Traumatic Brain Injury

SAN DIEGO—A recently discovered system known as the glymphatic system clears waste from the brain. It is most active during sleep and may have implications in headache and in neurodegenerative diseases associated with pathologic protein aggregation, including Parkinson’s disease and Alzheimer’s disease, said Helene Benveniste, MD, PhD, Professor of Anesthesiology and Vice Chair for Research at Stony Brook School of Medicine in New York. Data suggest that sleep, posture, and brain injury may affect this waste removal system.

“We look at the glymphatic pathway as a bit of an overlooked compartment of the vasculature or the perivascular space that is … facilitating solute and waste removal,” Dr. Benveniste said at the 58th Annual Scientific Meeting of the American Headache Society. Although most studies of the glymphatic system so far have been performed in rodents, “data are starting to come out showing that this system is also present in humans,” she said.

A Brainwide Pathway

The glymphatic system, which gets its name from the glial cells and lymphatic system that it mimics, may explain how the brain—one of the most metabolically active organs—clears excess fluids, solutes, and waste products without authentic lymph vessels, Dr. Benveniste said. The system consists of a brainwide pathway that facilitates the exchange of CSF with interstitial fluid to clear interstitial waste from the brain parenchyma. The waste is moved into perivenous pathways and ultimately cleared via cervical lymphatic vessels.

Researchers first described the concept of the glymphatic system in Science Translational Medicine in 2012. They injected fluorescent tracers into the cisterna magna and fluorescent-tagged amyloid beta into brain parenchyma of mice and observed distribution of the tracers along the glymphatic pathway using two-photon imaging. The paper’s senior author, Maiken Nedergaard, MD, DMSc, Professor of Neurosurgery and Translational Neuromedicine at the University of Rochester in New York, contacted Dr. Benveniste to develop a way to visualize the system using MRI, which they accomplished using a 9.4-T system and small molecular weight contrast dye injected via an intrathecal catheter inserted in the cisterna magna.

In 2015, researchers in Norway published a case report in Acta Radiologica Open supporting the existence of a glymphatic system in humans. They administered intrathecal gadobutrol to diagnose a CSF leak in a patient. The patient underwent 3D T1-weighted imaging at one hour and 4.5 hours. The distribution of gadobutrol into the brain was consistent with that observed in rodents and supports the concept of a glymphatic pathway in the human brain, the authors concluded.

Researchers still are evaluating the glymphatic system’s role in maintaining brain health and how it differs in humans and rodents. Aquaporin channels, which are crucial in facilitating CSF transport from the periarterial space and into the interstitial space to drive waste removal via the glymphatic pathway, may be positioned differently in rodents and humans, Dr. Benveniste said. In addition, waste clearance may be orders of magnitude slower in humans due to brain size and complexity, she said.

Factors Affecting Glymphatic Flow

In mice genetically modified to lack aquaporin channels, convective flow and waste removal via the glymphatic pathway are slowed down immensely.

After traumatic brain injury, glymphatic pathway function was reduced by approximately 60% in mice for at least one month, Iliff et al reported in the Journal of Neuroscience in 2014. In mice without aquaporin channels, however, glymphatic pathway dysfunction was further exacerbated, and those animals developed neurofibrillary pathology and neurodegeneration.

One of the most important factors affecting glymphatic flow is interstitial space volume, which increases by 40% to 60% during sleep, Dr. Benveniste said. Natural sleep and certain types of anesthetics dramatically increase interstitial space volume, Xie et al reported in Science in 2013. Likewise, awaking sleeping mice sharply reduces glymphatic flow. The authors concluded, “the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake CNS.”

Injecting a norepinephrine receptor antagonist intrathecally can stimulate intense glymphatic transport in animals in the awake state, indicating that noradrenergic tone may be responsible for the process, Dr. Benveniste said.

She and her colleagues studied glymphatic clearance in mice anesthetized with dexmedetomidine, which induces a state similar to stage 2 sleep, versus the inhalational anesthetic isoflurane. Glymphatic processing was much greater in rodents that received dexmedetomidine.

Sleep Position

Hedok Lee, PhD, Clinical Assistant Professor of Anesthesiology at Stony Brook School of Medicine, Dr. Benveniste, and colleagues studied the effect of body posture on brain glymphatic transport in rats. They found that glymphatic transport and amyloid beta clearance were most efficient in the lateral and supine positions, while the prone position (ie, most upright and mimicking awake posture) resulted in slower clearance.

“Right lateral seems to be the position where you have got the best efflux and influx,” Dr. Benveniste said. The findings suggest that sleep position’s effect on the glymphatic system may be relevant for imaging the system in humans, and ultimately for patient care.

—Jake Remaly

Suggested Reading

Eide PK, Ringstad G. MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. Acta Radiol Open. 2015;4(11):2058460115609635.

Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci. 2014;34(49):16180-16193.

Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111.

Lee H, Xie L, Yu M, et al. The effect of body posture on brain glymphatic transport. J Neurosci. 2015;35(31):11034-11044.
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377.

SAN DIEGO—A recently discovered system known as the glymphatic system clears waste from the brain. It is most active during sleep and may have implications in headache and in neurodegenerative diseases associated with pathologic protein aggregation, including Parkinson’s disease and Alzheimer’s disease, said Helene Benveniste, MD, PhD, Professor of Anesthesiology and Vice Chair for Research at Stony Brook School of Medicine in New York. Data suggest that sleep, posture, and brain injury may affect this waste removal system.

“We look at the glymphatic pathway as a bit of an overlooked compartment of the vasculature or the perivascular space that is … facilitating solute and waste removal,” Dr. Benveniste said at the 58th Annual Scientific Meeting of the American Headache Society. Although most studies of the glymphatic system so far have been performed in rodents, “data are starting to come out showing that this system is also present in humans,” she said.

A Brainwide Pathway

The glymphatic system, which gets its name from the glial cells and lymphatic system that it mimics, may explain how the brain—one of the most metabolically active organs—clears excess fluids, solutes, and waste products without authentic lymph vessels, Dr. Benveniste said. The system consists of a brainwide pathway that facilitates the exchange of CSF with interstitial fluid to clear interstitial waste from the brain parenchyma. The waste is moved into perivenous pathways and ultimately cleared via cervical lymphatic vessels.

Researchers first described the concept of the glymphatic system in Science Translational Medicine in 2012. They injected fluorescent tracers into the cisterna magna and fluorescent-tagged amyloid beta into brain parenchyma of mice and observed distribution of the tracers along the glymphatic pathway using two-photon imaging. The paper’s senior author, Maiken Nedergaard, MD, DMSc, Professor of Neurosurgery and Translational Neuromedicine at the University of Rochester in New York, contacted Dr. Benveniste to develop a way to visualize the system using MRI, which they accomplished using a 9.4-T system and small molecular weight contrast dye injected via an intrathecal catheter inserted in the cisterna magna.

In 2015, researchers in Norway published a case report in Acta Radiologica Open supporting the existence of a glymphatic system in humans. They administered intrathecal gadobutrol to diagnose a CSF leak in a patient. The patient underwent 3D T1-weighted imaging at one hour and 4.5 hours. The distribution of gadobutrol into the brain was consistent with that observed in rodents and supports the concept of a glymphatic pathway in the human brain, the authors concluded.

Researchers still are evaluating the glymphatic system’s role in maintaining brain health and how it differs in humans and rodents. Aquaporin channels, which are crucial in facilitating CSF transport from the periarterial space and into the interstitial space to drive waste removal via the glymphatic pathway, may be positioned differently in rodents and humans, Dr. Benveniste said. In addition, waste clearance may be orders of magnitude slower in humans due to brain size and complexity, she said.

Factors Affecting Glymphatic Flow

In mice genetically modified to lack aquaporin channels, convective flow and waste removal via the glymphatic pathway are slowed down immensely.

After traumatic brain injury, glymphatic pathway function was reduced by approximately 60% in mice for at least one month, Iliff et al reported in the Journal of Neuroscience in 2014. In mice without aquaporin channels, however, glymphatic pathway dysfunction was further exacerbated, and those animals developed neurofibrillary pathology and neurodegeneration.

One of the most important factors affecting glymphatic flow is interstitial space volume, which increases by 40% to 60% during sleep, Dr. Benveniste said. Natural sleep and certain types of anesthetics dramatically increase interstitial space volume, Xie et al reported in Science in 2013. Likewise, awaking sleeping mice sharply reduces glymphatic flow. The authors concluded, “the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake CNS.”

Injecting a norepinephrine receptor antagonist intrathecally can stimulate intense glymphatic transport in animals in the awake state, indicating that noradrenergic tone may be responsible for the process, Dr. Benveniste said.

She and her colleagues studied glymphatic clearance in mice anesthetized with dexmedetomidine, which induces a state similar to stage 2 sleep, versus the inhalational anesthetic isoflurane. Glymphatic processing was much greater in rodents that received dexmedetomidine.

Sleep Position

Hedok Lee, PhD, Clinical Assistant Professor of Anesthesiology at Stony Brook School of Medicine, Dr. Benveniste, and colleagues studied the effect of body posture on brain glymphatic transport in rats. They found that glymphatic transport and amyloid beta clearance were most efficient in the lateral and supine positions, while the prone position (ie, most upright and mimicking awake posture) resulted in slower clearance.

“Right lateral seems to be the position where you have got the best efflux and influx,” Dr. Benveniste said. The findings suggest that sleep position’s effect on the glymphatic system may be relevant for imaging the system in humans, and ultimately for patient care.

—Jake Remaly

Suggested Reading

Eide PK, Ringstad G. MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. Acta Radiol Open. 2015;4(11):2058460115609635.

Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci. 2014;34(49):16180-16193.

Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111.

Lee H, Xie L, Yu M, et al. The effect of body posture on brain glymphatic transport. J Neurosci. 2015;35(31):11034-11044.
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377.

SAN DIEGO—A recently discovered system known as the glymphatic system clears waste from the brain. It is most active during sleep and may have implications in headache and in neurodegenerative diseases associated with pathologic protein aggregation, including Parkinson’s disease and Alzheimer’s disease, said Helene Benveniste, MD, PhD, Professor of Anesthesiology and Vice Chair for Research at Stony Brook School of Medicine in New York. Data suggest that sleep, posture, and brain injury may affect this waste removal system.

“We look at the glymphatic pathway as a bit of an overlooked compartment of the vasculature or the perivascular space that is … facilitating solute and waste removal,” Dr. Benveniste said at the 58th Annual Scientific Meeting of the American Headache Society. Although most studies of the glymphatic system so far have been performed in rodents, “data are starting to come out showing that this system is also present in humans,” she said.

A Brainwide Pathway

The glymphatic system, which gets its name from the glial cells and lymphatic system that it mimics, may explain how the brain—one of the most metabolically active organs—clears excess fluids, solutes, and waste products without authentic lymph vessels, Dr. Benveniste said. The system consists of a brainwide pathway that facilitates the exchange of CSF with interstitial fluid to clear interstitial waste from the brain parenchyma. The waste is moved into perivenous pathways and ultimately cleared via cervical lymphatic vessels.

Researchers first described the concept of the glymphatic system in Science Translational Medicine in 2012. They injected fluorescent tracers into the cisterna magna and fluorescent-tagged amyloid beta into brain parenchyma of mice and observed distribution of the tracers along the glymphatic pathway using two-photon imaging. The paper’s senior author, Maiken Nedergaard, MD, DMSc, Professor of Neurosurgery and Translational Neuromedicine at the University of Rochester in New York, contacted Dr. Benveniste to develop a way to visualize the system using MRI, which they accomplished using a 9.4-T system and small molecular weight contrast dye injected via an intrathecal catheter inserted in the cisterna magna.

In 2015, researchers in Norway published a case report in Acta Radiologica Open supporting the existence of a glymphatic system in humans. They administered intrathecal gadobutrol to diagnose a CSF leak in a patient. The patient underwent 3D T1-weighted imaging at one hour and 4.5 hours. The distribution of gadobutrol into the brain was consistent with that observed in rodents and supports the concept of a glymphatic pathway in the human brain, the authors concluded.

Researchers still are evaluating the glymphatic system’s role in maintaining brain health and how it differs in humans and rodents. Aquaporin channels, which are crucial in facilitating CSF transport from the periarterial space and into the interstitial space to drive waste removal via the glymphatic pathway, may be positioned differently in rodents and humans, Dr. Benveniste said. In addition, waste clearance may be orders of magnitude slower in humans due to brain size and complexity, she said.

Factors Affecting Glymphatic Flow

In mice genetically modified to lack aquaporin channels, convective flow and waste removal via the glymphatic pathway are slowed down immensely.

After traumatic brain injury, glymphatic pathway function was reduced by approximately 60% in mice for at least one month, Iliff et al reported in the Journal of Neuroscience in 2014. In mice without aquaporin channels, however, glymphatic pathway dysfunction was further exacerbated, and those animals developed neurofibrillary pathology and neurodegeneration.

One of the most important factors affecting glymphatic flow is interstitial space volume, which increases by 40% to 60% during sleep, Dr. Benveniste said. Natural sleep and certain types of anesthetics dramatically increase interstitial space volume, Xie et al reported in Science in 2013. Likewise, awaking sleeping mice sharply reduces glymphatic flow. The authors concluded, “the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake CNS.”

Injecting a norepinephrine receptor antagonist intrathecally can stimulate intense glymphatic transport in animals in the awake state, indicating that noradrenergic tone may be responsible for the process, Dr. Benveniste said.

She and her colleagues studied glymphatic clearance in mice anesthetized with dexmedetomidine, which induces a state similar to stage 2 sleep, versus the inhalational anesthetic isoflurane. Glymphatic processing was much greater in rodents that received dexmedetomidine.

Sleep Position

Hedok Lee, PhD, Clinical Assistant Professor of Anesthesiology at Stony Brook School of Medicine, Dr. Benveniste, and colleagues studied the effect of body posture on brain glymphatic transport in rats. They found that glymphatic transport and amyloid beta clearance were most efficient in the lateral and supine positions, while the prone position (ie, most upright and mimicking awake posture) resulted in slower clearance.

