hernia repair 3 weeks later, the bone lesion was thoroughly examined. Radiographs showed an oblong, homogenous region of dense sclerosis in the diaphysis of the right tibia. The lesion had relatively well-defined margins and was located in the medullary cavity. Speculations were not obvious in the periphery of the lesion, which exhibited a sharp circumscription (Figures 1A, 1B). A well-defined lytic area was evident at the distal part of the lesion (Figure 1B). There was no periosteal reaction. Blood and serum chemistries were within normal limits, including serum calcium, phosphorus, and alkaline phosphatase. A conventional 3-phase bone scintigraphy (300 MBq) with technetium-99m HDP (hydroxydiphosphonate) indicated increased uptake in the area of the lesion but no other skeletal abnormality (Figure 2). Computed tomography (CT) showed that the lesion was purely intramedullary and densely blastic. The lesion originated from the medial cortex, which was thickened (Figure 3A). The lesion extended to the anterolateral cortex, which was thinned and included a lytic area. In the distal part of the lesion, the anterolateral cortex was thickened, included lytic areas, and exhibited an anterior portion of cortical destruction (Figure 3B). The fatty marrow adjacent to the region of sclerosis appeared normal. There was no evidence of extraosseous soft-tissue changes. On both T1- and T2-weighted magnetic resonance imaging (MRI), the lesion exhibited low-signal intensity. The lesion measured 10.8×2.2×1 cm. It originated from the medial cortical bone of the tibia, blended into the medullary cavity, and extended anteriorly towards and through the anterior cortex. The area of cortical destruction was clearly evident on the axial MRI. The periosteum was displaced and eroded anteriorly by focal radiating bony streaks. No enhancement was seen after the intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a contrast medium. There were no extraosseous soft-tissue changes. In the distal part of the lesion, sagittal and axial MRI showed a 1.2×0.8×0.7-cm well-defined ovoid focus, with characteristics of cystic degeneration that exhibited intermediate-signal intensity on T1-weighted MRI (Figure 4) and high-signal intensity on T2-weighted MRI.

An open biopsy was performed. Macroscopically, a wedge of compact bone measuring 3×1.7×0.6 cm was taken. Microscopic examination showed a thinned periphery of lamellar (mature) bone with haversian canals and, beneath it, woven (immature) bone with long-surface processes projecting within adjacent cancellous bone (Figure 5A). The woven bone contained loose vascular fibrous tissue. No osteoclasts were noted, and the very few osteoblasts lining the bone trabeculae were small, single-layered, and flat (Figure 5B). There was no evidence of neoplastic cells. There was no abnormality of the periosteum and the surrounding soft tissues.

The histology was pathognomonic of a giant bone island. No additional surgical intervention was recommended.

The postoperative course was uncomplicated, and the patient was discharged 2 weeks later. An above-the-knee plaster was recommended for 3 months and a below-the-knee splint for an additional 2-month period. Full weight-bearing was allowed only after the postsurgical sixth month to prevent an impending fracture. The tibial bowing was tender to pressure or palpation, and the patient reported mild spontaneous pain during follow-up. Radiographs 1 year after surgery indicated that the bone area removed for biopsy was replaced by compact bone. MRI performed 4 years after surgery showed that the volume of the lesion in relation to the host bone was not changed.

At the last follow-up 15 years after surgery, the anterior tibial bowing was not changed (Figure 6A), but the patient additionally complained of skin irritation after intense training wearing boots during military service. The radiographic appearance of the lesion was also not changed, while the periphery of the lesion exhibited scarce radiating bony streaks with rounded contours (Figures 6B, 6C). The clinical symptoms and signs from wearing military boots completely subsided after a couple of weeks’ rest from daily army activities, but the mild spontaneous pain and the local tenderness over the tibial bowing persisted.

