Neurology

A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?

A. Vitamin D supplementation

B. Vitamin B₁₂ supplementation

C. Calcium supplementation

D. Tai chi

Falls are a catastrophic problem in our elderly population, and are especially common in patients with Parkinson’s disease.

There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.¹ They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.

The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.² The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
 

The benefits of tai chi

Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.

Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.³ Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.

Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.⁴ Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).

Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.

2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.

3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934

4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.

A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?

A. Vitamin D supplementation

B. Vitamin B₁₂ supplementation

C. Calcium supplementation

D. Tai chi

Falls are a catastrophic problem in our elderly population, and are especially common in patients with Parkinson’s disease.

There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.¹ They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.

The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.² The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
 

The benefits of tai chi

Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.

Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.³ Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.

Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.⁴ Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).

Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.

2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.

3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934

4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.

A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?

A. Vitamin D supplementation

B. Vitamin B₁₂ supplementation

C. Calcium supplementation

D. Tai chi

Falls are a catastrophic problem in our elderly population, and are especially common in patients with Parkinson’s disease.

There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.¹ They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.

The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.² The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
 

The benefits of tai chi

Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.

Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.³ Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.

Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.⁴ Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).

Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.

2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.

3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934

4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.

A 45-year-old woman visited the clinic 6 weeks after having a stroke while on her motorcycle, which resulted in a crash. She had not been wearing a helmet and was uncertain if she had sustained a head injury. She said that during the hospital stay following the accident, she was diagnosed as hypertensive; she denied any other significant prior medical history.

Following the crash, she said she’d been experiencing weakness in her right arm and leg and had been unable to open her right eye. When her right eye was opened manually, she said she had double vision and sensitivity to light.

On exam, the patient had exotropia with hypotropia of her right eye. Additionally, she had anisocoria with an enlarged, nonreactive right pupil (FIGURE 1A). She was unable to adduct, supraduct, or infraduct her right eye (FIGURE 1B). Her cranial nerves were ­otherwise intact. On manual strength testing, she had 4/5 strength of both her right upper and lower extremities.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Third (oculomotor) nerve palsy

This patient had a complete third nerve palsy (TNP). This is defined as palsy involving all of the muscles innervated by the oculomotor nerve, with pupillary involvement.¹ The oculomotor nerve supplies motor innervation to the levator palpebrae superioris, superior rectus, medial rectus, inferior rectus, and inferior oblique muscles and parasympathetic innervation to the pupillary constrictor and ciliary muscles.² As a result, patients present with exotropia and hypotropia on exam with anisocoria. Diplopia, ptosis, and an enlarged pupil are classic symptoms of TNP.²

Computed tomography (CT) of the brain performed immediately after this patient’s accident demonstrated a 15-mm hemorrhage within the left basal ganglia with mild associated edema, and a small focus of hyperattenuation within the right aspect of the suprasellar cistern. There was no evidence of skull fracture. CT angiography (CTA) of the brain showed no evidence of aneurysm.

Diplopia, ptosis, and an enlarged pupil are classic symptoms of TNP.

Several days later, magnetic resonance imaging (MRI) of the brain confirmed prior CT findings and revealed hemorrhagic contusions along the anterior and medial left temporal lobe. Additionally, the MRI showed subtle subdural hemorrhages along the midline falx and right parietal region, as well as diffuse subarachnoid hemorrhage around both hemispheres, the interpeduncular cistern, and the suprasellar cistern (FIGURE 2). The basal ganglia hemorrhage was believed to have been a result of uncontrolled hypertension. The hemorrhage was responsible for her right-sided weakness and was the presumed cause of the accident. The other findings were due to head trauma. Her TNP was most likely caused by both compression and irritation of the right oculomotor nerve.

An uncommon occurrence

A population-based study identified the annual incidence of TNP to be 4 per 100,000.¹ The mean age of onset was 42 years. The incidence in patients older than 60 years was greater than the incidence in those younger than 60.² Isolated TNP occurred in approximately 40% of cases.²

Complete TNP is typically indicative of compression of the ipsilateral third nerve.² The most common region for third nerve injury is the subarachnoid space, where the oculomotor nerve is vulnerable to compression, often by an aneurysm arising from the junction of the internal carotid and posterior communicating arteries.³

Continue to: Incomplete TNP

Incomplete TNP is often microvascular in origin and requires evaluation for diabetes and hypertension. Microvascular TNP is ­frequently painful but usually self-resolves after 2 to 4 months.² Giant cell arteritis may also cause an isolated, painful TNP.²

A varied differential diagnosis and a TNP link to COVID-19

The differential diagnosis for TNP includes the following:

Orbital apex injury is usually seen after high-energy craniofacial trauma.⁴ Orbital apex fractures present with different signs and symptoms, depending on the degree of injury to neural and vascular structures. Various syndromes come into play, the most common being superior orbital fissure syndrome, which is characterized by dysfunction of cranial nerves III, IV, V, and VI.⁴ Features include ophthalmoplegia, upper eyelid ptosis, a nonreactive dilated pupil, anesthesia over the ipsilateral forehead, loss of corneal reflex, orbital pain, and proptosis.⁴ 

In patients with suspected orbital apex fractures, it’s important to assess for the presence of an optic neuropathy, an evolving orbital compartment syndrome, or a ruptured globe, because these 3 things may demand acute intervention.⁴ 

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disorder characterized by a slow, progressive paralysis of the extraocular muscles.⁵ Patients usually experience bilateral, symmetrical, progressive ptosis, followed by ophthalmoparesis months to years later. Ciliary and iris muscles are not involved. CPEO often occurs with other systemic features of mitochondrial dysfunction that can cause significant morbidity and mortality.⁵ 

Continue to: Graves ophthalmopathy

Graves ophthalmopathy arises from soft-tissue enlargement in the orbit, leading to increased pressure within the bony cavity.⁶ Approximately 40% of patients with Graves ophthalmopathy present with restrictive extraocular myopathy; however > 90% have eyelid retraction, as opposed to ptosis.⁷ 

Guillain-Barré syndrome (GBS) is an acute, demyelinating immune-mediated polyneuropathy involving the spinal roots, peripheral nerves, and often the cranial nerves.⁸ The Miller Fisher variant of GBS is characterized by bilateral ophthalmoparesis, areflexia, and ataxia.⁸ At the early stage of illness, the presentation may be similar to TNP.⁸ Brain imaging is normal in patients with GBS; the diagnosis is established via characteristic electromyography and cerebrospinal fluid findings.⁸ 

Myasthenia gravis often manifests with variable ptosis associated with diplopia.⁹ Symptoms may be unilateral or bilateral. The ice-pack test has been identified as a simple, preliminary test for ocular myasthenia. The test involves the application of an ice-pack over the lids for 5 minutes. A 50% reduction in at least 1 component of ocular deviation is considered a positive response.¹⁰ Its specificity reportedly reaches 100%, with a sensitivity of 80%.¹⁰

COVID-19 infection may also include neurologic manifestations. There are an increasing number of case reports of central nervous system abnormalities including TNP.^11,12 

Trauma, tumors, or an aneurysm could be at work in TNP

TNP associated with trauma usually develops secondary to compression from an expanding hematoma, although it may also be a result of irritation of the nerve from blood in the subarachnoid space.¹³ Estimates of the incidence of TNP due to trauma range from 12% to 26% of cases.^1,14 Vehicle-related injury is the most frequent cause of trauma-related TNP.¹⁴

Continue to: Pituitary tumors

Pituitary tumors most commonly involve the oculomotor nerve; 14% to 30% of pituitary tumors lead to TNP.¹³ Pituitary apoplexy secondary to infarction or hemorrhage is often associated with visual field defects and TNP.¹³

An underlying aneurysm manifests in a minority (10% to 15%) of patients presenting with TNP.³

Imaging is key to getting at the cause of TNP

The evaluation of patients presenting with acute TNP should be focused first on detecting an aneurysmal compressive lesion.³ CTA is the imaging modality of choice. 

Once an aneurysm has been ruled out, the work-up should include a lumbar puncture and an erythrocyte sedimentation rate. Older patients should be assessed for conditions such as hypertension or diabetes that put them at risk for microvascular disease.³ If microvascular TNP is unlikely, MRI with MR angiography is recommended to exclude other potential etiologies of TNP.³ If the patient is younger than 50 years of age, consider potential infectious and inflammatory etiologies (eg, giant cell arteritis).³

Treatment options are varied

The treatment of patients with TNP is specific to the disease state. For those patients with vascular risk factors and a presumptive diagnosis of microvascular TNP, it is reasonable to observe the patient for 2 to 3 months.³ Antiplatelet therapy is usually initiated. Patching 1 eye is useful in alleviating diplopia, particularly in the short term. In most cases, deficits related to TNP resolve over weeks to months. Deficits that persist beyond 6 months may require surgical intervention.

Continue to: "The tip of the iceberg"

 

 

TNP: “The tip of the iceberg”

TNP may signal a neurologic emergency, such as an aneurysm, or other conditions such as pituitary disease or giant cell arteritis. Any patient presenting with acute onset of TNP should undergo a noninvasive neuroimaging study.³

Our patient was treated for hypertension; however, she was lost to follow-up.

A 45-year-old woman visited the clinic 6 weeks after having a stroke while on her motorcycle, which resulted in a crash. She had not been wearing a helmet and was uncertain if she had sustained a head injury. She said that during the hospital stay following the accident, she was diagnosed as hypertensive; she denied any other significant prior medical history.

Following the crash, she said she’d been experiencing weakness in her right arm and leg and had been unable to open her right eye. When her right eye was opened manually, she said she had double vision and sensitivity to light.

On exam, the patient had exotropia with hypotropia of her right eye. Additionally, she had anisocoria with an enlarged, nonreactive right pupil (FIGURE 1A). She was unable to adduct, supraduct, or infraduct her right eye (FIGURE 1B). Her cranial nerves were ­otherwise intact. On manual strength testing, she had 4/5 strength of both her right upper and lower extremities.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Third (oculomotor) nerve palsy

This patient had a complete third nerve palsy (TNP). This is defined as palsy involving all of the muscles innervated by the oculomotor nerve, with pupillary involvement.¹ The oculomotor nerve supplies motor innervation to the levator palpebrae superioris, superior rectus, medial rectus, inferior rectus, and inferior oblique muscles and parasympathetic innervation to the pupillary constrictor and ciliary muscles.² As a result, patients present with exotropia and hypotropia on exam with anisocoria. Diplopia, ptosis, and an enlarged pupil are classic symptoms of TNP.²

Computed tomography (CT) of the brain performed immediately after this patient’s accident demonstrated a 15-mm hemorrhage within the left basal ganglia with mild associated edema, and a small focus of hyperattenuation within the right aspect of the suprasellar cistern. There was no evidence of skull fracture. CT angiography (CTA) of the brain showed no evidence of aneurysm.

Diplopia, ptosis, and an enlarged pupil are classic symptoms of TNP.

