Neurology

Even a mild blast to the brain can cause long-term, life-changing health problems, says Riyi Shi, professor of neuroscience and biomedical engineering at Purdue University in Lafayette, Indiana. However, the effects can be subtle: “The individual appears to be fine, and it’s difficult to tell if you just look at a person. But the fact is that these types of hits are multiplied over years and often ignored until someone reaches an age when other factors come into play.”

Treating the incidents sooner can help mitigate later-life issues, such as Parkinson disease (PD). Shi led a study that found checking the urine within 7 days following a blast incident—even a mild one—provides faster diagnosis when brain injury is suspected.

A simple urine analysis reveals elevations in the neurotoxin acrolein, Shi says, which is a biomarker for brain injury. In the study, the researchers evaluated the changes of α-synuclein and tyrosine hydroxylase, hallmarks of PD, and acrolein, a marker of oxidative stress. The researchers say in animal models of PD and traumatic brain injury (TBI), acrolein is “likely a point of pathogenic convergence.”

They found that after a single mild blast TBI, acrolein was elevated for up to a week, systemically in urine, and in whole brain tissue, specifically the substantia nigra and striatum. The elevation was accompanied by heightened α-synuclein oligomerization, dopaminergic dysregulation, and acrolein/α-synuclein interaction in the same brain regions. Taken together, the researchers say, the data suggest that acrolein likely plays a key role in inducing PD following blast TBI.

The presence of the biomarker “alerts us to the injury, creating an opportunity for intervention,” Shi says. “This early detection and subsequent treatment window could offer tremendous benefits for long-term patient neurologic health.”

Even a mild blast to the brain can cause long-term, life-changing health problems, says Riyi Shi, professor of neuroscience and biomedical engineering at Purdue University in Lafayette, Indiana. However, the effects can be subtle: “The individual appears to be fine, and it’s difficult to tell if you just look at a person. But the fact is that these types of hits are multiplied over years and often ignored until someone reaches an age when other factors come into play.”

Treating the incidents sooner can help mitigate later-life issues, such as Parkinson disease (PD). Shi led a study that found checking the urine within 7 days following a blast incident—even a mild one—provides faster diagnosis when brain injury is suspected.

A simple urine analysis reveals elevations in the neurotoxin acrolein, Shi says, which is a biomarker for brain injury. In the study, the researchers evaluated the changes of α-synuclein and tyrosine hydroxylase, hallmarks of PD, and acrolein, a marker of oxidative stress. The researchers say in animal models of PD and traumatic brain injury (TBI), acrolein is “likely a point of pathogenic convergence.”

They found that after a single mild blast TBI, acrolein was elevated for up to a week, systemically in urine, and in whole brain tissue, specifically the substantia nigra and striatum. The elevation was accompanied by heightened α-synuclein oligomerization, dopaminergic dysregulation, and acrolein/α-synuclein interaction in the same brain regions. Taken together, the researchers say, the data suggest that acrolein likely plays a key role in inducing PD following blast TBI.

The presence of the biomarker “alerts us to the injury, creating an opportunity for intervention,” Shi says. “This early detection and subsequent treatment window could offer tremendous benefits for long-term patient neurologic health.”

Even a mild blast to the brain can cause long-term, life-changing health problems, says Riyi Shi, professor of neuroscience and biomedical engineering at Purdue University in Lafayette, Indiana. However, the effects can be subtle: “The individual appears to be fine, and it’s difficult to tell if you just look at a person. But the fact is that these types of hits are multiplied over years and often ignored until someone reaches an age when other factors come into play.”

Treating the incidents sooner can help mitigate later-life issues, such as Parkinson disease (PD). Shi led a study that found checking the urine within 7 days following a blast incident—even a mild one—provides faster diagnosis when brain injury is suspected.

A simple urine analysis reveals elevations in the neurotoxin acrolein, Shi says, which is a biomarker for brain injury. In the study, the researchers evaluated the changes of α-synuclein and tyrosine hydroxylase, hallmarks of PD, and acrolein, a marker of oxidative stress. The researchers say in animal models of PD and traumatic brain injury (TBI), acrolein is “likely a point of pathogenic convergence.”

They found that after a single mild blast TBI, acrolein was elevated for up to a week, systemically in urine, and in whole brain tissue, specifically the substantia nigra and striatum. The elevation was accompanied by heightened α-synuclein oligomerization, dopaminergic dysregulation, and acrolein/α-synuclein interaction in the same brain regions. Taken together, the researchers say, the data suggest that acrolein likely plays a key role in inducing PD following blast TBI.

The presence of the biomarker “alerts us to the injury, creating an opportunity for intervention,” Shi says. “This early detection and subsequent treatment window could offer tremendous benefits for long-term patient neurologic health.”

A new study of children who were born with congenital heart disease (CHD) has found that they have increased odds of developing autism spectrum disorder.

“To our knowledge, this is the only study in which there has been a comparison between [autism spectrum disorder] and multiple CHD subtypes,” wrote Eric R. Sigmon, MD, of Emory University, Atlanta, and coauthors. “Our findings are consistent with previous studies of CHD developmental outcomes, which have shown an increased risk of developmental and academic delay after CHD diagnosis and treatment.” The study was published in Pediatrics.

To further investigate the association between CHD and autism, the researchers performed a case-control study using the Military Health System administrative database. They uncovered 8,760 cases of children with autism spectrum disorder and matched each one with three controls (n = 26,280). From that sample size, they identified 1,063 children with CHD: 401 in the autism spectrum disorder group and 662 in the control group.

Before analysis, children with autism spectrum disorder had an odds ratio of 1.85 of having any form of CHD, compared with controls (95% confidence interval, 1.63-2.10). After adjustment for covariates – including genetic syndromes, maternal age and morbidity, perinatal morbidity, and neonatal complications – the OR was 1.33 (95% CI, 1.16-1.52).

In the sensitivity analysis – which included only 593 children with CHD – the OR was a similar 1.32 (95% CI, 1.10-1.59).

Certain forms of CHD were more associated with autism spectrum disorder, including atrial septal defect (OR, 1.72; 95% CI, 1.07-2.74) and ventricular septal defect (OR, 1.65; 95% CI, 1.21-2.25). Left heart obstructive lesion was significantly associated with autism spectrum disorder after covariate adjustment (OR, 1.42; 95% CI, 1.04-1.93), but the finding was no longer significant in the sensitivity analysis.

The authors noted the potential limitations of their study, including the general weaknesses of administrative data, which they attempted to counter with the sensitive analysis. In addition, they recognized that children with either autism spectrum disorder or CHD “tend to present for care more frequently,” which could have created an ascertainment bias.

In an accompanying editorial, Johanna Calderon, PhD, David C. Bellinger, PhD, and Jane W. Newburger, MD, MPH, stated that more work needs to be done to further quantify the relationship between CHD and autism spectrum disorder (Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2019-2752). The three authors – all affiliated with Boston Children’s Hospital and Harvard Medical School, also in Boston – reiterated the acknowledgment from Dr. Sigmon and coauthors that the “etiologic pathways that might explain” the link between the two remains unknown. They also noted their surprise that autism spectrum disorder risk appears to be increased in children with modestly severe forms of CHD, stating that this finding required additional investigation.

“Despite the strengths of this study,” they wrote, “it raises more questions than answers.”

The study was funded by the Congressional Directed Medical Research Programs Autism Research Award. The authors reported no conflicts of interest.

SOURCE: Sigmon ER at al. Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2018-4114.

A new study of children who were born with congenital heart disease (CHD) has found that they have increased odds of developing autism spectrum disorder.

“To our knowledge, this is the only study in which there has been a comparison between [autism spectrum disorder] and multiple CHD subtypes,” wrote Eric R. Sigmon, MD, of Emory University, Atlanta, and coauthors. “Our findings are consistent with previous studies of CHD developmental outcomes, which have shown an increased risk of developmental and academic delay after CHD diagnosis and treatment.” The study was published in Pediatrics.

To further investigate the association between CHD and autism, the researchers performed a case-control study using the Military Health System administrative database. They uncovered 8,760 cases of children with autism spectrum disorder and matched each one with three controls (n = 26,280). From that sample size, they identified 1,063 children with CHD: 401 in the autism spectrum disorder group and 662 in the control group.

Before analysis, children with autism spectrum disorder had an odds ratio of 1.85 of having any form of CHD, compared with controls (95% confidence interval, 1.63-2.10). After adjustment for covariates – including genetic syndromes, maternal age and morbidity, perinatal morbidity, and neonatal complications – the OR was 1.33 (95% CI, 1.16-1.52).

In the sensitivity analysis – which included only 593 children with CHD – the OR was a similar 1.32 (95% CI, 1.10-1.59).

Certain forms of CHD were more associated with autism spectrum disorder, including atrial septal defect (OR, 1.72; 95% CI, 1.07-2.74) and ventricular septal defect (OR, 1.65; 95% CI, 1.21-2.25). Left heart obstructive lesion was significantly associated with autism spectrum disorder after covariate adjustment (OR, 1.42; 95% CI, 1.04-1.93), but the finding was no longer significant in the sensitivity analysis.

The authors noted the potential limitations of their study, including the general weaknesses of administrative data, which they attempted to counter with the sensitive analysis. In addition, they recognized that children with either autism spectrum disorder or CHD “tend to present for care more frequently,” which could have created an ascertainment bias.

In an accompanying editorial, Johanna Calderon, PhD, David C. Bellinger, PhD, and Jane W. Newburger, MD, MPH, stated that more work needs to be done to further quantify the relationship between CHD and autism spectrum disorder (Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2019-2752). The three authors – all affiliated with Boston Children’s Hospital and Harvard Medical School, also in Boston – reiterated the acknowledgment from Dr. Sigmon and coauthors that the “etiologic pathways that might explain” the link between the two remains unknown. They also noted their surprise that autism spectrum disorder risk appears to be increased in children with modestly severe forms of CHD, stating that this finding required additional investigation.

“Despite the strengths of this study,” they wrote, “it raises more questions than answers.”

The study was funded by the Congressional Directed Medical Research Programs Autism Research Award. The authors reported no conflicts of interest.

SOURCE: Sigmon ER at al. Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2018-4114.

A new study of children who were born with congenital heart disease (CHD) has found that they have increased odds of developing autism spectrum disorder.

“To our knowledge, this is the only study in which there has been a comparison between [autism spectrum disorder] and multiple CHD subtypes,” wrote Eric R. Sigmon, MD, of Emory University, Atlanta, and coauthors. “Our findings are consistent with previous studies of CHD developmental outcomes, which have shown an increased risk of developmental and academic delay after CHD diagnosis and treatment.” The study was published in Pediatrics.

To further investigate the association between CHD and autism, the researchers performed a case-control study using the Military Health System administrative database. They uncovered 8,760 cases of children with autism spectrum disorder and matched each one with three controls (n = 26,280). From that sample size, they identified 1,063 children with CHD: 401 in the autism spectrum disorder group and 662 in the control group.

Before analysis, children with autism spectrum disorder had an odds ratio of 1.85 of having any form of CHD, compared with controls (95% confidence interval, 1.63-2.10). After adjustment for covariates – including genetic syndromes, maternal age and morbidity, perinatal morbidity, and neonatal complications – the OR was 1.33 (95% CI, 1.16-1.52).

In the sensitivity analysis – which included only 593 children with CHD – the OR was a similar 1.32 (95% CI, 1.10-1.59).

Certain forms of CHD were more associated with autism spectrum disorder, including atrial septal defect (OR, 1.72; 95% CI, 1.07-2.74) and ventricular septal defect (OR, 1.65; 95% CI, 1.21-2.25). Left heart obstructive lesion was significantly associated with autism spectrum disorder after covariate adjustment (OR, 1.42; 95% CI, 1.04-1.93), but the finding was no longer significant in the sensitivity analysis.

The authors noted the potential limitations of their study, including the general weaknesses of administrative data, which they attempted to counter with the sensitive analysis. In addition, they recognized that children with either autism spectrum disorder or CHD “tend to present for care more frequently,” which could have created an ascertainment bias.

In an accompanying editorial, Johanna Calderon, PhD, David C. Bellinger, PhD, and Jane W. Newburger, MD, MPH, stated that more work needs to be done to further quantify the relationship between CHD and autism spectrum disorder (Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2019-2752). The three authors – all affiliated with Boston Children’s Hospital and Harvard Medical School, also in Boston – reiterated the acknowledgment from Dr. Sigmon and coauthors that the “etiologic pathways that might explain” the link between the two remains unknown. They also noted their surprise that autism spectrum disorder risk appears to be increased in children with modestly severe forms of CHD, stating that this finding required additional investigation.

“Despite the strengths of this study,” they wrote, “it raises more questions than answers.”

The study was funded by the Congressional Directed Medical Research Programs Autism Research Award. The authors reported no conflicts of interest.

SOURCE: Sigmon ER at al. Pediatrics. 2019 Oct 10. doi: 10.1542/peds.2018-4114.