“Right lateral seems to be the position where you have got the best efflux and influx,” Dr. Benveniste said. The findings suggest that sleep position’s effect on the glymphatic system may be relevant for imaging the system in humans, and ultimately for patient care.

—Jake Remaly

Suggested Reading

Eide PK, Ringstad G. MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. Acta Radiol Open. 2015;4(11):2058460115609635.

Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci. 2014;34(49):16180-16193.

Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111.

Lee H, Xie L, Yu M, et al. The effect of body posture on brain glymphatic transport. J Neurosci. 2015;35(31):11034-11044.
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377.

Adolescents who underwent cognitive behavioral therapy (CBT) as part of postconcussion care reported significantly lower levels of postconcussive and depressive symptoms, according to the results of a randomized trial published online ahead of print September 12 in Pediatrics.

“Affective symptoms, including depression and anxiety, commonly co-occur with cognitive and somatic symptoms and may prolong recovery from postconcussive symptoms, wrote Carolyn A. McCarty, PhD, Research Associate Professor of Pediatrics and Adjunct Research Associate Professor of Psychology at Seattle Children’s Hospital Center for Child Health Behavior and Development in Seattle, and her colleagues.

“The complexities of managing persistent postconcussive symptoms in conjunction with comorbid psychological symptoms create a significant burden for injured children and adolescents, their families, and schools.”

To determine the impact of CBT on persistent symptoms in adolescents with concussions, the researchers randomized 49 patients, ages 11 to 17, to usual care or a collaborative care plan that included usual care plus CBT.

Concussions were diagnosed by sports medicine or rehabilitative medicine specialists. The patients assigned to CBT received usual care management, CBT, and possible psychopharmacologic consultation. Control patients received usual concussion care, generally defined as an initial visit with a sports medicine physician and assessments at one, three, and six months. Usual care also could include MRI, sleep medication, and subthreshold exercise, depending on the patient. No serious adverse events were reported. The average age of the patients was 15, approximately 65% were girls, and 76% were white.

After six months, approximately 13% of the teens in the CBT group reported high levels of postconcussive symptoms, compared with 42% of controls. In addition, 78% of patients receiving CBT reported a depressive symptom reduction of more than 50%, compared with 46% of controls.

Overall, 83% of the patients receiving CBT and 87% of their parents were “very satisfied” with their care, compared with 46% of patients and 29% of parents in the control group.

“Although patients in both groups showed symptom reduction in the first three months, only those who received collaborative care demonstrated sustained improvements through six months of follow-up,” Dr. McCarty and her colleagues wrote.

The results were limited by several factors, including the small size of the study, the researchers said. However, the findings “prompt more investigation into the role of affective symptoms in perpetuating physical symptoms secondary to prolonged recovery from sports-related concussion” and also suggest that collaborative care can help improve persistent postconcussive symptoms in teens.The Seattle Sports Concussion Research Collaborative supported the study.

—Heidi Splete

Suggested Reading

McCarty CA, Zatzick D, Stein E, et al. Collaborative care for adolescents with persistent postconcussive symptoms: a randomized trial. Pediatrics. 2016 Sept 13 [Epub ahead of print].

Cordingley D, Girardin R, Reimer K, et al. Graded aerobic treadmill testing in pediatric sports-related concussion: safety, clinical use, and patient outcomes. J Neurosurg Pediatr. 2016 September 13 [Epub ahead of print].

Adolescents who underwent cognitive behavioral therapy (CBT) as part of postconcussion care reported significantly lower levels of postconcussive and depressive symptoms, according to the results of a randomized trial published online ahead of print September 12 in Pediatrics.

“Affective symptoms, including depression and anxiety, commonly co-occur with cognitive and somatic symptoms and may prolong recovery from postconcussive symptoms, wrote Carolyn A. McCarty, PhD, Research Associate Professor of Pediatrics and Adjunct Research Associate Professor of Psychology at Seattle Children’s Hospital Center for Child Health Behavior and Development in Seattle, and her colleagues.

“The complexities of managing persistent postconcussive symptoms in conjunction with comorbid psychological symptoms create a significant burden for injured children and adolescents, their families, and schools.”

To determine the impact of CBT on persistent symptoms in adolescents with concussions, the researchers randomized 49 patients, ages 11 to 17, to usual care or a collaborative care plan that included usual care plus CBT.

Concussions were diagnosed by sports medicine or rehabilitative medicine specialists. The patients assigned to CBT received usual care management, CBT, and possible psychopharmacologic consultation. Control patients received usual concussion care, generally defined as an initial visit with a sports medicine physician and assessments at one, three, and six months. Usual care also could include MRI, sleep medication, and subthreshold exercise, depending on the patient. No serious adverse events were reported. The average age of the patients was 15, approximately 65% were girls, and 76% were white.

After six months, approximately 13% of the teens in the CBT group reported high levels of postconcussive symptoms, compared with 42% of controls. In addition, 78% of patients receiving CBT reported a depressive symptom reduction of more than 50%, compared with 46% of controls.

Overall, 83% of the patients receiving CBT and 87% of their parents were “very satisfied” with their care, compared with 46% of patients and 29% of parents in the control group.

“Although patients in both groups showed symptom reduction in the first three months, only those who received collaborative care demonstrated sustained improvements through six months of follow-up,” Dr. McCarty and her colleagues wrote.

The results were limited by several factors, including the small size of the study, the researchers said. However, the findings “prompt more investigation into the role of affective symptoms in perpetuating physical symptoms secondary to prolonged recovery from sports-related concussion” and also suggest that collaborative care can help improve persistent postconcussive symptoms in teens.The Seattle Sports Concussion Research Collaborative supported the study.

—Heidi Splete

Suggested Reading

McCarty CA, Zatzick D, Stein E, et al. Collaborative care for adolescents with persistent postconcussive symptoms: a randomized trial. Pediatrics. 2016 Sept 13 [Epub ahead of print].

Cordingley D, Girardin R, Reimer K, et al. Graded aerobic treadmill testing in pediatric sports-related concussion: safety, clinical use, and patient outcomes. J Neurosurg Pediatr. 2016 September 13 [Epub ahead of print].

Adolescents who underwent cognitive behavioral therapy (CBT) as part of postconcussion care reported significantly lower levels of postconcussive and depressive symptoms, according to the results of a randomized trial published online ahead of print September 12 in Pediatrics.

“Affective symptoms, including depression and anxiety, commonly co-occur with cognitive and somatic symptoms and may prolong recovery from postconcussive symptoms, wrote Carolyn A. McCarty, PhD, Research Associate Professor of Pediatrics and Adjunct Research Associate Professor of Psychology at Seattle Children’s Hospital Center for Child Health Behavior and Development in Seattle, and her colleagues.

“The complexities of managing persistent postconcussive symptoms in conjunction with comorbid psychological symptoms create a significant burden for injured children and adolescents, their families, and schools.”

To determine the impact of CBT on persistent symptoms in adolescents with concussions, the researchers randomized 49 patients, ages 11 to 17, to usual care or a collaborative care plan that included usual care plus CBT.

Concussions were diagnosed by sports medicine or rehabilitative medicine specialists. The patients assigned to CBT received usual care management, CBT, and possible psychopharmacologic consultation. Control patients received usual concussion care, generally defined as an initial visit with a sports medicine physician and assessments at one, three, and six months. Usual care also could include MRI, sleep medication, and subthreshold exercise, depending on the patient. No serious adverse events were reported. The average age of the patients was 15, approximately 65% were girls, and 76% were white.

After six months, approximately 13% of the teens in the CBT group reported high levels of postconcussive symptoms, compared with 42% of controls. In addition, 78% of patients receiving CBT reported a depressive symptom reduction of more than 50%, compared with 46% of controls.

Overall, 83% of the patients receiving CBT and 87% of their parents were “very satisfied” with their care, compared with 46% of patients and 29% of parents in the control group.

“Although patients in both groups showed symptom reduction in the first three months, only those who received collaborative care demonstrated sustained improvements through six months of follow-up,” Dr. McCarty and her colleagues wrote.

The results were limited by several factors, including the small size of the study, the researchers said. However, the findings “prompt more investigation into the role of affective symptoms in perpetuating physical symptoms secondary to prolonged recovery from sports-related concussion” and also suggest that collaborative care can help improve persistent postconcussive symptoms in teens.The Seattle Sports Concussion Research Collaborative supported the study.

—Heidi Splete

Suggested Reading

McCarty CA, Zatzick D, Stein E, et al. Collaborative care for adolescents with persistent postconcussive symptoms: a randomized trial. Pediatrics. 2016 Sept 13 [Epub ahead of print].

Cordingley D, Girardin R, Reimer K, et al. Graded aerobic treadmill testing in pediatric sports-related concussion: safety, clinical use, and patient outcomes. J Neurosurg Pediatr. 2016 September 13 [Epub ahead of print].

 VANCOUVER—“Concussion is a public health epidemic,” said Amaal Starling, MD. “Neurologists are seeing more and more concussed patients every day.” At the 68th Annual Meeting of the American Academy of Neurology, Dr. Starling, who is an Assistant Professor of Neurology at the Mayo Clinic in Phoenix, provided a framework and a template for evaluating concussion in the outpatient setting.

“Prioritizing these patients into clinic is very important,” Dr. Starling said. She recommended expedited appointments for patients with a suspected concussion. “This will limit symptom exacerbation, provide an avenue for appropriate and quick symptomatic treatment, and prevent premature return to learn and return to play,” which may exacerbate symptoms and prolong recovery.

Outpatient Evaluation of Concussion

The patient history should always include the date of the injury and the injury description, which includes the mechanism of the injury, location of the impact, presence or absence of any whiplash injury, altered mental status or amnesia, as well as symptom progression. “How do the symptoms progress from the time of impact to the time the patient presents in the office?” Dr. Starling asked. “This will help you identify not only those immediate symptoms that occur, but also those delayed symptoms that can occur one to two days later. In addition, it will give you a time course of symptoms to determine if the patient has been worsening, improving, or has stayed about the same.”

Concussion has various symptoms that can be categorized in the following four domains: physical, cognitive, emotional, and sleep. The most frequently reported symptom is headache, followed by dizziness. To capture all of those symptom domains, Dr. Starling recommended using a postconcussion graded symptom checklist. “This can be effective at monitoring symptoms over time.”

It is also important to elicit risk factors for prolonged recovery. “If an individual has a personal history of migraine, they are at risk of having a prolonged recovery after the injury,” Dr. Starling said. “Even if they have no personal history of migraine, but if they have a family history of migraine, those individuals, per studies, have demonstrated a prolonged recovery after a concussion.” Other risk factors for a prolonged recovery include a history of learning disabilities, such as attention deficit disorder or dyslexia, and psychiatric disease, such as premorbid anxiety or depression.

A concussion history is also important because a prior concussion increases the risk of another concussion, as well as the risk of having a prolonged recovery. “Not only do you want to know how many concussions have occurred, but also the symptom duration and recovery course for those concussions.”

Since headache is the most common symptom after a concussion, it is important to evaluate headache when present. “In every headache history, it is important to look for red flags,” said Dr. Starling. She suggested using the mnemonic IFLOP to look for headache red flags in the setting of a concussion. IFLOP stands for Intractable vomiting, Focal neurologic symptoms and signs, changes in Level of awareness, Orthostatic headache, and Progressively worsening headache. When present, headache red flags should signal the need for neuroimaging. “For example, if someone is presenting with an orthostatic headache … I am concerned that they might have a CSF leak and I’ll want to get an MRI of the brain with and without contrast to look for diffuse pachymeningeal enhancement that we can see in that setting,” Dr. Starling said.

Management of a Concussed Patient

According to Dr. Starling, posttraumatic headaches should be treated according to their phenotypes. “If [the headache] has a migraine phenotype, treat it with migraine-specific medications. If it has a more cervicogenic phenotype, treat it that way.” The most common posttraumatic headache phenotype is migraine. That finding has been confirmed in the civilian as well as the military population. “But it is important to screen for other phenotypes that may also occur,” Dr. Starling advised.

Because patients with concussion seem to be at higher risk for medication overuse and medication overuse headache, a pre- and postinjury medication history is also important. “If they are using over-the-counter medications, you’ll want to know what they are using and how much.”

During the initial visit, it is also important to determine whether the patient has had any baseline testing. “If they had any computerized neurocognitive testing, obtain those results, Dr. Starling advised. “If they had a King-Devick test at baseline or pre season, obtain those results. If they have undergone gold-standard neuropsychometric testing or had a baseline neurologic examination or imaging, get those results so that you can compare postinjury [performance] to preinjury [performance].”

Regarding the physical examination in the outpatient setting, vitals are vital, Dr. Starling said. Many concussed athletes have autonomic dysfunction that looks like postural orthostatic tachycardia syndrome (POTS), although the prognosis is typically different. “When getting vitals, it is important to get orthostatic vitals—supine and then standing at one, five, and 10 minutes—to monitor for abnormal changes or an increase in the heart rate with standing.” The physical exam should also look for trigger points or any difficulties with range of motion of the neck. “These [findings] can give you avenues for therapeutic intervention,” Dr. Starling said. Additionally, the Dix–Hallpike maneuver can identify cases of benign paroxysmal positional vertigo, which can be treated with the Epley maneuver.

Mental status should be evaluated as part of a detailed neurologic examination. The Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Kokmen are well-validated tools for the evaluation of mental status. The Standardized Assessment of Concussion (SAC) is another tool that was developed to assess mental status. The SAC was validated on the sideline and is used by a wide array of health care providers from athletic trainers to the team physicians.

During the cranial nerve examination, Dr. Starling tests for anosmia. “That is concerning for gross structural changes on the inferior surface of the frontal lobe where the olfactory nerve lies.” Abnormalities suggest a need for neuroimaging. A typical pupillary assessment with a swinging pen light test also is an essential part of the evaluation, but Dr. Starling commented that in her patients with mild traumatic brain injury or concussion, she has rarely found any clinically significant abnormalities with that test. “But that’s not true for the evaluation of extraocular movement,” she said. “I look for not only nystagmus, abnormalities of smooth pursuit, and horizontal and vertical saccades, but I also look for near point convergence. Near point convergence of greater than 6 cm is abnormal in the majority of individuals that we will evaluate for concussion.” When it is abnormal, it correlates with oculomotor abnormalities in function. So, these people have more difficulty with oculomotor function in day-to-day life—difficulties with reading and motion sensitivity.