Several days later, magnetic resonance imaging (MRI) of the brain confirmed prior CT findings and revealed hemorrhagic contusions along the anterior and medial left temporal lobe. Additionally, the MRI showed subtle subdural hemorrhages along the midline falx and right parietal region, as well as diffuse subarachnoid hemorrhage around both hemispheres, the interpeduncular cistern, and the suprasellar cistern (FIGURE 2). The basal ganglia hemorrhage was believed to have been a result of uncontrolled hypertension. The hemorrhage was responsible for her right-sided weakness and was the presumed cause of the accident. The other findings were due to head trauma. Her TNP was most likely caused by both compression and irritation of the right oculomotor nerve.

An uncommon occurrence

A population-based study identified the annual incidence of TNP to be 4 per 100,000.¹ The mean age of onset was 42 years. The incidence in patients older than 60 years was greater than the incidence in those younger than 60.² Isolated TNP occurred in approximately 40% of cases.²

Complete TNP is typically indicative of compression of the ipsilateral third nerve.² The most common region for third nerve injury is the subarachnoid space, where the oculomotor nerve is vulnerable to compression, often by an aneurysm arising from the junction of the internal carotid and posterior communicating arteries.³

Continue to: Incomplete TNP

Incomplete TNP is often microvascular in origin and requires evaluation for diabetes and hypertension. Microvascular TNP is ­frequently painful but usually self-resolves after 2 to 4 months.² Giant cell arteritis may also cause an isolated, painful TNP.²

A varied differential diagnosis and a TNP link to COVID-19

The differential diagnosis for TNP includes the following:

Orbital apex injury is usually seen after high-energy craniofacial trauma.⁴ Orbital apex fractures present with different signs and symptoms, depending on the degree of injury to neural and vascular structures. Various syndromes come into play, the most common being superior orbital fissure syndrome, which is characterized by dysfunction of cranial nerves III, IV, V, and VI.⁴ Features include ophthalmoplegia, upper eyelid ptosis, a nonreactive dilated pupil, anesthesia over the ipsilateral forehead, loss of corneal reflex, orbital pain, and proptosis.⁴ 

In patients with suspected orbital apex fractures, it’s important to assess for the presence of an optic neuropathy, an evolving orbital compartment syndrome, or a ruptured globe, because these 3 things may demand acute intervention.⁴ 

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disorder characterized by a slow, progressive paralysis of the extraocular muscles.⁵ Patients usually experience bilateral, symmetrical, progressive ptosis, followed by ophthalmoparesis months to years later. Ciliary and iris muscles are not involved. CPEO often occurs with other systemic features of mitochondrial dysfunction that can cause significant morbidity and mortality.⁵ 

Continue to: Graves ophthalmopathy

Graves ophthalmopathy arises from soft-tissue enlargement in the orbit, leading to increased pressure within the bony cavity.⁶ Approximately 40% of patients with Graves ophthalmopathy present with restrictive extraocular myopathy; however > 90% have eyelid retraction, as opposed to ptosis.⁷ 

Guillain-Barré syndrome (GBS) is an acute, demyelinating immune-mediated polyneuropathy involving the spinal roots, peripheral nerves, and often the cranial nerves.⁸ The Miller Fisher variant of GBS is characterized by bilateral ophthalmoparesis, areflexia, and ataxia.⁸ At the early stage of illness, the presentation may be similar to TNP.⁸ Brain imaging is normal in patients with GBS; the diagnosis is established via characteristic electromyography and cerebrospinal fluid findings.⁸ 

Myasthenia gravis often manifests with variable ptosis associated with diplopia.⁹ Symptoms may be unilateral or bilateral. The ice-pack test has been identified as a simple, preliminary test for ocular myasthenia. The test involves the application of an ice-pack over the lids for 5 minutes. A 50% reduction in at least 1 component of ocular deviation is considered a positive response.¹⁰ Its specificity reportedly reaches 100%, with a sensitivity of 80%.¹⁰

COVID-19 infection may also include neurologic manifestations. There are an increasing number of case reports of central nervous system abnormalities including TNP.^11,12 

Trauma, tumors, or an aneurysm could be at work in TNP

TNP associated with trauma usually develops secondary to compression from an expanding hematoma, although it may also be a result of irritation of the nerve from blood in the subarachnoid space.¹³ Estimates of the incidence of TNP due to trauma range from 12% to 26% of cases.^1,14 Vehicle-related injury is the most frequent cause of trauma-related TNP.¹⁴

Continue to: Pituitary tumors

Pituitary tumors most commonly involve the oculomotor nerve; 14% to 30% of pituitary tumors lead to TNP.¹³ Pituitary apoplexy secondary to infarction or hemorrhage is often associated with visual field defects and TNP.¹³

An underlying aneurysm manifests in a minority (10% to 15%) of patients presenting with TNP.³

Imaging is key to getting at the cause of TNP

The evaluation of patients presenting with acute TNP should be focused first on detecting an aneurysmal compressive lesion.³ CTA is the imaging modality of choice. 

Once an aneurysm has been ruled out, the work-up should include a lumbar puncture and an erythrocyte sedimentation rate. Older patients should be assessed for conditions such as hypertension or diabetes that put them at risk for microvascular disease.³ If microvascular TNP is unlikely, MRI with MR angiography is recommended to exclude other potential etiologies of TNP.³ If the patient is younger than 50 years of age, consider potential infectious and inflammatory etiologies (eg, giant cell arteritis).³

Treatment options are varied

The treatment of patients with TNP is specific to the disease state. For those patients with vascular risk factors and a presumptive diagnosis of microvascular TNP, it is reasonable to observe the patient for 2 to 3 months.³ Antiplatelet therapy is usually initiated. Patching 1 eye is useful in alleviating diplopia, particularly in the short term. In most cases, deficits related to TNP resolve over weeks to months. Deficits that persist beyond 6 months may require surgical intervention.

Continue to: "The tip of the iceberg"

 

 

TNP: “The tip of the iceberg”

TNP may signal a neurologic emergency, such as an aneurysm, or other conditions such as pituitary disease or giant cell arteritis. Any patient presenting with acute onset of TNP should undergo a noninvasive neuroimaging study.³

Our patient was treated for hypertension; however, she was lost to follow-up.

A 45-year-old woman visited the clinic 6 weeks after having a stroke while on her motorcycle, which resulted in a crash. She had not been wearing a helmet and was uncertain if she had sustained a head injury. She said that during the hospital stay following the accident, she was diagnosed as hypertensive; she denied any other significant prior medical history.

Following the crash, she said she’d been experiencing weakness in her right arm and leg and had been unable to open her right eye. When her right eye was opened manually, she said she had double vision and sensitivity to light.

On exam, the patient had exotropia with hypotropia of her right eye. Additionally, she had anisocoria with an enlarged, nonreactive right pupil (FIGURE 1A). She was unable to adduct, supraduct, or infraduct her right eye (FIGURE 1B). Her cranial nerves were ­otherwise intact. On manual strength testing, she had 4/5 strength of both her right upper and lower extremities.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Third (oculomotor) nerve palsy

This patient had a complete third nerve palsy (TNP). This is defined as palsy involving all of the muscles innervated by the oculomotor nerve, with pupillary involvement.¹ The oculomotor nerve supplies motor innervation to the levator palpebrae superioris, superior rectus, medial rectus, inferior rectus, and inferior oblique muscles and parasympathetic innervation to the pupillary constrictor and ciliary muscles.² As a result, patients present with exotropia and hypotropia on exam with anisocoria. Diplopia, ptosis, and an enlarged pupil are classic symptoms of TNP.²

Computed tomography (CT) of the brain performed immediately after this patient’s accident demonstrated a 15-mm hemorrhage within the left basal ganglia with mild associated edema, and a small focus of hyperattenuation within the right aspect of the suprasellar cistern. There was no evidence of skull fracture. CT angiography (CTA) of the brain showed no evidence of aneurysm.

Diplopia, ptosis, and an enlarged pupil are classic symptoms of TNP.

Several days later, magnetic resonance imaging (MRI) of the brain confirmed prior CT findings and revealed hemorrhagic contusions along the anterior and medial left temporal lobe. Additionally, the MRI showed subtle subdural hemorrhages along the midline falx and right parietal region, as well as diffuse subarachnoid hemorrhage around both hemispheres, the interpeduncular cistern, and the suprasellar cistern (FIGURE 2). The basal ganglia hemorrhage was believed to have been a result of uncontrolled hypertension. The hemorrhage was responsible for her right-sided weakness and was the presumed cause of the accident. The other findings were due to head trauma. Her TNP was most likely caused by both compression and irritation of the right oculomotor nerve.

An uncommon occurrence

A population-based study identified the annual incidence of TNP to be 4 per 100,000.¹ The mean age of onset was 42 years. The incidence in patients older than 60 years was greater than the incidence in those younger than 60.² Isolated TNP occurred in approximately 40% of cases.²

Complete TNP is typically indicative of compression of the ipsilateral third nerve.² The most common region for third nerve injury is the subarachnoid space, where the oculomotor nerve is vulnerable to compression, often by an aneurysm arising from the junction of the internal carotid and posterior communicating arteries.³

Continue to: Incomplete TNP

Incomplete TNP is often microvascular in origin and requires evaluation for diabetes and hypertension. Microvascular TNP is ­frequently painful but usually self-resolves after 2 to 4 months.² Giant cell arteritis may also cause an isolated, painful TNP.²

A varied differential diagnosis and a TNP link to COVID-19

The differential diagnosis for TNP includes the following:

Orbital apex injury is usually seen after high-energy craniofacial trauma.⁴ Orbital apex fractures present with different signs and symptoms, depending on the degree of injury to neural and vascular structures. Various syndromes come into play, the most common being superior orbital fissure syndrome, which is characterized by dysfunction of cranial nerves III, IV, V, and VI.⁴ Features include ophthalmoplegia, upper eyelid ptosis, a nonreactive dilated pupil, anesthesia over the ipsilateral forehead, loss of corneal reflex, orbital pain, and proptosis.⁴ 

In patients with suspected orbital apex fractures, it’s important to assess for the presence of an optic neuropathy, an evolving orbital compartment syndrome, or a ruptured globe, because these 3 things may demand acute intervention.⁴ 

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disorder characterized by a slow, progressive paralysis of the extraocular muscles.⁵ Patients usually experience bilateral, symmetrical, progressive ptosis, followed by ophthalmoparesis months to years later. Ciliary and iris muscles are not involved. CPEO often occurs with other systemic features of mitochondrial dysfunction that can cause significant morbidity and mortality.⁵ 

Continue to: Graves ophthalmopathy

Graves ophthalmopathy arises from soft-tissue enlargement in the orbit, leading to increased pressure within the bony cavity.⁶ Approximately 40% of patients with Graves ophthalmopathy present with restrictive extraocular myopathy; however > 90% have eyelid retraction, as opposed to ptosis.⁷ 