Discussion

Giant bone islands are more likely to be associated with clinical symptoms than the usual small-sized bone island. Some degree of pain was detected in 8 of 10 patients with a giant bone island presented in the literature, but it was induced by trauma in 3 of them.¹⁴

Radiographic appearance is among the distinguishing diagnostic features of a giant bone island. It appears as an ovoid, round, or oblong, homogenously dense, single or multiple focus of sclerosis within the medullary cavity; it is oriented along the long axis of the host bone, and it exhibits peripheral pseudopodia or radiating spicules producing the typical “thorny” or “paintbrush” appearance.^8,16,17 It does not exhibit cortical penetration and it is not associated with periosteal reaction.10

The CT findings include a sclerotic and hyperdense focus with spiculated margins extending into the adjacent cancellous bone. The lack of bone destruction and soft-tissue mass are also diagnostic.^3,7 MRI findings will reflect the low-signal intensity characteristics of cortical bone on all pulse sequences.¹⁸

Enostoses usually exhibit no activity on skeletal scintigraphy, while giant lesions generally show increased radiotracer uptake.^{5,9-11,14,19-27} The latter may result from the increased amount of bone turnover, which is seen more often with larger lesions because of active bone deposition and remodeling.^20,21,23,28 Histopathology of a giant bone island appears identical to the well-described pathologic appearance of smaller bone islands. The lesion is composed of compact lamellar bone and haversian systems, which blend with the adjacent spongiosa. The surrounding cancellous bone forms thorn-like trabeculae radiating from the lesion and merging with the cancellous bone.^1,4,5,8,28

The presumptive diagnosis of a bone island is based on the clinical findings, imaging features, and follow-up examinations. An asymptomatic, isolated, sclerotic bone lesion showing the typical features of a bone island on plain radiography, CT, and MRI, whatever its size, that is nonactive on bone scan may be easily diagnosed. However, a symptomatic patient with a hot lesion on scintigraphy should be carefully observed. In addition, larger lesions may raise the suspicion of a neoplasm, such as a sclerotic variant of osteosarcoma. In such cases, an open biopsy may be undertaken. No specific treatment is required after the diagnosis has been confirmed. There is no literature to suggest that, after adequate biopsy confirmation, excision or resection is necessary. Follow-up radiographic examination of the lesion should be suggested to monitor for any potential growth.^2,10,23

The first giant bone island appearing in a child is presented in this report. The lack of a causative factor leading to the anterior tibial bowing indicated that the bone deformity was caused primarily by the lesion. The present case is unusual for the appearance of several atypical features, some of which have not been previously described. Peripheral radiating spiculated margin was absent on the patient’s initial radiographs and CT imaging. MRI indicated only the presence of radiating bony streaks that displaced and eroded the periosteum on the anterior border of the lesion. The CT findings that the lesion likely originated or was in close proximity with the medial cortex of the tibia were also atypical. It has been previously reported that spinal lesions located immediately below the cortex tend to fuse with the endosteal surface, while similar features may also be seen in the appendicular enostoses.^4,29 Other CT findings, such as the thinning of the overlying anterolateral cortical bone, as well as the cortical thickening at the periphery of the lesion associated with areas of soft-tissue attenuation and anterior cortical destruction, have not been described even in the atypical features of a giant bone island. The lytic area resembling a nidus that was evident at the distal part of the lesion was more likely consistent with an area of resorption, which, although rare, has been described on giant lesions.^2,9,29 The substantial amount of woven bone transforming to lamellar bone that was evident in the present patient’s microscopic features is also an atypical finding, although it may be expected to some degree in scintigraphically hot, large lesions.²⁸ The clinical and imaging progress of the lesion supported the diagnosis of a giant bone island. The degree of the anterior tibial bowing and the volume of the lesion in relation to the host bone were not changed throughout the follow-up period, indicating that the growth of the lesion followed the growth of the normal bone.

