Article

The abnormal upward curve to the fingernails was consistent with a diagnosis of koilonychia—otherwise known as spoon nails.

Koilonychia is an abnormal nail growth pattern where the distal nail matrix is depressed below its normal level, resulting in the spoon shape. The reverse, where the distal nail matrix is elevated in contrast to the proximal nail matrix, results in clubbing.¹

There are multiple factors and diseases that result in koilonychia, including lichen planus, psoriasis, nutritional deficiencies (including iron deficiency anemia), and endocrinopathies.¹ Lichen planus, which can cause koilonychia, often affects multiple nails and can also cause an associated central ridge pattern. Psoriasis may display a range of nail abnormalities; these include koilonychia, pitting onycholysis, and oil staining.

This patient did not have any signs or symptoms of psoriasis or lichen planus of her nails or skin. A review of her laboratory tests on file made no mention of anemia. Her chemistry profile—including liver tests, renal function tests, and protein levels—were all normal except for glucose levels, which was consistent with her prediabetes. Her thyroid function was also normal. No additional testing was performed since she had no symptoms, physical exam findings, or laboratory clues that pointed to other diseases or systemic processes.

The patient was advised to pick up over-the-counter nail strengtheners and to keep her fingernails trimmed short to minimize the likelihood of painful distal splitting that often occurs with brittle nails. Her physician advised her to follow up with the primary care team if she developed any new signs or symptoms.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The abnormal upward curve to the fingernails was consistent with a diagnosis of koilonychia—otherwise known as spoon nails.

Koilonychia is an abnormal nail growth pattern where the distal nail matrix is depressed below its normal level, resulting in the spoon shape. The reverse, where the distal nail matrix is elevated in contrast to the proximal nail matrix, results in clubbing.¹

There are multiple factors and diseases that result in koilonychia, including lichen planus, psoriasis, nutritional deficiencies (including iron deficiency anemia), and endocrinopathies.¹ Lichen planus, which can cause koilonychia, often affects multiple nails and can also cause an associated central ridge pattern. Psoriasis may display a range of nail abnormalities; these include koilonychia, pitting onycholysis, and oil staining.

This patient did not have any signs or symptoms of psoriasis or lichen planus of her nails or skin. A review of her laboratory tests on file made no mention of anemia. Her chemistry profile—including liver tests, renal function tests, and protein levels—were all normal except for glucose levels, which was consistent with her prediabetes. Her thyroid function was also normal. No additional testing was performed since she had no symptoms, physical exam findings, or laboratory clues that pointed to other diseases or systemic processes.

The patient was advised to pick up over-the-counter nail strengtheners and to keep her fingernails trimmed short to minimize the likelihood of painful distal splitting that often occurs with brittle nails. Her physician advised her to follow up with the primary care team if she developed any new signs or symptoms.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The abnormal upward curve to the fingernails was consistent with a diagnosis of koilonychia—otherwise known as spoon nails.

Koilonychia is an abnormal nail growth pattern where the distal nail matrix is depressed below its normal level, resulting in the spoon shape. The reverse, where the distal nail matrix is elevated in contrast to the proximal nail matrix, results in clubbing.¹

There are multiple factors and diseases that result in koilonychia, including lichen planus, psoriasis, nutritional deficiencies (including iron deficiency anemia), and endocrinopathies.¹ Lichen planus, which can cause koilonychia, often affects multiple nails and can also cause an associated central ridge pattern. Psoriasis may display a range of nail abnormalities; these include koilonychia, pitting onycholysis, and oil staining.

This patient did not have any signs or symptoms of psoriasis or lichen planus of her nails or skin. A review of her laboratory tests on file made no mention of anemia. Her chemistry profile—including liver tests, renal function tests, and protein levels—were all normal except for glucose levels, which was consistent with her prediabetes. Her thyroid function was also normal. No additional testing was performed since she had no symptoms, physical exam findings, or laboratory clues that pointed to other diseases or systemic processes.

The patient was advised to pick up over-the-counter nail strengtheners and to keep her fingernails trimmed short to minimize the likelihood of painful distal splitting that often occurs with brittle nails. Her physician advised her to follow up with the primary care team if she developed any new signs or symptoms.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Although an elevated and pigmented lesion should be considered for possible melanoma, this one had prominent telangiectasias and was proven to be a basal cell carcinoma (BCC) on biopsy.

While the literature often focuses on light-colored skin types and the high risk of skin cancers, individuals with darker skin can also get melanoma and nonmelanoma skin cancer. Half of the BCCs in African American people are pigmented BCCs, compared to less than 10% for Caucasian individuals. Individuals who are Hispanic have twice the likelihood of pigmented BCCs as those who are Caucasian.¹ Pigmented BCCs manifest as darker lesions, as occurred in this individual. Nonpigmented BCCs tend to be pink or pale in color.

Typically, superficial and very small, nodular BCCs can be successfully treated with 2 cycles of electrodesiccation and curettage. EDC should, however, be avoided in low-risk BCCs when these lesions occur in areas of secondary hair growth, such as the beard or scalp. This is because the epidermis follows the hair follicle, and in sites with deep hair follicles, EDC would have to get down to the subcutis to effectively clear the tumor.

For larger, nodular BCCs, full-thickness excision with adequate margins is warranted. For high-risk types, and those in high-risk areas near the nose, eyes, mouth, and ears, Mohs micrographic surgery is recommended to maximize the likelihood of complete excision while minimizing the loss of normal tissue.

Since the physician suspected this was a pigmented BCC, he performed a superficial shave biopsy on a small representative area of the lesion for diagnosis. This patient’s biopsy confirmed a nodular-type pigmented BCC. The lesion was removed in the office with 5-mm margins oriented along the resting skin tension lines with good closure and cosmetic results.

The patient was advised to have routine skin evaluations every 6 months due to the high risk of additional cancers. He was also advised to take oral niacinamide 500 mg twice daily, which can reduce the risk of actinic keratoses and nonmelanoma skin cancers by 15% and 23%, respectively, in those who have had lesions.²

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Although an elevated and pigmented lesion should be considered for possible melanoma, this one had prominent telangiectasias and was proven to be a basal cell carcinoma (BCC) on biopsy.