The rest of the cranial nerve examination can also help identify subtle focal deficits. Upper motor neuron exam techniques also can detect subtle changes, and abnormalities can suggest a need for neuroimaging. Dr. Starling also recommended a good screening evaluation of balance, such as the timed tandem gait measure.

The Concussion Toolbox

No biomarkers or tests will yield a 100% accurate diagnosis of concussion. “However, studies have repeatedly demonstrated that if we use the tools that are available, and if we use a combination of them, we are nearing 100% sensitivity and specificity,” Dr. Starling said. In her return-to-play clinic, all patients undergo the King–Devick test, neuropsychologic testing, and objective vestibular testing. If patients report autonomic or orthostatic symptoms, they also undergo autonomic testing. “Unless I’m concerned about a skull fracture, I don’t get a CT scan of the head,” Dr. Starling said. “But we do obtain an MRI of the brain in individuals who have focal neurologic deficits, risk factors for prolonged recovery, or who have had prior concussions.” Dr. Starling recommended susceptibility-weighted imaging and diffusion tensor imaging.

Management priorities for patients with concussion include providing symptomatic treatment and preventing reinjury while the brain is healing. “Multidisciplinary symptoms require multidisciplinary treatment,” Dr. Starling said. “In my assessment, I’ll have a list of symptoms and a list of targeted approaches for each individual symptom.”

Posttraumatic Headache

“It is amazing how often I still see individuals two, four, eight weeks post injury who have never received a medication for posttraumatic headache because they’ve been told that the headache is a result of the concussion and as the concussion gets better, the headache will go away,” Dr. Starling said. Treating posttraumatic headache can relieve suffering and help the patient participate in active rehabilitation. Appropriate treatment can also prevent overuse of over-the-counter combination analgesics, which can complicate the problem. Experts in the headache community also suggest that there is a risk of chronification in untreated posttraumatic headache.

While there is a dearth of randomized, prospective, double-blind trials to guide the treatment of posttraumatic headache, “there still is an approach that you can use,” Dr. Starling said. Look for headache red flags first, then identify the phenotype and establish the headache history. If the patient had frequent migraines pre injury, it may be an indication for early initiation of a preventive medication. Initiating acute treatment early—within days—is also a priority, as is strictly monitoring for medication overuse. Also consider the comorbidities. “You don’t want to make comorbid symptoms worse,” Dr. Starling said. “For example, avoid topiramate in a patient who is having cognitive domain symptoms. Avoid sedating medications in someone who is having a lot of fatigue. Avoid steroids in a patient who is having a lot of emotional lability or difficulty with insomnia. Keep comorbid symptoms in mind when picking medications for posttraumatic headache.”

Return-to-Learn and Return-to-Play Decisions

Dr. Starling recommended symptom-limited cognitive and physical activity in the recovery phase, as opposed to total physical and cognitive rest. “There’s actually been a recent study that was done looking at strict rest,” she said. “The control group had one to two days of rest, followed by return to school and gradual return to activity. The intervention group had five days of strict rest.… The group with strict rest had higher symptom severity scores and had a longer symptom recovery. Exaggerated or extreme rest may not be the answer. Rather, we need to gradually reengage individuals back into life and give them a specific plan for graduated return to life, which includes both cognitive, as well as physical, activity.”

Return-to-learn protocols must be individualized, but there are some common goals. Dr. Starling recommended a short period of brain rest. “Not complete sensory deprivation, but rather symptom-limited brain rest. That should be followed by a brain warm-up phase where we initiate some time-limited and symptom-limited reading time—five to 10 minutes, as tolerated—and gradually increase that over time. After that, we reengage that individual back into school with extensive accommodations, which include the number of hours they are in school, as well as the curriculum, so a higher value on quality rather than quantity, and then a lot of environmental adjustments—perhaps a room that is quieter, a room where the lights are a little dimmer, they are allowed to wear a hat in class or sunglasses in class.” To avoid the sensory stimulation that characterizes school hallways between classes, which can make patients feel worse, Dr. Starling recommended that patients leave class five minutes early, spend the passing period in the nurse’s office, and then go to the next class five minutes late.

The next goal in recovery is full-day school with academic accommodations, and finally a return to learn without any accommodations. This requires an education specialist or a neuropsychologist who can get an individualized history from the patient as to what his or her day entails. A detailed recovery plan is then put into writing and provided to the patient and the school. The plan is then revised every one to two weeks as the patient recovers.

Dr. Starling suggested that physical activity could be initiated even when individuals are still having symptoms, but in a symptom-limited manner. “There have been studies looking at controlled exercise as a therapeutic approach for concussion,” she said. In an initial, nonrandomized pilot study, an exertion protocol seemed to improve symptoms, promote a faster rate of recovery, and normalize cerebral blood flow abnormalities during a cognitive task. “Although more rigorous studies are definitely needed, I think we are in the right paradigm,” Dr. Starling said. “After initial rest, but not complete sensory deprivation, active rehabilitation can be initiated, even in the presence of symptoms, as long as we have subthreshold activity.” This strategy, she said, is recommended to reduce symptom severity, speed recovery, and ensure full recovery.

“With active rehabilitation, we have to be prescriptive about what individual patients do. We want to make sure they are not exacerbating their symptoms.” At the Mayo Clinic, Dr. Starling and her team use written, as well as verbal, instructions. “We set in writing a goal heart rate that we want that individual patient to reach. In the clinical setting, we use a recumbent bike to determine a goal heart rate that is subthreshold to their symptoms. We then ask the patient to engage in activity up to that heart rate every day for the next couple of days. As they tolerate this, they can increase it [by] five to 10 beats per minute every three to seven days, and then we reevaluate this every one to two weeks to determine what the next step is.”

Once the exertion protocol is completed, a more sports-specific return-to-play protocol can be initiated. “During a concussion, the player can become deconditioned from their specific sport, so a sport-specific return to play protocol is important in that setting,” Dr. Starling said.

Recommending retirement from high-risk athletic activity is, of course, an individualized decision in which various components of the history come into play. According to Dr. Starling, the red flags for retirement include reduced threshold for concussion, neuroimaging abnormalities, persistent cognitive impairment, and debilitating refractory headaches.

 VANCOUVER—“Concussion is a public health epidemic,” said Amaal Starling, MD. “Neurologists are seeing more and more concussed patients every day.” At the 68th Annual Meeting of the American Academy of Neurology, Dr. Starling, who is an Assistant Professor of Neurology at the Mayo Clinic in Phoenix, provided a framework and a template for evaluating concussion in the outpatient setting.

“Prioritizing these patients into clinic is very important,” Dr. Starling said. She recommended expedited appointments for patients with a suspected concussion. “This will limit symptom exacerbation, provide an avenue for appropriate and quick symptomatic treatment, and prevent premature return to learn and return to play,” which may exacerbate symptoms and prolong recovery.

Outpatient Evaluation of Concussion

The patient history should always include the date of the injury and the injury description, which includes the mechanism of the injury, location of the impact, presence or absence of any whiplash injury, altered mental status or amnesia, as well as symptom progression. “How do the symptoms progress from the time of impact to the time the patient presents in the office?” Dr. Starling asked. “This will help you identify not only those immediate symptoms that occur, but also those delayed symptoms that can occur one to two days later. In addition, it will give you a time course of symptoms to determine if the patient has been worsening, improving, or has stayed about the same.”

Concussion has various symptoms that can be categorized in the following four domains: physical, cognitive, emotional, and sleep. The most frequently reported symptom is headache, followed by dizziness. To capture all of those symptom domains, Dr. Starling recommended using a postconcussion graded symptom checklist. “This can be effective at monitoring symptoms over time.”

It is also important to elicit risk factors for prolonged recovery. “If an individual has a personal history of migraine, they are at risk of having a prolonged recovery after the injury,” Dr. Starling said. “Even if they have no personal history of migraine, but if they have a family history of migraine, those individuals, per studies, have demonstrated a prolonged recovery after a concussion.” Other risk factors for a prolonged recovery include a history of learning disabilities, such as attention deficit disorder or dyslexia, and psychiatric disease, such as premorbid anxiety or depression.

A concussion history is also important because a prior concussion increases the risk of another concussion, as well as the risk of having a prolonged recovery. “Not only do you want to know how many concussions have occurred, but also the symptom duration and recovery course for those concussions.”

Since headache is the most common symptom after a concussion, it is important to evaluate headache when present. “In every headache history, it is important to look for red flags,” said Dr. Starling. She suggested using the mnemonic IFLOP to look for headache red flags in the setting of a concussion. IFLOP stands for Intractable vomiting, Focal neurologic symptoms and signs, changes in Level of awareness, Orthostatic headache, and Progressively worsening headache. When present, headache red flags should signal the need for neuroimaging. “For example, if someone is presenting with an orthostatic headache … I am concerned that they might have a CSF leak and I’ll want to get an MRI of the brain with and without contrast to look for diffuse pachymeningeal enhancement that we can see in that setting,” Dr. Starling said.

Management of a Concussed Patient

According to Dr. Starling, posttraumatic headaches should be treated according to their phenotypes. “If [the headache] has a migraine phenotype, treat it with migraine-specific medications. If it has a more cervicogenic phenotype, treat it that way.” The most common posttraumatic headache phenotype is migraine. That finding has been confirmed in the civilian as well as the military population. “But it is important to screen for other phenotypes that may also occur,” Dr. Starling advised.

Because patients with concussion seem to be at higher risk for medication overuse and medication overuse headache, a pre- and postinjury medication history is also important. “If they are using over-the-counter medications, you’ll want to know what they are using and how much.”

During the initial visit, it is also important to determine whether the patient has had any baseline testing. “If they had any computerized neurocognitive testing, obtain those results, Dr. Starling advised. “If they had a King-Devick test at baseline or pre season, obtain those results. If they have undergone gold-standard neuropsychometric testing or had a baseline neurologic examination or imaging, get those results so that you can compare postinjury [performance] to preinjury [performance].”

Regarding the physical examination in the outpatient setting, vitals are vital, Dr. Starling said. Many concussed athletes have autonomic dysfunction that looks like postural orthostatic tachycardia syndrome (POTS), although the prognosis is typically different. “When getting vitals, it is important to get orthostatic vitals—supine and then standing at one, five, and 10 minutes—to monitor for abnormal changes or an increase in the heart rate with standing.” The physical exam should also look for trigger points or any difficulties with range of motion of the neck. “These [findings] can give you avenues for therapeutic intervention,” Dr. Starling said. Additionally, the Dix–Hallpike maneuver can identify cases of benign paroxysmal positional vertigo, which can be treated with the Epley maneuver.

Mental status should be evaluated as part of a detailed neurologic examination. The Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Kokmen are well-validated tools for the evaluation of mental status. The Standardized Assessment of Concussion (SAC) is another tool that was developed to assess mental status. The SAC was validated on the sideline and is used by a wide array of health care providers from athletic trainers to the team physicians.

During the cranial nerve examination, Dr. Starling tests for anosmia. “That is concerning for gross structural changes on the inferior surface of the frontal lobe where the olfactory nerve lies.” Abnormalities suggest a need for neuroimaging. A typical pupillary assessment with a swinging pen light test also is an essential part of the evaluation, but Dr. Starling commented that in her patients with mild traumatic brain injury or concussion, she has rarely found any clinically significant abnormalities with that test. “But that’s not true for the evaluation of extraocular movement,” she said. “I look for not only nystagmus, abnormalities of smooth pursuit, and horizontal and vertical saccades, but I also look for near point convergence. Near point convergence of greater than 6 cm is abnormal in the majority of individuals that we will evaluate for concussion.” When it is abnormal, it correlates with oculomotor abnormalities in function. So, these people have more difficulty with oculomotor function in day-to-day life—difficulties with reading and motion sensitivity.

The rest of the cranial nerve examination can also help identify subtle focal deficits. Upper motor neuron exam techniques also can detect subtle changes, and abnormalities can suggest a need for neuroimaging. Dr. Starling also recommended a good screening evaluation of balance, such as the timed tandem gait measure.

The Concussion Toolbox

No biomarkers or tests will yield a 100% accurate diagnosis of concussion. “However, studies have repeatedly demonstrated that if we use the tools that are available, and if we use a combination of them, we are nearing 100% sensitivity and specificity,” Dr. Starling said. In her return-to-play clinic, all patients undergo the King–Devick test, neuropsychologic testing, and objective vestibular testing. If patients report autonomic or orthostatic symptoms, they also undergo autonomic testing. “Unless I’m concerned about a skull fracture, I don’t get a CT scan of the head,” Dr. Starling said. “But we do obtain an MRI of the brain in individuals who have focal neurologic deficits, risk factors for prolonged recovery, or who have had prior concussions.” Dr. Starling recommended susceptibility-weighted imaging and diffusion tensor imaging.

Management priorities for patients with concussion include providing symptomatic treatment and preventing reinjury while the brain is healing. “Multidisciplinary symptoms require multidisciplinary treatment,” Dr. Starling said. “In my assessment, I’ll have a list of symptoms and a list of targeted approaches for each individual symptom.”

Posttraumatic Headache

“It is amazing how often I still see individuals two, four, eight weeks post injury who have never received a medication for posttraumatic headache because they’ve been told that the headache is a result of the concussion and as the concussion gets better, the headache will go away,” Dr. Starling said. Treating posttraumatic headache can relieve suffering and help the patient participate in active rehabilitation. Appropriate treatment can also prevent overuse of over-the-counter combination analgesics, which can complicate the problem. Experts in the headache community also suggest that there is a risk of chronification in untreated posttraumatic headache.