The differential diagnosis of a giant bone island includes a variety of benign tumors and tumor-like lesions, as well as malignant bone lesions.^{2,4,23,28,30,31} In the patient presented in this report, the diagnosis of an atypical sclerotic presentation of a nonossifying fibroma or healing stage of this lesion could be consistent with some of the CT findings, including the eccentric origin from the cortex associated with medial cortical thickening, the anterolateral cortical thinning, and the soft-tissue attenuation of cortical areas. In addition, unifocal osteofibrous dysplasia may also present with a long intracortical diaphyseal lucency within an area of marked cortical sclerosis and cause a bowing deformity. Both diagnoses were excluded, since no fibrous stroma was evident on the histologic examination of the lesion. A large or giant long-bone osteoma would be associated with the outer cortical margin of bone but would not involve the intramedullary space. The scintigraphically increased uptake of radioisotope, as well as the CT and MRI findings, were not consistent with the diagnosis of osteoid osteoma, osteoblastoma, or osteomyelitis. Although most imaging findings were consistent with a benign lesion, and contrast-enhanced MRI showed no increased vascularity, anterior cortical disruption necessitated a bone biopsy to rule out any potential malignancy.

The histopathology in association with the clinical and imaging findings indicated the diagnosis of a giant bone island. The increased proportion of maturing woven bone over lamellar bone indicated an active remodeling lesion that could be related to the patient’s age, since the clinical and radiographic features of the lesion were not changed after 15-year follow-up.

Conclusion

This is the first giant bone island diagnosed in a patient before puberty. Its greatest length was 10.8 cm, which is the longest reported in the literature. The imaging appearance included several atypical features that are very rare or have not been reported. Microscopic features indicated less mature lamellar bone and a prominent proportion of maturing woven bone. The clinical and the radiographic appearance of the lesion were not changed after 15-year follow-up.

 A bone island is a focus of normal cortical bone located within the medullary cavity. The vast majority of bone islands are small, measuring from 1 mm to 2 cm in size. They are found more frequently in adults than in children. The lesion can be virtually diagnosed on the basis of its characteristic clinical and imaging features. Differential diagnosis may be difficult when the lesion manifests itself uncharacteristically by being symptomatic, very large, and hot on bone scan.^1-4

The term giant bone island has been used to describe a large lesion1 that measures more than 2 cm in any dimension.⁵ Giant bone islands have been described only in adults,^1,5-15 and the longest bone island length reported is 10.5 cm.¹⁰ They are usually symptomatic and associated with increased radionuclide uptake on bone scintigraphy.¹⁴

The history and the clinical and imaging presentation of an even longer, symptomatic, and scintigraphically hot lesion in the tibial diaphysis of a 10-year-old boy is reported. The lesion further exhibited several atypical imaging features necessitating an open biopsy, which confirmed the diagnosis of a giant bone island. The pertinent differential diagnosis and the clinical and radiographic findings after 15-year follow-up are also presented and discussed. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 10-year-old boy was admitted for surgical repair of an inguinal hernia. Physical examination revealed a painless but tender anterior bowing of the right tibial diaphysis. The patient was a healthy-appearing white male with normal vital signs, gait, and posture. His parents noticed a slight protuberance of the tibia at age 2.5 years. No medical advice was asked for the bone swelling after that time. After recovery from the inguinal hernia repair 3 weeks later, the bone lesion was thoroughly examined. Radiographs showed an oblong, homogenous region of dense sclerosis in the diaphysis of the right tibia. The lesion had relatively well-defined margins and was located in the medullary cavity. Speculations were not obvious in the periphery of the lesion, which exhibited a sharp circumscription (Figures 1A, 1B). A well-defined lytic area was evident at the distal part of the lesion (Figure 1B). There was no periosteal reaction. Blood and serum chemistries were within normal limits, including serum calcium, phosphorus, and alkaline phosphatase. A conventional 3-phase bone scintigraphy (300 MBq) with technetium-99m HDP (hydroxydiphosphonate) indicated increased uptake in the area of the lesion but no other skeletal abnormality (Figure 2). Computed tomography (CT) showed that the lesion was purely intramedullary and densely blastic. The lesion originated from the medial cortex, which was thickened (Figure 3A). The lesion extended to the anterolateral cortex, which was thinned and included a lytic area. In the distal part of the lesion, the anterolateral cortex was thickened, included lytic areas, and exhibited an anterior portion of cortical destruction (Figure 3B). The fatty marrow adjacent to the region of sclerosis appeared normal. There was no evidence of extraosseous soft-tissue changes. On both T1- and T2-weighted magnetic resonance imaging (MRI), the lesion exhibited low-signal intensity. The lesion measured 10.8×2.2×1 cm. It originated from the medial cortical bone of the tibia, blended into the medullary cavity, and extended anteriorly towards and through the anterior cortex. The area of cortical destruction was clearly evident on the axial MRI. The periosteum was displaced and eroded anteriorly by focal radiating bony streaks. No enhancement was seen after the intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a contrast medium. There were no extraosseous soft-tissue changes. In the distal part of the lesion, sagittal and axial MRI showed a 1.2×0.8×0.7-cm well-defined ovoid focus, with characteristics of cystic degeneration that exhibited intermediate-signal intensity on T1-weighted MRI (Figure 4) and high-signal intensity on T2-weighted MRI.