Guillain-Barré syndrome (GBS) is an acute, demyelinating immune-mediated polyneuropathy involving the spinal roots, peripheral nerves, and often the cranial nerves.⁸ The Miller Fisher variant of GBS is characterized by bilateral ophthalmoparesis, areflexia, and ataxia.⁸ At the early stage of illness, the presentation may be similar to TNP.⁸ Brain imaging is normal in patients with GBS; the diagnosis is established via characteristic electromyography and cerebrospinal fluid findings.⁸ 

Myasthenia gravis often manifests with variable ptosis associated with diplopia.⁹ Symptoms may be unilateral or bilateral. The ice-pack test has been identified as a simple, preliminary test for ocular myasthenia. The test involves the application of an ice-pack over the lids for 5 minutes. A 50% reduction in at least 1 component of ocular deviation is considered a positive response.¹⁰ Its specificity reportedly reaches 100%, with a sensitivity of 80%.¹⁰

COVID-19 infection may also include neurologic manifestations. There are an increasing number of case reports of central nervous system abnormalities including TNP.^11,12 

Trauma, tumors, or an aneurysm could be at work in TNP

TNP associated with trauma usually develops secondary to compression from an expanding hematoma, although it may also be a result of irritation of the nerve from blood in the subarachnoid space.¹³ Estimates of the incidence of TNP due to trauma range from 12% to 26% of cases.^1,14 Vehicle-related injury is the most frequent cause of trauma-related TNP.¹⁴

Continue to: Pituitary tumors

Pituitary tumors most commonly involve the oculomotor nerve; 14% to 30% of pituitary tumors lead to TNP.¹³ Pituitary apoplexy secondary to infarction or hemorrhage is often associated with visual field defects and TNP.¹³

An underlying aneurysm manifests in a minority (10% to 15%) of patients presenting with TNP.³

Imaging is key to getting at the cause of TNP

The evaluation of patients presenting with acute TNP should be focused first on detecting an aneurysmal compressive lesion.³ CTA is the imaging modality of choice. 

Once an aneurysm has been ruled out, the work-up should include a lumbar puncture and an erythrocyte sedimentation rate. Older patients should be assessed for conditions such as hypertension or diabetes that put them at risk for microvascular disease.³ If microvascular TNP is unlikely, MRI with MR angiography is recommended to exclude other potential etiologies of TNP.³ If the patient is younger than 50 years of age, consider potential infectious and inflammatory etiologies (eg, giant cell arteritis).³

Treatment options are varied

The treatment of patients with TNP is specific to the disease state. For those patients with vascular risk factors and a presumptive diagnosis of microvascular TNP, it is reasonable to observe the patient for 2 to 3 months.³ Antiplatelet therapy is usually initiated. Patching 1 eye is useful in alleviating diplopia, particularly in the short term. In most cases, deficits related to TNP resolve over weeks to months. Deficits that persist beyond 6 months may require surgical intervention.

Continue to: "The tip of the iceberg"

 

 

TNP: “The tip of the iceberg”

TNP may signal a neurologic emergency, such as an aneurysm, or other conditions such as pituitary disease or giant cell arteritis. Any patient presenting with acute onset of TNP should undergo a noninvasive neuroimaging study.³

Our patient was treated for hypertension; however, she was lost to follow-up.

Perimenopausal women are using prescription sleep medications for long periods of time despite no evidence of efficacy, a new study shows.

“While there are good data from [randomized, controlled trials] that these medications improve sleep disturbances in the short term,” few studies have examined whether they provide long-term benefits, stated the authors of the paper, which was published in BMJ Open.

“The current observational study does not support use of sleep medications over the long term, as there were no self-reported differences at 1 or 2 years of follow-up comparing sleep medication users with nonusers,” author Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital, Boston, and colleagues wrote.

Women included in the analysis were drawn from the Study of Women’s Health Across the Nation (SWAN), an ongoing multicenter, longitudinal study examining women during the menopausal transition. The average age of the women included in the cohort was 49.5 years and approximately half were White. All women reported a sleep disturbance on at least 3 nights per week during a 2-week interval. At follow up, women were asked to use a Likert scale to rate three aspects of sleep: difficulty initiating sleep, frequent awakening, and waking up early. On the scale, 1 represented having no difficulties on any nights, 3 represented having difficulties 1-2 nights per week, and 5 represented having difficulty 5-7 nights per week.

Women already using prescription sleep medication at their baseline visit were excluded from the study. Medications used included benzodiazepines, selective BZD receptor agonists, and other hypnotics.

Over the 21 years of follow-up in the SWAN study (1995-2016), Dr. Solomon and colleagues identified 238 women using sleep medication and these were compared with a cohort of 447 propensity score–matched non–sleep medication uses. Overall, the 685 women included were similar in characteristics to each other as well as to the other potentially eligible women not included in the analysis.
 

Sleep disturbance patterns compared

At baseline, sleep disturbance patterns were similar between the two groups. Among medication users, the mean score for difficulty initiating sleep was 2.7 (95% confidence interval, 2.5-2.9), waking frequently 3.8 (95% CI, 3.6-3.9), and waking early 2.9 (95% CI, 2.7-3.1). Among the nonusers, the baseline scores were 2.6 (95% CI, 2.5-2.7), 3.7 (95% CI, 3.6-3.8), and 2.7 (95% CI, 2.5-2.8), respectively. After 1 year, there was no statistically significant difference in scores between the two groups. The average ratings for medication users were 2.6 (95% CI, 2.3-2.8) for difficulty initiating sleep, 3.8 (95% CI, 3.6-4.0) for waking frequently, and 2.8 (95% CI, 2.6-3.0) for waking early.

Average ratings among nonusers were 2.3 (95% CI, 2.2-2.4), 3.5 (95% CI, 3.3-3.6), and 2.5 (95% CI, 2.3-2.6), respectively.

After 2 years, there were still no statistically significant reductions in sleep disturbances among those taking prescription sleep medications, compared with those not taking medication.

The researchers noted that approximately half of the women in this cohort were current or past tobacco users and that 20% were moderate to heavy alcohol users.
 

More work-up, not more medication, needed

The study authors acknowledged the limitations of an observational study and noted that, since participants only reported medication use and sleep disturbances at annual visits, they did not know whether patients’ medication use was intermittent or of any interim outcomes. Additionally, the authors pointed out that those classified as “nonusers” may have been using over-the-counter medication.

“Investigations should look at detailed-use patterns, on a daily or weekly basis, with frequent outcomes data,” Dr. Solomon said in an interview. “While our data shed new light on chronic use, we only had data collected on an annual basis; daily or weekly data would provide more granular information.”

Regarding clinician prescribing practices, Dr. Solomon said, “short-term, intermittent use can be helpful, but use these agents sparingly” and “educate patients that chronic regular use of medications for sleep is not associated with improvement in sleep disturbances.”

Commenting on the study, Andrea Matsumura, MD, a sleep specialist at the Oregon Clinic in Portland, echoed this sentiment: “When someone says they are having trouble sleeping this is the tip of the iceberg and it warrants an evaluation to determine if someone has a breathing disorder, a circadian disorder, a life situation, or a type of insomnia that is driving the sleeplessness.”

“I think this study supports what we all should know,” Dr. Matsumura concluded. “Sleep aids are not meant to be used long term” and should not be used for longer than 2 weeks without further work-up.

Funding for this study was provided through a grant from the National Institutes of Health. Dr. Solomon has received salary support from research grants to Brigham and Women’s Hospital for unrelated work from AbbVie, Amgen, Corrona, Genentech and Pfizer. The other authors and Dr. Matsumura have reported no relevant financial relationships.

Perimenopausal women are using prescription sleep medications for long periods of time despite no evidence of efficacy, a new study shows.

“While there are good data from [randomized, controlled trials] that these medications improve sleep disturbances in the short term,” few studies have examined whether they provide long-term benefits, stated the authors of the paper, which was published in BMJ Open.

“The current observational study does not support use of sleep medications over the long term, as there were no self-reported differences at 1 or 2 years of follow-up comparing sleep medication users with nonusers,” author Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital, Boston, and colleagues wrote.

Women included in the analysis were drawn from the Study of Women’s Health Across the Nation (SWAN), an ongoing multicenter, longitudinal study examining women during the menopausal transition. The average age of the women included in the cohort was 49.5 years and approximately half were White. All women reported a sleep disturbance on at least 3 nights per week during a 2-week interval. At follow up, women were asked to use a Likert scale to rate three aspects of sleep: difficulty initiating sleep, frequent awakening, and waking up early. On the scale, 1 represented having no difficulties on any nights, 3 represented having difficulties 1-2 nights per week, and 5 represented having difficulty 5-7 nights per week.

Women already using prescription sleep medication at their baseline visit were excluded from the study. Medications used included benzodiazepines, selective BZD receptor agonists, and other hypnotics.

Over the 21 years of follow-up in the SWAN study (1995-2016), Dr. Solomon and colleagues identified 238 women using sleep medication and these were compared with a cohort of 447 propensity score–matched non–sleep medication uses. Overall, the 685 women included were similar in characteristics to each other as well as to the other potentially eligible women not included in the analysis.
 

Sleep disturbance patterns compared

At baseline, sleep disturbance patterns were similar between the two groups. Among medication users, the mean score for difficulty initiating sleep was 2.7 (95% confidence interval, 2.5-2.9), waking frequently 3.8 (95% CI, 3.6-3.9), and waking early 2.9 (95% CI, 2.7-3.1). Among the nonusers, the baseline scores were 2.6 (95% CI, 2.5-2.7), 3.7 (95% CI, 3.6-3.8), and 2.7 (95% CI, 2.5-2.8), respectively. After 1 year, there was no statistically significant difference in scores between the two groups. The average ratings for medication users were 2.6 (95% CI, 2.3-2.8) for difficulty initiating sleep, 3.8 (95% CI, 3.6-4.0) for waking frequently, and 2.8 (95% CI, 2.6-3.0) for waking early.

Average ratings among nonusers were 2.3 (95% CI, 2.2-2.4), 3.5 (95% CI, 3.3-3.6), and 2.5 (95% CI, 2.3-2.6), respectively.

After 2 years, there were still no statistically significant reductions in sleep disturbances among those taking prescription sleep medications, compared with those not taking medication.

The researchers noted that approximately half of the women in this cohort were current or past tobacco users and that 20% were moderate to heavy alcohol users.
 

More work-up, not more medication, needed

The study authors acknowledged the limitations of an observational study and noted that, since participants only reported medication use and sleep disturbances at annual visits, they did not know whether patients’ medication use was intermittent or of any interim outcomes. Additionally, the authors pointed out that those classified as “nonusers” may have been using over-the-counter medication.

“Investigations should look at detailed-use patterns, on a daily or weekly basis, with frequent outcomes data,” Dr. Solomon said in an interview. “While our data shed new light on chronic use, we only had data collected on an annual basis; daily or weekly data would provide more granular information.”