While there is a dearth of randomized, prospective, double-blind trials to guide the treatment of posttraumatic headache, “there still is an approach that you can use,” Dr. Starling said. Look for headache red flags first, then identify the phenotype and establish the headache history. If the patient had frequent migraines pre injury, it may be an indication for early initiation of a preventive medication. Initiating acute treatment early—within days—is also a priority, as is strictly monitoring for medication overuse. Also consider the comorbidities. “You don’t want to make comorbid symptoms worse,” Dr. Starling said. “For example, avoid topiramate in a patient who is having cognitive domain symptoms. Avoid sedating medications in someone who is having a lot of fatigue. Avoid steroids in a patient who is having a lot of emotional lability or difficulty with insomnia. Keep comorbid symptoms in mind when picking medications for posttraumatic headache.”

Return-to-Learn and Return-to-Play Decisions

Dr. Starling recommended symptom-limited cognitive and physical activity in the recovery phase, as opposed to total physical and cognitive rest. “There’s actually been a recent study that was done looking at strict rest,” she said. “The control group had one to two days of rest, followed by return to school and gradual return to activity. The intervention group had five days of strict rest.… The group with strict rest had higher symptom severity scores and had a longer symptom recovery. Exaggerated or extreme rest may not be the answer. Rather, we need to gradually reengage individuals back into life and give them a specific plan for graduated return to life, which includes both cognitive, as well as physical, activity.”

Return-to-learn protocols must be individualized, but there are some common goals. Dr. Starling recommended a short period of brain rest. “Not complete sensory deprivation, but rather symptom-limited brain rest. That should be followed by a brain warm-up phase where we initiate some time-limited and symptom-limited reading time—five to 10 minutes, as tolerated—and gradually increase that over time. After that, we reengage that individual back into school with extensive accommodations, which include the number of hours they are in school, as well as the curriculum, so a higher value on quality rather than quantity, and then a lot of environmental adjustments—perhaps a room that is quieter, a room where the lights are a little dimmer, they are allowed to wear a hat in class or sunglasses in class.” To avoid the sensory stimulation that characterizes school hallways between classes, which can make patients feel worse, Dr. Starling recommended that patients leave class five minutes early, spend the passing period in the nurse’s office, and then go to the next class five minutes late.

The next goal in recovery is full-day school with academic accommodations, and finally a return to learn without any accommodations. This requires an education specialist or a neuropsychologist who can get an individualized history from the patient as to what his or her day entails. A detailed recovery plan is then put into writing and provided to the patient and the school. The plan is then revised every one to two weeks as the patient recovers.

Dr. Starling suggested that physical activity could be initiated even when individuals are still having symptoms, but in a symptom-limited manner. “There have been studies looking at controlled exercise as a therapeutic approach for concussion,” she said. In an initial, nonrandomized pilot study, an exertion protocol seemed to improve symptoms, promote a faster rate of recovery, and normalize cerebral blood flow abnormalities during a cognitive task. “Although more rigorous studies are definitely needed, I think we are in the right paradigm,” Dr. Starling said. “After initial rest, but not complete sensory deprivation, active rehabilitation can be initiated, even in the presence of symptoms, as long as we have subthreshold activity.” This strategy, she said, is recommended to reduce symptom severity, speed recovery, and ensure full recovery.

“With active rehabilitation, we have to be prescriptive about what individual patients do. We want to make sure they are not exacerbating their symptoms.” At the Mayo Clinic, Dr. Starling and her team use written, as well as verbal, instructions. “We set in writing a goal heart rate that we want that individual patient to reach. In the clinical setting, we use a recumbent bike to determine a goal heart rate that is subthreshold to their symptoms. We then ask the patient to engage in activity up to that heart rate every day for the next couple of days. As they tolerate this, they can increase it [by] five to 10 beats per minute every three to seven days, and then we reevaluate this every one to two weeks to determine what the next step is.”

Once the exertion protocol is completed, a more sports-specific return-to-play protocol can be initiated. “During a concussion, the player can become deconditioned from their specific sport, so a sport-specific return to play protocol is important in that setting,” Dr. Starling said.

Recommending retirement from high-risk athletic activity is, of course, an individualized decision in which various components of the history come into play. According to Dr. Starling, the red flags for retirement include reduced threshold for concussion, neuroimaging abnormalities, persistent cognitive impairment, and debilitating refractory headaches.

 VANCOUVER—“Concussion is a public health epidemic,” said Amaal Starling, MD. “Neurologists are seeing more and more concussed patients every day.” At the 68th Annual Meeting of the American Academy of Neurology, Dr. Starling, who is an Assistant Professor of Neurology at the Mayo Clinic in Phoenix, provided a framework and a template for evaluating concussion in the outpatient setting.

“Prioritizing these patients into clinic is very important,” Dr. Starling said. She recommended expedited appointments for patients with a suspected concussion. “This will limit symptom exacerbation, provide an avenue for appropriate and quick symptomatic treatment, and prevent premature return to learn and return to play,” which may exacerbate symptoms and prolong recovery.

Outpatient Evaluation of Concussion

The patient history should always include the date of the injury and the injury description, which includes the mechanism of the injury, location of the impact, presence or absence of any whiplash injury, altered mental status or amnesia, as well as symptom progression. “How do the symptoms progress from the time of impact to the time the patient presents in the office?” Dr. Starling asked. “This will help you identify not only those immediate symptoms that occur, but also those delayed symptoms that can occur one to two days later. In addition, it will give you a time course of symptoms to determine if the patient has been worsening, improving, or has stayed about the same.”

Concussion has various symptoms that can be categorized in the following four domains: physical, cognitive, emotional, and sleep. The most frequently reported symptom is headache, followed by dizziness. To capture all of those symptom domains, Dr. Starling recommended using a postconcussion graded symptom checklist. “This can be effective at monitoring symptoms over time.”

It is also important to elicit risk factors for prolonged recovery. “If an individual has a personal history of migraine, they are at risk of having a prolonged recovery after the injury,” Dr. Starling said. “Even if they have no personal history of migraine, but if they have a family history of migraine, those individuals, per studies, have demonstrated a prolonged recovery after a concussion.” Other risk factors for a prolonged recovery include a history of learning disabilities, such as attention deficit disorder or dyslexia, and psychiatric disease, such as premorbid anxiety or depression.

A concussion history is also important because a prior concussion increases the risk of another concussion, as well as the risk of having a prolonged recovery. “Not only do you want to know how many concussions have occurred, but also the symptom duration and recovery course for those concussions.”

Since headache is the most common symptom after a concussion, it is important to evaluate headache when present. “In every headache history, it is important to look for red flags,” said Dr. Starling. She suggested using the mnemonic IFLOP to look for headache red flags in the setting of a concussion. IFLOP stands for Intractable vomiting, Focal neurologic symptoms and signs, changes in Level of awareness, Orthostatic headache, and Progressively worsening headache. When present, headache red flags should signal the need for neuroimaging. “For example, if someone is presenting with an orthostatic headache … I am concerned that they might have a CSF leak and I’ll want to get an MRI of the brain with and without contrast to look for diffuse pachymeningeal enhancement that we can see in that setting,” Dr. Starling said.

Management of a Concussed Patient

According to Dr. Starling, posttraumatic headaches should be treated according to their phenotypes. “If [the headache] has a migraine phenotype, treat it with migraine-specific medications. If it has a more cervicogenic phenotype, treat it that way.” The most common posttraumatic headache phenotype is migraine. That finding has been confirmed in the civilian as well as the military population. “But it is important to screen for other phenotypes that may also occur,” Dr. Starling advised.

Because patients with concussion seem to be at higher risk for medication overuse and medication overuse headache, a pre- and postinjury medication history is also important. “If they are using over-the-counter medications, you’ll want to know what they are using and how much.”

During the initial visit, it is also important to determine whether the patient has had any baseline testing. “If they had any computerized neurocognitive testing, obtain those results, Dr. Starling advised. “If they had a King-Devick test at baseline or pre season, obtain those results. If they have undergone gold-standard neuropsychometric testing or had a baseline neurologic examination or imaging, get those results so that you can compare postinjury [performance] to preinjury [performance].”

Regarding the physical examination in the outpatient setting, vitals are vital, Dr. Starling said. Many concussed athletes have autonomic dysfunction that looks like postural orthostatic tachycardia syndrome (POTS), although the prognosis is typically different. “When getting vitals, it is important to get orthostatic vitals—supine and then standing at one, five, and 10 minutes—to monitor for abnormal changes or an increase in the heart rate with standing.” The physical exam should also look for trigger points or any difficulties with range of motion of the neck. “These [findings] can give you avenues for therapeutic intervention,” Dr. Starling said. Additionally, the Dix–Hallpike maneuver can identify cases of benign paroxysmal positional vertigo, which can be treated with the Epley maneuver.

Mental status should be evaluated as part of a detailed neurologic examination. The Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Kokmen are well-validated tools for the evaluation of mental status. The Standardized Assessment of Concussion (SAC) is another tool that was developed to assess mental status. The SAC was validated on the sideline and is used by a wide array of health care providers from athletic trainers to the team physicians.

During the cranial nerve examination, Dr. Starling tests for anosmia. “That is concerning for gross structural changes on the inferior surface of the frontal lobe where the olfactory nerve lies.” Abnormalities suggest a need for neuroimaging. A typical pupillary assessment with a swinging pen light test also is an essential part of the evaluation, but Dr. Starling commented that in her patients with mild traumatic brain injury or concussion, she has rarely found any clinically significant abnormalities with that test. “But that’s not true for the evaluation of extraocular movement,” she said. “I look for not only nystagmus, abnormalities of smooth pursuit, and horizontal and vertical saccades, but I also look for near point convergence. Near point convergence of greater than 6 cm is abnormal in the majority of individuals that we will evaluate for concussion.” When it is abnormal, it correlates with oculomotor abnormalities in function. So, these people have more difficulty with oculomotor function in day-to-day life—difficulties with reading and motion sensitivity.

The rest of the cranial nerve examination can also help identify subtle focal deficits. Upper motor neuron exam techniques also can detect subtle changes, and abnormalities can suggest a need for neuroimaging. Dr. Starling also recommended a good screening evaluation of balance, such as the timed tandem gait measure.

The Concussion Toolbox

No biomarkers or tests will yield a 100% accurate diagnosis of concussion. “However, studies have repeatedly demonstrated that if we use the tools that are available, and if we use a combination of them, we are nearing 100% sensitivity and specificity,” Dr. Starling said. In her return-to-play clinic, all patients undergo the King–Devick test, neuropsychologic testing, and objective vestibular testing. If patients report autonomic or orthostatic symptoms, they also undergo autonomic testing. “Unless I’m concerned about a skull fracture, I don’t get a CT scan of the head,” Dr. Starling said. “But we do obtain an MRI of the brain in individuals who have focal neurologic deficits, risk factors for prolonged recovery, or who have had prior concussions.” Dr. Starling recommended susceptibility-weighted imaging and diffusion tensor imaging.

Management priorities for patients with concussion include providing symptomatic treatment and preventing reinjury while the brain is healing. “Multidisciplinary symptoms require multidisciplinary treatment,” Dr. Starling said. “In my assessment, I’ll have a list of symptoms and a list of targeted approaches for each individual symptom.”

Posttraumatic Headache

“It is amazing how often I still see individuals two, four, eight weeks post injury who have never received a medication for posttraumatic headache because they’ve been told that the headache is a result of the concussion and as the concussion gets better, the headache will go away,” Dr. Starling said. Treating posttraumatic headache can relieve suffering and help the patient participate in active rehabilitation. Appropriate treatment can also prevent overuse of over-the-counter combination analgesics, which can complicate the problem. Experts in the headache community also suggest that there is a risk of chronification in untreated posttraumatic headache.

While there is a dearth of randomized, prospective, double-blind trials to guide the treatment of posttraumatic headache, “there still is an approach that you can use,” Dr. Starling said. Look for headache red flags first, then identify the phenotype and establish the headache history. If the patient had frequent migraines pre injury, it may be an indication for early initiation of a preventive medication. Initiating acute treatment early—within days—is also a priority, as is strictly monitoring for medication overuse. Also consider the comorbidities. “You don’t want to make comorbid symptoms worse,” Dr. Starling said. “For example, avoid topiramate in a patient who is having cognitive domain symptoms. Avoid sedating medications in someone who is having a lot of fatigue. Avoid steroids in a patient who is having a lot of emotional lability or difficulty with insomnia. Keep comorbid symptoms in mind when picking medications for posttraumatic headache.”

Return-to-Learn and Return-to-Play Decisions

Dr. Starling recommended symptom-limited cognitive and physical activity in the recovery phase, as opposed to total physical and cognitive rest. “There’s actually been a recent study that was done looking at strict rest,” she said. “The control group had one to two days of rest, followed by return to school and gradual return to activity. The intervention group had five days of strict rest.… The group with strict rest had higher symptom severity scores and had a longer symptom recovery. Exaggerated or extreme rest may not be the answer. Rather, we need to gradually reengage individuals back into life and give them a specific plan for graduated return to life, which includes both cognitive, as well as physical, activity.”

Return-to-learn protocols must be individualized, but there are some common goals. Dr. Starling recommended a short period of brain rest. “Not complete sensory deprivation, but rather symptom-limited brain rest. That should be followed by a brain warm-up phase where we initiate some time-limited and symptom-limited reading time—five to 10 minutes, as tolerated—and gradually increase that over time. After that, we reengage that individual back into school with extensive accommodations, which include the number of hours they are in school, as well as the curriculum, so a higher value on quality rather than quantity, and then a lot of environmental adjustments—perhaps a room that is quieter, a room where the lights are a little dimmer, they are allowed to wear a hat in class or sunglasses in class.” To avoid the sensory stimulation that characterizes school hallways between classes, which can make patients feel worse, Dr. Starling recommended that patients leave class five minutes early, spend the passing period in the nurse’s office, and then go to the next class five minutes late.

The next goal in recovery is full-day school with academic accommodations, and finally a return to learn without any accommodations. This requires an education specialist or a neuropsychologist who can get an individualized history from the patient as to what his or her day entails. A detailed recovery plan is then put into writing and provided to the patient and the school. The plan is then revised every one to two weeks as the patient recovers.