While the literature often focuses on light-colored skin types and the high risk of skin cancers, individuals with darker skin can also get melanoma and nonmelanoma skin cancer. Half of the BCCs in African American people are pigmented BCCs, compared to less than 10% for Caucasian individuals. Individuals who are Hispanic have twice the likelihood of pigmented BCCs as those who are Caucasian.¹ Pigmented BCCs manifest as darker lesions, as occurred in this individual. Nonpigmented BCCs tend to be pink or pale in color.

Typically, superficial and very small, nodular BCCs can be successfully treated with 2 cycles of electrodesiccation and curettage. EDC should, however, be avoided in low-risk BCCs when these lesions occur in areas of secondary hair growth, such as the beard or scalp. This is because the epidermis follows the hair follicle, and in sites with deep hair follicles, EDC would have to get down to the subcutis to effectively clear the tumor.

For larger, nodular BCCs, full-thickness excision with adequate margins is warranted. For high-risk types, and those in high-risk areas near the nose, eyes, mouth, and ears, Mohs micrographic surgery is recommended to maximize the likelihood of complete excision while minimizing the loss of normal tissue.

Since the physician suspected this was a pigmented BCC, he performed a superficial shave biopsy on a small representative area of the lesion for diagnosis. This patient’s biopsy confirmed a nodular-type pigmented BCC. The lesion was removed in the office with 5-mm margins oriented along the resting skin tension lines with good closure and cosmetic results.

The patient was advised to have routine skin evaluations every 6 months due to the high risk of additional cancers. He was also advised to take oral niacinamide 500 mg twice daily, which can reduce the risk of actinic keratoses and nonmelanoma skin cancers by 15% and 23%, respectively, in those who have had lesions.²

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Although an elevated and pigmented lesion should be considered for possible melanoma, this one had prominent telangiectasias and was proven to be a basal cell carcinoma (BCC) on biopsy.

While the literature often focuses on light-colored skin types and the high risk of skin cancers, individuals with darker skin can also get melanoma and nonmelanoma skin cancer. Half of the BCCs in African American people are pigmented BCCs, compared to less than 10% for Caucasian individuals. Individuals who are Hispanic have twice the likelihood of pigmented BCCs as those who are Caucasian.¹ Pigmented BCCs manifest as darker lesions, as occurred in this individual. Nonpigmented BCCs tend to be pink or pale in color.

Typically, superficial and very small, nodular BCCs can be successfully treated with 2 cycles of electrodesiccation and curettage. EDC should, however, be avoided in low-risk BCCs when these lesions occur in areas of secondary hair growth, such as the beard or scalp. This is because the epidermis follows the hair follicle, and in sites with deep hair follicles, EDC would have to get down to the subcutis to effectively clear the tumor.

For larger, nodular BCCs, full-thickness excision with adequate margins is warranted. For high-risk types, and those in high-risk areas near the nose, eyes, mouth, and ears, Mohs micrographic surgery is recommended to maximize the likelihood of complete excision while minimizing the loss of normal tissue.

Since the physician suspected this was a pigmented BCC, he performed a superficial shave biopsy on a small representative area of the lesion for diagnosis. This patient’s biopsy confirmed a nodular-type pigmented BCC. The lesion was removed in the office with 5-mm margins oriented along the resting skin tension lines with good closure and cosmetic results.

The patient was advised to have routine skin evaluations every 6 months due to the high risk of additional cancers. He was also advised to take oral niacinamide 500 mg twice daily, which can reduce the risk of actinic keratoses and nonmelanoma skin cancers by 15% and 23%, respectively, in those who have had lesions.²

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

THE CASE

A 75-year-old man sought care from his primary care physician because his “fingernails and toenails [were] all falling off.” He did not feel ill and had no other complaints. His vital signs were unremarkable. He had no history of malignancies, chronic skin conditions, or systemic diseases. His fingernails and toenails were discolored and lifting from the proximal end of his nail beds (FIGURE). One of his great toenails had already fallen off, 1 thumb nail was minimally attached with the cuticle, and the rest of his nails were loose and in the process of separating from their nail beds. There was no nail pitting, rash, or joint swelling and tenderness.

The patient reported that while on vacation in Hawaii 3 weeks earlier, he had sought care at an urgent care clinic for a painless rash on his hands and the soles of his feet. At that time, he did not feel ill or have mouth ulcers, penile discharge, or arthralgia. There had been no recent changes to his prescription medications, which included finasteride, terazosin, omeprazole, and an albuterol inhaler. He denied taking over-the-counter medications or supplements.

The physical exam at the urgent care had revealed multiple blotchy, dark, 0.5- to 1-cm nonpruritic lesions that were desquamating. No oral lesions were seen. He had been given a diagnosis of hand-foot-mouth disease (HFMD) and reassured that it would resolve on its own in about 10 days.

THE DIAGNOSIS

Several possible diagnoses for nail disorders came to mind with this patient, including onychomycosis, onychoschizia, onycholysis, and onychomadesis.

Onychomycosis is a chronic fungal infection of the nail that affects toenails more often than fingernails.¹ The most common form is distal subungual onychomycosis, which begins distally and slowly migrates proximally through the nail matrix.¹ Often onychomycosis affects only a few nails unless the patient is elderly or has comorbid conditions, and the nails rarely separate from the nail bed.

Onychoschizia involves lamellar splitting and peeling of the dorsal surface of the nail plate.² Usually white discolorations appear on the distal edges of the nail.³ It is more common in women than in men and is often caused by nail dehydration from repeated excessive immersion in water with detergents or recurrent application of nail polish.² However, the nails do not separate from the nail bed, and usually only the fingernails are involved.

Onycholysis is a nail attachment disorder in which the nail plate distally separates from the nail bed. Areas of separation will appear white or yellow. There are many etiologies for onycholysis, including trauma, psoriasis, fungal infection, and contact irritant reactions.³ It also can be caused by medications and thyroid disease.^3,4

Continue to: Onychomadesis

Onychomadesis, sometimes considered a severe form of Beau’s line,^5,6 is defined by the spontaneous separation of the nail plate from the nail matrix. Although the nail will initially remain attached, proximal shedding will eventually occur.⁷ When several nails are involved, a systemic source—such as an acute infection, autoimmune disease, medication, malignancy (eg, cutaneous T-cell lymphoma), Kawasaki disease, skin disorders (eg, pemphigus vulgaris or keratosis punctata et planters), or chemotherapy—may be the cause.^6-8 If only a few nails are involved, it may be associated with trauma, and in rare cases, onychomadesis can be idiopathic.^5,7

In this case, all signs pointed to onychomadesis. All of the patient’s nails were affected (discolored and lifting), his nail loss involved spontaneous proximal separation of the nail plate from the nail matrix, and he had a recent previous infection: HFMD.