Regarding clinician prescribing practices, Dr. Solomon said, “short-term, intermittent use can be helpful, but use these agents sparingly” and “educate patients that chronic regular use of medications for sleep is not associated with improvement in sleep disturbances.”

Commenting on the study, Andrea Matsumura, MD, a sleep specialist at the Oregon Clinic in Portland, echoed this sentiment: “When someone says they are having trouble sleeping this is the tip of the iceberg and it warrants an evaluation to determine if someone has a breathing disorder, a circadian disorder, a life situation, or a type of insomnia that is driving the sleeplessness.”

“I think this study supports what we all should know,” Dr. Matsumura concluded. “Sleep aids are not meant to be used long term” and should not be used for longer than 2 weeks without further work-up.

Funding for this study was provided through a grant from the National Institutes of Health. Dr. Solomon has received salary support from research grants to Brigham and Women’s Hospital for unrelated work from AbbVie, Amgen, Corrona, Genentech and Pfizer. The other authors and Dr. Matsumura have reported no relevant financial relationships.

Perimenopausal women are using prescription sleep medications for long periods of time despite no evidence of efficacy, a new study shows.

“While there are good data from [randomized, controlled trials] that these medications improve sleep disturbances in the short term,” few studies have examined whether they provide long-term benefits, stated the authors of the paper, which was published in BMJ Open.

“The current observational study does not support use of sleep medications over the long term, as there were no self-reported differences at 1 or 2 years of follow-up comparing sleep medication users with nonusers,” author Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital, Boston, and colleagues wrote.

Women included in the analysis were drawn from the Study of Women’s Health Across the Nation (SWAN), an ongoing multicenter, longitudinal study examining women during the menopausal transition. The average age of the women included in the cohort was 49.5 years and approximately half were White. All women reported a sleep disturbance on at least 3 nights per week during a 2-week interval. At follow up, women were asked to use a Likert scale to rate three aspects of sleep: difficulty initiating sleep, frequent awakening, and waking up early. On the scale, 1 represented having no difficulties on any nights, 3 represented having difficulties 1-2 nights per week, and 5 represented having difficulty 5-7 nights per week.

Women already using prescription sleep medication at their baseline visit were excluded from the study. Medications used included benzodiazepines, selective BZD receptor agonists, and other hypnotics.

Over the 21 years of follow-up in the SWAN study (1995-2016), Dr. Solomon and colleagues identified 238 women using sleep medication and these were compared with a cohort of 447 propensity score–matched non–sleep medication uses. Overall, the 685 women included were similar in characteristics to each other as well as to the other potentially eligible women not included in the analysis.
 

Sleep disturbance patterns compared

At baseline, sleep disturbance patterns were similar between the two groups. Among medication users, the mean score for difficulty initiating sleep was 2.7 (95% confidence interval, 2.5-2.9), waking frequently 3.8 (95% CI, 3.6-3.9), and waking early 2.9 (95% CI, 2.7-3.1). Among the nonusers, the baseline scores were 2.6 (95% CI, 2.5-2.7), 3.7 (95% CI, 3.6-3.8), and 2.7 (95% CI, 2.5-2.8), respectively. After 1 year, there was no statistically significant difference in scores between the two groups. The average ratings for medication users were 2.6 (95% CI, 2.3-2.8) for difficulty initiating sleep, 3.8 (95% CI, 3.6-4.0) for waking frequently, and 2.8 (95% CI, 2.6-3.0) for waking early.

Average ratings among nonusers were 2.3 (95% CI, 2.2-2.4), 3.5 (95% CI, 3.3-3.6), and 2.5 (95% CI, 2.3-2.6), respectively.

After 2 years, there were still no statistically significant reductions in sleep disturbances among those taking prescription sleep medications, compared with those not taking medication.

The researchers noted that approximately half of the women in this cohort were current or past tobacco users and that 20% were moderate to heavy alcohol users.
 

More work-up, not more medication, needed

The study authors acknowledged the limitations of an observational study and noted that, since participants only reported medication use and sleep disturbances at annual visits, they did not know whether patients’ medication use was intermittent or of any interim outcomes. Additionally, the authors pointed out that those classified as “nonusers” may have been using over-the-counter medication.

“Investigations should look at detailed-use patterns, on a daily or weekly basis, with frequent outcomes data,” Dr. Solomon said in an interview. “While our data shed new light on chronic use, we only had data collected on an annual basis; daily or weekly data would provide more granular information.”

Regarding clinician prescribing practices, Dr. Solomon said, “short-term, intermittent use can be helpful, but use these agents sparingly” and “educate patients that chronic regular use of medications for sleep is not associated with improvement in sleep disturbances.”

Commenting on the study, Andrea Matsumura, MD, a sleep specialist at the Oregon Clinic in Portland, echoed this sentiment: “When someone says they are having trouble sleeping this is the tip of the iceberg and it warrants an evaluation to determine if someone has a breathing disorder, a circadian disorder, a life situation, or a type of insomnia that is driving the sleeplessness.”

“I think this study supports what we all should know,” Dr. Matsumura concluded. “Sleep aids are not meant to be used long term” and should not be used for longer than 2 weeks without further work-up.

Funding for this study was provided through a grant from the National Institutes of Health. Dr. Solomon has received salary support from research grants to Brigham and Women’s Hospital for unrelated work from AbbVie, Amgen, Corrona, Genentech and Pfizer. The other authors and Dr. Matsumura have reported no relevant financial relationships.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

High adolescent body mass index is tied to increasing risks of stroke in young adulthood in both men and women, results of a large, population-based cohort study show.

Copyright American Stroke Association

High and even high-normal body mass index (BMI) were linked to increased ischemic stroke risk, regardless of whether or not individuals had diabetes.

Overweight and obese adolescent groups in the study had a roughly two- to threefold increased risk of ischemic stroke, which was apparent even before age 30 years in the study that was based on records of Israeli adolescents evaluated prior to mandatory military service.

These findings highlight the importance of treating and preventing high BMI among adolescence, study coauthor Gilad Twig, MD, MPH, PhD, said in a press release.

“Adults who survive stroke earlier in life face poor functional outcomes, which can lead to unemployment, depression and anxiety,” said Dr. Twig, associate professor in the department of military medicine in The Hebrew University in Jerusalem.

The costs of stroke prevention and care, already high, are expected to become even higher as the adolescent obesity prevalence goes up, fueling further increases in stroke rate, Dr. Twig added.

This is believed to be the first study showing that stroke risk is associated with higher BMI values in both men and women, not just men, Dr. Twig and coauthors said in their article, published May 13, 2021 in the journal Stroke. Previous studies assessing the stroke-BMI relationship in adolescents were based on records of Swedish men evaluated during military conscription at age 18.

In the present study, Dr. Twig and coauthors assessed the linkage between adolescent BMI and first stroke event in 1.9 million male and female adolescents in Israel who were evaluated 1 year prior to mandatory military service, between the years of 1985 and 2013.

They cross-referenced that information with stroke events in a national registry to which all hospitals in Israel are required to report.

The adolescents were about 17 years of age on average at the time of evaluation, 58% were male, and 84% were born in Israel. The mean age at the beginning of follow-up for stroke was about 31 years.

Over the follow-up period, investigators identified 1,088 first stroke events, including 921 ischemic and 167 hemorrhagic strokes.

A gradual increase in stroke rate was seen across BMI categories for ischemic strokes, but not so much for hemorrhagic strokes, investigators found.

Hazard ratios for first ischemic stroke event were 1.4 (95% confidence interval, 1.2-1.6) for the high-normal BMI group, 2.0 (95% CI, 1.6-2.4) for the overweight group, and 3.5 (95% CI, 2.8-4.5) for the obese group after adjusting for age and sex at beginning of follow-up, investigators reported.

When the adjusted results were stratified by presence or absence of diabetes, estimates were similar to what was seen in the overall risk model, they added.

Among those young adults who developed ischemic stroke, 43% smoked, 29% had high blood pressure, 17% had diabetes, and 32% had abnormal lipids at the time of diagnosis, the reported data showed.

The clinical and public health implications of these findings could be substantial, since strokes are associated with worse medical and socioeconomic outcomes in younger as compared with older individuals, according to Dr. Twig and coauthors.

Younger individuals with stroke have a higher risk of recurrent stroke, heart attack, long-term care, or death, they said. Moreover, about half of young-adult stroke survivors have poor functional outcomes, and their risk of unemployment and depression/anxiety is higher than in young individuals without stroke.

One limitation of the study is that follow-up BMI data were not available for all participants. As a result, the contribution of obesity to stroke risk over time could not be assessed, and the independent risk of BMI during adolescence could not be determined. In addition, the authors said the study underrepresents orthodox and ultraorthodox Jewish women, as they are not obligated to serve in the Israeli military.

The study authors had no disclosures related to the study, which was supported by a medical corps Israel Defense Forces research grant.

High adolescent body mass index is tied to increasing risks of stroke in young adulthood in both men and women, results of a large, population-based cohort study show.

Copyright American Stroke Association

High and even high-normal body mass index (BMI) were linked to increased ischemic stroke risk, regardless of whether or not individuals had diabetes.

Overweight and obese adolescent groups in the study had a roughly two- to threefold increased risk of ischemic stroke, which was apparent even before age 30 years in the study that was based on records of Israeli adolescents evaluated prior to mandatory military service.

These findings highlight the importance of treating and preventing high BMI among adolescence, study coauthor Gilad Twig, MD, MPH, PhD, said in a press release.

“Adults who survive stroke earlier in life face poor functional outcomes, which can lead to unemployment, depression and anxiety,” said Dr. Twig, associate professor in the department of military medicine in The Hebrew University in Jerusalem.

The costs of stroke prevention and care, already high, are expected to become even higher as the adolescent obesity prevalence goes up, fueling further increases in stroke rate, Dr. Twig added.

This is believed to be the first study showing that stroke risk is associated with higher BMI values in both men and women, not just men, Dr. Twig and coauthors said in their article, published May 13, 2021 in the journal Stroke. Previous studies assessing the stroke-BMI relationship in adolescents were based on records of Swedish men evaluated during military conscription at age 18.

In the present study, Dr. Twig and coauthors assessed the linkage between adolescent BMI and first stroke event in 1.9 million male and female adolescents in Israel who were evaluated 1 year prior to mandatory military service, between the years of 1985 and 2013.

They cross-referenced that information with stroke events in a national registry to which all hospitals in Israel are required to report.

The adolescents were about 17 years of age on average at the time of evaluation, 58% were male, and 84% were born in Israel. The mean age at the beginning of follow-up for stroke was about 31 years.

Over the follow-up period, investigators identified 1,088 first stroke events, including 921 ischemic and 167 hemorrhagic strokes.

A gradual increase in stroke rate was seen across BMI categories for ischemic strokes, but not so much for hemorrhagic strokes, investigators found.