An open biopsy was performed. Macroscopically, a wedge of compact bone measuring 3×1.7×0.6 cm was taken. Microscopic examination showed a thinned periphery of lamellar (mature) bone with haversian canals and, beneath it, woven (immature) bone with long-surface processes projecting within adjacent cancellous bone (Figure 5A). The woven bone contained loose vascular fibrous tissue. No osteoclasts were noted, and the very few osteoblasts lining the bone trabeculae were small, single-layered, and flat (Figure 5B). There was no evidence of neoplastic cells. There was no abnormality of the periosteum and the surrounding soft tissues.

The histology was pathognomonic of a giant bone island. No additional surgical intervention was recommended.

The postoperative course was uncomplicated, and the patient was discharged 2 weeks later. An above-the-knee plaster was recommended for 3 months and a below-the-knee splint for an additional 2-month period. Full weight-bearing was allowed only after the postsurgical sixth month to prevent an impending fracture. The tibial bowing was tender to pressure or palpation, and the patient reported mild spontaneous pain during follow-up. Radiographs 1 year after surgery indicated that the bone area removed for biopsy was replaced by compact bone. MRI performed 4 years after surgery showed that the volume of the lesion in relation to the host bone was not changed.

At the last follow-up 15 years after surgery, the anterior tibial bowing was not changed (Figure 6A), but the patient additionally complained of skin irritation after intense training wearing boots during military service. The radiographic appearance of the lesion was also not changed, while the periphery of the lesion exhibited scarce radiating bony streaks with rounded contours (Figures 6B, 6C). The clinical symptoms and signs from wearing military boots completely subsided after a couple of weeks’ rest from daily army activities, but the mild spontaneous pain and the local tenderness over the tibial bowing persisted.

Discussion

Giant bone islands are more likely to be associated with clinical symptoms than the usual small-sized bone island. Some degree of pain was detected in 8 of 10 patients with a giant bone island presented in the literature, but it was induced by trauma in 3 of them.¹⁴

Radiographic appearance is among the distinguishing diagnostic features of a giant bone island. It appears as an ovoid, round, or oblong, homogenously dense, single or multiple focus of sclerosis within the medullary cavity; it is oriented along the long axis of the host bone, and it exhibits peripheral pseudopodia or radiating spicules producing the typical “thorny” or “paintbrush” appearance.^8,16,17 It does not exhibit cortical penetration and it is not associated with periosteal reaction.10

The CT findings include a sclerotic and hyperdense focus with spiculated margins extending into the adjacent cancellous bone. The lack of bone destruction and soft-tissue mass are also diagnostic.^3,7 MRI findings will reflect the low-signal intensity characteristics of cortical bone on all pulse sequences.¹⁸