DISCUSSION

Onychomadesis is a rare nail-shedding disorder thought to be caused by the temporary arrest of the nail matrix.⁸ It is a potential late complication of infection, such as HFMD,⁹ and was first reported in children in Chicago in 2000.¹⁰ Since then, onychomadesis has been noted in children in many countries.⁸ Reports of onychomadesis following HFMD in adults are rare, but it may be underreported because HFMD is more common in children and symptoms are usually minor in adults.¹¹

Onychomadesis following hand-foot-mouth disease (HFMD) may be underreported in adults because HFMD is more common in children and symptoms in adults are minor.

Molecular studies have associated onychomadesis with coxsackievirus (CV)A6 and CVA10.⁴ Other serotypes associated with onychomadesis include CVB1, CVB2, CVA5, CVA16, and enteroviruses 71 and 9.⁴ Most known outbreaks seem to be caused by CVA6.⁴

No treatment is needed for onychomadesis; physicians can reassure patients that normal nail growth will begin within 1 to 4 months. Because onychomadesis is rare, it does not have its own billing code, so one can use code L60.8 for “Other nail disorders.”¹²

Our patient was seen in the primary care clinic 3 months after his initial visit. At that time, his nails were no longer discolored and no other abnormalities were present. All of the nails on his fingers and toes were firmly attached and growing normally.

THE TAKEAWAY

The sudden asymptomatic loss of multiple fingernails and toenails—especially with proximal nail shedding—is a rare disorder known as onychomadesis. It can be caused by various etiologies and can be a late complication of HFMD or other viral infections. Onychomadesis should be considered when evaluating older patients, particularly when all of their nails are involved after a viral infection.

CORRESPONDENCE
Jon F. Peters, MD, MS, FAAFP, 14486 SE Lyon Court, Happy Valley, OR 97086; peters-nw@comcast.net

THE CASE

A 75-year-old man sought care from his primary care physician because his “fingernails and toenails [were] all falling off.” He did not feel ill and had no other complaints. His vital signs were unremarkable. He had no history of malignancies, chronic skin conditions, or systemic diseases. His fingernails and toenails were discolored and lifting from the proximal end of his nail beds (FIGURE). One of his great toenails had already fallen off, 1 thumb nail was minimally attached with the cuticle, and the rest of his nails were loose and in the process of separating from their nail beds. There was no nail pitting, rash, or joint swelling and tenderness.

The patient reported that while on vacation in Hawaii 3 weeks earlier, he had sought care at an urgent care clinic for a painless rash on his hands and the soles of his feet. At that time, he did not feel ill or have mouth ulcers, penile discharge, or arthralgia. There had been no recent changes to his prescription medications, which included finasteride, terazosin, omeprazole, and an albuterol inhaler. He denied taking over-the-counter medications or supplements.

The physical exam at the urgent care had revealed multiple blotchy, dark, 0.5- to 1-cm nonpruritic lesions that were desquamating. No oral lesions were seen. He had been given a diagnosis of hand-foot-mouth disease (HFMD) and reassured that it would resolve on its own in about 10 days.

THE DIAGNOSIS

Several possible diagnoses for nail disorders came to mind with this patient, including onychomycosis, onychoschizia, onycholysis, and onychomadesis.

Onychomycosis is a chronic fungal infection of the nail that affects toenails more often than fingernails.¹ The most common form is distal subungual onychomycosis, which begins distally and slowly migrates proximally through the nail matrix.¹ Often onychomycosis affects only a few nails unless the patient is elderly or has comorbid conditions, and the nails rarely separate from the nail bed.

Onychoschizia involves lamellar splitting and peeling of the dorsal surface of the nail plate.² Usually white discolorations appear on the distal edges of the nail.³ It is more common in women than in men and is often caused by nail dehydration from repeated excessive immersion in water with detergents or recurrent application of nail polish.² However, the nails do not separate from the nail bed, and usually only the fingernails are involved.

Onycholysis is a nail attachment disorder in which the nail plate distally separates from the nail bed. Areas of separation will appear white or yellow. There are many etiologies for onycholysis, including trauma, psoriasis, fungal infection, and contact irritant reactions.³ It also can be caused by medications and thyroid disease.^3,4

Continue to: Onychomadesis

Onychomadesis, sometimes considered a severe form of Beau’s line,^5,6 is defined by the spontaneous separation of the nail plate from the nail matrix. Although the nail will initially remain attached, proximal shedding will eventually occur.⁷ When several nails are involved, a systemic source—such as an acute infection, autoimmune disease, medication, malignancy (eg, cutaneous T-cell lymphoma), Kawasaki disease, skin disorders (eg, pemphigus vulgaris or keratosis punctata et planters), or chemotherapy—may be the cause.^6-8 If only a few nails are involved, it may be associated with trauma, and in rare cases, onychomadesis can be idiopathic.^5,7

In this case, all signs pointed to onychomadesis. All of the patient’s nails were affected (discolored and lifting), his nail loss involved spontaneous proximal separation of the nail plate from the nail matrix, and he had a recent previous infection: HFMD.

DISCUSSION

Onychomadesis is a rare nail-shedding disorder thought to be caused by the temporary arrest of the nail matrix.⁸ It is a potential late complication of infection, such as HFMD,⁹ and was first reported in children in Chicago in 2000.¹⁰ Since then, onychomadesis has been noted in children in many countries.⁸ Reports of onychomadesis following HFMD in adults are rare, but it may be underreported because HFMD is more common in children and symptoms are usually minor in adults.¹¹

Onychomadesis following hand-foot-mouth disease (HFMD) may be underreported in adults because HFMD is more common in children and symptoms in adults are minor.

Molecular studies have associated onychomadesis with coxsackievirus (CV)A6 and CVA10.⁴ Other serotypes associated with onychomadesis include CVB1, CVB2, CVA5, CVA16, and enteroviruses 71 and 9.⁴ Most known outbreaks seem to be caused by CVA6.⁴

No treatment is needed for onychomadesis; physicians can reassure patients that normal nail growth will begin within 1 to 4 months. Because onychomadesis is rare, it does not have its own billing code, so one can use code L60.8 for “Other nail disorders.”¹²

Our patient was seen in the primary care clinic 3 months after his initial visit. At that time, his nails were no longer discolored and no other abnormalities were present. All of the nails on his fingers and toes were firmly attached and growing normally.