Hazard ratios for first ischemic stroke event were 1.4 (95% confidence interval, 1.2-1.6) for the high-normal BMI group, 2.0 (95% CI, 1.6-2.4) for the overweight group, and 3.5 (95% CI, 2.8-4.5) for the obese group after adjusting for age and sex at beginning of follow-up, investigators reported.

When the adjusted results were stratified by presence or absence of diabetes, estimates were similar to what was seen in the overall risk model, they added.

Among those young adults who developed ischemic stroke, 43% smoked, 29% had high blood pressure, 17% had diabetes, and 32% had abnormal lipids at the time of diagnosis, the reported data showed.

The clinical and public health implications of these findings could be substantial, since strokes are associated with worse medical and socioeconomic outcomes in younger as compared with older individuals, according to Dr. Twig and coauthors.

Younger individuals with stroke have a higher risk of recurrent stroke, heart attack, long-term care, or death, they said. Moreover, about half of young-adult stroke survivors have poor functional outcomes, and their risk of unemployment and depression/anxiety is higher than in young individuals without stroke.

One limitation of the study is that follow-up BMI data were not available for all participants. As a result, the contribution of obesity to stroke risk over time could not be assessed, and the independent risk of BMI during adolescence could not be determined. In addition, the authors said the study underrepresents orthodox and ultraorthodox Jewish women, as they are not obligated to serve in the Israeli military.

The study authors had no disclosures related to the study, which was supported by a medical corps Israel Defense Forces research grant.

High adolescent body mass index is tied to increasing risks of stroke in young adulthood in both men and women, results of a large, population-based cohort study show.

Copyright American Stroke Association

High and even high-normal body mass index (BMI) were linked to increased ischemic stroke risk, regardless of whether or not individuals had diabetes.

Overweight and obese adolescent groups in the study had a roughly two- to threefold increased risk of ischemic stroke, which was apparent even before age 30 years in the study that was based on records of Israeli adolescents evaluated prior to mandatory military service.

These findings highlight the importance of treating and preventing high BMI among adolescence, study coauthor Gilad Twig, MD, MPH, PhD, said in a press release.

“Adults who survive stroke earlier in life face poor functional outcomes, which can lead to unemployment, depression and anxiety,” said Dr. Twig, associate professor in the department of military medicine in The Hebrew University in Jerusalem.

The costs of stroke prevention and care, already high, are expected to become even higher as the adolescent obesity prevalence goes up, fueling further increases in stroke rate, Dr. Twig added.

This is believed to be the first study showing that stroke risk is associated with higher BMI values in both men and women, not just men, Dr. Twig and coauthors said in their article, published May 13, 2021 in the journal Stroke. Previous studies assessing the stroke-BMI relationship in adolescents were based on records of Swedish men evaluated during military conscription at age 18.

In the present study, Dr. Twig and coauthors assessed the linkage between adolescent BMI and first stroke event in 1.9 million male and female adolescents in Israel who were evaluated 1 year prior to mandatory military service, between the years of 1985 and 2013.

They cross-referenced that information with stroke events in a national registry to which all hospitals in Israel are required to report.

The adolescents were about 17 years of age on average at the time of evaluation, 58% were male, and 84% were born in Israel. The mean age at the beginning of follow-up for stroke was about 31 years.

Over the follow-up period, investigators identified 1,088 first stroke events, including 921 ischemic and 167 hemorrhagic strokes.

A gradual increase in stroke rate was seen across BMI categories for ischemic strokes, but not so much for hemorrhagic strokes, investigators found.

Hazard ratios for first ischemic stroke event were 1.4 (95% confidence interval, 1.2-1.6) for the high-normal BMI group, 2.0 (95% CI, 1.6-2.4) for the overweight group, and 3.5 (95% CI, 2.8-4.5) for the obese group after adjusting for age and sex at beginning of follow-up, investigators reported.

When the adjusted results were stratified by presence or absence of diabetes, estimates were similar to what was seen in the overall risk model, they added.

Among those young adults who developed ischemic stroke, 43% smoked, 29% had high blood pressure, 17% had diabetes, and 32% had abnormal lipids at the time of diagnosis, the reported data showed.

The clinical and public health implications of these findings could be substantial, since strokes are associated with worse medical and socioeconomic outcomes in younger as compared with older individuals, according to Dr. Twig and coauthors.

Younger individuals with stroke have a higher risk of recurrent stroke, heart attack, long-term care, or death, they said. Moreover, about half of young-adult stroke survivors have poor functional outcomes, and their risk of unemployment and depression/anxiety is higher than in young individuals without stroke.

One limitation of the study is that follow-up BMI data were not available for all participants. As a result, the contribution of obesity to stroke risk over time could not be assessed, and the independent risk of BMI during adolescence could not be determined. In addition, the authors said the study underrepresents orthodox and ultraorthodox Jewish women, as they are not obligated to serve in the Israeli military.

The study authors had no disclosures related to the study, which was supported by a medical corps Israel Defense Forces research grant.

Attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) often coexist in children and adults, but the range of cognitive abilities can vary widely in these patients. Researchers from around the world are leveraging symptom, cognitive assessment, and neurobiological measures to gain insights on how individuals with ADHD/ASD approach and solve problems.

Several experts discussed the progress of their research during the session, “Overlap and differences of ADHD and autism – new findings of functional imaging and cognition studies” at the World Congress on ADHD – Virtual Event.

“The overlap of these two disorders is a critical issue for our field,” said Sarah Karalunas, PhD, assistant professor of clinical psychology at Purdue University, West Lafayette, Ind., who moderated the session. Clinicians are often asked to make differential diagnoses between these two disorders. Only recently has the DSM-5 allowed their codiagnosis. “There’s increasing recognition that there may be shared cognitive and physiological features that reflect their shared risk and account for the high levels of symptom overlap,” said Dr. Karalunas.
 

Shared cognitive markers

Under the DSM’s change, “it’s now recognized that an estimated 20%-60% of children with ASD have comorbidities with ADHD, and around 20%-40% of children with ADHD have ASD symptoms,” said Beth Johnson, PhD, a research fellow with the Turner Institute for Brain and Mental Health at Monash University, Melbourne.

The shared overlap on genetic traits and comorbidities such as intellectual disability, anxiety, depression, and oppositional defiant disorder, make it difficult for clinicians to predict clinical outcomes, noted Dr. Johnson.

“We’re now understanding that they’re likely to be multiple autisms and ADHDs, that these symptoms exist on a spectrum of severity or ability,” she said. Dr. Johnson discussed a data-driven subtyping approach based on neurocognitive and symptom profiles in children with ADHD. The aim was to better understand how symptoms are managed across ADHD, ASD and comorbid ASD-ADHD.

As part of this research, her team recruited 295 controls and 117 children with ADHD who underwent clinical phenotyping and also completed working memory tasks, stop signal, and sustained attention tasks.

The researchers divided the children into four stable clusters based on the ADHD rating scale and autism questionnaire data: high ASD/ADHD traits, high ADHD/low ASD, low ADHD/moderate ASD, and low ADHD/ASD. Approximately half of the children with ADHD showed moderate to high ASD symptoms. Looking at neurocognition across the tasks, unsurprisingly, performance was lowest among the high-ASD/ADHD children, with performance on the stop signal being the most pronounced. “Notably, performance on the working memory task worsened with increasing ADHD symptoms,” she reported.
 

Drift model identifies information processing

Dr. Karalunas has also compared subgroups of ADHD and ASD children. “Our analysis examined whether cognitive impairments in ASD reflect a shared risk mechanism or co-occurring ADHD symptoms and why we see an overlap in these types of impairments,” she said.

Her study included 509 children with ADHD, 97 with ASD, and 301 controls (typical development). All three groups underwent a full cognitive assessment battery that measured attention arousal, basic processing speed, and working memory. Those tasks were collapsed into a series of variables as well as a set of tasks measuring response inhibition, switching, interference control, reward discounting, and measure of reaction time variability.

Four cognitive profiles emerged: a typically developing group, an ADHD group, an ASD group with low levels of ADHD symptoms and an ASD group with high levels of ADHD symptoms.

The ADHD group did worse on many of the tasks than the control group, and the ASD group with low ADHD levels also did poorly relative to the typically developing sample. This shows that autism – even in absence of co-occurring ADHD – demonstrates more cognitive impairment than typically developing kids. The ADHD group with high levels of autism did the most poorly across all of the tasks.

The findings also revealed a symptom severity pattern: the group with fewer symptoms did the best and the group with the most symptoms did the worst. “Overall, this reflects severity of impairment,” said Dr. Karalunas.

To identify measures more specific to either ADHD or autism, Dr. Karalunas and colleagues did a follow-up analysis to characterize cognitive performance. To accomplish this, they applied a drift-diffusion model to the same four cognitive profiles. The model assessed three parameters: drift rate, which relates to the speed or efficiency of information processing, boundary separation or speed accuracy trade-offs (impulsivity), and nondecision time such as motor preparation.

Using the same four cognitive profiles, they found that the ADHD group had slower drift rate relative to the control, although the two groups did not differ on boundary separation, which meant there were no differences on waiting to need to respond. The ADHD group had faster nondecision times. “This is a classic pattern, shown in the literature,” said Dr. Karalunas.
 

In other results, an interesting pattern began to evolve

Both ASD groups, for example, had much wider boundary separations, which meant they were waiting to be sure before they responded than the ADHD or typically developing groups. In contrast, the two ADHD groups had much faster non-decision times, whereas the two non-ADHD groups had similar nondecisions times.

Unlike the previous analysis, which saw a symptom severity pattern develop, “we’re getting two parameters that seem to track much more specifically to specific symptom domains,” observed Dr. Karalunas.

The results suggest there’s a substantial overlap in cognitive impairments in ADHD/ASD. “But we have pretty strong evidence at this point that these similarities are not accounted for by symptom overlap, especially for things like response and inhibition, working memory and processing speed. These seem to be independently related to ADHD and autism, regardless of the level of comorbid ADHD symptoms in the autism group,” said Dr. Karalunas.

The hope is to expand on these types of analyses to address the interaction of cognition-emotion and social cognition, and empirically define groups based on cognitive performance, she said.
 

Neurocognitive studies

Researchers have also been studying neural networks to assess ASD and ADHD. Roselyne Chauvin, PhD, a postdoctoral associate at Washington University, St. Louis, discussed the concept of “a task generic connectome,” in which researchers look for a common network between targeted task paradigms to get closer to a common alteration across impairments.

In her research, Dr. Chauvin and colleagues looked at connectivity modulations across three tasks: working memory, reward processing tasks, and stop signal tasks, comparing ADHD patients to siblings and controls. The ADHD group showed reduced sensitivity or a smaller number of connections modulated in the tasks compared with the other groups. Researchers wondered where those missed connections were located.

Dividing the cohorts into task generic and task specific groups, Dr. Chauvin and colleagues found that the ADHD group lacked common processing skills. They were also able to identify reproducible missing circuits in the ADHD participants. Among the cohorts, there was a higher modulation of task-specific edges in the ADHD group.