Enostoses usually exhibit no activity on skeletal scintigraphy, while giant lesions generally show increased radiotracer uptake.^{5,9-11,14,19-27} The latter may result from the increased amount of bone turnover, which is seen more often with larger lesions because of active bone deposition and remodeling.^20,21,23,28 Histopathology of a giant bone island appears identical to the well-described pathologic appearance of smaller bone islands. The lesion is composed of compact lamellar bone and haversian systems, which blend with the adjacent spongiosa. The surrounding cancellous bone forms thorn-like trabeculae radiating from the lesion and merging with the cancellous bone.^1,4,5,8,28

The presumptive diagnosis of a bone island is based on the clinical findings, imaging features, and follow-up examinations. An asymptomatic, isolated, sclerotic bone lesion showing the typical features of a bone island on plain radiography, CT, and MRI, whatever its size, that is nonactive on bone scan may be easily diagnosed. However, a symptomatic patient with a hot lesion on scintigraphy should be carefully observed. In addition, larger lesions may raise the suspicion of a neoplasm, such as a sclerotic variant of osteosarcoma. In such cases, an open biopsy may be undertaken. No specific treatment is required after the diagnosis has been confirmed. There is no literature to suggest that, after adequate biopsy confirmation, excision or resection is necessary. Follow-up radiographic examination of the lesion should be suggested to monitor for any potential growth.^2,10,23

The first giant bone island appearing in a child is presented in this report. The lack of a causative factor leading to the anterior tibial bowing indicated that the bone deformity was caused primarily by the lesion. The present case is unusual for the appearance of several atypical features, some of which have not been previously described. Peripheral radiating spiculated margin was absent on the patient’s initial radiographs and CT imaging. MRI indicated only the presence of radiating bony streaks that displaced and eroded the periosteum on the anterior border of the lesion. The CT findings that the lesion likely originated or was in close proximity with the medial cortex of the tibia were also atypical. It has been previously reported that spinal lesions located immediately below the cortex tend to fuse with the endosteal surface, while similar features may also be seen in the appendicular enostoses.^4,29 Other CT findings, such as the thinning of the overlying anterolateral cortical bone, as well as the cortical thickening at the periphery of the lesion associated with areas of soft-tissue attenuation and anterior cortical destruction, have not been described even in the atypical features of a giant bone island. The lytic area resembling a nidus that was evident at the distal part of the lesion was more likely consistent with an area of resorption, which, although rare, has been described on giant lesions.^2,9,29 The substantial amount of woven bone transforming to lamellar bone that was evident in the present patient’s microscopic features is also an atypical finding, although it may be expected to some degree in scintigraphically hot, large lesions.²⁸ The clinical and imaging progress of the lesion supported the diagnosis of a giant bone island. The degree of the anterior tibial bowing and the volume of the lesion in relation to the host bone were not changed throughout the follow-up period, indicating that the growth of the lesion followed the growth of the normal bone.

The differential diagnosis of a giant bone island includes a variety of benign tumors and tumor-like lesions, as well as malignant bone lesions.^{2,4,23,28,30,31} In the patient presented in this report, the diagnosis of an atypical sclerotic presentation of a nonossifying fibroma or healing stage of this lesion could be consistent with some of the CT findings, including the eccentric origin from the cortex associated with medial cortical thickening, the anterolateral cortical thinning, and the soft-tissue attenuation of cortical areas. In addition, unifocal osteofibrous dysplasia may also present with a long intracortical diaphyseal lucency within an area of marked cortical sclerosis and cause a bowing deformity. Both diagnoses were excluded, since no fibrous stroma was evident on the histologic examination of the lesion. A large or giant long-bone osteoma would be associated with the outer cortical margin of bone but would not involve the intramedullary space. The scintigraphically increased uptake of radioisotope, as well as the CT and MRI findings, were not consistent with the diagnosis of osteoid osteoma, osteoblastoma, or osteomyelitis. Although most imaging findings were consistent with a benign lesion, and contrast-enhanced MRI showed no increased vascularity, anterior cortical disruption necessitated a bone biopsy to rule out any potential malignancy.