THE TAKEAWAY

The sudden asymptomatic loss of multiple fingernails and toenails—especially with proximal nail shedding—is a rare disorder known as onychomadesis. It can be caused by various etiologies and can be a late complication of HFMD or other viral infections. Onychomadesis should be considered when evaluating older patients, particularly when all of their nails are involved after a viral infection.

CORRESPONDENCE
Jon F. Peters, MD, MS, FAAFP, 14486 SE Lyon Court, Happy Valley, OR 97086; peters-nw@comcast.net

THE CASE

A 75-year-old man sought care from his primary care physician because his “fingernails and toenails [were] all falling off.” He did not feel ill and had no other complaints. His vital signs were unremarkable. He had no history of malignancies, chronic skin conditions, or systemic diseases. His fingernails and toenails were discolored and lifting from the proximal end of his nail beds (FIGURE). One of his great toenails had already fallen off, 1 thumb nail was minimally attached with the cuticle, and the rest of his nails were loose and in the process of separating from their nail beds. There was no nail pitting, rash, or joint swelling and tenderness.

The patient reported that while on vacation in Hawaii 3 weeks earlier, he had sought care at an urgent care clinic for a painless rash on his hands and the soles of his feet. At that time, he did not feel ill or have mouth ulcers, penile discharge, or arthralgia. There had been no recent changes to his prescription medications, which included finasteride, terazosin, omeprazole, and an albuterol inhaler. He denied taking over-the-counter medications or supplements.

The physical exam at the urgent care had revealed multiple blotchy, dark, 0.5- to 1-cm nonpruritic lesions that were desquamating. No oral lesions were seen. He had been given a diagnosis of hand-foot-mouth disease (HFMD) and reassured that it would resolve on its own in about 10 days.

THE DIAGNOSIS

Several possible diagnoses for nail disorders came to mind with this patient, including onychomycosis, onychoschizia, onycholysis, and onychomadesis.

Onychomycosis is a chronic fungal infection of the nail that affects toenails more often than fingernails.¹ The most common form is distal subungual onychomycosis, which begins distally and slowly migrates proximally through the nail matrix.¹ Often onychomycosis affects only a few nails unless the patient is elderly or has comorbid conditions, and the nails rarely separate from the nail bed.

Onychoschizia involves lamellar splitting and peeling of the dorsal surface of the nail plate.² Usually white discolorations appear on the distal edges of the nail.³ It is more common in women than in men and is often caused by nail dehydration from repeated excessive immersion in water with detergents or recurrent application of nail polish.² However, the nails do not separate from the nail bed, and usually only the fingernails are involved.

Onycholysis is a nail attachment disorder in which the nail plate distally separates from the nail bed. Areas of separation will appear white or yellow. There are many etiologies for onycholysis, including trauma, psoriasis, fungal infection, and contact irritant reactions.³ It also can be caused by medications and thyroid disease.^3,4

Continue to: Onychomadesis

Onychomadesis, sometimes considered a severe form of Beau’s line,^5,6 is defined by the spontaneous separation of the nail plate from the nail matrix. Although the nail will initially remain attached, proximal shedding will eventually occur.⁷ When several nails are involved, a systemic source—such as an acute infection, autoimmune disease, medication, malignancy (eg, cutaneous T-cell lymphoma), Kawasaki disease, skin disorders (eg, pemphigus vulgaris or keratosis punctata et planters), or chemotherapy—may be the cause.^6-8 If only a few nails are involved, it may be associated with trauma, and in rare cases, onychomadesis can be idiopathic.^5,7

In this case, all signs pointed to onychomadesis. All of the patient’s nails were affected (discolored and lifting), his nail loss involved spontaneous proximal separation of the nail plate from the nail matrix, and he had a recent previous infection: HFMD.

DISCUSSION

Onychomadesis is a rare nail-shedding disorder thought to be caused by the temporary arrest of the nail matrix.⁸ It is a potential late complication of infection, such as HFMD,⁹ and was first reported in children in Chicago in 2000.¹⁰ Since then, onychomadesis has been noted in children in many countries.⁸ Reports of onychomadesis following HFMD in adults are rare, but it may be underreported because HFMD is more common in children and symptoms are usually minor in adults.¹¹

Onychomadesis following hand-foot-mouth disease (HFMD) may be underreported in adults because HFMD is more common in children and symptoms in adults are minor.

Molecular studies have associated onychomadesis with coxsackievirus (CV)A6 and CVA10.⁴ Other serotypes associated with onychomadesis include CVB1, CVB2, CVA5, CVA16, and enteroviruses 71 and 9.⁴ Most known outbreaks seem to be caused by CVA6.⁴

No treatment is needed for onychomadesis; physicians can reassure patients that normal nail growth will begin within 1 to 4 months. Because onychomadesis is rare, it does not have its own billing code, so one can use code L60.8 for “Other nail disorders.”¹²

Our patient was seen in the primary care clinic 3 months after his initial visit. At that time, his nails were no longer discolored and no other abnormalities were present. All of the nails on his fingers and toes were firmly attached and growing normally.

THE TAKEAWAY

The sudden asymptomatic loss of multiple fingernails and toenails—especially with proximal nail shedding—is a rare disorder known as onychomadesis. It can be caused by various etiologies and can be a late complication of HFMD or other viral infections. Onychomadesis should be considered when evaluating older patients, particularly when all of their nails are involved after a viral infection.

CORRESPONDENCE
Jon F. Peters, MD, MS, FAAFP, 14486 SE Lyon Court, Happy Valley, OR 97086; peters-nw@comcast.net

Evidence summary

Mixed results, Yes, but no evidence of harm in continuing RAAS therapy

A 2014 cohort study assessed the effect of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) on all-cause mortality in US veterans (N = 141,413) with non-dialysis chronic kidney disease (CKD)—defined as either a stable estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² or a stable eGFR ≥ 60 mL/min/1.73 m² and an elevated urine microalbumin measurement.¹ In an intention-to-treat analysis, ACEI/ARB treatment was associated with a significantly decreased risk for all-cause mortality (hazard ratio [HR] = 0.81; 95% CI, 0.78-0.84).