STOCKHOLM – The Age-Related Multiple Sclerosis Severity (ARMSS) score can be used to create a measurement that predicts a patient’s future level of disability, according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. The resulting measurement is stable, not highly sensitive to age, and appropriate for research applications. “It could give a clinician an earlier indication of the potential disease course of a patient,” said Ryan Ramanujam, PhD, assistant professor of translational neuroepidemiology at Karolinska Institutet in Stockholm.

Researchers who study MS use various scores to measure disease severity, including the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS). These scores cannot predict a patient’s future status, however, and they do not remain stable throughout the course of a patient’s disease. Fitting a linear model over a series of scores over time can provide a misleading impression of a patient’s disease progression. “What we need is a metric to give a holistic overview of disease course, regardless of when it’s measured in a patient’s disease progression,” said Dr. Ramanujam. Such a measurement could aid the search for genes that affect MS severity, he added.
 

Examining disability by patient age

Dr. Ramanujam and colleagues constructed their measure using the ARMSS score, which ranks EDSS score by age instead of by disease duration. The ARMSS score ranges from 0 to 10, and the median value is 5 for all patients at a given age. Investigators can calculate the score using a previously published global matrix of values for ARMSS and MSSS available in the R package ms.sev.

The investigators found that the ARMSS score is slightly superior to the MSSS in detecting small increases in EDSS. One benefit of the ARMSS score, compared with the MSSS, is that it allows investigators to study patients for whom time of disease onset is unknown. The ARMSS score also removes potential systematic bias that might result from a neurologist’s retrospective assignment of date of disease onset, said Dr. Ramanujam.

He and his colleagues used ARMSS to compare patients’ disease course with what is expected for that patient (i.e., an ARMSS that remains stable at 5). They extracted data for 15,831 patients participating in the Swedish MS registry, including age and EDSS score at each neurological visit. Eligible patients had serial EDSS scores for 10 years. Dr. Ramanujam and colleagues included 4,514 patients in their analysis.
 

Measures at 2 years correlated with those at 10 years

The researchers created what they called the ARMSS integral by calculating the ARMSS score’s change from 5 at each examination (e.g., −0.5 or 1). “The ARMSS integral can be thought of as the cumulative disability that a patient accrues over his or her disease course, relative to the average patient, who had the disease for the same ages,” said Dr. Ramanujam. At 2 years of follow-up and at 10 years of follow-up, the distribution of ARMSS integrals for the study population followed a normal pattern.

Next, the investigators sought to compare patients by standardizing their follow-up time. To do this, they calculated what they called the ARMSS-rate by dividing each patient’s ARMSS integral by the number of years of follow-up. The ARMSS-rate offers a “snapshot of disease severity and progression,” said Dr. Ramanujam. When the researchers compared ARMSS-rates at 2 years and 10 years for each patient, they found that the measure was “extremely stable over time and strongly correlated with future disability.” The correlation improved slightly when the researchers compared ARMSS-rates at 4 years and 10 years.

The investigators then categorized patients based on their ARMSS-rate at 2 years (e.g., 0 to 1, 1 to 2, 2 to 3). When they compared the values in these categories with the median ARMSS-rates for the same individuals over the subsequent 8 years, they found strong group-level correlations.

To analyze correlations on an individual level, Dr. Ramanujam and colleagues examined the ability of different metrics at the time closest to 2 years of follow-up to predict those measured at 10 years. They assigned the value 1 to the most severe quartile of outcomes and the value 0 to all other quartiles. For predictors and outcomes, the investigators examined ARMSS-rate and the integral of progression index, which they calculated using the integral of EDSS. They also included EDSS at 10 years as an outcome for progression index.

For predicting the subsequent 8 years of ARMSS-rates, ARMSS-rate at 2 years had an area under the curve (AUC) of 0.921. When the investigators performed the same analysis using a cohort of patients with MS from British Columbia, Canada, they obtained an AUC of 0.887. Progression index at 2 years had an AUC of 0.61 for predicting the most severe quartile of the next 8 years. Compared with this result, ARMSS integral up to 2 years was slightly better at predicting EDSS at 10 years, said Dr. Ramanujam. The progression index poorly predicted the most severe quartile of EDSS at 10 years.

The main limitation of the ARMSS integral and ARMSS-rate is that they are based on EDSS, he added. The EDSS gives great weight to mobility and largely does not measure cognitive disability. “Future metrics could therefore include additional data such as MRI, Symbol Digit Modalities Test, or neurofilament light levels,” said Dr. Ramanujam. “Also, self-assessment could be one area to improve in the future.”

Dr. Ramanujam had no conflicts of interest to disclose. He receives funding from the MultipleMS Project, which is part of the EU Horizon 2020 Framework.

egreb@mdedge.com

SOURCE: Manouchehrinia A et al. ECTRIMS 2019. Abstract 218.

STOCKHOLM – The Age-Related Multiple Sclerosis Severity (ARMSS) score can be used to create a measurement that predicts a patient’s future level of disability, according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. The resulting measurement is stable, not highly sensitive to age, and appropriate for research applications. “It could give a clinician an earlier indication of the potential disease course of a patient,” said Ryan Ramanujam, PhD, assistant professor of translational neuroepidemiology at Karolinska Institutet in Stockholm.

Researchers who study MS use various scores to measure disease severity, including the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS). These scores cannot predict a patient’s future status, however, and they do not remain stable throughout the course of a patient’s disease. Fitting a linear model over a series of scores over time can provide a misleading impression of a patient’s disease progression. “What we need is a metric to give a holistic overview of disease course, regardless of when it’s measured in a patient’s disease progression,” said Dr. Ramanujam. Such a measurement could aid the search for genes that affect MS severity, he added.
 

Examining disability by patient age

Dr. Ramanujam and colleagues constructed their measure using the ARMSS score, which ranks EDSS score by age instead of by disease duration. The ARMSS score ranges from 0 to 10, and the median value is 5 for all patients at a given age. Investigators can calculate the score using a previously published global matrix of values for ARMSS and MSSS available in the R package ms.sev.

The investigators found that the ARMSS score is slightly superior to the MSSS in detecting small increases in EDSS. One benefit of the ARMSS score, compared with the MSSS, is that it allows investigators to study patients for whom time of disease onset is unknown. The ARMSS score also removes potential systematic bias that might result from a neurologist’s retrospective assignment of date of disease onset, said Dr. Ramanujam.

He and his colleagues used ARMSS to compare patients’ disease course with what is expected for that patient (i.e., an ARMSS that remains stable at 5). They extracted data for 15,831 patients participating in the Swedish MS registry, including age and EDSS score at each neurological visit. Eligible patients had serial EDSS scores for 10 years. Dr. Ramanujam and colleagues included 4,514 patients in their analysis.
 

Measures at 2 years correlated with those at 10 years

The researchers created what they called the ARMSS integral by calculating the ARMSS score’s change from 5 at each examination (e.g., −0.5 or 1). “The ARMSS integral can be thought of as the cumulative disability that a patient accrues over his or her disease course, relative to the average patient, who had the disease for the same ages,” said Dr. Ramanujam. At 2 years of follow-up and at 10 years of follow-up, the distribution of ARMSS integrals for the study population followed a normal pattern.

Next, the investigators sought to compare patients by standardizing their follow-up time. To do this, they calculated what they called the ARMSS-rate by dividing each patient’s ARMSS integral by the number of years of follow-up. The ARMSS-rate offers a “snapshot of disease severity and progression,” said Dr. Ramanujam. When the researchers compared ARMSS-rates at 2 years and 10 years for each patient, they found that the measure was “extremely stable over time and strongly correlated with future disability.” The correlation improved slightly when the researchers compared ARMSS-rates at 4 years and 10 years.

The investigators then categorized patients based on their ARMSS-rate at 2 years (e.g., 0 to 1, 1 to 2, 2 to 3). When they compared the values in these categories with the median ARMSS-rates for the same individuals over the subsequent 8 years, they found strong group-level correlations.

To analyze correlations on an individual level, Dr. Ramanujam and colleagues examined the ability of different metrics at the time closest to 2 years of follow-up to predict those measured at 10 years. They assigned the value 1 to the most severe quartile of outcomes and the value 0 to all other quartiles. For predictors and outcomes, the investigators examined ARMSS-rate and the integral of progression index, which they calculated using the integral of EDSS. They also included EDSS at 10 years as an outcome for progression index.

For predicting the subsequent 8 years of ARMSS-rates, ARMSS-rate at 2 years had an area under the curve (AUC) of 0.921. When the investigators performed the same analysis using a cohort of patients with MS from British Columbia, Canada, they obtained an AUC of 0.887. Progression index at 2 years had an AUC of 0.61 for predicting the most severe quartile of the next 8 years. Compared with this result, ARMSS integral up to 2 years was slightly better at predicting EDSS at 10 years, said Dr. Ramanujam. The progression index poorly predicted the most severe quartile of EDSS at 10 years.

The main limitation of the ARMSS integral and ARMSS-rate is that they are based on EDSS, he added. The EDSS gives great weight to mobility and largely does not measure cognitive disability. “Future metrics could therefore include additional data such as MRI, Symbol Digit Modalities Test, or neurofilament light levels,” said Dr. Ramanujam. “Also, self-assessment could be one area to improve in the future.”

Dr. Ramanujam had no conflicts of interest to disclose. He receives funding from the MultipleMS Project, which is part of the EU Horizon 2020 Framework.

egreb@mdedge.com

SOURCE: Manouchehrinia A et al. ECTRIMS 2019. Abstract 218.

STOCKHOLM – The Age-Related Multiple Sclerosis Severity (ARMSS) score can be used to create a measurement that predicts a patient’s future level of disability, according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. The resulting measurement is stable, not highly sensitive to age, and appropriate for research applications. “It could give a clinician an earlier indication of the potential disease course of a patient,” said Ryan Ramanujam, PhD, assistant professor of translational neuroepidemiology at Karolinska Institutet in Stockholm.

Researchers who study MS use various scores to measure disease severity, including the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS). These scores cannot predict a patient’s future status, however, and they do not remain stable throughout the course of a patient’s disease. Fitting a linear model over a series of scores over time can provide a misleading impression of a patient’s disease progression. “What we need is a metric to give a holistic overview of disease course, regardless of when it’s measured in a patient’s disease progression,” said Dr. Ramanujam. Such a measurement could aid the search for genes that affect MS severity, he added.
 

Examining disability by patient age

Dr. Ramanujam and colleagues constructed their measure using the ARMSS score, which ranks EDSS score by age instead of by disease duration. The ARMSS score ranges from 0 to 10, and the median value is 5 for all patients at a given age. Investigators can calculate the score using a previously published global matrix of values for ARMSS and MSSS available in the R package ms.sev.

The investigators found that the ARMSS score is slightly superior to the MSSS in detecting small increases in EDSS. One benefit of the ARMSS score, compared with the MSSS, is that it allows investigators to study patients for whom time of disease onset is unknown. The ARMSS score also removes potential systematic bias that might result from a neurologist’s retrospective assignment of date of disease onset, said Dr. Ramanujam.

He and his colleagues used ARMSS to compare patients’ disease course with what is expected for that patient (i.e., an ARMSS that remains stable at 5). They extracted data for 15,831 patients participating in the Swedish MS registry, including age and EDSS score at each neurological visit. Eligible patients had serial EDSS scores for 10 years. Dr. Ramanujam and colleagues included 4,514 patients in their analysis.
 

Measures at 2 years correlated with those at 10 years

The researchers created what they called the ARMSS integral by calculating the ARMSS score’s change from 5 at each examination (e.g., −0.5 or 1). “The ARMSS integral can be thought of as the cumulative disability that a patient accrues over his or her disease course, relative to the average patient, who had the disease for the same ages,” said Dr. Ramanujam. At 2 years of follow-up and at 10 years of follow-up, the distribution of ARMSS integrals for the study population followed a normal pattern.

Next, the investigators sought to compare patients by standardizing their follow-up time. To do this, they calculated what they called the ARMSS-rate by dividing each patient’s ARMSS integral by the number of years of follow-up. The ARMSS-rate offers a “snapshot of disease severity and progression,” said Dr. Ramanujam. When the researchers compared ARMSS-rates at 2 years and 10 years for each patient, they found that the measure was “extremely stable over time and strongly correlated with future disability.” The correlation improved slightly when the researchers compared ARMSS-rates at 4 years and 10 years.

The investigators then categorized patients based on their ARMSS-rate at 2 years (e.g., 0 to 1, 1 to 2, 2 to 3). When they compared the values in these categories with the median ARMSS-rates for the same individuals over the subsequent 8 years, they found strong group-level correlations.

To analyze correlations on an individual level, Dr. Ramanujam and colleagues examined the ability of different metrics at the time closest to 2 years of follow-up to predict those measured at 10 years. They assigned the value 1 to the most severe quartile of outcomes and the value 0 to all other quartiles. For predictors and outcomes, the investigators examined ARMSS-rate and the integral of progression index, which they calculated using the integral of EDSS. They also included EDSS at 10 years as an outcome for progression index.