The histopathology in association with the clinical and imaging findings indicated the diagnosis of a giant bone island. The increased proportion of maturing woven bone over lamellar bone indicated an active remodeling lesion that could be related to the patient’s age, since the clinical and radiographic features of the lesion were not changed after 15-year follow-up.

Conclusion

This is the first giant bone island diagnosed in a patient before puberty. Its greatest length was 10.8 cm, which is the longest reported in the literature. The imaging appearance included several atypical features that are very rare or have not been reported. Microscopic features indicated less mature lamellar bone and a prominent proportion of maturing woven bone. The clinical and the radiographic appearance of the lesion were not changed after 15-year follow-up.

 A bone island is a focus of normal cortical bone located within the medullary cavity. The vast majority of bone islands are small, measuring from 1 mm to 2 cm in size. They are found more frequently in adults than in children. The lesion can be virtually diagnosed on the basis of its characteristic clinical and imaging features. Differential diagnosis may be difficult when the lesion manifests itself uncharacteristically by being symptomatic, very large, and hot on bone scan.^1-4

The term giant bone island has been used to describe a large lesion1 that measures more than 2 cm in any dimension.⁵ Giant bone islands have been described only in adults,^1,5-15 and the longest bone island length reported is 10.5 cm.¹⁰ They are usually symptomatic and associated with increased radionuclide uptake on bone scintigraphy.¹⁴

The history and the clinical and imaging presentation of an even longer, symptomatic, and scintigraphically hot lesion in the tibial diaphysis of a 10-year-old boy is reported. The lesion further exhibited several atypical imaging features necessitating an open biopsy, which confirmed the diagnosis of a giant bone island. The pertinent differential diagnosis and the clinical and radiographic findings after 15-year follow-up are also presented and discussed. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 10-year-old boy was admitted for surgical repair of an inguinal hernia. Physical examination revealed a painless but tender anterior bowing of the right tibial diaphysis. The patient was a healthy-appearing white male with normal vital signs, gait, and posture. His parents noticed a slight protuberance of the tibia at age 2.5 years. No medical advice was asked for the bone swelling after that time. After recovery from the inguinal hernia repair 3 weeks later, the bone lesion was thoroughly examined. Radiographs showed an oblong, homogenous region of dense sclerosis in the diaphysis of the right tibia. The lesion had relatively well-defined margins and was located in the medullary cavity. Speculations were not obvious in the periphery of the lesion, which exhibited a sharp circumscription (Figures 1A, 1B). A well-defined lytic area was evident at the distal part of the lesion (Figure 1B). There was no periosteal reaction. Blood and serum chemistries were within normal limits, including serum calcium, phosphorus, and alkaline phosphatase. A conventional 3-phase bone scintigraphy (300 MBq) with technetium-99m HDP (hydroxydiphosphonate) indicated increased uptake in the area of the lesion but no other skeletal abnormality (Figure 2). Computed tomography (CT) showed that the lesion was purely intramedullary and densely blastic. The lesion originated from the medial cortex, which was thickened (Figure 3A). The lesion extended to the anterolateral cortex, which was thinned and included a lytic area. In the distal part of the lesion, the anterolateral cortex was thickened, included lytic areas, and exhibited an anterior portion of cortical destruction (Figure 3B). The fatty marrow adjacent to the region of sclerosis appeared normal. There was no evidence of extraosseous soft-tissue changes. On both T1- and T2-weighted magnetic resonance imaging (MRI), the lesion exhibited low-signal intensity. The lesion measured 10.8×2.2×1 cm. It originated from the medial cortical bone of the tibia, blended into the medullary cavity, and extended anteriorly towards and through the anterior cortex. The area of cortical destruction was clearly evident on the axial MRI. The periosteum was displaced and eroded anteriorly by focal radiating bony streaks. No enhancement was seen after the intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a contrast medium. There were no extraosseous soft-tissue changes. In the distal part of the lesion, sagittal and axial MRI showed a 1.2×0.8×0.7-cm well-defined ovoid focus, with characteristics of cystic degeneration that exhibited intermediate-signal intensity on T1-weighted MRI (Figure 4) and high-signal intensity on T2-weighted MRI.