The ADHD patients seemed to be using more task-tailored alternative strategies that were more challenging and suboptimal.

She also previewed her ongoing work with the EU-AIMS Longitudinal European Autism Project (LEAP) database to study ASD-ADHD comorbidity. In this project, she and her colleagues looked at several tasks: probing emotion processing, inhibitory control, theory of mind, and reward anticipation. Comparing ASD groups with or without ADHD comorbidity or a shared connection, she and her team were able to devise a functional profile predictive of ADHD severity. As an example, “for the connection only used by the ASD with ADHD comorbidity, the more they were using those connections of higher amplitude in the modulation, inside this subset of connection, the higher they would have ADHD severity,” said Dr. Chauvin.

Neural correlates of different behavioral and cognitive profiles haven’t been widely studied, according to Charlotte Tye, PhD, who’s based at the Institute of Psychiatry, Psychology & Neuroscience, King’s College, London. Electroencephalography is a useful technique for understanding the neural correlates of cognitive impairments and teasing apart different models of co-occurrence in ASD and ADHD. 

Dr. Tye and colleagues tested this approach in a cohort of boys aged 8-13 years diagnosed with ASD and/or ADHD, measuring EEG while the children did various continuous performance tasks to assess changes in brain activity. Examining P3 amplitude (event-related potential components) they found that children with ADHD or ADHD+ASD showed an attenuated amplitude of the P3, compared with typically developing children and those with ASD.

“This suggests children with an ADHD diagnosis exhibited reduced inhibitory control,” said Dr. Tye. In contrast, children with ASD showed reduced conflict monitoring as indexed by altered N2 amplitude across task conditions.

These, and other studies conducted by Dr. Tye and colleagues indicate that children with ADHD show reduced neural responses during attentional processing, whereas autistic children show typical neural responses, supporting specific profiles.

“Autistic children with a diagnosis of ADHD appear to show the unique patterns of neural responses of autism and ADHD, supporting an additive co-occurrence rather than a distinct condition. This contributes to identification of transdiagnostic subgroups within neurodevelopmental conditions for targeting of personalized intervention, and suggests that children with co-occurring autism and ADHD require support for both conditions,” said Dr. Tye.

An important takeaway from all of these findings is “we can’t look just at how someone does overall on a single test,” said Dr. Karalunas in an interview. “There is a tremendous amount of variability between people who have the same diagnosis, and our research really needs to account for this.”

Attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) often coexist in children and adults, but the range of cognitive abilities can vary widely in these patients. Researchers from around the world are leveraging symptom, cognitive assessment, and neurobiological measures to gain insights on how individuals with ADHD/ASD approach and solve problems.

Several experts discussed the progress of their research during the session, “Overlap and differences of ADHD and autism – new findings of functional imaging and cognition studies” at the World Congress on ADHD – Virtual Event.

“The overlap of these two disorders is a critical issue for our field,” said Sarah Karalunas, PhD, assistant professor of clinical psychology at Purdue University, West Lafayette, Ind., who moderated the session. Clinicians are often asked to make differential diagnoses between these two disorders. Only recently has the DSM-5 allowed their codiagnosis. “There’s increasing recognition that there may be shared cognitive and physiological features that reflect their shared risk and account for the high levels of symptom overlap,” said Dr. Karalunas.
 

Shared cognitive markers

Under the DSM’s change, “it’s now recognized that an estimated 20%-60% of children with ASD have comorbidities with ADHD, and around 20%-40% of children with ADHD have ASD symptoms,” said Beth Johnson, PhD, a research fellow with the Turner Institute for Brain and Mental Health at Monash University, Melbourne.

The shared overlap on genetic traits and comorbidities such as intellectual disability, anxiety, depression, and oppositional defiant disorder, make it difficult for clinicians to predict clinical outcomes, noted Dr. Johnson.

“We’re now understanding that they’re likely to be multiple autisms and ADHDs, that these symptoms exist on a spectrum of severity or ability,” she said. Dr. Johnson discussed a data-driven subtyping approach based on neurocognitive and symptom profiles in children with ADHD. The aim was to better understand how symptoms are managed across ADHD, ASD and comorbid ASD-ADHD.

As part of this research, her team recruited 295 controls and 117 children with ADHD who underwent clinical phenotyping and also completed working memory tasks, stop signal, and sustained attention tasks.

The researchers divided the children into four stable clusters based on the ADHD rating scale and autism questionnaire data: high ASD/ADHD traits, high ADHD/low ASD, low ADHD/moderate ASD, and low ADHD/ASD. Approximately half of the children with ADHD showed moderate to high ASD symptoms. Looking at neurocognition across the tasks, unsurprisingly, performance was lowest among the high-ASD/ADHD children, with performance on the stop signal being the most pronounced. “Notably, performance on the working memory task worsened with increasing ADHD symptoms,” she reported.
 

Drift model identifies information processing

Dr. Karalunas has also compared subgroups of ADHD and ASD children. “Our analysis examined whether cognitive impairments in ASD reflect a shared risk mechanism or co-occurring ADHD symptoms and why we see an overlap in these types of impairments,” she said.

Her study included 509 children with ADHD, 97 with ASD, and 301 controls (typical development). All three groups underwent a full cognitive assessment battery that measured attention arousal, basic processing speed, and working memory. Those tasks were collapsed into a series of variables as well as a set of tasks measuring response inhibition, switching, interference control, reward discounting, and measure of reaction time variability.

Four cognitive profiles emerged: a typically developing group, an ADHD group, an ASD group with low levels of ADHD symptoms and an ASD group with high levels of ADHD symptoms.

The ADHD group did worse on many of the tasks than the control group, and the ASD group with low ADHD levels also did poorly relative to the typically developing sample. This shows that autism – even in absence of co-occurring ADHD – demonstrates more cognitive impairment than typically developing kids. The ADHD group with high levels of autism did the most poorly across all of the tasks.

The findings also revealed a symptom severity pattern: the group with fewer symptoms did the best and the group with the most symptoms did the worst. “Overall, this reflects severity of impairment,” said Dr. Karalunas.

To identify measures more specific to either ADHD or autism, Dr. Karalunas and colleagues did a follow-up analysis to characterize cognitive performance. To accomplish this, they applied a drift-diffusion model to the same four cognitive profiles. The model assessed three parameters: drift rate, which relates to the speed or efficiency of information processing, boundary separation or speed accuracy trade-offs (impulsivity), and nondecision time such as motor preparation.

Using the same four cognitive profiles, they found that the ADHD group had slower drift rate relative to the control, although the two groups did not differ on boundary separation, which meant there were no differences on waiting to need to respond. The ADHD group had faster nondecision times. “This is a classic pattern, shown in the literature,” said Dr. Karalunas.
 

In other results, an interesting pattern began to evolve

Both ASD groups, for example, had much wider boundary separations, which meant they were waiting to be sure before they responded than the ADHD or typically developing groups. In contrast, the two ADHD groups had much faster non-decision times, whereas the two non-ADHD groups had similar nondecisions times.

Unlike the previous analysis, which saw a symptom severity pattern develop, “we’re getting two parameters that seem to track much more specifically to specific symptom domains,” observed Dr. Karalunas.

The results suggest there’s a substantial overlap in cognitive impairments in ADHD/ASD. “But we have pretty strong evidence at this point that these similarities are not accounted for by symptom overlap, especially for things like response and inhibition, working memory and processing speed. These seem to be independently related to ADHD and autism, regardless of the level of comorbid ADHD symptoms in the autism group,” said Dr. Karalunas.

The hope is to expand on these types of analyses to address the interaction of cognition-emotion and social cognition, and empirically define groups based on cognitive performance, she said.
 

Neurocognitive studies

Researchers have also been studying neural networks to assess ASD and ADHD. Roselyne Chauvin, PhD, a postdoctoral associate at Washington University, St. Louis, discussed the concept of “a task generic connectome,” in which researchers look for a common network between targeted task paradigms to get closer to a common alteration across impairments.

In her research, Dr. Chauvin and colleagues looked at connectivity modulations across three tasks: working memory, reward processing tasks, and stop signal tasks, comparing ADHD patients to siblings and controls. The ADHD group showed reduced sensitivity or a smaller number of connections modulated in the tasks compared with the other groups. Researchers wondered where those missed connections were located.

Dividing the cohorts into task generic and task specific groups, Dr. Chauvin and colleagues found that the ADHD group lacked common processing skills. They were also able to identify reproducible missing circuits in the ADHD participants. Among the cohorts, there was a higher modulation of task-specific edges in the ADHD group.

The ADHD patients seemed to be using more task-tailored alternative strategies that were more challenging and suboptimal.

She also previewed her ongoing work with the EU-AIMS Longitudinal European Autism Project (LEAP) database to study ASD-ADHD comorbidity. In this project, she and her colleagues looked at several tasks: probing emotion processing, inhibitory control, theory of mind, and reward anticipation. Comparing ASD groups with or without ADHD comorbidity or a shared connection, she and her team were able to devise a functional profile predictive of ADHD severity. As an example, “for the connection only used by the ASD with ADHD comorbidity, the more they were using those connections of higher amplitude in the modulation, inside this subset of connection, the higher they would have ADHD severity,” said Dr. Chauvin.

Neural correlates of different behavioral and cognitive profiles haven’t been widely studied, according to Charlotte Tye, PhD, who’s based at the Institute of Psychiatry, Psychology & Neuroscience, King’s College, London. Electroencephalography is a useful technique for understanding the neural correlates of cognitive impairments and teasing apart different models of co-occurrence in ASD and ADHD. 

Dr. Tye and colleagues tested this approach in a cohort of boys aged 8-13 years diagnosed with ASD and/or ADHD, measuring EEG while the children did various continuous performance tasks to assess changes in brain activity. Examining P3 amplitude (event-related potential components) they found that children with ADHD or ADHD+ASD showed an attenuated amplitude of the P3, compared with typically developing children and those with ASD.

“This suggests children with an ADHD diagnosis exhibited reduced inhibitory control,” said Dr. Tye. In contrast, children with ASD showed reduced conflict monitoring as indexed by altered N2 amplitude across task conditions.

These, and other studies conducted by Dr. Tye and colleagues indicate that children with ADHD show reduced neural responses during attentional processing, whereas autistic children show typical neural responses, supporting specific profiles.

“Autistic children with a diagnosis of ADHD appear to show the unique patterns of neural responses of autism and ADHD, supporting an additive co-occurrence rather than a distinct condition. This contributes to identification of transdiagnostic subgroups within neurodevelopmental conditions for targeting of personalized intervention, and suggests that children with co-occurring autism and ADHD require support for both conditions,” said Dr. Tye.

An important takeaway from all of these findings is “we can’t look just at how someone does overall on a single test,” said Dr. Karalunas in an interview. “There is a tremendous amount of variability between people who have the same diagnosis, and our research really needs to account for this.”

Attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) often coexist in children and adults, but the range of cognitive abilities can vary widely in these patients. Researchers from around the world are leveraging symptom, cognitive assessment, and neurobiological measures to gain insights on how individuals with ADHD/ASD approach and solve problems.

Several experts discussed the progress of their research during the session, “Overlap and differences of ADHD and autism – new findings of functional imaging and cognition studies” at the World Congress on ADHD – Virtual Event.

“The overlap of these two disorders is a critical issue for our field,” said Sarah Karalunas, PhD, assistant professor of clinical psychology at Purdue University, West Lafayette, Ind., who moderated the session. Clinicians are often asked to make differential diagnoses between these two disorders. Only recently has the DSM-5 allowed their codiagnosis. “There’s increasing recognition that there may be shared cognitive and physiological features that reflect their shared risk and account for the high levels of symptom overlap,” said Dr. Karalunas.
 

Shared cognitive markers

Under the DSM’s change, “it’s now recognized that an estimated 20%-60% of children with ASD have comorbidities with ADHD, and around 20%-40% of children with ADHD have ASD symptoms,” said Beth Johnson, PhD, a research fellow with the Turner Institute for Brain and Mental Health at Monash University, Melbourne.

The shared overlap on genetic traits and comorbidities such as intellectual disability, anxiety, depression, and oppositional defiant disorder, make it difficult for clinicians to predict clinical outcomes, noted Dr. Johnson.

“We’re now understanding that they’re likely to be multiple autisms and ADHDs, that these symptoms exist on a spectrum of severity or ability,” she said. Dr. Johnson discussed a data-driven subtyping approach based on neurocognitive and symptom profiles in children with ADHD. The aim was to better understand how symptoms are managed across ADHD, ASD and comorbid ASD-ADHD.

As part of this research, her team recruited 295 controls and 117 children with ADHD who underwent clinical phenotyping and also completed working memory tasks, stop signal, and sustained attention tasks.

The researchers divided the children into four stable clusters based on the ADHD rating scale and autism questionnaire data: high ASD/ADHD traits, high ADHD/low ASD, low ADHD/moderate ASD, and low ADHD/ASD. Approximately half of the children with ADHD showed moderate to high ASD symptoms. Looking at neurocognition across the tasks, unsurprisingly, performance was lowest among the high-ASD/ADHD children, with performance on the stop signal being the most pronounced. “Notably, performance on the working memory task worsened with increasing ADHD symptoms,” she reported.
 

Drift model identifies information processing

Dr. Karalunas has also compared subgroups of ADHD and ASD children. “Our analysis examined whether cognitive impairments in ASD reflect a shared risk mechanism or co-occurring ADHD symptoms and why we see an overlap in these types of impairments,” she said.

Her study included 509 children with ADHD, 97 with ASD, and 301 controls (typical development). All three groups underwent a full cognitive assessment battery that measured attention arousal, basic processing speed, and working memory. Those tasks were collapsed into a series of variables as well as a set of tasks measuring response inhibition, switching, interference control, reward discounting, and measure of reaction time variability.

Four cognitive profiles emerged: a typically developing group, an ADHD group, an ASD group with low levels of ADHD symptoms and an ASD group with high levels of ADHD symptoms.

The ADHD group did worse on many of the tasks than the control group, and the ASD group with low ADHD levels also did poorly relative to the typically developing sample. This shows that autism – even in absence of co-occurring ADHD – demonstrates more cognitive impairment than typically developing kids. The ADHD group with high levels of autism did the most poorly across all of the tasks.

The findings also revealed a symptom severity pattern: the group with fewer symptoms did the best and the group with the most symptoms did the worst. “Overall, this reflects severity of impairment,” said Dr. Karalunas.

To identify measures more specific to either ADHD or autism, Dr. Karalunas and colleagues did a follow-up analysis to characterize cognitive performance. To accomplish this, they applied a drift-diffusion model to the same four cognitive profiles. The model assessed three parameters: drift rate, which relates to the speed or efficiency of information processing, boundary separation or speed accuracy trade-offs (impulsivity), and nondecision time such as motor preparation.

Using the same four cognitive profiles, they found that the ADHD group had slower drift rate relative to the control, although the two groups did not differ on boundary separation, which meant there were no differences on waiting to need to respond. The ADHD group had faster nondecision times. “This is a classic pattern, shown in the literature,” said Dr. Karalunas.
 

In other results, an interesting pattern began to evolve

Both ASD groups, for example, had much wider boundary separations, which meant they were waiting to be sure before they responded than the ADHD or typically developing groups. In contrast, the two ADHD groups had much faster non-decision times, whereas the two non-ADHD groups had similar nondecisions times.

Unlike the previous analysis, which saw a symptom severity pattern develop, “we’re getting two parameters that seem to track much more specifically to specific symptom domains,” observed Dr. Karalunas.

The results suggest there’s a substantial overlap in cognitive impairments in ADHD/ASD. “But we have pretty strong evidence at this point that these similarities are not accounted for by symptom overlap, especially for things like response and inhibition, working memory and processing speed. These seem to be independently related to ADHD and autism, regardless of the level of comorbid ADHD symptoms in the autism group,” said Dr. Karalunas.

The hope is to expand on these types of analyses to address the interaction of cognition-emotion and social cognition, and empirically define groups based on cognitive performance, she said.
 

Neurocognitive studies

Researchers have also been studying neural networks to assess ASD and ADHD. Roselyne Chauvin, PhD, a postdoctoral associate at Washington University, St. Louis, discussed the concept of “a task generic connectome,” in which researchers look for a common network between targeted task paradigms to get closer to a common alteration across impairments.

In her research, Dr. Chauvin and colleagues looked at connectivity modulations across three tasks: working memory, reward processing tasks, and stop signal tasks, comparing ADHD patients to siblings and controls. The ADHD group showed reduced sensitivity or a smaller number of connections modulated in the tasks compared with the other groups. Researchers wondered where those missed connections were located.

Dividing the cohorts into task generic and task specific groups, Dr. Chauvin and colleagues found that the ADHD group lacked common processing skills. They were also able to identify reproducible missing circuits in the ADHD participants. Among the cohorts, there was a higher modulation of task-specific edges in the ADHD group.

The ADHD patients seemed to be using more task-tailored alternative strategies that were more challenging and suboptimal.

She also previewed her ongoing work with the EU-AIMS Longitudinal European Autism Project (LEAP) database to study ASD-ADHD comorbidity. In this project, she and her colleagues looked at several tasks: probing emotion processing, inhibitory control, theory of mind, and reward anticipation. Comparing ASD groups with or without ADHD comorbidity or a shared connection, she and her team were able to devise a functional profile predictive of ADHD severity. As an example, “for the connection only used by the ASD with ADHD comorbidity, the more they were using those connections of higher amplitude in the modulation, inside this subset of connection, the higher they would have ADHD severity,” said Dr. Chauvin.

Neural correlates of different behavioral and cognitive profiles haven’t been widely studied, according to Charlotte Tye, PhD, who’s based at the Institute of Psychiatry, Psychology & Neuroscience, King’s College, London. Electroencephalography is a useful technique for understanding the neural correlates of cognitive impairments and teasing apart different models of co-occurrence in ASD and ADHD. 

Dr. Tye and colleagues tested this approach in a cohort of boys aged 8-13 years diagnosed with ASD and/or ADHD, measuring EEG while the children did various continuous performance tasks to assess changes in brain activity. Examining P3 amplitude (event-related potential components) they found that children with ADHD or ADHD+ASD showed an attenuated amplitude of the P3, compared with typically developing children and those with ASD.

“This suggests children with an ADHD diagnosis exhibited reduced inhibitory control,” said Dr. Tye. In contrast, children with ASD showed reduced conflict monitoring as indexed by altered N2 amplitude across task conditions.

These, and other studies conducted by Dr. Tye and colleagues indicate that children with ADHD show reduced neural responses during attentional processing, whereas autistic children show typical neural responses, supporting specific profiles.

“Autistic children with a diagnosis of ADHD appear to show the unique patterns of neural responses of autism and ADHD, supporting an additive co-occurrence rather than a distinct condition. This contributes to identification of transdiagnostic subgroups within neurodevelopmental conditions for targeting of personalized intervention, and suggests that children with co-occurring autism and ADHD require support for both conditions,” said Dr. Tye.

An important takeaway from all of these findings is “we can’t look just at how someone does overall on a single test,” said Dr. Karalunas in an interview. “There is a tremendous amount of variability between people who have the same diagnosis, and our research really needs to account for this.”

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Chronic insomnia is often underrecognized and misunderstood in primary care, sleep expert Christopher Lettieri, MD, told attendees at the annual meeting of the American College of Physicians.

Too often, medications are the treatment of choice, and when used long term they can perpetuate a problematic cycle, said Dr. Lettieri, professor in pulmonary, critical care, and sleep medicine at Johns Hopkins University, Baltimore.

However, medications alone won’t work without other behavior modifications and they come with potential side effects, he said in his talk. Prescription medications typically don’t treat the cause of the insomnia, just the symptoms.

“In the 15 years I’ve been practicing sleep medicine, I can honestly say I only have a handful of patients that I treat with long-term pharmacotherapy,” Dr. Lettieri said.

He said he typically uses pharmacotherapy only when conservative measures have failed or to help jump-start patients to behavior modifications.

Restricted sleep is a good place to start for chronic insomnia, he continued.

Physicians should ask patients the latest time they can wake up to make it to school, work, etc. If that time is 6 a.m., the goal is to move bedtime back to 10 p.m.–11 p.m. If the patient, however, is unable to sleep until 12:30 a.m., move bedtime there, he said.

Though the 5.5-hour window is not ideal, it’s better to get into bed when ready for sleep. From there, try to get the patient to move bedtime back 15 minutes each week as they train themselves to fall asleep earlier, he said.

“I promise you this works in the majority of patients and doesn’t require any medication. You can also accomplish this with one or two office visits, so it is not a huge drain on resources,” he said.
 

Sleep specialists in short supply

Cognitive-behavioral therapy (CBT) is “without question the best way to treat chronic insomnia and it’s recommended as first-line therapy by all published guidelines,” Dr. Lettieri said.

He defined chronic insomnia as happening most nights over at least 3 months. It affects twice as many women as men.

CBT offers a formalized way of changing sleep patterns with the help of an expert in sleep behavior disorders. It combines cognitive therapies with education about sleep and stimulus control and uses techniques such as mindfulness and relaxation.

However, most programs take 4-8 sessions with a sleep medicine provider and are usually not covered by insurance. In addition, the number of insomnia specialists is not nearly adequate to meet demand, he added.

Online and mobile-platform CBT programs are widely effective, Dr. Lettieri said. Many are free and all are convenient for patients to use. He said many of his patients use Sleepio, but many other online programs are effective.