A 2018 meta-analysis analyzed data from 9 RCTs comparing RAAS blockade therapy to placebo or alternative antihypertensive agents in patients with non-dialysis CKD stages 3 to 5.² Although the meta-analysis authors focused on patients with comorbid diabetes and non-dialysis CKD (N = 9797), some included studies had a mixed population (ie, only a subset of patients had diabetes). This, among other variances in characteristics, participants, interventions, and endpoints, resulted in different numbers of participants included in the data extraction and analysis of outcomes. Overall, there was no difference between the RAAS group and the control group in terms of all-cause mortality (N = 5309; risk ratio [RR] = 0.97; 95% CI, 0.85-1.10), cardiovascular mortality (N = 3748; RR = 1.03; 95% CI, 0.75-1.41), or adverse events (N = 1822; RR = 1.05; 95% CI, 0.89-1.25). Compared to the control group, the RAAS group was less likely to experience a nonfatal cardiovascular event (N = 6138; RR = 0.90; 95% CI, 0.81-1.00). For the composite endpoint of need for renal replacement therapy/doubling of serum creatinine, RAAS therapy was associated with reduced risk in both the overall population (N = 5202; RR = 0.81; 95% CI, 0.70-0.92) and in patients with comorbid diabetes (N = 3314; RR = 0.78; 95% CI, 0.67-0.90).

A 2022 open-label trial (STOP ACEi) randomly assigned 411 patients with stage 4 or 5 CKD to either continue (N = 205) or discontinue (N = 206) RAAS inhibitor therapy.³ The primary outcome measure was eGFR at 3 years. The difference in the rate of decline in eGFR between groups was –0.7% (95% CI, –2.5 to 1.0; P = .42), favoring the group that continued therapy.

Recommendations from others

After reviewing data from multiple clinical trials, the authors of the 2018 report from the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF–KDOQI) concluded that the decision to continue or stop RAAS therapy in patients with advanced CKD should be individualized.⁴ Criteria that should be considered in the decision-making process include the presence or absence of large acute declines in eGFR (> 20% in the absence of a significant decrease in proteinuria), hypotension, or acute kidney injury with significant risk for worsening.

In 2021, the Renal Association and the Association of British Clinical Diabetologists published updated clinical practice guidelines for the management of hypertension and RAAS blockade in adults with diabetic kidney disease.⁵ Collective data indicated that, although outcomes varied based on type of diabetes (1 vs 2) and degree of proteinuria, blockade therapy overall led to improved outcomes; this was hypothesized to be due to the effects of reduced blood pressure. However, discontinuation of RAAS blockade therapy may be warranted when the patient (1) has a potassium level > 5 mmol/L pretreatment or ≥ 6 mmol/L with treatment, (2) demonstrates a decrease in eGFR > 25% or an increase in serum creatinine > 30% upon initiation of blockade, without another cause of renal deterioration, (3) is pregnant, or (4) has an acute illness with fluid depletion (in which case, RAAS therapy can be restarted 24 to 48 hours after recovery).

Editor’s takeaway

Evidence supports continuation of RAAS blockade, particularly in patients with significant comorbidities (diabetes and cardiovascular disease). Study data indicate continuation is either beneficial or neutral to further morbidity. The only caveat is that these patients should have their renal function and potassium level continuously monitored. The evidence should provide reassurance to patients and physicians that continuation is the correct course of action.

Evidence summary

Mixed results, Yes, but no evidence of harm in continuing RAAS therapy

A 2014 cohort study assessed the effect of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) on all-cause mortality in US veterans (N = 141,413) with non-dialysis chronic kidney disease (CKD)—defined as either a stable estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² or a stable eGFR ≥ 60 mL/min/1.73 m² and an elevated urine microalbumin measurement.¹ In an intention-to-treat analysis, ACEI/ARB treatment was associated with a significantly decreased risk for all-cause mortality (hazard ratio [HR] = 0.81; 95% CI, 0.78-0.84).

A 2018 meta-analysis analyzed data from 9 RCTs comparing RAAS blockade therapy to placebo or alternative antihypertensive agents in patients with non-dialysis CKD stages 3 to 5.² Although the meta-analysis authors focused on patients with comorbid diabetes and non-dialysis CKD (N = 9797), some included studies had a mixed population (ie, only a subset of patients had diabetes). This, among other variances in characteristics, participants, interventions, and endpoints, resulted in different numbers of participants included in the data extraction and analysis of outcomes. Overall, there was no difference between the RAAS group and the control group in terms of all-cause mortality (N = 5309; risk ratio [RR] = 0.97; 95% CI, 0.85-1.10), cardiovascular mortality (N = 3748; RR = 1.03; 95% CI, 0.75-1.41), or adverse events (N = 1822; RR = 1.05; 95% CI, 0.89-1.25). Compared to the control group, the RAAS group was less likely to experience a nonfatal cardiovascular event (N = 6138; RR = 0.90; 95% CI, 0.81-1.00). For the composite endpoint of need for renal replacement therapy/doubling of serum creatinine, RAAS therapy was associated with reduced risk in both the overall population (N = 5202; RR = 0.81; 95% CI, 0.70-0.92) and in patients with comorbid diabetes (N = 3314; RR = 0.78; 95% CI, 0.67-0.90).

A 2022 open-label trial (STOP ACEi) randomly assigned 411 patients with stage 4 or 5 CKD to either continue (N = 205) or discontinue (N = 206) RAAS inhibitor therapy.³ The primary outcome measure was eGFR at 3 years. The difference in the rate of decline in eGFR between groups was –0.7% (95% CI, –2.5 to 1.0; P = .42), favoring the group that continued therapy.

Recommendations from others

After reviewing data from multiple clinical trials, the authors of the 2018 report from the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF–KDOQI) concluded that the decision to continue or stop RAAS therapy in patients with advanced CKD should be individualized.⁴ Criteria that should be considered in the decision-making process include the presence or absence of large acute declines in eGFR (> 20% in the absence of a significant decrease in proteinuria), hypotension, or acute kidney injury with significant risk for worsening.