An open biopsy was performed. Macroscopically, a wedge of compact bone measuring 3×1.7×0.6 cm was taken. Microscopic examination showed a thinned periphery of lamellar (mature) bone with haversian canals and, beneath it, woven (immature) bone with long-surface processes projecting within adjacent cancellous bone (Figure 5A). The woven bone contained loose vascular fibrous tissue. No osteoclasts were noted, and the very few osteoblasts lining the bone trabeculae were small, single-layered, and flat (Figure 5B). There was no evidence of neoplastic cells. There was no abnormality of the periosteum and the surrounding soft tissues.

The histology was pathognomonic of a giant bone island. No additional surgical intervention was recommended.

The postoperative course was uncomplicated, and the patient was discharged 2 weeks later. An above-the-knee plaster was recommended for 3 months and a below-the-knee splint for an additional 2-month period. Full weight-bearing was allowed only after the postsurgical sixth month to prevent an impending fracture. The tibial bowing was tender to pressure or palpation, and the patient reported mild spontaneous pain during follow-up. Radiographs 1 year after surgery indicated that the bone area removed for biopsy was replaced by compact bone. MRI performed 4 years after surgery showed that the volume of the lesion in relation to the host bone was not changed.

At the last follow-up 15 years after surgery, the anterior tibial bowing was not changed (Figure 6A), but the patient additionally complained of skin irritation after intense training wearing boots during military service. The radiographic appearance of the lesion was also not changed, while the periphery of the lesion exhibited scarce radiating bony streaks with rounded contours (Figures 6B, 6C). The clinical symptoms and signs from wearing military boots completely subsided after a couple of weeks’ rest from daily army activities, but the mild spontaneous pain and the local tenderness over the tibial bowing persisted.

Discussion

Giant bone islands are more likely to be associated with clinical symptoms than the usual small-sized bone island. Some degree of pain was detected in 8 of 10 patients with a giant bone island presented in the literature, but it was induced by trauma in 3 of them.¹⁴

Radiographic appearance is among the distinguishing diagnostic features of a giant bone island. It appears as an ovoid, round, or oblong, homogenously dense, single or multiple focus of sclerosis within the medullary cavity; it is oriented along the long axis of the host bone, and it exhibits peripheral pseudopodia or radiating spicules producing the typical “thorny” or “paintbrush” appearance.^8,16,17 It does not exhibit cortical penetration and it is not associated with periosteal reaction.10

The CT findings include a sclerotic and hyperdense focus with spiculated margins extending into the adjacent cancellous bone. The lack of bone destruction and soft-tissue mass are also diagnostic.^3,7 MRI findings will reflect the low-signal intensity characteristics of cortical bone on all pulse sequences.¹⁸

Enostoses usually exhibit no activity on skeletal scintigraphy, while giant lesions generally show increased radiotracer uptake.^{5,9-11,14,19-27} The latter may result from the increased amount of bone turnover, which is seen more often with larger lesions because of active bone deposition and remodeling.^20,21,23,28 Histopathology of a giant bone island appears identical to the well-described pathologic appearance of smaller bone islands. The lesion is composed of compact lamellar bone and haversian systems, which blend with the adjacent spongiosa. The surrounding cancellous bone forms thorn-like trabeculae radiating from the lesion and merging with the cancellous bone.^1,4,5,8,28