“You can provide sufficient therapy for many of your patients and reserve CBT for patients who can’t be fixed with more conservative measures,” he said.
 

Insomnia among older patients

Interest in helping older patients with insomnia dominated the chat session associated with the talk.

Insomnia increases with age and older patients have often been using prescription or over-the-counter sleep aids for decades.

Additionally, “insomnia is the second-most common reason why people get admitted to long-term care facilities, second only to urinary incontinence,” Dr. Lettieri said.

If physicians use medications with older patients, he said, extra caution is needed. Older people have more neurocognitive impairments than younger adults and may already be taking several other medications. Sleep medications may come with longer elimination half-lives. Polypharmacy may increase risk for falls and have other consequences.

“If you have to go to a medication, try something simple like melatonin,” he said, adding that it should be pharmaceutical grade and extended release.

Also, bright lights during the day, movement throughout the day, and dim lights closer to bedtime are especially important for the elderly, Dr. Lettieri said.

Andrew Corr, MD, a geriatric specialist in primary care with the Riverside (Calif.) Medical Clinic, said in an interview the main message he will take back to his physician group is more CBT and less medication.

He said that, although he has long known CBT is the top first-line treatment, it is difficult to find experts in his area who are trained to do CBT for insomnia, so he was glad to hear online programs and self-directed reading are typically effective.

He also said there’s a common misperception that there’s no harm in prescribing medications such as trazodone (Desyrel), an antidepressant commonly used off label as a sleep aid.

Dr. Lettieri’s talk highlighted his recommendation against using trazodone for sleep. “Despite several recommendations against its use for insomnia, it is still commonly prescribed. You just shouldn’t use it for insomnia,” Dr. Lettieri said.

“It has no measurable effect in a third of patients and at least unacceptable side effects in another third.  Right off the bat, it’s not efficacious in two thirds of patients.”

Additionally, priapism, a prolonged erection, has been associated with trazodone, Dr. Lettieri said, “and I have literally never met a patient on trazodone who was counseled about this.”

Trazodone also has a black box warning from the Food and Drug Administration warning about increased risk for suicidal thoughts.

Dr. Lettieri and Dr. Corr disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Chronic insomnia is often underrecognized and misunderstood in primary care, sleep expert Christopher Lettieri, MD, told attendees at the annual meeting of the American College of Physicians.

Too often, medications are the treatment of choice, and when used long term they can perpetuate a problematic cycle, said Dr. Lettieri, professor in pulmonary, critical care, and sleep medicine at Johns Hopkins University, Baltimore.

However, medications alone won’t work without other behavior modifications and they come with potential side effects, he said in his talk. Prescription medications typically don’t treat the cause of the insomnia, just the symptoms.

“In the 15 years I’ve been practicing sleep medicine, I can honestly say I only have a handful of patients that I treat with long-term pharmacotherapy,” Dr. Lettieri said.

He said he typically uses pharmacotherapy only when conservative measures have failed or to help jump-start patients to behavior modifications.

Restricted sleep is a good place to start for chronic insomnia, he continued.

Physicians should ask patients the latest time they can wake up to make it to school, work, etc. If that time is 6 a.m., the goal is to move bedtime back to 10 p.m.–11 p.m. If the patient, however, is unable to sleep until 12:30 a.m., move bedtime there, he said.

Though the 5.5-hour window is not ideal, it’s better to get into bed when ready for sleep. From there, try to get the patient to move bedtime back 15 minutes each week as they train themselves to fall asleep earlier, he said.

“I promise you this works in the majority of patients and doesn’t require any medication. You can also accomplish this with one or two office visits, so it is not a huge drain on resources,” he said.
 

Sleep specialists in short supply

Cognitive-behavioral therapy (CBT) is “without question the best way to treat chronic insomnia and it’s recommended as first-line therapy by all published guidelines,” Dr. Lettieri said.

He defined chronic insomnia as happening most nights over at least 3 months. It affects twice as many women as men.

CBT offers a formalized way of changing sleep patterns with the help of an expert in sleep behavior disorders. It combines cognitive therapies with education about sleep and stimulus control and uses techniques such as mindfulness and relaxation.

However, most programs take 4-8 sessions with a sleep medicine provider and are usually not covered by insurance. In addition, the number of insomnia specialists is not nearly adequate to meet demand, he added.

Online and mobile-platform CBT programs are widely effective, Dr. Lettieri said. Many are free and all are convenient for patients to use. He said many of his patients use Sleepio, but many other online programs are effective.

“You can provide sufficient therapy for many of your patients and reserve CBT for patients who can’t be fixed with more conservative measures,” he said.
 

Insomnia among older patients

Interest in helping older patients with insomnia dominated the chat session associated with the talk.

Insomnia increases with age and older patients have often been using prescription or over-the-counter sleep aids for decades.

Additionally, “insomnia is the second-most common reason why people get admitted to long-term care facilities, second only to urinary incontinence,” Dr. Lettieri said.

If physicians use medications with older patients, he said, extra caution is needed. Older people have more neurocognitive impairments than younger adults and may already be taking several other medications. Sleep medications may come with longer elimination half-lives. Polypharmacy may increase risk for falls and have other consequences.

“If you have to go to a medication, try something simple like melatonin,” he said, adding that it should be pharmaceutical grade and extended release.

Also, bright lights during the day, movement throughout the day, and dim lights closer to bedtime are especially important for the elderly, Dr. Lettieri said.

Andrew Corr, MD, a geriatric specialist in primary care with the Riverside (Calif.) Medical Clinic, said in an interview the main message he will take back to his physician group is more CBT and less medication.

He said that, although he has long known CBT is the top first-line treatment, it is difficult to find experts in his area who are trained to do CBT for insomnia, so he was glad to hear online programs and self-directed reading are typically effective.

He also said there’s a common misperception that there’s no harm in prescribing medications such as trazodone (Desyrel), an antidepressant commonly used off label as a sleep aid.

Dr. Lettieri’s talk highlighted his recommendation against using trazodone for sleep. “Despite several recommendations against its use for insomnia, it is still commonly prescribed. You just shouldn’t use it for insomnia,” Dr. Lettieri said.

“It has no measurable effect in a third of patients and at least unacceptable side effects in another third.  Right off the bat, it’s not efficacious in two thirds of patients.”

Additionally, priapism, a prolonged erection, has been associated with trazodone, Dr. Lettieri said, “and I have literally never met a patient on trazodone who was counseled about this.”

Trazodone also has a black box warning from the Food and Drug Administration warning about increased risk for suicidal thoughts.

Dr. Lettieri and Dr. Corr disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Chronic insomnia is often underrecognized and misunderstood in primary care, sleep expert Christopher Lettieri, MD, told attendees at the annual meeting of the American College of Physicians.

Too often, medications are the treatment of choice, and when used long term they can perpetuate a problematic cycle, said Dr. Lettieri, professor in pulmonary, critical care, and sleep medicine at Johns Hopkins University, Baltimore.

However, medications alone won’t work without other behavior modifications and they come with potential side effects, he said in his talk. Prescription medications typically don’t treat the cause of the insomnia, just the symptoms.

“In the 15 years I’ve been practicing sleep medicine, I can honestly say I only have a handful of patients that I treat with long-term pharmacotherapy,” Dr. Lettieri said.

He said he typically uses pharmacotherapy only when conservative measures have failed or to help jump-start patients to behavior modifications.

Restricted sleep is a good place to start for chronic insomnia, he continued.

Physicians should ask patients the latest time they can wake up to make it to school, work, etc. If that time is 6 a.m., the goal is to move bedtime back to 10 p.m.–11 p.m. If the patient, however, is unable to sleep until 12:30 a.m., move bedtime there, he said.

Though the 5.5-hour window is not ideal, it’s better to get into bed when ready for sleep. From there, try to get the patient to move bedtime back 15 minutes each week as they train themselves to fall asleep earlier, he said.

“I promise you this works in the majority of patients and doesn’t require any medication. You can also accomplish this with one or two office visits, so it is not a huge drain on resources,” he said.
 

Sleep specialists in short supply

Cognitive-behavioral therapy (CBT) is “without question the best way to treat chronic insomnia and it’s recommended as first-line therapy by all published guidelines,” Dr. Lettieri said.

He defined chronic insomnia as happening most nights over at least 3 months. It affects twice as many women as men.

CBT offers a formalized way of changing sleep patterns with the help of an expert in sleep behavior disorders. It combines cognitive therapies with education about sleep and stimulus control and uses techniques such as mindfulness and relaxation.

However, most programs take 4-8 sessions with a sleep medicine provider and are usually not covered by insurance. In addition, the number of insomnia specialists is not nearly adequate to meet demand, he added.

Online and mobile-platform CBT programs are widely effective, Dr. Lettieri said. Many are free and all are convenient for patients to use. He said many of his patients use Sleepio, but many other online programs are effective.

“You can provide sufficient therapy for many of your patients and reserve CBT for patients who can’t be fixed with more conservative measures,” he said.
 

Insomnia among older patients

Interest in helping older patients with insomnia dominated the chat session associated with the talk.

Insomnia increases with age and older patients have often been using prescription or over-the-counter sleep aids for decades.

Additionally, “insomnia is the second-most common reason why people get admitted to long-term care facilities, second only to urinary incontinence,” Dr. Lettieri said.

If physicians use medications with older patients, he said, extra caution is needed. Older people have more neurocognitive impairments than younger adults and may already be taking several other medications. Sleep medications may come with longer elimination half-lives. Polypharmacy may increase risk for falls and have other consequences.

“If you have to go to a medication, try something simple like melatonin,” he said, adding that it should be pharmaceutical grade and extended release.

Also, bright lights during the day, movement throughout the day, and dim lights closer to bedtime are especially important for the elderly, Dr. Lettieri said.

Andrew Corr, MD, a geriatric specialist in primary care with the Riverside (Calif.) Medical Clinic, said in an interview the main message he will take back to his physician group is more CBT and less medication.

He said that, although he has long known CBT is the top first-line treatment, it is difficult to find experts in his area who are trained to do CBT for insomnia, so he was glad to hear online programs and self-directed reading are typically effective.

He also said there’s a common misperception that there’s no harm in prescribing medications such as trazodone (Desyrel), an antidepressant commonly used off label as a sleep aid.

Dr. Lettieri’s talk highlighted his recommendation against using trazodone for sleep. “Despite several recommendations against its use for insomnia, it is still commonly prescribed. You just shouldn’t use it for insomnia,” Dr. Lettieri said.

“It has no measurable effect in a third of patients and at least unacceptable side effects in another third.  Right off the bat, it’s not efficacious in two thirds of patients.”

Additionally, priapism, a prolonged erection, has been associated with trazodone, Dr. Lettieri said, “and I have literally never met a patient on trazodone who was counseled about this.”

Trazodone also has a black box warning from the Food and Drug Administration warning about increased risk for suicidal thoughts.

Dr. Lettieri and Dr. Corr disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.