For predicting the subsequent 8 years of ARMSS-rates, ARMSS-rate at 2 years had an area under the curve (AUC) of 0.921. When the investigators performed the same analysis using a cohort of patients with MS from British Columbia, Canada, they obtained an AUC of 0.887. Progression index at 2 years had an AUC of 0.61 for predicting the most severe quartile of the next 8 years. Compared with this result, ARMSS integral up to 2 years was slightly better at predicting EDSS at 10 years, said Dr. Ramanujam. The progression index poorly predicted the most severe quartile of EDSS at 10 years.

The main limitation of the ARMSS integral and ARMSS-rate is that they are based on EDSS, he added. The EDSS gives great weight to mobility and largely does not measure cognitive disability. “Future metrics could therefore include additional data such as MRI, Symbol Digit Modalities Test, or neurofilament light levels,” said Dr. Ramanujam. “Also, self-assessment could be one area to improve in the future.”

Dr. Ramanujam had no conflicts of interest to disclose. He receives funding from the MultipleMS Project, which is part of the EU Horizon 2020 Framework.

egreb@mdedge.com

SOURCE: Manouchehrinia A et al. ECTRIMS 2019. Abstract 218.

STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.

“High-intensive memory-strategy interventions exert the largest effects on hippocampal memory function” in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.

To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.

Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.

After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.

To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.

Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.

Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.

Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.

“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.

Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.

Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
 

koakes@mdedge.com

SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.

STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.

“High-intensive memory-strategy interventions exert the largest effects on hippocampal memory function” in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.

To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.

Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.

After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.

To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.

Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.

Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.

Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.

“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.

Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.

Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
 

koakes@mdedge.com

SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.

STOCKHOLM – Cognitive rehabilitation to address memory deficits in multiple sclerosis (MS) can take a page from efforts to help those with other conditions, but practitioners and patients should realize that more intensive interventions are likely to be of greater benefit in MS.

“High-intensive memory-strategy interventions exert the largest effects on hippocampal memory function” in addressing the memory problems frequently seen in MS, Piet Bouman reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Hippocampal pathology can underlie the high-impact memory deficits that are seen frequently in patients with MS, noted Mr. Bouman, a doctoral student at Amsterdam University Medical Centers, and his collaborators. However, they observed, which strategies might best ameliorate hippocampal memory loss for those with MS is an open question.

To address this knowledge gap, Mr. Bouman and his coauthors conducted a systematic review and meta-analysis that aimed to determine which memory interventions in current use most help hippocampal memory functioning. The authors did not limit the review to MS, but included other conditions where hippocampal lesions, atrophy, or changes in connection or functioning may affect memory. These include healthy aging, mild cognitive impairment, and Alzheimer’s disease.

Included in the search for studies were those that used either cognitive or exercise interventions and also evaluated both visuospatial and verbal memory using validated measures, such as the Brief Visuospatial Memory Test or the California Verbal Learning Test.

After reviewing an initial 6,697 articles, the authors used Cochrane criteria to eliminate studies that were at high risk of bias. In the end, 141 studies were selected for the final review, and 82 of these were included in the meta-analysis. Eighteen studies involving 895 individuals addressed healthy aging; 39 studies enrolled 2,256 patients with mild cognitive impairment; 8 studies enrolled 223 patients with Alzheimer’s disease; and 26 studies involving 1,174 patients looked at cognitive impairment in the MS population.

To express the efficacy of the interventions across the various studies, Mr. Bouman and collaborators used the ratio of the difference in mean outcomes between groups and the standard deviation in outcome among participants. This ratio, commonly used to harmonize data in meta-analyses, is termed standardized mean difference.

Individuals representing the healthy aging population saw the most benefit from interventions to address memory loss, with a standardized mean difference of 0.48. Patients with mild cognitive impairment saw a standardized mean difference of 0.46, followed by patients with Alzheimer’s disease with a standardized mean difference of 0.43. Patients with MS lagged far behind in their response to interventions to improve memory, with a standardized mean difference of 0.34.

Looking at the different kinds of interventions, exercise interventions showed moderate effectiveness, with a standardized mean difference of 0.46. By contrast, high intensity cognitive training working on memory strategies was the most effective intervention, said Mr. Bouman and his coauthors: This intervention showed a standardized mean difference of 1.03.

Among the varying conditions associated with hippocampal memory loss, MS-related memory problems saw the least response to intervention, “which might be a result of a more widespread pattern of cognitive decline in MS,” noted Mr. Bouman and coauthors.

“Future studies should work from the realization that memory rehabilitation in MS might require a different approach” than that used in healthy aging, mild cognitive impairment, and Alzheimer’s disease, wrote the authors.

Their review revealed “persistent methodological flaws” in the literature, they noted. These included small sample sizes and selection bias.

Mr. Bouman reported that he had no disclosures. One coauthor reported financial relationships with Sanofi Genzyme, Merck-Serono and Biogen Idec. Another reported financial relationships with Merck-Serono, Bogen, Novartis, Genzyme, and Teva Pharmaceuticals.
 

koakes@mdedge.com

SOURCE: Bouman P et al. ECTRIMS 2019. Abstract P1439.

Children with eosinophilic esophagitis often experience respiratory and motor disturbances during sleep, which appear related to dysregulated sleep architecture, Rasintra Siriwat, MD, and colleagues have ascertained.

©Alex Vasilev/Fotolia.com

Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.

The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m². A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.

Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.

Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).

All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.

“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.

The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).

Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.

“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”

Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.

msullivan@mdedge.com

SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.

Children with eosinophilic esophagitis often experience respiratory and motor disturbances during sleep, which appear related to dysregulated sleep architecture, Rasintra Siriwat, MD, and colleagues have ascertained.

©Alex Vasilev/Fotolia.com

Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.

The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m². A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.

Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.

Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).

All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.

“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.

The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).

Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.

“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”

Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.

msullivan@mdedge.com

SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.

Children with eosinophilic esophagitis often experience respiratory and motor disturbances during sleep, which appear related to dysregulated sleep architecture, Rasintra Siriwat, MD, and colleagues have ascertained.

©Alex Vasilev/Fotolia.com

Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.

The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m². A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.

Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.

Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).

All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.

“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.

The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).

Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.

“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”

Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.

msullivan@mdedge.com

SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.

ROCKVILLE, MD – Those suffering from rare diseases could see treatments being developed at a faster pace thanks to a research tool developed by the National Organization for Rare Disorders (NORD) and the Critical Path Institute (C-Path). Developed with grant money from the Food and Drug Administration, the platform, currently named the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP), is designed to “promote the sharing of existing patient level data and encourage the standardization of new data collection,” according to information provided at a launch event held Sept. 18, 2019.

By integrating data in a regulatory-grade format suitable for analytics, the RDCA-DAP hopes to accelerate the understanding of disease progression – including source of variability to optimize the characterization of subpopulations – develop clinical outcome measures and biomarkers, facilitate the development of mathematical models of disease, and promote innovative clinical trial designs.

The RDCA-DAP works as a database that will house patient-level data from a variety of sources, including clinical trials, longitudinal observational studies, patient registries, and other sources, such as real-world data collected from electronic health records across a wide range of rare diseases from all over the world. Data will then be made available to researchers to help speed the development of new treatments.

“The database and analytics we are creating will enable us to obtain new insight into these rare diseases,” C-Path President and CEO Joseph Scheeren, PharmD, said at the launch event. “Not only within specific diseases, but also we hope across related diseases.”

Gregory Twachtman/MDedge News

The key to the platform’s success will be data. “We need access to clinical data from the industry, patient groups, and academia,” Dr. Scheeren said. “Even more so, the RDCA-DAP will need to incorporate data from many sources. In addition to data from clinical trials conducted by industry and academia, we will want to access data from patients, hospitals, and any organization that can provide data.”

Dr. Scheeren said the data will take many forms, including numeric data, images, genomic information, and other forms of clinical information.

“The database will be able to handle these diverse datasets,” he said, adding that C-Path is preparing to be able to analyze the data sets “with the most sophisticated tools available.”

Dr. Scheeren made a call for all interested stakeholders with rare disease data to contribute to the platform.

Gregory Twachtman/MDedge News

NORD President and CEO Peter Saltonstall echoed that call. “We need data. We are accepting it immediately.”

Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, applauded the new platform. “I think foundations and patient advocacy groups and others that have been trying to help in this space have realized that simply funding basic research, although it is necessary and really important, it is not enough to get those therapies in the hands of doctors and patients,” she said. “You have to enable translation of research for that disease.”

gtwachtman@mdedge.com

ROCKVILLE, MD – Those suffering from rare diseases could see treatments being developed at a faster pace thanks to a research tool developed by the National Organization for Rare Disorders (NORD) and the Critical Path Institute (C-Path). Developed with grant money from the Food and Drug Administration, the platform, currently named the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP), is designed to “promote the sharing of existing patient level data and encourage the standardization of new data collection,” according to information provided at a launch event held Sept. 18, 2019.

By integrating data in a regulatory-grade format suitable for analytics, the RDCA-DAP hopes to accelerate the understanding of disease progression – including source of variability to optimize the characterization of subpopulations – develop clinical outcome measures and biomarkers, facilitate the development of mathematical models of disease, and promote innovative clinical trial designs.

The RDCA-DAP works as a database that will house patient-level data from a variety of sources, including clinical trials, longitudinal observational studies, patient registries, and other sources, such as real-world data collected from electronic health records across a wide range of rare diseases from all over the world. Data will then be made available to researchers to help speed the development of new treatments.

“The database and analytics we are creating will enable us to obtain new insight into these rare diseases,” C-Path President and CEO Joseph Scheeren, PharmD, said at the launch event. “Not only within specific diseases, but also we hope across related diseases.”

Gregory Twachtman/MDedge News

The key to the platform’s success will be data. “We need access to clinical data from the industry, patient groups, and academia,” Dr. Scheeren said. “Even more so, the RDCA-DAP will need to incorporate data from many sources. In addition to data from clinical trials conducted by industry and academia, we will want to access data from patients, hospitals, and any organization that can provide data.”

Dr. Scheeren said the data will take many forms, including numeric data, images, genomic information, and other forms of clinical information.

“The database will be able to handle these diverse datasets,” he said, adding that C-Path is preparing to be able to analyze the data sets “with the most sophisticated tools available.”

Dr. Scheeren made a call for all interested stakeholders with rare disease data to contribute to the platform.

Gregory Twachtman/MDedge News

NORD President and CEO Peter Saltonstall echoed that call. “We need data. We are accepting it immediately.”

Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, applauded the new platform. “I think foundations and patient advocacy groups and others that have been trying to help in this space have realized that simply funding basic research, although it is necessary and really important, it is not enough to get those therapies in the hands of doctors and patients,” she said. “You have to enable translation of research for that disease.”

gtwachtman@mdedge.com

ROCKVILLE, MD – Those suffering from rare diseases could see treatments being developed at a faster pace thanks to a research tool developed by the National Organization for Rare Disorders (NORD) and the Critical Path Institute (C-Path). Developed with grant money from the Food and Drug Administration, the platform, currently named the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP), is designed to “promote the sharing of existing patient level data and encourage the standardization of new data collection,” according to information provided at a launch event held Sept. 18, 2019.

By integrating data in a regulatory-grade format suitable for analytics, the RDCA-DAP hopes to accelerate the understanding of disease progression – including source of variability to optimize the characterization of subpopulations – develop clinical outcome measures and biomarkers, facilitate the development of mathematical models of disease, and promote innovative clinical trial designs.

The RDCA-DAP works as a database that will house patient-level data from a variety of sources, including clinical trials, longitudinal observational studies, patient registries, and other sources, such as real-world data collected from electronic health records across a wide range of rare diseases from all over the world. Data will then be made available to researchers to help speed the development of new treatments.

“The database and analytics we are creating will enable us to obtain new insight into these rare diseases,” C-Path President and CEO Joseph Scheeren, PharmD, said at the launch event. “Not only within specific diseases, but also we hope across related diseases.”

Gregory Twachtman/MDedge News

The key to the platform’s success will be data. “We need access to clinical data from the industry, patient groups, and academia,” Dr. Scheeren said. “Even more so, the RDCA-DAP will need to incorporate data from many sources. In addition to data from clinical trials conducted by industry and academia, we will want to access data from patients, hospitals, and any organization that can provide data.”

Dr. Scheeren said the data will take many forms, including numeric data, images, genomic information, and other forms of clinical information.

“The database will be able to handle these diverse datasets,” he said, adding that C-Path is preparing to be able to analyze the data sets “with the most sophisticated tools available.”

Dr. Scheeren made a call for all interested stakeholders with rare disease data to contribute to the platform.

Gregory Twachtman/MDedge News

NORD President and CEO Peter Saltonstall echoed that call. “We need data. We are accepting it immediately.”

Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, applauded the new platform. “I think foundations and patient advocacy groups and others that have been trying to help in this space have realized that simply funding basic research, although it is necessary and really important, it is not enough to get those therapies in the hands of doctors and patients,” she said. “You have to enable translation of research for that disease.”

gtwachtman@mdedge.com

A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.

Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.

A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm³ in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.

Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.

Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.

Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.

A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.

Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.

“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”

The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.

“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.

Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.

SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.