In 2021, the Renal Association and the Association of British Clinical Diabetologists published updated clinical practice guidelines for the management of hypertension and RAAS blockade in adults with diabetic kidney disease.⁵ Collective data indicated that, although outcomes varied based on type of diabetes (1 vs 2) and degree of proteinuria, blockade therapy overall led to improved outcomes; this was hypothesized to be due to the effects of reduced blood pressure. However, discontinuation of RAAS blockade therapy may be warranted when the patient (1) has a potassium level > 5 mmol/L pretreatment or ≥ 6 mmol/L with treatment, (2) demonstrates a decrease in eGFR > 25% or an increase in serum creatinine > 30% upon initiation of blockade, without another cause of renal deterioration, (3) is pregnant, or (4) has an acute illness with fluid depletion (in which case, RAAS therapy can be restarted 24 to 48 hours after recovery).

Editor’s takeaway

Evidence supports continuation of RAAS blockade, particularly in patients with significant comorbidities (diabetes and cardiovascular disease). Study data indicate continuation is either beneficial or neutral to further morbidity. The only caveat is that these patients should have their renal function and potassium level continuously monitored. The evidence should provide reassurance to patients and physicians that continuation is the correct course of action.

Evidence summary

Mixed results, Yes, but no evidence of harm in continuing RAAS therapy

A 2014 cohort study assessed the effect of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) on all-cause mortality in US veterans (N = 141,413) with non-dialysis chronic kidney disease (CKD)—defined as either a stable estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² or a stable eGFR ≥ 60 mL/min/1.73 m² and an elevated urine microalbumin measurement.¹ In an intention-to-treat analysis, ACEI/ARB treatment was associated with a significantly decreased risk for all-cause mortality (hazard ratio [HR] = 0.81; 95% CI, 0.78-0.84).

A 2018 meta-analysis analyzed data from 9 RCTs comparing RAAS blockade therapy to placebo or alternative antihypertensive agents in patients with non-dialysis CKD stages 3 to 5.² Although the meta-analysis authors focused on patients with comorbid diabetes and non-dialysis CKD (N = 9797), some included studies had a mixed population (ie, only a subset of patients had diabetes). This, among other variances in characteristics, participants, interventions, and endpoints, resulted in different numbers of participants included in the data extraction and analysis of outcomes. Overall, there was no difference between the RAAS group and the control group in terms of all-cause mortality (N = 5309; risk ratio [RR] = 0.97; 95% CI, 0.85-1.10), cardiovascular mortality (N = 3748; RR = 1.03; 95% CI, 0.75-1.41), or adverse events (N = 1822; RR = 1.05; 95% CI, 0.89-1.25). Compared to the control group, the RAAS group was less likely to experience a nonfatal cardiovascular event (N = 6138; RR = 0.90; 95% CI, 0.81-1.00). For the composite endpoint of need for renal replacement therapy/doubling of serum creatinine, RAAS therapy was associated with reduced risk in both the overall population (N = 5202; RR = 0.81; 95% CI, 0.70-0.92) and in patients with comorbid diabetes (N = 3314; RR = 0.78; 95% CI, 0.67-0.90).

A 2022 open-label trial (STOP ACEi) randomly assigned 411 patients with stage 4 or 5 CKD to either continue (N = 205) or discontinue (N = 206) RAAS inhibitor therapy.³ The primary outcome measure was eGFR at 3 years. The difference in the rate of decline in eGFR between groups was –0.7% (95% CI, –2.5 to 1.0; P = .42), favoring the group that continued therapy.

Recommendations from others

After reviewing data from multiple clinical trials, the authors of the 2018 report from the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF–KDOQI) concluded that the decision to continue or stop RAAS therapy in patients with advanced CKD should be individualized.⁴ Criteria that should be considered in the decision-making process include the presence or absence of large acute declines in eGFR (> 20% in the absence of a significant decrease in proteinuria), hypotension, or acute kidney injury with significant risk for worsening.

In 2021, the Renal Association and the Association of British Clinical Diabetologists published updated clinical practice guidelines for the management of hypertension and RAAS blockade in adults with diabetic kidney disease.⁵ Collective data indicated that, although outcomes varied based on type of diabetes (1 vs 2) and degree of proteinuria, blockade therapy overall led to improved outcomes; this was hypothesized to be due to the effects of reduced blood pressure. However, discontinuation of RAAS blockade therapy may be warranted when the patient (1) has a potassium level > 5 mmol/L pretreatment or ≥ 6 mmol/L with treatment, (2) demonstrates a decrease in eGFR > 25% or an increase in serum creatinine > 30% upon initiation of blockade, without another cause of renal deterioration, (3) is pregnant, or (4) has an acute illness with fluid depletion (in which case, RAAS therapy can be restarted 24 to 48 hours after recovery).

Editor’s takeaway

Evidence supports continuation of RAAS blockade, particularly in patients with significant comorbidities (diabetes and cardiovascular disease). Study data indicate continuation is either beneficial or neutral to further morbidity. The only caveat is that these patients should have their renal function and potassium level continuously monitored. The evidence should provide reassurance to patients and physicians that continuation is the correct course of action.

Approximately 6.5 million people in the United States have an intellectual disability, the most common type of developmental disability.¹ People with disabilities are 3 times more likely to have heart disease, stroke, or diabetes than adults without disabilities.²

Sports as a treatment modality are not used to full advantage to combat these conditions in people with intellectual/developmental disabilities (IDDs). Participation in sport activities can lead to weight loss, reduce risk for cardiovascular disease, and optimize physical health. Sports also can help enhance social and communication skills and improve quality of life for this patient population (TABLE).^3-6 

However, a 2014 report found that while inactive adults with disabilities (hearing, vision, cognition, mobility) were 50% more likely to report 1 or more chronic diseases than those who were physically active, only 44% of adults with disabilities who visited a health professional in the previous 12 months received a physical activity recommendation.⁷  In addition, more than 50% of adults with disabilities are not meeting US recommended exercise guidelines.^7-9

Family physicians may not feel they have adequate training to counsel patients with IDDs. Additional limiting factors include dependence on caregivers for exercise participation, expense, transportation difficulties, a lack of choice in sporting activities, and the patient’s level of motivation.¹⁰The guidance reviewed here details how to modify the pre-participation sports physical exam specifically for patients with IDDs. It also provides sport and exercise recommendations for patients with 3 disabilities: Down syndrome, cerebral palsy, and autism spectrum disorder.