Dr. Starling suggested that physical activity could be initiated even when individuals are still having symptoms, but in a symptom-limited manner. “There have been studies looking at controlled exercise as a therapeutic approach for concussion,” she said. In an initial, nonrandomized pilot study, an exertion protocol seemed to improve symptoms, promote a faster rate of recovery, and normalize cerebral blood flow abnormalities during a cognitive task. “Although more rigorous studies are definitely needed, I think we are in the right paradigm,” Dr. Starling said. “After initial rest, but not complete sensory deprivation, active rehabilitation can be initiated, even in the presence of symptoms, as long as we have subthreshold activity.” This strategy, she said, is recommended to reduce symptom severity, speed recovery, and ensure full recovery.

“With active rehabilitation, we have to be prescriptive about what individual patients do. We want to make sure they are not exacerbating their symptoms.” At the Mayo Clinic, Dr. Starling and her team use written, as well as verbal, instructions. “We set in writing a goal heart rate that we want that individual patient to reach. In the clinical setting, we use a recumbent bike to determine a goal heart rate that is subthreshold to their symptoms. We then ask the patient to engage in activity up to that heart rate every day for the next couple of days. As they tolerate this, they can increase it [by] five to 10 beats per minute every three to seven days, and then we reevaluate this every one to two weeks to determine what the next step is.”

Once the exertion protocol is completed, a more sports-specific return-to-play protocol can be initiated. “During a concussion, the player can become deconditioned from their specific sport, so a sport-specific return to play protocol is important in that setting,” Dr. Starling said.

Recommending retirement from high-risk athletic activity is, of course, an individualized decision in which various components of the history come into play. According to Dr. Starling, the red flags for retirement include reduced threshold for concussion, neuroimaging abnormalities, persistent cognitive impairment, and debilitating refractory headaches.

SAN DIEGO—New or worse headaches may persist five years after traumatic brain injury (TBI), according to results of a prospective study presented at the 58th Annual Scientific Meeting of the American Headache Society. “Results suggest that ongoing assessment and treatment of headache after TBI is needed as headache remains a potential problem even five years post injury,” the researchers said.

Headache is one of the most common symptoms in patients with TBI, but the characteristics of headache after brain injury are not well defined, and prior estimates of the prevalence of headache after TBI have been based on retrospective studies.

To assess the natural history and features of headache after TBI, Sylvia Lucas, MD, PhD, Clinical Professor of Neurology and Neurological Surgery at the University of Washington in Seattle, and colleagues conducted a prospective study in civilian patients with TBI. Participants were enrolled during inpatient rehabilitation hospitalizations at seven centers. Researchers conducted follow-up phone interviews with participants at three, six, 12, and 60 months. One-year follow-up data were published in the Journal of Neurotrauma in 2011.

Sylvia Lucas, MD, PhD

The investigators obtained five-year follow-up data for 316 participants. Participants had an average age of 42. Seventy-two percent were male, 73% were white, and 74% had completed high school. Most injuries involved motor vehicle crashes, and patients mostly had moderate to severe TBI. Patients may have sustained other injuries in addition to TBI. Only 17% had pre-injury headaches.

High Prevalence

Compared with pre-injury, the prevalence of new or worse headache was high and remained so over time: 38% at baseline, 37% at three months, 33% at six months, 34% at one year, and 35% at five years. Average headache pain on a 0-to-10 scale remained high over time, ranging from 5.5 at baseline to 5.7 at five years. Headache Impact Test scores showed a substantial impact of headache on quality of life, with mean scores of 57.1 at three months and 56.5 at five years. The proportion of patients with headaches occurring several times per week or daily was 50% at three months and 36% at five years.

Patients may have had subsequent concussions or new-onset primary headache disorders during the study, but the researchers believe that most of the headaches are related to the initial injury.

Dr. Lucas and colleagues determined whether patients’ headache characteristics matched those of primary headache disorders described in the International Classification of Headache Disorders, second edition (ICHD-2). They found that migraine was the most common headache type (approximately 59%), followed by tension-type headache (approximately 14%). About a quarter of the headaches were not classifiable using ICHD-2 criteria.

Effective Interventions?

Neurologists should educate primary care physicians about the persistent nature of headache after TBI. “Be prepared never to cut those strings to your patients because they may be back really needing help to deal with their headaches,” Dr. Lucas said.

Future studies should assess the effectiveness of interventions. “The next step is treatment studies to look at whether the frequency, severity, and the impact of headache after TBI can be decreased with effective pharmacologic or nonpharmacologic methods,” Dr. Lucas concluded.

—Jake Remaly

SAN DIEGO—New or worse headaches may persist five years after traumatic brain injury (TBI), according to results of a prospective study presented at the 58th Annual Scientific Meeting of the American Headache Society. “Results suggest that ongoing assessment and treatment of headache after TBI is needed as headache remains a potential problem even five years post injury,” the researchers said.

Headache is one of the most common symptoms in patients with TBI, but the characteristics of headache after brain injury are not well defined, and prior estimates of the prevalence of headache after TBI have been based on retrospective studies.

To assess the natural history and features of headache after TBI, Sylvia Lucas, MD, PhD, Clinical Professor of Neurology and Neurological Surgery at the University of Washington in Seattle, and colleagues conducted a prospective study in civilian patients with TBI. Participants were enrolled during inpatient rehabilitation hospitalizations at seven centers. Researchers conducted follow-up phone interviews with participants at three, six, 12, and 60 months. One-year follow-up data were published in the Journal of Neurotrauma in 2011.

Sylvia Lucas, MD, PhD

The investigators obtained five-year follow-up data for 316 participants. Participants had an average age of 42. Seventy-two percent were male, 73% were white, and 74% had completed high school. Most injuries involved motor vehicle crashes, and patients mostly had moderate to severe TBI. Patients may have sustained other injuries in addition to TBI. Only 17% had pre-injury headaches.

High Prevalence

Compared with pre-injury, the prevalence of new or worse headache was high and remained so over time: 38% at baseline, 37% at three months, 33% at six months, 34% at one year, and 35% at five years. Average headache pain on a 0-to-10 scale remained high over time, ranging from 5.5 at baseline to 5.7 at five years. Headache Impact Test scores showed a substantial impact of headache on quality of life, with mean scores of 57.1 at three months and 56.5 at five years. The proportion of patients with headaches occurring several times per week or daily was 50% at three months and 36% at five years.

Patients may have had subsequent concussions or new-onset primary headache disorders during the study, but the researchers believe that most of the headaches are related to the initial injury.

Dr. Lucas and colleagues determined whether patients’ headache characteristics matched those of primary headache disorders described in the International Classification of Headache Disorders, second edition (ICHD-2). They found that migraine was the most common headache type (approximately 59%), followed by tension-type headache (approximately 14%). About a quarter of the headaches were not classifiable using ICHD-2 criteria.

Effective Interventions?

Neurologists should educate primary care physicians about the persistent nature of headache after TBI. “Be prepared never to cut those strings to your patients because they may be back really needing help to deal with their headaches,” Dr. Lucas said.

Future studies should assess the effectiveness of interventions. “The next step is treatment studies to look at whether the frequency, severity, and the impact of headache after TBI can be decreased with effective pharmacologic or nonpharmacologic methods,” Dr. Lucas concluded.

—Jake Remaly

SAN DIEGO—New or worse headaches may persist five years after traumatic brain injury (TBI), according to results of a prospective study presented at the 58th Annual Scientific Meeting of the American Headache Society. “Results suggest that ongoing assessment and treatment of headache after TBI is needed as headache remains a potential problem even five years post injury,” the researchers said.

Headache is one of the most common symptoms in patients with TBI, but the characteristics of headache after brain injury are not well defined, and prior estimates of the prevalence of headache after TBI have been based on retrospective studies.

To assess the natural history and features of headache after TBI, Sylvia Lucas, MD, PhD, Clinical Professor of Neurology and Neurological Surgery at the University of Washington in Seattle, and colleagues conducted a prospective study in civilian patients with TBI. Participants were enrolled during inpatient rehabilitation hospitalizations at seven centers. Researchers conducted follow-up phone interviews with participants at three, six, 12, and 60 months. One-year follow-up data were published in the Journal of Neurotrauma in 2011.

Sylvia Lucas, MD, PhD

The investigators obtained five-year follow-up data for 316 participants. Participants had an average age of 42. Seventy-two percent were male, 73% were white, and 74% had completed high school. Most injuries involved motor vehicle crashes, and patients mostly had moderate to severe TBI. Patients may have sustained other injuries in addition to TBI. Only 17% had pre-injury headaches.

High Prevalence

Compared with pre-injury, the prevalence of new or worse headache was high and remained so over time: 38% at baseline, 37% at three months, 33% at six months, 34% at one year, and 35% at five years. Average headache pain on a 0-to-10 scale remained high over time, ranging from 5.5 at baseline to 5.7 at five years. Headache Impact Test scores showed a substantial impact of headache on quality of life, with mean scores of 57.1 at three months and 56.5 at five years. The proportion of patients with headaches occurring several times per week or daily was 50% at three months and 36% at five years.

Patients may have had subsequent concussions or new-onset primary headache disorders during the study, but the researchers believe that most of the headaches are related to the initial injury.

Dr. Lucas and colleagues determined whether patients’ headache characteristics matched those of primary headache disorders described in the International Classification of Headache Disorders, second edition (ICHD-2). They found that migraine was the most common headache type (approximately 59%), followed by tension-type headache (approximately 14%). About a quarter of the headaches were not classifiable using ICHD-2 criteria.

Effective Interventions?

Neurologists should educate primary care physicians about the persistent nature of headache after TBI. “Be prepared never to cut those strings to your patients because they may be back really needing help to deal with their headaches,” Dr. Lucas said.

Future studies should assess the effectiveness of interventions. “The next step is treatment studies to look at whether the frequency, severity, and the impact of headache after TBI can be decreased with effective pharmacologic or nonpharmacologic methods,” Dr. Lucas concluded.

—Jake Remaly

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

More than 24,000 veterans who received examinations but were not diagnosed with traumatic brain injuries (TBIs) will be eligible for new medical examinations, the VA has announced. Due to confusing guidance documents, the original examinations were not conducted by a psychiatrist, physiatrist, neurosurgeon, or neurologist as mandated by VA policy. The 24,000 veterans may be eligible for additional benefits and service-connected compensation based on the results of the new examinations.

“Traumatic Brain Injury is a signature injury in veterans returning from the conflicts in Iraq and Afghanistan, and VA is proud to be an organization that sets the bar high for supporting these, and all, veterans,” said Secretary of Veterans Affairs Robert McDonald in a statement. “Providing support for veterans suffering from a TBI is a priority and a privilege, and we must make certain they receive a just and fair rating for their disabilities.”

The current VA policy dates to 2007 and requires that a specialist complete a TBI examination when VA does not have a prior diagnosis. However, given the rapidly changing science around TBI since 2007, the VA has issued multiple additional guidance documents. These additional guidance documents, the VA notes, “created confusion regarding the policy.” 

“We let these veterans down,” Secretary McDonald said. “That is why we are taking every step necessary to grant equitable relief to those affected to ensure they receive the full benefits to which they are entitled.”

Veterans will not be required to submit new claims and the VA has pledged to contact the identified patients to offer them a new examination. According to the VA > 13,000 veterans are already receiving 10% or higher service-connected compensation benefits for TBI.

More than 24,000 veterans who received examinations but were not diagnosed with traumatic brain injuries (TBIs) will be eligible for new medical examinations, the VA has announced. Due to confusing guidance documents, the original examinations were not conducted by a psychiatrist, physiatrist, neurosurgeon, or neurologist as mandated by VA policy. The 24,000 veterans may be eligible for additional benefits and service-connected compensation based on the results of the new examinations.

“Traumatic Brain Injury is a signature injury in veterans returning from the conflicts in Iraq and Afghanistan, and VA is proud to be an organization that sets the bar high for supporting these, and all, veterans,” said Secretary of Veterans Affairs Robert McDonald in a statement. “Providing support for veterans suffering from a TBI is a priority and a privilege, and we must make certain they receive a just and fair rating for their disabilities.”

The current VA policy dates to 2007 and requires that a specialist complete a TBI examination when VA does not have a prior diagnosis. However, given the rapidly changing science around TBI since 2007, the VA has issued multiple additional guidance documents. These additional guidance documents, the VA notes, “created confusion regarding the policy.” 

“We let these veterans down,” Secretary McDonald said. “That is why we are taking every step necessary to grant equitable relief to those affected to ensure they receive the full benefits to which they are entitled.”

Veterans will not be required to submit new claims and the VA has pledged to contact the identified patients to offer them a new examination. According to the VA > 13,000 veterans are already receiving 10% or higher service-connected compensation benefits for TBI.

More than 24,000 veterans who received examinations but were not diagnosed with traumatic brain injuries (TBIs) will be eligible for new medical examinations, the VA has announced. Due to confusing guidance documents, the original examinations were not conducted by a psychiatrist, physiatrist, neurosurgeon, or neurologist as mandated by VA policy. The 24,000 veterans may be eligible for additional benefits and service-connected compensation based on the results of the new examinations.

“Traumatic Brain Injury is a signature injury in veterans returning from the conflicts in Iraq and Afghanistan, and VA is proud to be an organization that sets the bar high for supporting these, and all, veterans,” said Secretary of Veterans Affairs Robert McDonald in a statement. “Providing support for veterans suffering from a TBI is a priority and a privilege, and we must make certain they receive a just and fair rating for their disabilities.”

The current VA policy dates to 2007 and requires that a specialist complete a TBI examination when VA does not have a prior diagnosis. However, given the rapidly changing science around TBI since 2007, the VA has issued multiple additional guidance documents. These additional guidance documents, the VA notes, “created confusion regarding the policy.” 

“We let these veterans down,” Secretary McDonald said. “That is why we are taking every step necessary to grant equitable relief to those affected to ensure they receive the full benefits to which they are entitled.”

Veterans will not be required to submit new claims and the VA has pledged to contact the identified patients to offer them a new examination. According to the VA > 13,000 veterans are already receiving 10% or higher service-connected compensation benefits for TBI.