*Updated 10/14/2019.

A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.

Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.

A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm³ in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.

Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.

Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.

Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.

A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.

Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.

“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”

The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.

“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.

Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.

SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.

*Updated 10/14/2019.

A study of 305 cases of acute flaccid myelitis has found further evidence of a viral etiology but is yet to identify a single pathogen as the primary cause.

Writing in Pediatrics, researchers published an analysis of patients presenting with acute flaccid limb weakness from January 2015 to December 2017 across 43 states.

A total of 25 cases were judged as probable for acute flaccid myelitis (AFM) because they met clinical criteria and had a white blood cell count above 5 cells per mm³ in cerebrospinal fluid, while 193 were judged as confirmed cases based on the additional presence of spinal cord gray matter lesions on MRI.

Overall, 83% of patients had experienced fever, cough, runny nose, vomiting, and/or diarrhea for a median of 5 days before limb weakness began. Two-thirds of patients had experienced a respiratory illness, 62% had experienced a fever, and 29% had experienced gastrointestinal illness.

Overall, 47% of the 193 patients who had specimens tested at a Centers for Disease Control and Prevention or non-CDC laboratory had a pathogen found at any site, 10% had a pathogen detected from a sterile site such as cerebrospinal fluid or sera, and 42% had a pathogen detected from a nonsterile site.

Among 72 patients who had serum specimens tested at the CDC, 2 were positive for enteroviruses. Among the 90 patients who had upper respiratory specimens tested, 36% were positive for either enteroviruses or rhinoviruses.

A number of stool specimens were also tested; 15% were positive for enteroviruses or rhinoviruses and one was positive for parechovirus.

Cerebrospinal fluid was tested in 170 patients, of which 4 were positive for enteroviruses. The testing also found adenovirus, Epstein-Barr virus, human herpesvirus 6, and mycoplasma in six patients. Sera testing of 123 patients found 9 were positive for enteroviruses, West Nile virus, mycoplasma, and coxsackievirus B.

“In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM,” wrote Tracy Ayers, PhD, from the National Center for Immunization and Respiratory Diseases, and coauthors. “We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including [enteroviruses].”

The authors of an accompanying editorial noted that the clinical syndrome of acute flaccid paralysis caused by myelitis in the gray matter of the spinal cord has previously been associated with a range of viruses, including poliovirus, enteroviruses, and flaviviruses, so a single etiology to explain all cases would not be expected.

“The central question remains: What is driving seasonal biennial nationwide outbreaks of AFM since 2014?” wrote Kevin Messaca, MD, and colleagues from the University of Colorado at Denver, Aurora.

Two authors declared consultancies, grants, and research contracts with the pharmaceutical sector. No other conflicts of interest were declared. One editorial author declared funding from the National Institute of Allergy and Infectious Diseases.

SOURCE: Ayers T et al. Pediatrics. 2019 Oct 7. doi: 10.1542/peds.2019-1619.

*Updated 10/14/2019.

Teenage girls with ADHD may be at greater risk of pregnancy than their unaffected peers, which suggests they may benefit from targeted interventions to prevent teen pregnancy.

Rawpixel/Thinkstock

A Swedish nationwide cohort study published in JAMA Network Open examined data from 384,103 nulliparous women and girls who gave birth between 2007-2014, of whom, 6,410 (1.7%) had received treatment for ADHD.

While the overall rate of teenage births was 3%, the rate among women and girls with ADHD was 15.3%, which represents a greater than sixfold higher odds of giving birth below the age of 20 years (odds ratio, 6.23; 95% confidence interval, 5.80-6.68).

“Becoming a mother at such early age is associated with long-term adverse outcomes for both women and their children,” wrote Charlotte Skoglund, PhD, of the department of clinical neuroscience at the Karolinska Institute in Stockholm and coauthors. “Consequently, our findings argue for an improvement in the standard of care for women and girls with ADHD, including active efforts to prevent teenage pregnancies and address comorbid medical and psychiatric conditions.”

The study also found women and girls with ADHD were significantly more likely to be underweight (OR, 1.29; 95% CI, 1.12-1.49) or have a body mass index greater than 40 kg/m² (OR, 2.01; 95% CI, 1.60-2.52) when compared with those without ADHD.

They were also six times more likely to smoke, were nearly seven times more likely to continue smoking into their third trimester of pregnancy, and had a 20-fold higher odds of alcohol and substance use disorder. Among individuals who had been diagnosed with ADHD, 7.6% continued to use stimulant and nonstimulant ADHD medication during pregnancy, and 16.4% used antidepressants during pregnancy.

Psychiatric comorbidities were also significantly more common among individuals with ADHD in the year preceding pregnancy, compared with those without ADHD. The authors saw a 17-fold higher odds of receiving a diagnosis of bipolar disorder, nearly 8-fold higher odds of a diagnosis of schizophrenia or other psychotic disorder, and 22-fold higher odds of being diagnosed with emotionally unstable personality disorder among women and girls with ADHD versus those without.

The authors commented that antenatal care should focus on trying to reduce such obstetric risk factors in these women, but also pointed out that ADHD in women and girls was still underdiagnosed and undertreated.

Commenting on the association between ADHD and teenage pregnancy, the authors noted that women and girls with ADHD may be less likely to receive adequate contraceptive counseling and less likely to access, respond to, and act on counseling. They may also experience more adverse effects from hormonal contraceptives.

While Swedish youth clinics enable easier and low-cost access to counseling and contraception, the authors called for greater collaboration between psychiatric care clinics and specialized youth clinics to provide adequate care for women and girls with ADHD.

Three authors declared advisory board positions, grants, personal fees, and speakers’ fees from the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Skoglund C et al. JAMA Netw Open. 2019 Oct 2. doi: 10.1001/jamanetworkopen.2019.12463

Teenage girls with ADHD may be at greater risk of pregnancy than their unaffected peers, which suggests they may benefit from targeted interventions to prevent teen pregnancy.

Rawpixel/Thinkstock

A Swedish nationwide cohort study published in JAMA Network Open examined data from 384,103 nulliparous women and girls who gave birth between 2007-2014, of whom, 6,410 (1.7%) had received treatment for ADHD.

While the overall rate of teenage births was 3%, the rate among women and girls with ADHD was 15.3%, which represents a greater than sixfold higher odds of giving birth below the age of 20 years (odds ratio, 6.23; 95% confidence interval, 5.80-6.68).

“Becoming a mother at such early age is associated with long-term adverse outcomes for both women and their children,” wrote Charlotte Skoglund, PhD, of the department of clinical neuroscience at the Karolinska Institute in Stockholm and coauthors. “Consequently, our findings argue for an improvement in the standard of care for women and girls with ADHD, including active efforts to prevent teenage pregnancies and address comorbid medical and psychiatric conditions.”

The study also found women and girls with ADHD were significantly more likely to be underweight (OR, 1.29; 95% CI, 1.12-1.49) or have a body mass index greater than 40 kg/m² (OR, 2.01; 95% CI, 1.60-2.52) when compared with those without ADHD.

They were also six times more likely to smoke, were nearly seven times more likely to continue smoking into their third trimester of pregnancy, and had a 20-fold higher odds of alcohol and substance use disorder. Among individuals who had been diagnosed with ADHD, 7.6% continued to use stimulant and nonstimulant ADHD medication during pregnancy, and 16.4% used antidepressants during pregnancy.

Psychiatric comorbidities were also significantly more common among individuals with ADHD in the year preceding pregnancy, compared with those without ADHD. The authors saw a 17-fold higher odds of receiving a diagnosis of bipolar disorder, nearly 8-fold higher odds of a diagnosis of schizophrenia or other psychotic disorder, and 22-fold higher odds of being diagnosed with emotionally unstable personality disorder among women and girls with ADHD versus those without.

The authors commented that antenatal care should focus on trying to reduce such obstetric risk factors in these women, but also pointed out that ADHD in women and girls was still underdiagnosed and undertreated.

Commenting on the association between ADHD and teenage pregnancy, the authors noted that women and girls with ADHD may be less likely to receive adequate contraceptive counseling and less likely to access, respond to, and act on counseling. They may also experience more adverse effects from hormonal contraceptives.

While Swedish youth clinics enable easier and low-cost access to counseling and contraception, the authors called for greater collaboration between psychiatric care clinics and specialized youth clinics to provide adequate care for women and girls with ADHD.

Three authors declared advisory board positions, grants, personal fees, and speakers’ fees from the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Skoglund C et al. JAMA Netw Open. 2019 Oct 2. doi: 10.1001/jamanetworkopen.2019.12463

Teenage girls with ADHD may be at greater risk of pregnancy than their unaffected peers, which suggests they may benefit from targeted interventions to prevent teen pregnancy.

Rawpixel/Thinkstock

A Swedish nationwide cohort study published in JAMA Network Open examined data from 384,103 nulliparous women and girls who gave birth between 2007-2014, of whom, 6,410 (1.7%) had received treatment for ADHD.

While the overall rate of teenage births was 3%, the rate among women and girls with ADHD was 15.3%, which represents a greater than sixfold higher odds of giving birth below the age of 20 years (odds ratio, 6.23; 95% confidence interval, 5.80-6.68).

“Becoming a mother at such early age is associated with long-term adverse outcomes for both women and their children,” wrote Charlotte Skoglund, PhD, of the department of clinical neuroscience at the Karolinska Institute in Stockholm and coauthors. “Consequently, our findings argue for an improvement in the standard of care for women and girls with ADHD, including active efforts to prevent teenage pregnancies and address comorbid medical and psychiatric conditions.”

The study also found women and girls with ADHD were significantly more likely to be underweight (OR, 1.29; 95% CI, 1.12-1.49) or have a body mass index greater than 40 kg/m² (OR, 2.01; 95% CI, 1.60-2.52) when compared with those without ADHD.

They were also six times more likely to smoke, were nearly seven times more likely to continue smoking into their third trimester of pregnancy, and had a 20-fold higher odds of alcohol and substance use disorder. Among individuals who had been diagnosed with ADHD, 7.6% continued to use stimulant and nonstimulant ADHD medication during pregnancy, and 16.4% used antidepressants during pregnancy.

Psychiatric comorbidities were also significantly more common among individuals with ADHD in the year preceding pregnancy, compared with those without ADHD. The authors saw a 17-fold higher odds of receiving a diagnosis of bipolar disorder, nearly 8-fold higher odds of a diagnosis of schizophrenia or other psychotic disorder, and 22-fold higher odds of being diagnosed with emotionally unstable personality disorder among women and girls with ADHD versus those without.

The authors commented that antenatal care should focus on trying to reduce such obstetric risk factors in these women, but also pointed out that ADHD in women and girls was still underdiagnosed and undertreated.

Commenting on the association between ADHD and teenage pregnancy, the authors noted that women and girls with ADHD may be less likely to receive adequate contraceptive counseling and less likely to access, respond to, and act on counseling. They may also experience more adverse effects from hormonal contraceptives.

While Swedish youth clinics enable easier and low-cost access to counseling and contraception, the authors called for greater collaboration between psychiatric care clinics and specialized youth clinics to provide adequate care for women and girls with ADHD.

Three authors declared advisory board positions, grants, personal fees, and speakers’ fees from the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Skoglund C et al. JAMA Netw Open. 2019 Oct 2. doi: 10.1001/jamanetworkopen.2019.12463

Over the last 3 decades, the endoscope has become a highly valued visualization tool in neurosurgery, applicable to a broad range of neurosurgical procedures. Following the pace of technological innovations, the quality of the instrumentation has greatly improved along with the status of endoscopy in the neurosurgical field. The use of the endoscope in interdisciplinary extended transnasal approaches revolutionized skull-base surgery.¹ Transcranial neurosurgery took advantage of the endoscope for inspection, endoscope-assisted, and endoscope-controlled procedures, although the main visualization tool during these interventions remains the operating microscope.

At present, endoscopy has applications in a variety of neurosurgical procedures including transnasal approaches for pituitary and other skull-base tumors, third ventriculostomy, and resection of intraventricular tumors. The range of application is expanding to include extracranial procedures such as peripheral nerve and spine surgery.

From Li KW, Nelson C, Suk I, Jallo GI. Neuroendoscopy: past, present, and future. Neurosurg Focus 2005; 19(6):E1. Figure used with permission.

CURRENT CONCEPTS

Hopf and Perneczky² defined the terminology regarding endoscopic procedures and divided them into 3 categories:

Pure endoscopic neurosurgery, ie, procedures performed through working channels under complete endoscopic visualization and with endoscopic instrumentation (Figure 1).³

Endoscope-controlled microsurgery, ie, operations performed with standard microsurgical instruments under endoscopic visualization—the microscope is not used (Figure 2).

Endoscope-assisted neurosurgery, ie, the use of both microscope and endoscope during the same intervention. In endoscopic inspection the endoscope is solely used as an adjunctive tool for visualization and not for surgical manipulations.