The presumptive diagnosis of a bone island is based on the clinical findings, imaging features, and follow-up examinations. An asymptomatic, isolated, sclerotic bone lesion showing the typical features of a bone island on plain radiography, CT, and MRI, whatever its size, that is nonactive on bone scan may be easily diagnosed. However, a symptomatic patient with a hot lesion on scintigraphy should be carefully observed. In addition, larger lesions may raise the suspicion of a neoplasm, such as a sclerotic variant of osteosarcoma. In such cases, an open biopsy may be undertaken. No specific treatment is required after the diagnosis has been confirmed. There is no literature to suggest that, after adequate biopsy confirmation, excision or resection is necessary. Follow-up radiographic examination of the lesion should be suggested to monitor for any potential growth.^2,10,23

The first giant bone island appearing in a child is presented in this report. The lack of a causative factor leading to the anterior tibial bowing indicated that the bone deformity was caused primarily by the lesion. The present case is unusual for the appearance of several atypical features, some of which have not been previously described. Peripheral radiating spiculated margin was absent on the patient’s initial radiographs and CT imaging. MRI indicated only the presence of radiating bony streaks that displaced and eroded the periosteum on the anterior border of the lesion. The CT findings that the lesion likely originated or was in close proximity with the medial cortex of the tibia were also atypical. It has been previously reported that spinal lesions located immediately below the cortex tend to fuse with the endosteal surface, while similar features may also be seen in the appendicular enostoses.^4,29 Other CT findings, such as the thinning of the overlying anterolateral cortical bone, as well as the cortical thickening at the periphery of the lesion associated with areas of soft-tissue attenuation and anterior cortical destruction, have not been described even in the atypical features of a giant bone island. The lytic area resembling a nidus that was evident at the distal part of the lesion was more likely consistent with an area of resorption, which, although rare, has been described on giant lesions.^2,9,29 The substantial amount of woven bone transforming to lamellar bone that was evident in the present patient’s microscopic features is also an atypical finding, although it may be expected to some degree in scintigraphically hot, large lesions.²⁸ The clinical and imaging progress of the lesion supported the diagnosis of a giant bone island. The degree of the anterior tibial bowing and the volume of the lesion in relation to the host bone were not changed throughout the follow-up period, indicating that the growth of the lesion followed the growth of the normal bone.

The differential diagnosis of a giant bone island includes a variety of benign tumors and tumor-like lesions, as well as malignant bone lesions.^{2,4,23,28,30,31} In the patient presented in this report, the diagnosis of an atypical sclerotic presentation of a nonossifying fibroma or healing stage of this lesion could be consistent with some of the CT findings, including the eccentric origin from the cortex associated with medial cortical thickening, the anterolateral cortical thinning, and the soft-tissue attenuation of cortical areas. In addition, unifocal osteofibrous dysplasia may also present with a long intracortical diaphyseal lucency within an area of marked cortical sclerosis and cause a bowing deformity. Both diagnoses were excluded, since no fibrous stroma was evident on the histologic examination of the lesion. A large or giant long-bone osteoma would be associated with the outer cortical margin of bone but would not involve the intramedullary space. The scintigraphically increased uptake of radioisotope, as well as the CT and MRI findings, were not consistent with the diagnosis of osteoid osteoma, osteoblastoma, or osteomyelitis. Although most imaging findings were consistent with a benign lesion, and contrast-enhanced MRI showed no increased vascularity, anterior cortical disruption necessitated a bone biopsy to rule out any potential malignancy.

The histopathology in association with the clinical and imaging findings indicated the diagnosis of a giant bone island. The increased proportion of maturing woven bone over lamellar bone indicated an active remodeling lesion that could be related to the patient’s age, since the clinical and radiographic features of the lesion were not changed after 15-year follow-up.

Conclusion

This is the first giant bone island diagnosed in a patient before puberty. Its greatest length was 10.8 cm, which is the longest reported in the literature. The imaging appearance included several atypical features that are very rare or have not been reported. Microscopic features indicated less mature lamellar bone and a prominent proportion of maturing woven bone. The clinical and the radiographic appearance of the lesion were not changed after 15-year follow-up.