Stem Cell Transplantation Is Safe in Hemorrhagic Stroke

Intraventricular transplantation using bone marrow mesenchymal stem cells is safe in patients with hemorrhagic stroke, according to research presented by Asra Al Fauzi, MD, a neurosurgeon at Soetomo General Hospital in Surabaya, Indonesia.

This study examined a group of eight patients with supratentorial hemorrhagic stroke. All patients had received six months of treatment and had stable neurologic deficits and NIH Stroke Scale (NIHSS) scores of five to 25. Clinical outcomes were measured using the NIHSS scale six months after transplantation. Bone marrow was aspirated and taken from the patient to whom it was to be administered under aseptic conditions. Expansion of mesenchymal stem cells took three to four weeks. All patients were administered a mean of 20 × 106 cells intraventricularly.

Results showed improvement of the NIHSS score in five patients after treatment; three patients had no change in status. No important adverse events associated with transplant or surgery were observed during a six-month follow up. The study demonstrates that bone marrow mesenchymal stem cell can be transplanted intraventricularly with excellent tolerance and without complications, said Dr. Al Fauzi. Stem cell transplantation aiming to restore function in stroke is safe and feasible. Further randomized controlled trials are needed to evaluate its efficacy.

How Does Surgery for Cerebral Arteriovenous Malformation Affect Pulsatility and Resistance?

Embolization reduces flow in cerebral arteriovenous malformations (AVMs) before surgical resection, but changes in pulsatility index (PI) and resistance index (RI) are unknown. Sophia F. Shakur, MD, a neurosurgery resident at the University of Chicago Medical Center, and colleagues measured PI and RI in AVM arterial feeders before and after embolization or surgery.

The researchers reviewed the records of patients who underwent AVM embolization and surgical resection at a single institution between 2007 and 2014.Patients who had PI, RI, and flows obtained using quantitative magnetic resonance angiography were retrospectively reviewed. Hemodynamic parameters were compared between the feeder and contralateral artery before and after embolization or surgery.

Thirty-two patients with 48 feeder arteries underwent embolization (mean 1.3 sessions). Another 32 patients with 49 feeder arteries had surgery with or without preoperative embolization. Before treatment, flow volume rate and mean, systolic and diastolic flow velocities were significantly higher in feeders versus contralateral counterparts. PI and RI were significantly lower in feeder vessels, compared with contralateral vessels. After embolization, mean, systolic, and diastolic flow velocities increased significantly, but PI and RI did not change significantly. However, after surgery, mean, systolic, and diastolic flow velocities within feeders decreased significantly, and PI and RI normalized to match the indices of their contralateral counterparts.

Following partial AVM embolization, PI and RI were unchanged, and flow velocities in feeder arteries increased significantly, likely due to redistribution of flow through residual nidus. Complete surgical resection resulted in normalization of PI and RI and a concomitant decrease in flow velocities.

Temporal Evolution of ICP and PRx May Have Prognostic Significance

Studies of large cohorts of patients with traumatic brain injury (TBI) have shown that intracranial pressure (ICP) and the pressure reactivity index (PRx) are independently associated with patient outcome. How these parameters evolve over the course of the stay in an intensive care unit, and the question of whether this evolution has any prognostic importance, has not been well studied, however.

Hadie Adams, MD, a postdoctoral fellow at Johns Hopkins School of Medicine in Baltimore, and colleagues monitored ICP and PRx in 573 patients with severe TBI in a regional neurocritical care unit. Data were calculated in 12-hour epochs for the first 168 hours (ie, seven days) after the time of incident. Data were stratified by the presence of diffuse TBI (dTBI) or space occupying lesions (SOL), as well as by fatal or nonfatal outcome at six months post injury. Mixed linear modeling was used to assess change of ICP and PRx over time to detect differences in mortality.

Mean ICP peaked at between 24 hours and 36 hours after injury, but only in patients who died. The difference in mean ICP between patients with fatal and nonfatal outcome was significant for the first 120 hours after ictus. For PRx, patients with a fatal outcome also had higher (ie, more impaired) PRx throughout the first 168 hours after ictus. The separation of ICP and PRx was greatest in the first 72 hours after ictus. Also, mean differences of ICP and PRx between the outcome groups were more pronounced in patients with dTBI than those with SOL.

In this cohort of 573 patients with TBI and high-resolution physiologic data, ICP and PRx displayed a distinctive temporal evolution. Importantly, early ICP and PRx allowed for the clearest prognostic delineation, said Dr. Adams.

The optimal thresholds, prognostic significance, and clinical correlations of ICP and PRx are likely to be time-dependent, he added.

How Common Is Position-Related Neuropraxia In Spine Surgery?

Gurpreet Surinder Gandhoke, MD, a neurosurgeon in Pittsburgh, and colleagues examined the incidence of position-related neuropraxia in 4,489 consecutive patients undergoing spine surgery at a university hospital. Some patients in the group had peripheral nerve injury from positioning. The authors observed intraoperative monitoring (IOM) changes related to arm and leg positioning and calculated their sensitivity and specificity in predicting the development of a new position-related peripheral nerve injury. Impact of length of surgery and other variables, including age, sex, BMI, diabetes, hypertension, coronary artery disease, cardiovascular disease, and a history of smoking on the development of a new peripheral nerve injury were defined.

Patients were in the following positions: arms abducted and flexed at the elbow (64.7%), arms tucked at the side (35%), and the lateral position (0.3%). Thirteen of 4,489 patients developed a new positioning-related peripheral nerve deficit, 54% developed meralgia paresthetica, and 46% developed ulnar neuropathy.

Seventy-two patients (1.6%) developed IOM changes from positioning, and all of these patients underwent a repositioning maneuver. One of these 72 patients (1.3%) developed a new position-related nerve deficit. Of the 98.4% of patients who did not develop position-related IOM changes, 0.3% developed a new position-related nerve deficit.

Sensitivity of IOM to detect a new position-related nerve deficit was 7.69%, and the specificity was 98.41%. Neither length of surgery nor any analyzed patient-related variable significantly affected the development of a new neuropraxia. The incidence of a new position-related nerve deficit in spine surgery was less than 0.3%. IOM had high specificity and low sensitivity in detecting a positioning-related deficit.

Stem Cell Transplantation Is Safe in Hemorrhagic Stroke

Intraventricular transplantation using bone marrow mesenchymal stem cells is safe in patients with hemorrhagic stroke, according to research presented by Asra Al Fauzi, MD, a neurosurgeon at Soetomo General Hospital in Surabaya, Indonesia.

This study examined a group of eight patients with supratentorial hemorrhagic stroke. All patients had received six months of treatment and had stable neurologic deficits and NIH Stroke Scale (NIHSS) scores of five to 25. Clinical outcomes were measured using the NIHSS scale six months after transplantation. Bone marrow was aspirated and taken from the patient to whom it was to be administered under aseptic conditions. Expansion of mesenchymal stem cells took three to four weeks. All patients were administered a mean of 20 × 106 cells intraventricularly.

Results showed improvement of the NIHSS score in five patients after treatment; three patients had no change in status. No important adverse events associated with transplant or surgery were observed during a six-month follow up. The study demonstrates that bone marrow mesenchymal stem cell can be transplanted intraventricularly with excellent tolerance and without complications, said Dr. Al Fauzi. Stem cell transplantation aiming to restore function in stroke is safe and feasible. Further randomized controlled trials are needed to evaluate its efficacy.

How Does Surgery for Cerebral Arteriovenous Malformation Affect Pulsatility and Resistance?

Embolization reduces flow in cerebral arteriovenous malformations (AVMs) before surgical resection, but changes in pulsatility index (PI) and resistance index (RI) are unknown. Sophia F. Shakur, MD, a neurosurgery resident at the University of Chicago Medical Center, and colleagues measured PI and RI in AVM arterial feeders before and after embolization or surgery.

The researchers reviewed the records of patients who underwent AVM embolization and surgical resection at a single institution between 2007 and 2014.Patients who had PI, RI, and flows obtained using quantitative magnetic resonance angiography were retrospectively reviewed. Hemodynamic parameters were compared between the feeder and contralateral artery before and after embolization or surgery.

Thirty-two patients with 48 feeder arteries underwent embolization (mean 1.3 sessions). Another 32 patients with 49 feeder arteries had surgery with or without preoperative embolization. Before treatment, flow volume rate and mean, systolic and diastolic flow velocities were significantly higher in feeders versus contralateral counterparts. PI and RI were significantly lower in feeder vessels, compared with contralateral vessels. After embolization, mean, systolic, and diastolic flow velocities increased significantly, but PI and RI did not change significantly. However, after surgery, mean, systolic, and diastolic flow velocities within feeders decreased significantly, and PI and RI normalized to match the indices of their contralateral counterparts.

Following partial AVM embolization, PI and RI were unchanged, and flow velocities in feeder arteries increased significantly, likely due to redistribution of flow through residual nidus. Complete surgical resection resulted in normalization of PI and RI and a concomitant decrease in flow velocities.

Temporal Evolution of ICP and PRx May Have Prognostic Significance

Studies of large cohorts of patients with traumatic brain injury (TBI) have shown that intracranial pressure (ICP) and the pressure reactivity index (PRx) are independently associated with patient outcome. How these parameters evolve over the course of the stay in an intensive care unit, and the question of whether this evolution has any prognostic importance, has not been well studied, however.

Hadie Adams, MD, a postdoctoral fellow at Johns Hopkins School of Medicine in Baltimore, and colleagues monitored ICP and PRx in 573 patients with severe TBI in a regional neurocritical care unit. Data were calculated in 12-hour epochs for the first 168 hours (ie, seven days) after the time of incident. Data were stratified by the presence of diffuse TBI (dTBI) or space occupying lesions (SOL), as well as by fatal or nonfatal outcome at six months post injury. Mixed linear modeling was used to assess change of ICP and PRx over time to detect differences in mortality.

Mean ICP peaked at between 24 hours and 36 hours after injury, but only in patients who died. The difference in mean ICP between patients with fatal and nonfatal outcome was significant for the first 120 hours after ictus. For PRx, patients with a fatal outcome also had higher (ie, more impaired) PRx throughout the first 168 hours after ictus. The separation of ICP and PRx was greatest in the first 72 hours after ictus. Also, mean differences of ICP and PRx between the outcome groups were more pronounced in patients with dTBI than those with SOL.

In this cohort of 573 patients with TBI and high-resolution physiologic data, ICP and PRx displayed a distinctive temporal evolution. Importantly, early ICP and PRx allowed for the clearest prognostic delineation, said Dr. Adams.

The optimal thresholds, prognostic significance, and clinical correlations of ICP and PRx are likely to be time-dependent, he added.

How Common Is Position-Related Neuropraxia In Spine Surgery?

Gurpreet Surinder Gandhoke, MD, a neurosurgeon in Pittsburgh, and colleagues examined the incidence of position-related neuropraxia in 4,489 consecutive patients undergoing spine surgery at a university hospital. Some patients in the group had peripheral nerve injury from positioning. The authors observed intraoperative monitoring (IOM) changes related to arm and leg positioning and calculated their sensitivity and specificity in predicting the development of a new position-related peripheral nerve injury. Impact of length of surgery and other variables, including age, sex, BMI, diabetes, hypertension, coronary artery disease, cardiovascular disease, and a history of smoking on the development of a new peripheral nerve injury were defined.

Patients were in the following positions: arms abducted and flexed at the elbow (64.7%), arms tucked at the side (35%), and the lateral position (0.3%). Thirteen of 4,489 patients developed a new positioning-related peripheral nerve deficit, 54% developed meralgia paresthetica, and 46% developed ulnar neuropathy.

Seventy-two patients (1.6%) developed IOM changes from positioning, and all of these patients underwent a repositioning maneuver. One of these 72 patients (1.3%) developed a new position-related nerve deficit. Of the 98.4% of patients who did not develop position-related IOM changes, 0.3% developed a new position-related nerve deficit.

Sensitivity of IOM to detect a new position-related nerve deficit was 7.69%, and the specificity was 98.41%. Neither length of surgery nor any analyzed patient-related variable significantly affected the development of a new neuropraxia. The incidence of a new position-related nerve deficit in spine surgery was less than 0.3%. IOM had high specificity and low sensitivity in detecting a positioning-related deficit.

Stem Cell Transplantation Is Safe in Hemorrhagic Stroke

Intraventricular transplantation using bone marrow mesenchymal stem cells is safe in patients with hemorrhagic stroke, according to research presented by Asra Al Fauzi, MD, a neurosurgeon at Soetomo General Hospital in Surabaya, Indonesia.

This study examined a group of eight patients with supratentorial hemorrhagic stroke. All patients had received six months of treatment and had stable neurologic deficits and NIH Stroke Scale (NIHSS) scores of five to 25. Clinical outcomes were measured using the NIHSS scale six months after transplantation. Bone marrow was aspirated and taken from the patient to whom it was to be administered under aseptic conditions. Expansion of mesenchymal stem cells took three to four weeks. All patients were administered a mean of 20 × 106 cells intraventricularly.

Results showed improvement of the NIHSS score in five patients after treatment; three patients had no change in status. No important adverse events associated with transplant or surgery were observed during a six-month follow up. The study demonstrates that bone marrow mesenchymal stem cell can be transplanted intraventricularly with excellent tolerance and without complications, said Dr. Al Fauzi. Stem cell transplantation aiming to restore function in stroke is safe and feasible. Further randomized controlled trials are needed to evaluate its efficacy.

How Does Surgery for Cerebral Arteriovenous Malformation Affect Pulsatility and Resistance?

Embolization reduces flow in cerebral arteriovenous malformations (AVMs) before surgical resection, but changes in pulsatility index (PI) and resistance index (RI) are unknown. Sophia F. Shakur, MD, a neurosurgery resident at the University of Chicago Medical Center, and colleagues measured PI and RI in AVM arterial feeders before and after embolization or surgery.