Worth noting: As is true for adults without disabilities, those with IDDs should participate in at least 150 minutes of moderate-intensity, or 75 minutes of vigorous intensity, aerobic physical activity each week.⁹ Recommend muscle-­strengthening activities be performed at least 2 days each week.⁹

Exercise recommendations for patients with Down syndrome

One in every 700 babies receives a diagnosis of Down syndrome.¹¹ Among its many possible manifestations—which include intellectual disability, heart disease, and diabetes—Down syndrome is associated with an increased risk for obesity, which makes exercise an extremely important lifestyle modification for these patients. Obesity can lead to obstructive sleep apnea causing cor pulmonale and even premature death. Continuous positive airway pressure intervention can be difficult in terms of patient compliance. However, weight loss through exercise and sports is an effective intervention to mitigate these obesity-related health comorbidities. 

Pre-participation exam. A focused history and physical exam are often conducted before a patient engages in organized competitive or recreational sports. The pre-­participation sports physical exam typically focuses on cardiac, neurologic, hereditary, and musculoskeletal disorders. While we recommend including these baseline elements as part of the exam for patients with disabilities, we also recommend modifying the exam to include disability-specific screening for associated comorbidities.

Continue to: For patients with Down syndrome...

For patients with Down syndrome, a complete pre-participation sports physical exam is warranted. Inquire specifically about neck pain or dislocations, heart murmur, cardiac surgery, seizures, sleep issues, history of congenital abdominal defect, hematologic malignancy, and bone pain as part of the focused physical exam.

Look for evidence of patellofemoral instability, pes planus, scoliosis, hallux deformities, decreased muscle tone, and muscular weakness. Check for cataracts and perform a thorough cardiovascular exam to assess for murmur or signs of chronic hypoxia, such as cyanosis. If a heart murmur is detected, refer the patient to a cardiologist.

Patients with Down syndrome are also at increased risk for atlantoaxial instability. A thorough neurologic evaluation to screen for this condition is indicated; however, routine radiologic screening is not needed.¹²

An annual complete blood cell count and thyroid-stimulating hormone test are recommended for all children with Down syndrome.¹³ For patients with Down syndrome who are 13 to 21 years of age, an echocardiogram also is recommended for concerning symptoms.¹³ Ferritin levels also should be assessed annually for patients who are younger than 13 years of age to check for iron-deficiency anemia.¹³ Consider high-risk screening strategies for patients with diabetes and metabolic syndrome.

Special considerations. Patients with Down syndrome were found to be injured more frequently than individuals with other disabilities during the Special Olympics.¹⁴ These patients may be hypersensitive to pain with prolonged pain responses, or unable to verbally communicate their pain or injury.¹⁵

Continue to: The complexity of pain assessment...

The complexity of pain assessment in patients with Down syndrome may increase the difficulty of accurately diagnosing an injury, leading to underdiagnosis or overdiagnosis. To increase accuracy of pain assessment in this setting, we recommend using the Wong-Baker FACES Pain Rating Scale or a numeric pain rating scale in verbal patients.¹⁵ In nonverbal patients, facial expressions are reliable indicators of pain.

Which exercise? Healthy patients with Down syndrome can participate in any sport. Aerobic exercise can help lower body fat, reduce oxidative stress, and improve blood flow.⁶ Muscle-strengthening exercises can lead to improved daily functioning and balance. Strength training and aerobic exercise benefit aging patients with Down syndrome who are struggling with obesity. Such exercise also helps increase bone mineral density and improve cardiovascular fitness, especially when initiated at a young age. Consistent exercise promotes positive health outcomes throughout the lifespan.¹⁶

Exercise recommendations for patients with cerebral palsy

Cerebral palsy, the most common motor disability in children, is associated with intellectual disability, seizures, respiratory insufficiency, scoliosis, osteoporosis, mood disorders, dysphagia, and speech and hearing impairment.¹⁷ The increasing survival of premature babies born with cerebral palsy and the growing prevalence of adults with the condition point to the importance of expanding one’s knowledge of how best to care for this population.¹⁸

Pre-participation exam. In addition to a complete sport physical exam, it’s important to further evaluate patients with cerebral palsy for epilepsy, joint contractures, muscle weakness, spinal deformities, and respiratory insufficiency. The Gross Motor Function Classification system, commonly used for patients with cerebral palsy, scores functional ability in 5 levels.¹⁸ Patients at Level I are the most mobile; patients at Level V need wheelchair transport in all settings.

Consider sports and exercise a vital therapeutic modality— something beyond a form of recreation.

Further evaluation of spinal deformities can be initiated with x-ray screening. Consider ordering dual x-ray absorptiometry scans to evaluate bone mass.¹⁷

Continue to: Special considerations

Special considerations. Patients with cerebral palsy have a heightened risk for depression and anxiety.¹⁹ Mental health can be assessed via the General Anxiety Disorder-7, the Patient Health ­Questionnaire-9, and the Ask Suicide-­Screening Questions tools, among others. Mental health screening may need to be adjusted depending on the patient’s level of cognition and ability to communicate. The patient’s caregiver also can provide supplemental information.

Consider screening vitamin D levels in patients with cerebral palsy. Approximately 50% of adults with cerebral palsy are vitamin D–deficient secondary to sedentary behavior and lack of sun exposure.^20-22

Optimal medical management has been shown to decrease muscle spasticity and may be beneficial before initiating an exercise program. For patients with moderate-to-­severe symptoms, referral for physical therapy to further improve gross motor function and spasticity may be required before initiating an exercise program.

Which exercise? Individuals with cerebral palsy spend 76% to 99% of their waking hours being sedentary.⁵   Consequently, they typically have decreased cardiorespiratory endurance and decreased muscle strength. Strength training may improve muscle spasticity, gross motor function, joint health, and respiratory insufficiency.⁵ Even in those who function at Level IV-V of the Gross Motor Function Classification system, exercise reduces vertebral fractures and improves time spent standing.²³ By improving endurance, spasticity, and strength with exercise, deconditioning can be mitigated.

Involvement in sports promotes peer interactions, personal interests, and positive self-identity. It can give a newfound passion for life. Additionally, families of children with disabilities who engage in leisure activities together have less caregiver burden.^24,25 Sporting activities offer a way to optimize psychosocial well-being for the patient and the entire family.

Continue to: Dance promotes functionality...