Enhanced area and surgical dissection

Technical innovations are probably the major reason for the growing role of endoscopy in neurosurgery over the last 3 decades.⁴ High-definition imaging, neuronavigation, new instruments, an interdisciplinary approach mostly with ear, nose, and throat (ENT) surgeons, and detailed anatomic studies led to the breakthrough of endoscopic endonasal extended approaches in skull-base surgery.⁵

These endoscopic techniques allow the neurosurgeon to optimize tumor resection, increasing the area of surgical dissection without increasing the size of the surgical approach, thereby limiting perioperative morbidity due to surgical manipulation of eloquent brain structures. Endoscopy offers direct illumination of the operative field, magnification, and the ability to look around corners with angled optics.

However, while angled endoscopic optics provide various visual perspectives, the surgical issue is not only to see but also to work on and around remote structures. Microsurgical endoscope-assisted manipulations require optimal working angles that are guaranteed only by a sufficiently large craniotomy. As an example, a dissection study by Chaynes et al⁶ highlights that a craniotomy that is too narrow often hinders a sufficient exploration of the entire cerebellopontine angle. Most neuro­surgeons are familiar with the operating microscope. The microscopic field of inspection is 3-dimensional (3D) and of high quality. However, the light stream is straight and thus limited in the narrow and angled corridor of the cerebellopontine angle or in the perimesencephalic cisterns. In these situations, the angled optic of the endoscope offers the advantage of being able to look around the corner with the appropriate amount of direct illumination.⁷

 

 

Peripheral nerve surgery

Minimally invasive endoscopic approaches are also being used in peripheral nerve surgery, especially carpal tunnel decompression. The first carpal tunnel release treated endoscopically was performed by Okutsu et al in the late 1980s.⁸ Since that time, endoscopic carpal tunnel decompression has become very common and is the preferred method for many surgeons, using either single-portal or dual-portal techniques. Although the superiority of endoscopic over conventional minimally invasive microsurgical peripheral nerve surgeries has not been proven, large series of endoscopic carpal tunnel decompressions have reported low complication rates and excellent success rates with high patient satisfaction scores.^8,9

Visualization of the spinal canal

Expanding the use of the endoscope to spine surgery, endoscopic explorations of the interlaminar spaces after having completed open surgical laminectomies have been reported since the early 1980s,¹⁰ while endoscope-assisted interlaminar procedures started in the late 1990s.^11–13 The development of fully endoscopic transforaminal or interlaminar approaches for lumbar stenosis or lumbar disk herniation has been ongoing in the last 2 decades. The rationale for direct endoscopic visualization of the spinal canal is to reduce scarring of the epidural space, which might affect the outcome of possible revision surgeries (recurrent disk herniation), and to reduce injury to the paraspinal muscles, which may reduce postoperative incisional pain and length of hospital stay. Major limiting factors for fully endoscopic spine surgeries such as the narrow working channels (which are limited by the osseous perimeter of the neuroforamina, as well as the pelvis and abdominal structures) and the learning curve for the surgeons are, however, still matters of debate and restrict the use of endoscopy to very carefully selected cases.^14,15

Pediatric craniosynostosis

Recently, the use of the endoscope has extended to treatment of craniosynostosis in pediatric patients, historically treated with large and occasionally staged craniotomic approaches. A meta-analysis of the literature showed statistically significant reductions in blood loss and rates of perioperative complications, reoperation, and transfusion compared with open approaches.¹⁶

Technical limitations

While neurosurgeons increasingly advocate the use of the endoscope in their practice, the development of instruments for endoscopic surgery does not always follow the same pace. There are technical problems with current rigid endoscopes and ergonomic limitations of the endoscope-assisted techniques in trans­cranial neurosurgery. The endoscope itself occupies space in an already limited surgical corridor like the posterior fossa, the parasellar space, or the intraventricular region. The ideal endoscope is thin and sturdy, does not generate heat, and provides high-resolution images. In addition, a self-irrigating feature could minimize the need to remove and reinsert the endoscope for cleaning. Finally, most intracranial surgery is extremely delicate and requires bimanual dissection. The ideal endoscope should also be easily integrated with a holder that allows the surgeon to easily transition between static and dynamic endoscope movements.

Newer flexible fiberscopes with even smaller diameters are likely to be launched on the market in the near future. When working in a surgical corridor less than 10 mm wide, this difference could be substantial.

In addition, surgical instruments specifically designed for endoscopic endonasal procedures are needed for microdissection in these regions, which were previously only visible but not reachable endoscopically. These include tools such as malleable suctions and curettes, rotatable back-biting microscissors, and malleable bipolar instruments (Figure 3).

IMPACT OF NEUROENDOSCOPY IN CURRENT CLINICAL PRACTICE

The introduction of endoscopy in neurosurgery changed many treatment paradigms and had an important impact on morbidity and outcomes. In this section, we discuss the specific indications, contraindications, and expected benefit of endoscopic vs open surgical approaches applied to neurosurgical pathology at the present time.

Skull-base tumors and CSF leaks

The use of the endoscope in skull-base surgery was originally applied to purely midline intrasellar tumors without suprasellar or lateral extension beyond the carotid cave. Ideal cases were intrasellar pituitary microadenomas not responding to medical treatment or Rathke cleft cysts.

These pathologies were traditionally addressed via microscopic craniotomic approaches and later through sublabial or transnasal transsphenoidal approaches. Traditional transsphenoidal approaches were highly invasive for the oral mucosa, causing delayed healing, oral dysesthesia, and, in some cases, loss of the superior dental arch (sublabial) or limited visualization and surgical maneuverability (microscopic endonasal).

The endoscope offered better visualization and surgical freedom, thus allowing higher resection rates to be achieved. Resection of purely intrasellar pathology with preservation of the diaphragma sellae as a barrier to the subarachnoid cysterns and third ventricle guaranteed a lower incidence of cerebrospinal fluid (CSF) leaks.

New endoscope optics with varied angles, together with dedicated long surgical instruments with low steric volume, offered a large variety of new endonasal surgical corridors, so-called expanded endonasal approaches on the sagittal and coronal planes, as discussed in detail by Kassam et al.^17–19 These allowed endoscopic treatment of invasive tumors extending on the coronary plane into the suprasellar region or invading the cavernous sinuses (pituitary macroadenomas, craniopharyngiomas).

Highly specialized centers with expertise in endoscopic skull-base surgery can now also offer pure endoscopic treatment for some selected cases of lesions located far laterally to the cavernous sinus, such as trigeminal schwannomas, or along the sagittal plane like olfactory groove or tuberculum sellae meningiomas and clival lesions (chordomas, chondrosarcomas).

As one might expect, the increase in surgical complexity corresponded to an increase in complication rates. For example, the incidence of CSF leaks varied from 5% for standard midline transsphenoidal approaches to 11% for expanded endonasal approaches.^20,21 The consolidation of the use of the endoscope and the cooperation with ENT surgeons led to the development of surgical strategies to prevent and reduce the incidence of CSF leaks, such as the use of “rescue flaps,” nasoseptal flaps, or temporoparietal fascia flaps.^21–23

The development of such techniques allowed endoscopic endonasal approaches to be used in treatment of other pathologies, such as spontaneous CSF leaks, treated in the past with large transcranial repairs that carried high morbidity rates due to the surgical frontal lobe retraction and injury to the olfactory mucosa.^24,25 Progress in the field of neuroendoscopy therefore led to the creation of specialized endoscopic skull-base surgery centers, including neurosurgery, ENT, ophthalmology, and endocrinology services.

In clinical practice, when evaluating a patient with intracranial skull-base pathology amenable to endoscopic resection, one should consider referring the patient not only to a neurosurgeon, but also to an ENT surgeon for preoperative assessment of the sinonasal cavities. The same concept applies to postsurgical follow-up, which is mostly performed by the ENT physician to assess nasal mucosa healing and nasal hygiene.

 

 

Ventricular neuroendoscopy

The introduction of endoscopic third ventriculostomy created the opportunity to offer a more physiologic treatment in selected patients with obstructive hydrocephalus by creating an internal CSF diversion through the basal cisterns. Two advantages of this procedure are that it does not create dependence on a CSF shunt, and it eliminates the related risks of shunt infection and malfunction. Its drawback is the recurrence rate of hydrocephalus (around 58% at 2 years of follow-up) due to formation of scarring in the perforated Lilie­quist membrane, which may require repeat surgery or conversion to CSF shunting.^26,27

Neuroendoscopic approaches are also used in cases of purely intraventricular pathology such as colloid cyst or choroid plexus papillomas. The concept behind neuroendoscopy is to achieve maximal resection in a minimally invasive way, using the natural cavity of the cerebral ventricles and reducing the need for brain retraction and, in particular, the risk of injury of the fornix (therefore causing memory deficits) of open transventricular approaches and of the corpus callosum necessary in inter­hemispheric approaches. Large tumor size and inability to tolerate a longer surgical procedure can be relative contraindications to a pure endoscopic approach to these lesions.

Degenerative spine disease

In recent years there has been a growing interest in the use of endoscopy for selected cases of degenerative lumbar spondylosis (generally, lateral disk herniation above the L5-S1 level or spinal canal stenosis). This approach has been shown to reduce postoperative incisional pain, scarring of the epidural space affecting the outcome of possible revision surgeries (recurrent disc herniation), and length of hospital stay.^14,15 Information on surgical nuances should be provided when consulting on selected patients with lumbar degenerative disease resistant to conservative treatment.

Carpal tunnel syndrome

Although endoscopic carpal tunnel release is controversial, its supporters report smaller incision size and lower recurrence rates due to better visualization of the entire carpal ligament compared with open surgery, with high patient satisfaction scores.^8,9,28

Craniosynostosis

Increasing data from specialized centers show that early endoscopic suturectomy is an effective treatment option alone or when combined with open surgeries for patients with syndromic and nonsyndromic craniosynostosis. The aesthetic advantage of small incisions (which can also be achieved with some open techniques) is accompanied by significant reductions in blood loss (median 162.4 mL), operative time (median 112.38 minutes), length of stay (median 2.56 days), and rates of perioperative complications (odds ratio 0.58), reoperation (odds ratio 0.37), and transfusion (odds ratio 0.09) compared with open approaches.¹⁶

SURGICAL TRAINING

Today’s patients expect high-quality healthcare, and they approach their surgeons with an enormous amount of information collected through unlimited Web-based access or peer-group blogs. In this respect, the pressure on young surgeons to achieve excellent results is high and growing from the very beginning of their careers.

Residency training programs differ in each country, and surgical standards usually focus on open microscopic procedures rather than newly developed endoscopic techniques. Endoscopic pituitary adenoma surgery, the most frequent neuroendoscopic procedure, is still performed mostly by experienced neurosurgeons, not trainees. Moreover, many training institutions might not offer pediatric neurosurgery care, limiting exposure to endoscopic third ventriculostomy procedures. The European Union of Medical Specialists, responsible for harmonizing and improving the quality of training of medical specialists in Europe, set low neuroendoscopic surgical requirements for trainees to complete their residency programs (minimum of 0 to optimum of 5 total transcranial or transsphenoidal pituitary adenoma resections as first operator, 10 procedures as assistant, and a minimum of 2 to an optimum of 4 endoscopic third ventriculostomies as first operator).²⁹

The need to develop training programs in neuroendoscopy is especially urgent because endoscopic surgery has a steeper learning curve than conventional microneurosurgery. In particular, endoscopy requires a good deal of dexterity and hand-eye coordination, which surgeons consider the main pitfall of neuroendoscopy. For such reasons, many accredited clinical fellowship programs have been developed inside and outside North America that offer intensive training in endoscopic skull-base surgery and pediatric neurosurgery after residency.

Some clinical studies have shown that the complication rate of neuroendoscopy is 15% to 18%.^27,30 In view of this statistic, it is ethically questionable to perform a randomized study to prospectively compare microscopic and endoscopic procedures. Surgeons specialize in one technique or the other, experience their own learning curve, and do not randomly decide which tool to use. Furthermore, every intracranial surgical exploration is unique and somewhat difficult to compare with each other without the risk of bias.

 

 

FURTHER DEVELOPMENTS

Multivariable rigid endoscopes like the EndoCAMeleon (Karl Storz, Tuttlingen, Germany) or the EndActive (Karl Storz, Tuttlingen, Germany) for cerebellopontine angle surgery represent a starting point to overcome some of the aforementioned limitations.^31,32 They are inserted in the surgical field with a direct 0° angulation view into the operative site beyond neurovascular structures that need to be preserved and that obstruct the microscopic view. Once the final position is reached, the field of view is directed toward the region of interest without moving the endoscope tip.

The EndoCAMeleon is a rigid rod-lens endoscope, steerable in one plane from –10° to +120° by a fine optomechanical mechanism. Anatomic laboratory testing found it to be superior in terms of usability and visualization compared with rigid fixed-angle endoscopes.^₃₁ The first clinical experiences have been promising; however, ergonomics and the limited perspective of a single plane of rotation leave room for improvement.

The EndActive endoscope might overcome such limitations.³³ This device is a rigid videoendoscope connected to a laptop (video data) and USB port (control and power supply); thus, it weighs less and can be held in one hand like a microsurgical instrument. The endoscopic imaging system allows the operator to simultaneously see a 160° wide-angle view of the site and an inset of a specific region of interest. The surgeon can hold the device like a microsurgical instrument in one hand and control movements precisely due to its reduced weight and ergonomic shape.