The researchers reviewed the records of patients who underwent AVM embolization and surgical resection at a single institution between 2007 and 2014.Patients who had PI, RI, and flows obtained using quantitative magnetic resonance angiography were retrospectively reviewed. Hemodynamic parameters were compared between the feeder and contralateral artery before and after embolization or surgery.

Thirty-two patients with 48 feeder arteries underwent embolization (mean 1.3 sessions). Another 32 patients with 49 feeder arteries had surgery with or without preoperative embolization. Before treatment, flow volume rate and mean, systolic and diastolic flow velocities were significantly higher in feeders versus contralateral counterparts. PI and RI were significantly lower in feeder vessels, compared with contralateral vessels. After embolization, mean, systolic, and diastolic flow velocities increased significantly, but PI and RI did not change significantly. However, after surgery, mean, systolic, and diastolic flow velocities within feeders decreased significantly, and PI and RI normalized to match the indices of their contralateral counterparts.

Following partial AVM embolization, PI and RI were unchanged, and flow velocities in feeder arteries increased significantly, likely due to redistribution of flow through residual nidus. Complete surgical resection resulted in normalization of PI and RI and a concomitant decrease in flow velocities.

Temporal Evolution of ICP and PRx May Have Prognostic Significance

Studies of large cohorts of patients with traumatic brain injury (TBI) have shown that intracranial pressure (ICP) and the pressure reactivity index (PRx) are independently associated with patient outcome. How these parameters evolve over the course of the stay in an intensive care unit, and the question of whether this evolution has any prognostic importance, has not been well studied, however.

Hadie Adams, MD, a postdoctoral fellow at Johns Hopkins School of Medicine in Baltimore, and colleagues monitored ICP and PRx in 573 patients with severe TBI in a regional neurocritical care unit. Data were calculated in 12-hour epochs for the first 168 hours (ie, seven days) after the time of incident. Data were stratified by the presence of diffuse TBI (dTBI) or space occupying lesions (SOL), as well as by fatal or nonfatal outcome at six months post injury. Mixed linear modeling was used to assess change of ICP and PRx over time to detect differences in mortality.

Mean ICP peaked at between 24 hours and 36 hours after injury, but only in patients who died. The difference in mean ICP between patients with fatal and nonfatal outcome was significant for the first 120 hours after ictus. For PRx, patients with a fatal outcome also had higher (ie, more impaired) PRx throughout the first 168 hours after ictus. The separation of ICP and PRx was greatest in the first 72 hours after ictus. Also, mean differences of ICP and PRx between the outcome groups were more pronounced in patients with dTBI than those with SOL.

In this cohort of 573 patients with TBI and high-resolution physiologic data, ICP and PRx displayed a distinctive temporal evolution. Importantly, early ICP and PRx allowed for the clearest prognostic delineation, said Dr. Adams.

The optimal thresholds, prognostic significance, and clinical correlations of ICP and PRx are likely to be time-dependent, he added.

How Common Is Position-Related Neuropraxia In Spine Surgery?

Gurpreet Surinder Gandhoke, MD, a neurosurgeon in Pittsburgh, and colleagues examined the incidence of position-related neuropraxia in 4,489 consecutive patients undergoing spine surgery at a university hospital. Some patients in the group had peripheral nerve injury from positioning. The authors observed intraoperative monitoring (IOM) changes related to arm and leg positioning and calculated their sensitivity and specificity in predicting the development of a new position-related peripheral nerve injury. Impact of length of surgery and other variables, including age, sex, BMI, diabetes, hypertension, coronary artery disease, cardiovascular disease, and a history of smoking on the development of a new peripheral nerve injury were defined.

Patients were in the following positions: arms abducted and flexed at the elbow (64.7%), arms tucked at the side (35%), and the lateral position (0.3%). Thirteen of 4,489 patients developed a new positioning-related peripheral nerve deficit, 54% developed meralgia paresthetica, and 46% developed ulnar neuropathy.

Seventy-two patients (1.6%) developed IOM changes from positioning, and all of these patients underwent a repositioning maneuver. One of these 72 patients (1.3%) developed a new position-related nerve deficit. Of the 98.4% of patients who did not develop position-related IOM changes, 0.3% developed a new position-related nerve deficit.

Sensitivity of IOM to detect a new position-related nerve deficit was 7.69%, and the specificity was 98.41%. Neither length of surgery nor any analyzed patient-related variable significantly affected the development of a new neuropraxia. The incidence of a new position-related nerve deficit in spine surgery was less than 0.3%. IOM had high specificity and low sensitivity in detecting a positioning-related deficit.

VANCOUVER—Prescribed rest is an important component of treating concussion, but it may not be the most appropriate intervention for all patients and may worsen symptoms in some cases, said Anthony P. Kontos, PhD, at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Anthony P. Kontos, PhD

“We need to move the discussion on concussion toward more active and targeted treatments,” said Dr. Kontos, Research Director of the University of Pittsburgh Medical Center (UPMC) Sports Medicine Concussion Program.Concussion is a heterogeneous injury with varying clinical profiles and recovery trajectories. Approaches to treatment should account for these differences and involve multidisciplinary teams when necessary, he said.

In October 2015, Dr. Kontos, Michael “Micky” Collins, PhD, and David O. Okonkwo, MD, PhD, directed a meeting with 37 participants from the fields of neurology, neuropsychology, neurosurgery, primary care, athletic training, and physical therapy to create a summary agreement that can assist clinicians with concussion treatment.

Nineteen guests, including representatives from professional sports organizations, the military, and public health, also attended the Targeted Evaluation and Active Management (TEAM) Approach to Treating Concussion meeting. The National Football League and UPMC sponsored the meeting, which was held in Pittsburgh.

Consensus documents have predominantly focused on things like the various definitions of concussion, how to assess concussion, and how to manage it, said Dr. Kontos. “We really wanted to focus on more of that end point of treatment and potentially more active treatment,” he said.

The TEAM participants developed and agreed upon 17 statements, which they plan to publish. At the AAN meeting, Dr. Kontos provided a brief review of some of the statements and discussed them in the context of recent research.

Rest’s Benefits and Limitations

Physical and cognitive rest, as part of an individualized treatment plan, are currently “the foundation of sport-related concussion management,” according to National Collegiate Athletic Association interassociation concussion guidelines. Rest after concussion conserves needed energy in the brain and reduces the likelihood of second impact syndrome and other catastrophic events, Dr. Kontos said. Furthermore, some studies have suggested that rest improves recovery. Brown et al reported in 2014 that athletes who self-reported more cognitive activity after a concussion took longer to recover than those who reported less cognitive activity.

However, the evidence to support rest is limited. In 2013, the Institute of Medicine and National Research Council published a report on sports-related concussion in youth that found little evidence regarding the efficacy of rest following concussion or to inform the best timing and approach for return to activity. Their statement “still resonates now,” Dr. Kontos said. “There’s very little empirical data to support what we do with rest. It’s largely an across-the-board policy that’s not data-driven, and we need to change that.” The TEAM group agreed “there is limited empirical evidence for the effectiveness of prescribed physical and cognitive rest, with no multisite trials for prescribed rest following concussion.”

Prescribed rest can have psychologic consequences, including emotional distress, depression, and anxiety. Rest allows individuals time to ruminate on their injury, which can exacerbate symptoms in self-report. Individuals who somaticize are particularly vulnerable to this effect. Jeremy M. Root, MD, of Children’s National Medical Center in Washington, DC, Dr. Kontos, and colleagues reported in April in the Journal of Pediatrics that patients who had high somatization scores were approximately five to seven times more likely to report an increase in symptoms at two weeks and four weeks, compared with those who were not in the highest quartile of somatization.

In addition, patients who are prescribed rest may think, “Wow, I must have a really bad injury such that I can’t do anything for a week.” This contextual framing effect may also influence the outcome, said Dr. Kontos.

Thomas et al in 2015 published the results of a randomized controlled trial that found that, after a concussion, patients ages 11 to 22 who were prescribed five days’ rest reported more daily postconcussive symptoms, compared with patients who were prescribed two days’ rest with progressive return to activity. Symptoms peaked at four days, and differences between groups remained at 10 days. “They have higher symptoms when they’re told to rest longer than if they’re told to rest less,” Dr. Kontos said. Clinically, there was no significant difference between groups in neurocognitive or balance outcomes, however.

The effect of treatment on the number of postconcussive symptoms may not be that straightforward, however. When Dr. Kontos, Dr. Thomas, and colleagues reanalyzed the data to look at patients who only reported symptoms (eg, headache, nausea, dizziness) but did not otherwise have early signs of concussion (eg, loss of consciousness, posttraumatic amnesia, disorientation, confusion), the symptoms-only group reported more symptoms at 10 days when prescribed five days’ rest, compared with two days’ rest with progressive return to activity. Patients who had early signs of concussion, however, reported fewer symptoms when prescribed five days’ rest versus two days’ rest with progressive return to activity.

“We have a sort of dichotomy here. We don’t want to say rest is bad. It may be very good for these people who have a high organic level or severity to their injury, and we may need to think in terms of resting them longer, whereas these patients [with symptoms only] certainly need to get more active, probably earlier in the process,” Dr. Kontos said.

Activity and social interaction may provide benefits. Miller et al in 2013 reported that environmental enrichment, including cognitive, physical, and social activity, is associated with improved outcome and sparing of hippocampal atrophy in the chronic stages of traumatic brain injury.

The TEAM group agreed, “Active treatment strategies may be initiated early in recovery following concussion.” The group also agreed, “strict brain rest (eg, ‘cocoon’ therapy) is not indicated and may have detrimental effects on patients following concussion.”

A Heterogeneous Injury

A focal point of the TEAM meeting was the concept of various clinical profiles of concussion. The group agreed, “Concussions are characterized by diverse symptoms and impairments in function resulting in different clinical profiles and recovery trajectories.”

“We need to think in terms of what type of concussion does this individual have and is it multiple types,” such as cognitive-fatigue, vestibular, or ocular, said Dr. Kontos. “We don’t typically just see one of these.” For example, a patient may have a predominant vestibular concussion with some posttraumatic migraine and neck involvement. “Oftentimes we see misdiagnoses when people show up. They’ve been diagnosed with cognitive issues when in reality they’re having vision or oculomotor difficulties.”

There are many potential approaches to categorizing, classifying, or profiling concussion, including those that consider posttraumatic mood and migraine as modifying factors, he said.

Multidisciplinary Teams

In addition, the TEAM group stated, “thorough multidomain assessment is warranted to properly evaluate the clinical profiles of concussion.” Various experts may be needed to assess cognitive, exertional, oculomotor, vestibular, and other symptoms and impairment.

As part of a multidisciplinary team, a neurologist, neuropsychologist, or primary care physician could “serve as kind of a point guard, to use a basketball analogy,” said Dr. Kontos. When an aspect of a patient’s assessment or treatment needs to be addressed more in depth, such as with regard to medication, vestibular therapy, or imaging, the patient may be referred to experts in those areas. “We try to work as a team and work back through the point guard to coordinate that care system,” he said. Telemedicine might allow for multidisciplinary treatment in remote geographic areas where establishing multidisciplinary teams otherwise might not be feasible, Dr. Kontos noted.

“Pharmacological therapy may be indicated in selected circumstances to treat certain symptoms and impairments related to concussion,” the TEAM group agreed.There is “very little” evidence for medicine in concussion, and drugs can exacerbate symptoms in some situations, Dr. Kontos said. Randomized controlled trials will help researchers better understand medication’s role in treating concussion.

More Active Treatment

In particular, patients who do not receive appropriate management after a concussion and then go to a clinic several months later with chronic symptoms may benefit from more active approaches to treatment, such as brisk walking.

Dr. Kontos described the case of an ice hockey player who was prescribed rest following a first concussion. After resting, the athlete began a return-to-play protocol that focused on aerobic exertion with no dynamic movements. As soon as the player returned to the ice, however, dizziness and headache came flooding back.

Several months later, the athlete was referred to a concussion clinic. The patient underwent a thorough evaluation that included vestibular and oculomotor assessments. Clinicians determined that the athlete needed more active treatment, including vision training and walking with head movements. In three weeks, the athlete returned to the ice. About a week later, the athlete resumed full-contact ice hockey.

“Prescribing rest is not the only approach,” Dr. Kontos said. “We need to move the discussion in different directions. We need to be more active with certain people and we need to be more targeted with our approaches.”

—Jake Remaly

VANCOUVER—Prescribed rest is an important component of treating concussion, but it may not be the most appropriate intervention for all patients and may worsen symptoms in some cases, said Anthony P. Kontos, PhD, at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Anthony P. Kontos, PhD

“We need to move the discussion on concussion toward more active and targeted treatments,” said Dr. Kontos, Research Director of the University of Pittsburgh Medical Center (UPMC) Sports Medicine Concussion Program.Concussion is a heterogeneous injury with varying clinical profiles and recovery trajectories. Approaches to treatment should account for these differences and involve multidisciplinary teams when necessary, he said.

In October 2015, Dr. Kontos, Michael “Micky” Collins, PhD, and David O. Okonkwo, MD, PhD, directed a meeting with 37 participants from the fields of neurology, neuropsychology, neurosurgery, primary care, athletic training, and physical therapy to create a summary agreement that can assist clinicians with concussion treatment.

Nineteen guests, including representatives from professional sports organizations, the military, and public health, also attended the Targeted Evaluation and Active Management (TEAM) Approach to Treating Concussion meeting. The National Football League and UPMC sponsored the meeting, which was held in Pittsburgh.

Consensus documents have predominantly focused on things like the various definitions of concussion, how to assess concussion, and how to manage it, said Dr. Kontos. “We really wanted to focus on more of that end point of treatment and potentially more active treatment,” he said.

The TEAM participants developed and agreed upon 17 statements, which they plan to publish. At the AAN meeting, Dr. Kontos provided a brief review of some of the statements and discussed them in the context of recent research.

Rest’s Benefits and Limitations

Physical and cognitive rest, as part of an individualized treatment plan, are currently “the foundation of sport-related concussion management,” according to National Collegiate Athletic Association interassociation concussion guidelines. Rest after concussion conserves needed energy in the brain and reduces the likelihood of second impact syndrome and other catastrophic events, Dr. Kontos said. Furthermore, some studies have suggested that rest improves recovery. Brown et al reported in 2014 that athletes who self-reported more cognitive activity after a concussion took longer to recover than those who reported less cognitive activity.