The multiplanar variable-view rigid endoscope has proven to be useful for working on diverse anatomic structures such as intracranial vessels and cranial nerves. The device is effective in narrow working spaces where even small movements can jeopardize the delicate surrounding structures. The multiplanar variable-viewing mechanism in a compact device offers advantages in terms of safety and ergonomics. Improving the usability will probably optimize the applicability of those endoscopic devices in neurosurgery. A major drawback of the current prototype is poor image resolution, which will probably soon be overcome with the ongoing progress in electronic microchip technology.

The addition of laser technology to endoscopic techniques offers a huge potential to neurosurgery but has achieved little acceptance to date. The reasons include concern regarding heat production, uncontrollable and distant penetration, and tissue interaction. Experiences with a 2-micron continuous­- wave laser (RevoLix Jr, LISA Laser Products, Katlenburg-Lindau, Germany) for neuroendoscopic intraventricular procedures proved this laser to be a valuable and useful tool with safe applicability for endoscopic intracranial procedures in patients of all ages.³⁴

Parallel to the launch of video screens for other uses with higher image definition, the image quality on the 2D endoscope cameras has been constantly improving over the last years. At the same time, the introduction of modern 3D endoscopic monitors is promising. However, 3D endoscopes have some disadvantages compared with the 2D endoscopes. First, the smallest 3D endoscopes are 4 mm in diameter, compared with 2.7 mm for 2D endoscopes. Moreover, the field of view with the 3D endoscope is less than half of that with conventional 2D endoscopes.³⁴ When working in and around a region with critical neurovascular structures in close proximity, this loss of field of view can result in an increase in iatrogenic injury from the endoscope. In addition, 3D endoscopes require special glasses, generating a potential obstacle to the seamless integration of visual information from the microscope and endoscope. Finally, some surgeons experience vertigo when looking at the 3D picture through the glasses, which limits its universal applicability.

CONCLUSIONS

Using the endoscope and microscope as complementary and not competing tools allows surgeons to benefit from both technologies at the same time.^35,36 The intraoperative combination of these 2 powerful visualization tools expands the effectiveness of microsurgical procedures and has the potential to further improve surgical results and reduce surgical risks. With endoscope-assisted microsurgery, visualization is often far superior to surgical maneuverability.

Endoscopic neurosurgery will likely be influenced by further innovations in optical physics, electronics, and robotics. Specific implementations in endoscopic systems are likely to pave the way for remarkable progress in minimally invasive surgery, such as robotic surgical technology, further miniaturization of devices, improvements in 3D endoscopy, multiport endoscopy, and new designs for surgical instruments. Future progress in flexible endoscopes and wireless capsule or camera technology may reduce our dependence on rigid rod lens systems. Rigid variable-view endoscopes will bring endoscopes closer to ideal attributes utilizing newer instrumentation that is tailored to specific indications and techniques.^37,38 Extension of the visual field by the feature of a movable optic lens may allow the neurosurgeon to use tailored keyhole approaches to treat pathologies in smaller surgical corridors with less trauma and greater efficacy.

Over the last 3 decades, the endoscope has become a highly valued visualization tool in neurosurgery, applicable to a broad range of neurosurgical procedures. Following the pace of technological innovations, the quality of the instrumentation has greatly improved along with the status of endoscopy in the neurosurgical field. The use of the endoscope in interdisciplinary extended transnasal approaches revolutionized skull-base surgery.¹ Transcranial neurosurgery took advantage of the endoscope for inspection, endoscope-assisted, and endoscope-controlled procedures, although the main visualization tool during these interventions remains the operating microscope.

At present, endoscopy has applications in a variety of neurosurgical procedures including transnasal approaches for pituitary and other skull-base tumors, third ventriculostomy, and resection of intraventricular tumors. The range of application is expanding to include extracranial procedures such as peripheral nerve and spine surgery.

From Li KW, Nelson C, Suk I, Jallo GI. Neuroendoscopy: past, present, and future. Neurosurg Focus 2005; 19(6):E1. Figure used with permission.

CURRENT CONCEPTS

Hopf and Perneczky² defined the terminology regarding endoscopic procedures and divided them into 3 categories:

Pure endoscopic neurosurgery, ie, procedures performed through working channels under complete endoscopic visualization and with endoscopic instrumentation (Figure 1).³

Endoscope-controlled microsurgery, ie, operations performed with standard microsurgical instruments under endoscopic visualization—the microscope is not used (Figure 2).

Endoscope-assisted neurosurgery, ie, the use of both microscope and endoscope during the same intervention. In endoscopic inspection the endoscope is solely used as an adjunctive tool for visualization and not for surgical manipulations.

Enhanced area and surgical dissection

Technical innovations are probably the major reason for the growing role of endoscopy in neurosurgery over the last 3 decades.⁴ High-definition imaging, neuronavigation, new instruments, an interdisciplinary approach mostly with ear, nose, and throat (ENT) surgeons, and detailed anatomic studies led to the breakthrough of endoscopic endonasal extended approaches in skull-base surgery.⁵

These endoscopic techniques allow the neurosurgeon to optimize tumor resection, increasing the area of surgical dissection without increasing the size of the surgical approach, thereby limiting perioperative morbidity due to surgical manipulation of eloquent brain structures. Endoscopy offers direct illumination of the operative field, magnification, and the ability to look around corners with angled optics.

However, while angled endoscopic optics provide various visual perspectives, the surgical issue is not only to see but also to work on and around remote structures. Microsurgical endoscope-assisted manipulations require optimal working angles that are guaranteed only by a sufficiently large craniotomy. As an example, a dissection study by Chaynes et al⁶ highlights that a craniotomy that is too narrow often hinders a sufficient exploration of the entire cerebellopontine angle. Most neuro­surgeons are familiar with the operating microscope. The microscopic field of inspection is 3-dimensional (3D) and of high quality. However, the light stream is straight and thus limited in the narrow and angled corridor of the cerebellopontine angle or in the perimesencephalic cisterns. In these situations, the angled optic of the endoscope offers the advantage of being able to look around the corner with the appropriate amount of direct illumination.⁷

 

 

Peripheral nerve surgery

Minimally invasive endoscopic approaches are also being used in peripheral nerve surgery, especially carpal tunnel decompression. The first carpal tunnel release treated endoscopically was performed by Okutsu et al in the late 1980s.⁸ Since that time, endoscopic carpal tunnel decompression has become very common and is the preferred method for many surgeons, using either single-portal or dual-portal techniques. Although the superiority of endoscopic over conventional minimally invasive microsurgical peripheral nerve surgeries has not been proven, large series of endoscopic carpal tunnel decompressions have reported low complication rates and excellent success rates with high patient satisfaction scores.^8,9

Visualization of the spinal canal

Expanding the use of the endoscope to spine surgery, endoscopic explorations of the interlaminar spaces after having completed open surgical laminectomies have been reported since the early 1980s,¹⁰ while endoscope-assisted interlaminar procedures started in the late 1990s.^11–13 The development of fully endoscopic transforaminal or interlaminar approaches for lumbar stenosis or lumbar disk herniation has been ongoing in the last 2 decades. The rationale for direct endoscopic visualization of the spinal canal is to reduce scarring of the epidural space, which might affect the outcome of possible revision surgeries (recurrent disk herniation), and to reduce injury to the paraspinal muscles, which may reduce postoperative incisional pain and length of hospital stay. Major limiting factors for fully endoscopic spine surgeries such as the narrow working channels (which are limited by the osseous perimeter of the neuroforamina, as well as the pelvis and abdominal structures) and the learning curve for the surgeons are, however, still matters of debate and restrict the use of endoscopy to very carefully selected cases.^14,15

Pediatric craniosynostosis

Recently, the use of the endoscope has extended to treatment of craniosynostosis in pediatric patients, historically treated with large and occasionally staged craniotomic approaches. A meta-analysis of the literature showed statistically significant reductions in blood loss and rates of perioperative complications, reoperation, and transfusion compared with open approaches.¹⁶

Technical limitations

While neurosurgeons increasingly advocate the use of the endoscope in their practice, the development of instruments for endoscopic surgery does not always follow the same pace. There are technical problems with current rigid endoscopes and ergonomic limitations of the endoscope-assisted techniques in trans­cranial neurosurgery. The endoscope itself occupies space in an already limited surgical corridor like the posterior fossa, the parasellar space, or the intraventricular region. The ideal endoscope is thin and sturdy, does not generate heat, and provides high-resolution images. In addition, a self-irrigating feature could minimize the need to remove and reinsert the endoscope for cleaning. Finally, most intracranial surgery is extremely delicate and requires bimanual dissection. The ideal endoscope should also be easily integrated with a holder that allows the surgeon to easily transition between static and dynamic endoscope movements.

Newer flexible fiberscopes with even smaller diameters are likely to be launched on the market in the near future. When working in a surgical corridor less than 10 mm wide, this difference could be substantial.

In addition, surgical instruments specifically designed for endoscopic endonasal procedures are needed for microdissection in these regions, which were previously only visible but not reachable endoscopically. These include tools such as malleable suctions and curettes, rotatable back-biting microscissors, and malleable bipolar instruments (Figure 3).

IMPACT OF NEUROENDOSCOPY IN CURRENT CLINICAL PRACTICE

The introduction of endoscopy in neurosurgery changed many treatment paradigms and had an important impact on morbidity and outcomes. In this section, we discuss the specific indications, contraindications, and expected benefit of endoscopic vs open surgical approaches applied to neurosurgical pathology at the present time.

Skull-base tumors and CSF leaks

The use of the endoscope in skull-base surgery was originally applied to purely midline intrasellar tumors without suprasellar or lateral extension beyond the carotid cave. Ideal cases were intrasellar pituitary microadenomas not responding to medical treatment or Rathke cleft cysts.

These pathologies were traditionally addressed via microscopic craniotomic approaches and later through sublabial or transnasal transsphenoidal approaches. Traditional transsphenoidal approaches were highly invasive for the oral mucosa, causing delayed healing, oral dysesthesia, and, in some cases, loss of the superior dental arch (sublabial) or limited visualization and surgical maneuverability (microscopic endonasal).

The endoscope offered better visualization and surgical freedom, thus allowing higher resection rates to be achieved. Resection of purely intrasellar pathology with preservation of the diaphragma sellae as a barrier to the subarachnoid cysterns and third ventricle guaranteed a lower incidence of cerebrospinal fluid (CSF) leaks.

New endoscope optics with varied angles, together with dedicated long surgical instruments with low steric volume, offered a large variety of new endonasal surgical corridors, so-called expanded endonasal approaches on the sagittal and coronal planes, as discussed in detail by Kassam et al.^17–19 These allowed endoscopic treatment of invasive tumors extending on the coronary plane into the suprasellar region or invading the cavernous sinuses (pituitary macroadenomas, craniopharyngiomas).

Highly specialized centers with expertise in endoscopic skull-base surgery can now also offer pure endoscopic treatment for some selected cases of lesions located far laterally to the cavernous sinus, such as trigeminal schwannomas, or along the sagittal plane like olfactory groove or tuberculum sellae meningiomas and clival lesions (chordomas, chondrosarcomas).

As one might expect, the increase in surgical complexity corresponded to an increase in complication rates. For example, the incidence of CSF leaks varied from 5% for standard midline transsphenoidal approaches to 11% for expanded endonasal approaches.^20,21 The consolidation of the use of the endoscope and the cooperation with ENT surgeons led to the development of surgical strategies to prevent and reduce the incidence of CSF leaks, such as the use of “rescue flaps,” nasoseptal flaps, or temporoparietal fascia flaps.^21–23

The development of such techniques allowed endoscopic endonasal approaches to be used in treatment of other pathologies, such as spontaneous CSF leaks, treated in the past with large transcranial repairs that carried high morbidity rates due to the surgical frontal lobe retraction and injury to the olfactory mucosa.^24,25 Progress in the field of neuroendoscopy therefore led to the creation of specialized endoscopic skull-base surgery centers, including neurosurgery, ENT, ophthalmology, and endocrinology services.

In clinical practice, when evaluating a patient with intracranial skull-base pathology amenable to endoscopic resection, one should consider referring the patient not only to a neurosurgeon, but also to an ENT surgeon for preoperative assessment of the sinonasal cavities. The same concept applies to postsurgical follow-up, which is mostly performed by the ENT physician to assess nasal mucosa healing and nasal hygiene.

 

 

Ventricular neuroendoscopy

The introduction of endoscopic third ventriculostomy created the opportunity to offer a more physiologic treatment in selected patients with obstructive hydrocephalus by creating an internal CSF diversion through the basal cisterns. Two advantages of this procedure are that it does not create dependence on a CSF shunt, and it eliminates the related risks of shunt infection and malfunction. Its drawback is the recurrence rate of hydrocephalus (around 58% at 2 years of follow-up) due to formation of scarring in the perforated Lilie­quist membrane, which may require repeat surgery or conversion to CSF shunting.^26,27

Neuroendoscopic approaches are also used in cases of purely intraventricular pathology such as colloid cyst or choroid plexus papillomas. The concept behind neuroendoscopy is to achieve maximal resection in a minimally invasive way, using the natural cavity of the cerebral ventricles and reducing the need for brain retraction and, in particular, the risk of injury of the fornix (therefore causing memory deficits) of open transventricular approaches and of the corpus callosum necessary in inter­hemispheric approaches. Large tumor size and inability to tolerate a longer surgical procedure can be relative contraindications to a pure endoscopic approach to these lesions.

Degenerative spine disease

In recent years there has been a growing interest in the use of endoscopy for selected cases of degenerative lumbar spondylosis (generally, lateral disk herniation above the L5-S1 level or spinal canal stenosis). This approach has been shown to reduce postoperative incisional pain, scarring of the epidural space affecting the outcome of possible revision surgeries (recurrent disc herniation), and length of hospital stay.^14,15 Information on surgical nuances should be provided when consulting on selected patients with lumbar degenerative disease resistant to conservative treatment.

Carpal tunnel syndrome

Although endoscopic carpal tunnel release is controversial, its supporters report smaller incision size and lower recurrence rates due to better visualization of the entire carpal ligament compared with open surgery, with high patient satisfaction scores.^8,9,28

Craniosynostosis

Increasing data from specialized centers show that early endoscopic suturectomy is an effective treatment option alone or when combined with open surgeries for patients with syndromic and nonsyndromic craniosynostosis. The aesthetic advantage of small incisions (which can also be achieved with some open techniques) is accompanied by significant reductions in blood loss (median 162.4 mL), operative time (median 112.38 minutes), length of stay (median 2.56 days), and rates of perioperative complications (odds ratio 0.58), reoperation (odds ratio 0.37), and transfusion (odds ratio 0.09) compared with open approaches.¹⁶

SURGICAL TRAINING

Today’s patients expect high-quality healthcare, and they approach their surgeons with an enormous amount of information collected through unlimited Web-based access or peer-group blogs. In this respect, the pressure on young surgeons to achieve excellent results is high and growing from the very beginning of their careers.

Residency training programs differ in each country, and surgical standards usually focus on open microscopic procedures rather than newly developed endoscopic techniques. Endoscopic pituitary adenoma surgery, the most frequent neuroendoscopic procedure, is still performed mostly by experienced neurosurgeons, not trainees. Moreover, many training institutions might not offer pediatric neurosurgery care, limiting exposure to endoscopic third ventriculostomy procedures. The European Union of Medical Specialists, responsible for harmonizing and improving the quality of training of medical specialists in Europe, set low neuroendoscopic surgical requirements for trainees to complete their residency programs (minimum of 0 to optimum of 5 total transcranial or transsphenoidal pituitary adenoma resections as first operator, 10 procedures as assistant, and a minimum of 2 to an optimum of 4 endoscopic third ventriculostomies as first operator).²⁹

The need to develop training programs in neuroendoscopy is especially urgent because endoscopic surgery has a steeper learning curve than conventional microneurosurgery. In particular, endoscopy requires a good deal of dexterity and hand-eye coordination, which surgeons consider the main pitfall of neuroendoscopy. For such reasons, many accredited clinical fellowship programs have been developed inside and outside North America that offer intensive training in endoscopic skull-base surgery and pediatric neurosurgery after residency.

Some clinical studies have shown that the complication rate of neuroendoscopy is 15% to 18%.^27,30 In view of this statistic, it is ethically questionable to perform a randomized study to prospectively compare microscopic and endoscopic procedures. Surgeons specialize in one technique or the other, experience their own learning curve, and do not randomly decide which tool to use. Furthermore, every intracranial surgical exploration is unique and somewhat difficult to compare with each other without the risk of bias.

 

 

FURTHER DEVELOPMENTS

Multivariable rigid endoscopes like the EndoCAMeleon (Karl Storz, Tuttlingen, Germany) or the EndActive (Karl Storz, Tuttlingen, Germany) for cerebellopontine angle surgery represent a starting point to overcome some of the aforementioned limitations.^31,32 They are inserted in the surgical field with a direct 0° angulation view into the operative site beyond neurovascular structures that need to be preserved and that obstruct the microscopic view. Once the final position is reached, the field of view is directed toward the region of interest without moving the endoscope tip.

The EndoCAMeleon is a rigid rod-lens endoscope, steerable in one plane from –10° to +120° by a fine optomechanical mechanism. Anatomic laboratory testing found it to be superior in terms of usability and visualization compared with rigid fixed-angle endoscopes.^₃₁ The first clinical experiences have been promising; however, ergonomics and the limited perspective of a single plane of rotation leave room for improvement.

The EndActive endoscope might overcome such limitations.³³ This device is a rigid videoendoscope connected to a laptop (video data) and USB port (control and power supply); thus, it weighs less and can be held in one hand like a microsurgical instrument. The endoscopic imaging system allows the operator to simultaneously see a 160° wide-angle view of the site and an inset of a specific region of interest. The surgeon can hold the device like a microsurgical instrument in one hand and control movements precisely due to its reduced weight and ergonomic shape.

The multiplanar variable-view rigid endoscope has proven to be useful for working on diverse anatomic structures such as intracranial vessels and cranial nerves. The device is effective in narrow working spaces where even small movements can jeopardize the delicate surrounding structures. The multiplanar variable-viewing mechanism in a compact device offers advantages in terms of safety and ergonomics. Improving the usability will probably optimize the applicability of those endoscopic devices in neurosurgery. A major drawback of the current prototype is poor image resolution, which will probably soon be overcome with the ongoing progress in electronic microchip technology.

The addition of laser technology to endoscopic techniques offers a huge potential to neurosurgery but has achieved little acceptance to date. The reasons include concern regarding heat production, uncontrollable and distant penetration, and tissue interaction. Experiences with a 2-micron continuous­- wave laser (RevoLix Jr, LISA Laser Products, Katlenburg-Lindau, Germany) for neuroendoscopic intraventricular procedures proved this laser to be a valuable and useful tool with safe applicability for endoscopic intracranial procedures in patients of all ages.³⁴

Parallel to the launch of video screens for other uses with higher image definition, the image quality on the 2D endoscope cameras has been constantly improving over the last years. At the same time, the introduction of modern 3D endoscopic monitors is promising. However, 3D endoscopes have some disadvantages compared with the 2D endoscopes. First, the smallest 3D endoscopes are 4 mm in diameter, compared with 2.7 mm for 2D endoscopes. Moreover, the field of view with the 3D endoscope is less than half of that with conventional 2D endoscopes.³⁴ When working in and around a region with critical neurovascular structures in close proximity, this loss of field of view can result in an increase in iatrogenic injury from the endoscope. In addition, 3D endoscopes require special glasses, generating a potential obstacle to the seamless integration of visual information from the microscope and endoscope. Finally, some surgeons experience vertigo when looking at the 3D picture through the glasses, which limits its universal applicability.

CONCLUSIONS

Using the endoscope and microscope as complementary and not competing tools allows surgeons to benefit from both technologies at the same time.^35,36 The intraoperative combination of these 2 powerful visualization tools expands the effectiveness of microsurgical procedures and has the potential to further improve surgical results and reduce surgical risks. With endoscope-assisted microsurgery, visualization is often far superior to surgical maneuverability.

Endoscopic neurosurgery will likely be influenced by further innovations in optical physics, electronics, and robotics. Specific implementations in endoscopic systems are likely to pave the way for remarkable progress in minimally invasive surgery, such as robotic surgical technology, further miniaturization of devices, improvements in 3D endoscopy, multiport endoscopy, and new designs for surgical instruments. Future progress in flexible endoscopes and wireless capsule or camera technology may reduce our dependence on rigid rod lens systems. Rigid variable-view endoscopes will bring endoscopes closer to ideal attributes utilizing newer instrumentation that is tailored to specific indications and techniques.^37,38 Extension of the visual field by the feature of a movable optic lens may allow the neurosurgeon to use tailored keyhole approaches to treat pathologies in smaller surgical corridors with less trauma and greater efficacy.

Over the last 3 decades, the endoscope has become a highly valued visualization tool in neurosurgery, applicable to a broad range of neurosurgical procedures. Following the pace of technological innovations, the quality of the instrumentation has greatly improved along with the status of endoscopy in the neurosurgical field. The use of the endoscope in interdisciplinary extended transnasal approaches revolutionized skull-base surgery.¹ Transcranial neurosurgery took advantage of the endoscope for inspection, endoscope-assisted, and endoscope-controlled procedures, although the main visualization tool during these interventions remains the operating microscope.

At present, endoscopy has applications in a variety of neurosurgical procedures including transnasal approaches for pituitary and other skull-base tumors, third ventriculostomy, and resection of intraventricular tumors. The range of application is expanding to include extracranial procedures such as peripheral nerve and spine surgery.

From Li KW, Nelson C, Suk I, Jallo GI. Neuroendoscopy: past, present, and future. Neurosurg Focus 2005; 19(6):E1. Figure used with permission.

CURRENT CONCEPTS

Hopf and Perneczky² defined the terminology regarding endoscopic procedures and divided them into 3 categories:

Pure endoscopic neurosurgery, ie, procedures performed through working channels under complete endoscopic visualization and with endoscopic instrumentation (Figure 1).³

Endoscope-controlled microsurgery, ie, operations performed with standard microsurgical instruments under endoscopic visualization—the microscope is not used (Figure 2).

Endoscope-assisted neurosurgery, ie, the use of both microscope and endoscope during the same intervention. In endoscopic inspection the endoscope is solely used as an adjunctive tool for visualization and not for surgical manipulations.

Enhanced area and surgical dissection

Technical innovations are probably the major reason for the growing role of endoscopy in neurosurgery over the last 3 decades.⁴ High-definition imaging, neuronavigation, new instruments, an interdisciplinary approach mostly with ear, nose, and throat (ENT) surgeons, and detailed anatomic studies led to the breakthrough of endoscopic endonasal extended approaches in skull-base surgery.⁵

These endoscopic techniques allow the neurosurgeon to optimize tumor resection, increasing the area of surgical dissection without increasing the size of the surgical approach, thereby limiting perioperative morbidity due to surgical manipulation of eloquent brain structures. Endoscopy offers direct illumination of the operative field, magnification, and the ability to look around corners with angled optics.

However, while angled endoscopic optics provide various visual perspectives, the surgical issue is not only to see but also to work on and around remote structures. Microsurgical endoscope-assisted manipulations require optimal working angles that are guaranteed only by a sufficiently large craniotomy. As an example, a dissection study by Chaynes et al⁶ highlights that a craniotomy that is too narrow often hinders a sufficient exploration of the entire cerebellopontine angle. Most neuro­surgeons are familiar with the operating microscope. The microscopic field of inspection is 3-dimensional (3D) and of high quality. However, the light stream is straight and thus limited in the narrow and angled corridor of the cerebellopontine angle or in the perimesencephalic cisterns. In these situations, the angled optic of the endoscope offers the advantage of being able to look around the corner with the appropriate amount of direct illumination.⁷

 

 

Peripheral nerve surgery

Minimally invasive endoscopic approaches are also being used in peripheral nerve surgery, especially carpal tunnel decompression. The first carpal tunnel release treated endoscopically was performed by Okutsu et al in the late 1980s.⁸ Since that time, endoscopic carpal tunnel decompression has become very common and is the preferred method for many surgeons, using either single-portal or dual-portal techniques. Although the superiority of endoscopic over conventional minimally invasive microsurgical peripheral nerve surgeries has not been proven, large series of endoscopic carpal tunnel decompressions have reported low complication rates and excellent success rates with high patient satisfaction scores.^8,9

Visualization of the spinal canal

Expanding the use of the endoscope to spine surgery, endoscopic explorations of the interlaminar spaces after having completed open surgical laminectomies have been reported since the early 1980s,¹⁰ while endoscope-assisted interlaminar procedures started in the late 1990s.^11–13 The development of fully endoscopic transforaminal or interlaminar approaches for lumbar stenosis or lumbar disk herniation has been ongoing in the last 2 decades. The rationale for direct endoscopic visualization of the spinal canal is to reduce scarring of the epidural space, which might affect the outcome of possible revision surgeries (recurrent disk herniation), and to reduce injury to the paraspinal muscles, which may reduce postoperative incisional pain and length of hospital stay. Major limiting factors for fully endoscopic spine surgeries such as the narrow working channels (which are limited by the osseous perimeter of the neuroforamina, as well as the pelvis and abdominal structures) and the learning curve for the surgeons are, however, still matters of debate and restrict the use of endoscopy to very carefully selected cases.^14,15

Pediatric craniosynostosis

Recently, the use of the endoscope has extended to treatment of craniosynostosis in pediatric patients, historically treated with large and occasionally staged craniotomic approaches. A meta-analysis of the literature showed statistically significant reductions in blood loss and rates of perioperative complications, reoperation, and transfusion compared with open approaches.¹⁶

Technical limitations

While neurosurgeons increasingly advocate the use of the endoscope in their practice, the development of instruments for endoscopic surgery does not always follow the same pace. There are technical problems with current rigid endoscopes and ergonomic limitations of the endoscope-assisted techniques in trans­cranial neurosurgery. The endoscope itself occupies space in an already limited surgical corridor like the posterior fossa, the parasellar space, or the intraventricular region. The ideal endoscope is thin and sturdy, does not generate heat, and provides high-resolution images. In addition, a self-irrigating feature could minimize the need to remove and reinsert the endoscope for cleaning. Finally, most intracranial surgery is extremely delicate and requires bimanual dissection. The ideal endoscope should also be easily integrated with a holder that allows the surgeon to easily transition between static and dynamic endoscope movements.