However, the evidence to support rest is limited. In 2013, the Institute of Medicine and National Research Council published a report on sports-related concussion in youth that found little evidence regarding the efficacy of rest following concussion or to inform the best timing and approach for return to activity. Their statement “still resonates now,” Dr. Kontos said. “There’s very little empirical data to support what we do with rest. It’s largely an across-the-board policy that’s not data-driven, and we need to change that.” The TEAM group agreed “there is limited empirical evidence for the effectiveness of prescribed physical and cognitive rest, with no multisite trials for prescribed rest following concussion.”

Prescribed rest can have psychologic consequences, including emotional distress, depression, and anxiety. Rest allows individuals time to ruminate on their injury, which can exacerbate symptoms in self-report. Individuals who somaticize are particularly vulnerable to this effect. Jeremy M. Root, MD, of Children’s National Medical Center in Washington, DC, Dr. Kontos, and colleagues reported in April in the Journal of Pediatrics that patients who had high somatization scores were approximately five to seven times more likely to report an increase in symptoms at two weeks and four weeks, compared with those who were not in the highest quartile of somatization.

In addition, patients who are prescribed rest may think, “Wow, I must have a really bad injury such that I can’t do anything for a week.” This contextual framing effect may also influence the outcome, said Dr. Kontos.

Thomas et al in 2015 published the results of a randomized controlled trial that found that, after a concussion, patients ages 11 to 22 who were prescribed five days’ rest reported more daily postconcussive symptoms, compared with patients who were prescribed two days’ rest with progressive return to activity. Symptoms peaked at four days, and differences between groups remained at 10 days. “They have higher symptoms when they’re told to rest longer than if they’re told to rest less,” Dr. Kontos said. Clinically, there was no significant difference between groups in neurocognitive or balance outcomes, however.

The effect of treatment on the number of postconcussive symptoms may not be that straightforward, however. When Dr. Kontos, Dr. Thomas, and colleagues reanalyzed the data to look at patients who only reported symptoms (eg, headache, nausea, dizziness) but did not otherwise have early signs of concussion (eg, loss of consciousness, posttraumatic amnesia, disorientation, confusion), the symptoms-only group reported more symptoms at 10 days when prescribed five days’ rest, compared with two days’ rest with progressive return to activity. Patients who had early signs of concussion, however, reported fewer symptoms when prescribed five days’ rest versus two days’ rest with progressive return to activity.

“We have a sort of dichotomy here. We don’t want to say rest is bad. It may be very good for these people who have a high organic level or severity to their injury, and we may need to think in terms of resting them longer, whereas these patients [with symptoms only] certainly need to get more active, probably earlier in the process,” Dr. Kontos said.

Activity and social interaction may provide benefits. Miller et al in 2013 reported that environmental enrichment, including cognitive, physical, and social activity, is associated with improved outcome and sparing of hippocampal atrophy in the chronic stages of traumatic brain injury.

The TEAM group agreed, “Active treatment strategies may be initiated early in recovery following concussion.” The group also agreed, “strict brain rest (eg, ‘cocoon’ therapy) is not indicated and may have detrimental effects on patients following concussion.”

A Heterogeneous Injury

A focal point of the TEAM meeting was the concept of various clinical profiles of concussion. The group agreed, “Concussions are characterized by diverse symptoms and impairments in function resulting in different clinical profiles and recovery trajectories.”

“We need to think in terms of what type of concussion does this individual have and is it multiple types,” such as cognitive-fatigue, vestibular, or ocular, said Dr. Kontos. “We don’t typically just see one of these.” For example, a patient may have a predominant vestibular concussion with some posttraumatic migraine and neck involvement. “Oftentimes we see misdiagnoses when people show up. They’ve been diagnosed with cognitive issues when in reality they’re having vision or oculomotor difficulties.”

There are many potential approaches to categorizing, classifying, or profiling concussion, including those that consider posttraumatic mood and migraine as modifying factors, he said.

Multidisciplinary Teams

In addition, the TEAM group stated, “thorough multidomain assessment is warranted to properly evaluate the clinical profiles of concussion.” Various experts may be needed to assess cognitive, exertional, oculomotor, vestibular, and other symptoms and impairment.

As part of a multidisciplinary team, a neurologist, neuropsychologist, or primary care physician could “serve as kind of a point guard, to use a basketball analogy,” said Dr. Kontos. When an aspect of a patient’s assessment or treatment needs to be addressed more in depth, such as with regard to medication, vestibular therapy, or imaging, the patient may be referred to experts in those areas. “We try to work as a team and work back through the point guard to coordinate that care system,” he said. Telemedicine might allow for multidisciplinary treatment in remote geographic areas where establishing multidisciplinary teams otherwise might not be feasible, Dr. Kontos noted.

“Pharmacological therapy may be indicated in selected circumstances to treat certain symptoms and impairments related to concussion,” the TEAM group agreed.There is “very little” evidence for medicine in concussion, and drugs can exacerbate symptoms in some situations, Dr. Kontos said. Randomized controlled trials will help researchers better understand medication’s role in treating concussion.

More Active Treatment

In particular, patients who do not receive appropriate management after a concussion and then go to a clinic several months later with chronic symptoms may benefit from more active approaches to treatment, such as brisk walking.

Dr. Kontos described the case of an ice hockey player who was prescribed rest following a first concussion. After resting, the athlete began a return-to-play protocol that focused on aerobic exertion with no dynamic movements. As soon as the player returned to the ice, however, dizziness and headache came flooding back.

Several months later, the athlete was referred to a concussion clinic. The patient underwent a thorough evaluation that included vestibular and oculomotor assessments. Clinicians determined that the athlete needed more active treatment, including vision training and walking with head movements. In three weeks, the athlete returned to the ice. About a week later, the athlete resumed full-contact ice hockey.

“Prescribing rest is not the only approach,” Dr. Kontos said. “We need to move the discussion in different directions. We need to be more active with certain people and we need to be more targeted with our approaches.”

—Jake Remaly

VANCOUVER—Prescribed rest is an important component of treating concussion, but it may not be the most appropriate intervention for all patients and may worsen symptoms in some cases, said Anthony P. Kontos, PhD, at the 68th Annual Meeting of the American Academy of Neurology (AAN).

Anthony P. Kontos, PhD

“We need to move the discussion on concussion toward more active and targeted treatments,” said Dr. Kontos, Research Director of the University of Pittsburgh Medical Center (UPMC) Sports Medicine Concussion Program.Concussion is a heterogeneous injury with varying clinical profiles and recovery trajectories. Approaches to treatment should account for these differences and involve multidisciplinary teams when necessary, he said.

In October 2015, Dr. Kontos, Michael “Micky” Collins, PhD, and David O. Okonkwo, MD, PhD, directed a meeting with 37 participants from the fields of neurology, neuropsychology, neurosurgery, primary care, athletic training, and physical therapy to create a summary agreement that can assist clinicians with concussion treatment.

Nineteen guests, including representatives from professional sports organizations, the military, and public health, also attended the Targeted Evaluation and Active Management (TEAM) Approach to Treating Concussion meeting. The National Football League and UPMC sponsored the meeting, which was held in Pittsburgh.

Consensus documents have predominantly focused on things like the various definitions of concussion, how to assess concussion, and how to manage it, said Dr. Kontos. “We really wanted to focus on more of that end point of treatment and potentially more active treatment,” he said.

The TEAM participants developed and agreed upon 17 statements, which they plan to publish. At the AAN meeting, Dr. Kontos provided a brief review of some of the statements and discussed them in the context of recent research.

Rest’s Benefits and Limitations

Physical and cognitive rest, as part of an individualized treatment plan, are currently “the foundation of sport-related concussion management,” according to National Collegiate Athletic Association interassociation concussion guidelines. Rest after concussion conserves needed energy in the brain and reduces the likelihood of second impact syndrome and other catastrophic events, Dr. Kontos said. Furthermore, some studies have suggested that rest improves recovery. Brown et al reported in 2014 that athletes who self-reported more cognitive activity after a concussion took longer to recover than those who reported less cognitive activity.

However, the evidence to support rest is limited. In 2013, the Institute of Medicine and National Research Council published a report on sports-related concussion in youth that found little evidence regarding the efficacy of rest following concussion or to inform the best timing and approach for return to activity. Their statement “still resonates now,” Dr. Kontos said. “There’s very little empirical data to support what we do with rest. It’s largely an across-the-board policy that’s not data-driven, and we need to change that.” The TEAM group agreed “there is limited empirical evidence for the effectiveness of prescribed physical and cognitive rest, with no multisite trials for prescribed rest following concussion.”

Prescribed rest can have psychologic consequences, including emotional distress, depression, and anxiety. Rest allows individuals time to ruminate on their injury, which can exacerbate symptoms in self-report. Individuals who somaticize are particularly vulnerable to this effect. Jeremy M. Root, MD, of Children’s National Medical Center in Washington, DC, Dr. Kontos, and colleagues reported in April in the Journal of Pediatrics that patients who had high somatization scores were approximately five to seven times more likely to report an increase in symptoms at two weeks and four weeks, compared with those who were not in the highest quartile of somatization.

In addition, patients who are prescribed rest may think, “Wow, I must have a really bad injury such that I can’t do anything for a week.” This contextual framing effect may also influence the outcome, said Dr. Kontos.

Thomas et al in 2015 published the results of a randomized controlled trial that found that, after a concussion, patients ages 11 to 22 who were prescribed five days’ rest reported more daily postconcussive symptoms, compared with patients who were prescribed two days’ rest with progressive return to activity. Symptoms peaked at four days, and differences between groups remained at 10 days. “They have higher symptoms when they’re told to rest longer than if they’re told to rest less,” Dr. Kontos said. Clinically, there was no significant difference between groups in neurocognitive or balance outcomes, however.

The effect of treatment on the number of postconcussive symptoms may not be that straightforward, however. When Dr. Kontos, Dr. Thomas, and colleagues reanalyzed the data to look at patients who only reported symptoms (eg, headache, nausea, dizziness) but did not otherwise have early signs of concussion (eg, loss of consciousness, posttraumatic amnesia, disorientation, confusion), the symptoms-only group reported more symptoms at 10 days when prescribed five days’ rest, compared with two days’ rest with progressive return to activity. Patients who had early signs of concussion, however, reported fewer symptoms when prescribed five days’ rest versus two days’ rest with progressive return to activity.

“We have a sort of dichotomy here. We don’t want to say rest is bad. It may be very good for these people who have a high organic level or severity to their injury, and we may need to think in terms of resting them longer, whereas these patients [with symptoms only] certainly need to get more active, probably earlier in the process,” Dr. Kontos said.

Activity and social interaction may provide benefits. Miller et al in 2013 reported that environmental enrichment, including cognitive, physical, and social activity, is associated with improved outcome and sparing of hippocampal atrophy in the chronic stages of traumatic brain injury.

The TEAM group agreed, “Active treatment strategies may be initiated early in recovery following concussion.” The group also agreed, “strict brain rest (eg, ‘cocoon’ therapy) is not indicated and may have detrimental effects on patients following concussion.”

A Heterogeneous Injury

A focal point of the TEAM meeting was the concept of various clinical profiles of concussion. The group agreed, “Concussions are characterized by diverse symptoms and impairments in function resulting in different clinical profiles and recovery trajectories.”

“We need to think in terms of what type of concussion does this individual have and is it multiple types,” such as cognitive-fatigue, vestibular, or ocular, said Dr. Kontos. “We don’t typically just see one of these.” For example, a patient may have a predominant vestibular concussion with some posttraumatic migraine and neck involvement. “Oftentimes we see misdiagnoses when people show up. They’ve been diagnosed with cognitive issues when in reality they’re having vision or oculomotor difficulties.”

There are many potential approaches to categorizing, classifying, or profiling concussion, including those that consider posttraumatic mood and migraine as modifying factors, he said.

Multidisciplinary Teams

In addition, the TEAM group stated, “thorough multidomain assessment is warranted to properly evaluate the clinical profiles of concussion.” Various experts may be needed to assess cognitive, exertional, oculomotor, vestibular, and other symptoms and impairment.

As part of a multidisciplinary team, a neurologist, neuropsychologist, or primary care physician could “serve as kind of a point guard, to use a basketball analogy,” said Dr. Kontos. When an aspect of a patient’s assessment or treatment needs to be addressed more in depth, such as with regard to medication, vestibular therapy, or imaging, the patient may be referred to experts in those areas. “We try to work as a team and work back through the point guard to coordinate that care system,” he said. Telemedicine might allow for multidisciplinary treatment in remote geographic areas where establishing multidisciplinary teams otherwise might not be feasible, Dr. Kontos noted.

“Pharmacological therapy may be indicated in selected circumstances to treat certain symptoms and impairments related to concussion,” the TEAM group agreed.There is “very little” evidence for medicine in concussion, and drugs can exacerbate symptoms in some situations, Dr. Kontos said. Randomized controlled trials will help researchers better understand medication’s role in treating concussion.

More Active Treatment

In particular, patients who do not receive appropriate management after a concussion and then go to a clinic several months later with chronic symptoms may benefit from more active approaches to treatment, such as brisk walking.

Dr. Kontos described the case of an ice hockey player who was prescribed rest following a first concussion. After resting, the athlete began a return-to-play protocol that focused on aerobic exertion with no dynamic movements. As soon as the player returned to the ice, however, dizziness and headache came flooding back.

Several months later, the athlete was referred to a concussion clinic. The patient underwent a thorough evaluation that included vestibular and oculomotor assessments. Clinicians determined that the athlete needed more active treatment, including vision training and walking with head movements. In three weeks, the athlete returned to the ice. About a week later, the athlete resumed full-contact ice hockey.

“Prescribing rest is not the only approach,” Dr. Kontos said. “We need to move the discussion in different directions. We need to be more active with certain people and we need to be more targeted with our approaches.”

—Jake Remaly