Newer flexible fiberscopes with even smaller diameters are likely to be launched on the market in the near future. When working in a surgical corridor less than 10 mm wide, this difference could be substantial.

In addition, surgical instruments specifically designed for endoscopic endonasal procedures are needed for microdissection in these regions, which were previously only visible but not reachable endoscopically. These include tools such as malleable suctions and curettes, rotatable back-biting microscissors, and malleable bipolar instruments (Figure 3).

IMPACT OF NEUROENDOSCOPY IN CURRENT CLINICAL PRACTICE

The introduction of endoscopy in neurosurgery changed many treatment paradigms and had an important impact on morbidity and outcomes. In this section, we discuss the specific indications, contraindications, and expected benefit of endoscopic vs open surgical approaches applied to neurosurgical pathology at the present time.

Skull-base tumors and CSF leaks

The use of the endoscope in skull-base surgery was originally applied to purely midline intrasellar tumors without suprasellar or lateral extension beyond the carotid cave. Ideal cases were intrasellar pituitary microadenomas not responding to medical treatment or Rathke cleft cysts.

These pathologies were traditionally addressed via microscopic craniotomic approaches and later through sublabial or transnasal transsphenoidal approaches. Traditional transsphenoidal approaches were highly invasive for the oral mucosa, causing delayed healing, oral dysesthesia, and, in some cases, loss of the superior dental arch (sublabial) or limited visualization and surgical maneuverability (microscopic endonasal).

The endoscope offered better visualization and surgical freedom, thus allowing higher resection rates to be achieved. Resection of purely intrasellar pathology with preservation of the diaphragma sellae as a barrier to the subarachnoid cysterns and third ventricle guaranteed a lower incidence of cerebrospinal fluid (CSF) leaks.

New endoscope optics with varied angles, together with dedicated long surgical instruments with low steric volume, offered a large variety of new endonasal surgical corridors, so-called expanded endonasal approaches on the sagittal and coronal planes, as discussed in detail by Kassam et al.^17–19 These allowed endoscopic treatment of invasive tumors extending on the coronary plane into the suprasellar region or invading the cavernous sinuses (pituitary macroadenomas, craniopharyngiomas).

Highly specialized centers with expertise in endoscopic skull-base surgery can now also offer pure endoscopic treatment for some selected cases of lesions located far laterally to the cavernous sinus, such as trigeminal schwannomas, or along the sagittal plane like olfactory groove or tuberculum sellae meningiomas and clival lesions (chordomas, chondrosarcomas).

As one might expect, the increase in surgical complexity corresponded to an increase in complication rates. For example, the incidence of CSF leaks varied from 5% for standard midline transsphenoidal approaches to 11% for expanded endonasal approaches.^20,21 The consolidation of the use of the endoscope and the cooperation with ENT surgeons led to the development of surgical strategies to prevent and reduce the incidence of CSF leaks, such as the use of “rescue flaps,” nasoseptal flaps, or temporoparietal fascia flaps.^21–23

The development of such techniques allowed endoscopic endonasal approaches to be used in treatment of other pathologies, such as spontaneous CSF leaks, treated in the past with large transcranial repairs that carried high morbidity rates due to the surgical frontal lobe retraction and injury to the olfactory mucosa.^24,25 Progress in the field of neuroendoscopy therefore led to the creation of specialized endoscopic skull-base surgery centers, including neurosurgery, ENT, ophthalmology, and endocrinology services.

In clinical practice, when evaluating a patient with intracranial skull-base pathology amenable to endoscopic resection, one should consider referring the patient not only to a neurosurgeon, but also to an ENT surgeon for preoperative assessment of the sinonasal cavities. The same concept applies to postsurgical follow-up, which is mostly performed by the ENT physician to assess nasal mucosa healing and nasal hygiene.

 

 

Ventricular neuroendoscopy

The introduction of endoscopic third ventriculostomy created the opportunity to offer a more physiologic treatment in selected patients with obstructive hydrocephalus by creating an internal CSF diversion through the basal cisterns. Two advantages of this procedure are that it does not create dependence on a CSF shunt, and it eliminates the related risks of shunt infection and malfunction. Its drawback is the recurrence rate of hydrocephalus (around 58% at 2 years of follow-up) due to formation of scarring in the perforated Lilie­quist membrane, which may require repeat surgery or conversion to CSF shunting.^26,27

Neuroendoscopic approaches are also used in cases of purely intraventricular pathology such as colloid cyst or choroid plexus papillomas. The concept behind neuroendoscopy is to achieve maximal resection in a minimally invasive way, using the natural cavity of the cerebral ventricles and reducing the need for brain retraction and, in particular, the risk of injury of the fornix (therefore causing memory deficits) of open transventricular approaches and of the corpus callosum necessary in inter­hemispheric approaches. Large tumor size and inability to tolerate a longer surgical procedure can be relative contraindications to a pure endoscopic approach to these lesions.

Degenerative spine disease

In recent years there has been a growing interest in the use of endoscopy for selected cases of degenerative lumbar spondylosis (generally, lateral disk herniation above the L5-S1 level or spinal canal stenosis). This approach has been shown to reduce postoperative incisional pain, scarring of the epidural space affecting the outcome of possible revision surgeries (recurrent disc herniation), and length of hospital stay.^14,15 Information on surgical nuances should be provided when consulting on selected patients with lumbar degenerative disease resistant to conservative treatment.

Carpal tunnel syndrome

Although endoscopic carpal tunnel release is controversial, its supporters report smaller incision size and lower recurrence rates due to better visualization of the entire carpal ligament compared with open surgery, with high patient satisfaction scores.^8,9,28

Craniosynostosis

Increasing data from specialized centers show that early endoscopic suturectomy is an effective treatment option alone or when combined with open surgeries for patients with syndromic and nonsyndromic craniosynostosis. The aesthetic advantage of small incisions (which can also be achieved with some open techniques) is accompanied by significant reductions in blood loss (median 162.4 mL), operative time (median 112.38 minutes), length of stay (median 2.56 days), and rates of perioperative complications (odds ratio 0.58), reoperation (odds ratio 0.37), and transfusion (odds ratio 0.09) compared with open approaches.¹⁶

SURGICAL TRAINING

Today’s patients expect high-quality healthcare, and they approach their surgeons with an enormous amount of information collected through unlimited Web-based access or peer-group blogs. In this respect, the pressure on young surgeons to achieve excellent results is high and growing from the very beginning of their careers.

Residency training programs differ in each country, and surgical standards usually focus on open microscopic procedures rather than newly developed endoscopic techniques. Endoscopic pituitary adenoma surgery, the most frequent neuroendoscopic procedure, is still performed mostly by experienced neurosurgeons, not trainees. Moreover, many training institutions might not offer pediatric neurosurgery care, limiting exposure to endoscopic third ventriculostomy procedures. The European Union of Medical Specialists, responsible for harmonizing and improving the quality of training of medical specialists in Europe, set low neuroendoscopic surgical requirements for trainees to complete their residency programs (minimum of 0 to optimum of 5 total transcranial or transsphenoidal pituitary adenoma resections as first operator, 10 procedures as assistant, and a minimum of 2 to an optimum of 4 endoscopic third ventriculostomies as first operator).²⁹

The need to develop training programs in neuroendoscopy is especially urgent because endoscopic surgery has a steeper learning curve than conventional microneurosurgery. In particular, endoscopy requires a good deal of dexterity and hand-eye coordination, which surgeons consider the main pitfall of neuroendoscopy. For such reasons, many accredited clinical fellowship programs have been developed inside and outside North America that offer intensive training in endoscopic skull-base surgery and pediatric neurosurgery after residency.

Some clinical studies have shown that the complication rate of neuroendoscopy is 15% to 18%.^27,30 In view of this statistic, it is ethically questionable to perform a randomized study to prospectively compare microscopic and endoscopic procedures. Surgeons specialize in one technique or the other, experience their own learning curve, and do not randomly decide which tool to use. Furthermore, every intracranial surgical exploration is unique and somewhat difficult to compare with each other without the risk of bias.

 

 

FURTHER DEVELOPMENTS

Multivariable rigid endoscopes like the EndoCAMeleon (Karl Storz, Tuttlingen, Germany) or the EndActive (Karl Storz, Tuttlingen, Germany) for cerebellopontine angle surgery represent a starting point to overcome some of the aforementioned limitations.^31,32 They are inserted in the surgical field with a direct 0° angulation view into the operative site beyond neurovascular structures that need to be preserved and that obstruct the microscopic view. Once the final position is reached, the field of view is directed toward the region of interest without moving the endoscope tip.

The EndoCAMeleon is a rigid rod-lens endoscope, steerable in one plane from –10° to +120° by a fine optomechanical mechanism. Anatomic laboratory testing found it to be superior in terms of usability and visualization compared with rigid fixed-angle endoscopes.^₃₁ The first clinical experiences have been promising; however, ergonomics and the limited perspective of a single plane of rotation leave room for improvement.

The EndActive endoscope might overcome such limitations.³³ This device is a rigid videoendoscope connected to a laptop (video data) and USB port (control and power supply); thus, it weighs less and can be held in one hand like a microsurgical instrument. The endoscopic imaging system allows the operator to simultaneously see a 160° wide-angle view of the site and an inset of a specific region of interest. The surgeon can hold the device like a microsurgical instrument in one hand and control movements precisely due to its reduced weight and ergonomic shape.

The multiplanar variable-view rigid endoscope has proven to be useful for working on diverse anatomic structures such as intracranial vessels and cranial nerves. The device is effective in narrow working spaces where even small movements can jeopardize the delicate surrounding structures. The multiplanar variable-viewing mechanism in a compact device offers advantages in terms of safety and ergonomics. Improving the usability will probably optimize the applicability of those endoscopic devices in neurosurgery. A major drawback of the current prototype is poor image resolution, which will probably soon be overcome with the ongoing progress in electronic microchip technology.

The addition of laser technology to endoscopic techniques offers a huge potential to neurosurgery but has achieved little acceptance to date. The reasons include concern regarding heat production, uncontrollable and distant penetration, and tissue interaction. Experiences with a 2-micron continuous­- wave laser (RevoLix Jr, LISA Laser Products, Katlenburg-Lindau, Germany) for neuroendoscopic intraventricular procedures proved this laser to be a valuable and useful tool with safe applicability for endoscopic intracranial procedures in patients of all ages.³⁴

Parallel to the launch of video screens for other uses with higher image definition, the image quality on the 2D endoscope cameras has been constantly improving over the last years. At the same time, the introduction of modern 3D endoscopic monitors is promising. However, 3D endoscopes have some disadvantages compared with the 2D endoscopes. First, the smallest 3D endoscopes are 4 mm in diameter, compared with 2.7 mm for 2D endoscopes. Moreover, the field of view with the 3D endoscope is less than half of that with conventional 2D endoscopes.³⁴ When working in and around a region with critical neurovascular structures in close proximity, this loss of field of view can result in an increase in iatrogenic injury from the endoscope. In addition, 3D endoscopes require special glasses, generating a potential obstacle to the seamless integration of visual information from the microscope and endoscope. Finally, some surgeons experience vertigo when looking at the 3D picture through the glasses, which limits its universal applicability.

CONCLUSIONS

Using the endoscope and microscope as complementary and not competing tools allows surgeons to benefit from both technologies at the same time.^35,36 The intraoperative combination of these 2 powerful visualization tools expands the effectiveness of microsurgical procedures and has the potential to further improve surgical results and reduce surgical risks. With endoscope-assisted microsurgery, visualization is often far superior to surgical maneuverability.

Endoscopic neurosurgery will likely be influenced by further innovations in optical physics, electronics, and robotics. Specific implementations in endoscopic systems are likely to pave the way for remarkable progress in minimally invasive surgery, such as robotic surgical technology, further miniaturization of devices, improvements in 3D endoscopy, multiport endoscopy, and new designs for surgical instruments. Future progress in flexible endoscopes and wireless capsule or camera technology may reduce our dependence on rigid rod lens systems. Rigid variable-view endoscopes will bring endoscopes closer to ideal attributes utilizing newer instrumentation that is tailored to specific indications and techniques.^37,38 Extension of the visual field by the feature of a movable optic lens may allow the neurosurgeon to use tailored keyhole approaches to treat pathologies in smaller surgical corridors with less trauma and greater efficacy.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.