Dance promotes functionality and psychosocial adjustment.²⁶ Hippotherapy, defined as therapy and rehabilitation during which the patient interacts with horses, can diminish muscle spasticity.²⁷ Aquatic therapy also may increase muscle strength.²⁸

Sports for patients with autism spectrum disorder

Autism spectrum disorder is defined as persistent deficits in social communication and social interaction that are usually evident in the first 3 years of life.²⁹ Autism can manifest with or without intellectual or language impairment. Patients with autism commonly have difficulty processing sensory stimuli and can experience “sensory overload.” More than half have a coexisting mental health disorder, such as attention-deficit/hyperactivity disorder, anxiety, depression, schizophrenia, or bipolar disorder.³⁰

Vigorous exercise is associated with a reduction in stereotypic behaviors, hyperactivity, aggression, and self-injury in patients with autism spectrum disorder.

Aversions to foods and food selectivity, as well as adverse effects from medical treatment of autism-related agitation, result in a higher incidence of obesity in patients with autism.^31,32 

Pre-participation exam. In addition to a comprehensive pre-participation exam, the Autism Spectrum Syndrome Questionnaire (ASSQ) and Modified Checklist for Autism in Toddlers are tools to screen school-age children with normal cognition to mild intellectual disability.³³ These questionnaires have limitations, however. For example, ASSQ has limited ability to identify the female autistic phenotype.³⁴ As such, these are solely screening tools. Final diagnosis is based on clinical judgment.

Special considerations. Include screening for constipation or diarrhea, fiber intake, food aversions, and common mental health comorbidities using Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria.²⁹ Psychiatric referral may be necessary if certain previously undiagnosed condition(s) become apparent. The patient’s caregiver can provide supplemental information 

Continue to: During the physical exam...

During the physical exam, limit sensory stimuli as much as possible, including lights and sounds. Verbalize components of the exam before touching a patient with autism who is sensitive to physical touch.

Which exercise? Participation in sports is an effective therapy for autism and can help patients develop communication skills and promote socialization. Vigorous exercise is associated with a reduction in stereotypic behaviors, hyperactivity, aggression, and self-injury.³ Sports also can offer an alternative channel for social interaction. Children with autism may have impaired or delayed motor skills, and exercise can improve motor skill proficiency.⁴

The prevalence of feeding problems in children with autism spectrum disorder is estimated to be as high as 90%, and close to 70% are selective eaters.^31,35,36 For those with gastrointestinal disorders, exercise can exert positive effects on the microbiome-gut-brain axis.³⁷ Additionally, patients with autism are much more likely to be overweight or obese.³² Physical activity offers those with autism health benefits similar to those for the general population.³²

Children with autism spectrum disorder have similar odds of injury, including serious injury, relative to population controls.³⁸ Karate and swimming are among the most researched sports therapy options for patients with autism.^38-40 Both are shown to improve motor ability and reduce communication deficits. 

Summing up

The literature, although limited, demonstrates that exercise and sports improve the health and well-being of people with IDDs throughout the lifespan, especially if childhood exercise/­sports involvement is maintained.

Exercise participation increases based on the individual’s desire to be fit and active, skills practice, peer involvement, family support, accessible facilities, and skilled staff.

Encourage your patients to participate in sports, but be aware of factors that can limit (or facilitate) participation.⁴¹ Exercise participation increases based on, among other things, the individual’s desire to be fit and active, skills practice, peer involvement, family support, accessible facilities, and skilled staff.¹⁰

Additional resources that can help people with IDDs access sports and recreational activities include the Special Olympics; Paralympics; YMCA; after-school programs; The American College of Sports Medicine; The National Center on Health, Physical Activity, and Disability; and disability-certified inclusive fitness trainers.

CORRESPONDENCE 
Kristina Jones, BS, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612; kjones15@usf.edu

Approximately 6.5 million people in the United States have an intellectual disability, the most common type of developmental disability.¹ People with disabilities are 3 times more likely to have heart disease, stroke, or diabetes than adults without disabilities.²

Sports as a treatment modality are not used to full advantage to combat these conditions in people with intellectual/developmental disabilities (IDDs). Participation in sport activities can lead to weight loss, reduce risk for cardiovascular disease, and optimize physical health. Sports also can help enhance social and communication skills and improve quality of life for this patient population (TABLE).^3-6 

However, a 2014 report found that while inactive adults with disabilities (hearing, vision, cognition, mobility) were 50% more likely to report 1 or more chronic diseases than those who were physically active, only 44% of adults with disabilities who visited a health professional in the previous 12 months received a physical activity recommendation.⁷  In addition, more than 50% of adults with disabilities are not meeting US recommended exercise guidelines.^7-9

Family physicians may not feel they have adequate training to counsel patients with IDDs. Additional limiting factors include dependence on caregivers for exercise participation, expense, transportation difficulties, a lack of choice in sporting activities, and the patient’s level of motivation.¹⁰The guidance reviewed here details how to modify the pre-participation sports physical exam specifically for patients with IDDs. It also provides sport and exercise recommendations for patients with 3 disabilities: Down syndrome, cerebral palsy, and autism spectrum disorder.

Worth noting: As is true for adults without disabilities, those with IDDs should participate in at least 150 minutes of moderate-intensity, or 75 minutes of vigorous intensity, aerobic physical activity each week.⁹ Recommend muscle-­strengthening activities be performed at least 2 days each week.⁹

Exercise recommendations for patients with Down syndrome

One in every 700 babies receives a diagnosis of Down syndrome.¹¹ Among its many possible manifestations—which include intellectual disability, heart disease, and diabetes—Down syndrome is associated with an increased risk for obesity, which makes exercise an extremely important lifestyle modification for these patients. Obesity can lead to obstructive sleep apnea causing cor pulmonale and even premature death. Continuous positive airway pressure intervention can be difficult in terms of patient compliance. However, weight loss through exercise and sports is an effective intervention to mitigate these obesity-related health comorbidities. 

Pre-participation exam. A focused history and physical exam are often conducted before a patient engages in organized competitive or recreational sports. The pre-­participation sports physical exam typically focuses on cardiac, neurologic, hereditary, and musculoskeletal disorders. While we recommend including these baseline elements as part of the exam for patients with disabilities, we also recommend modifying the exam to include disability-specific screening for associated comorbidities.

Continue to: For patients with Down syndrome...

For patients with Down syndrome, a complete pre-participation sports physical exam is warranted. Inquire specifically about neck pain or dislocations, heart murmur, cardiac surgery, seizures, sleep issues, history of congenital abdominal defect, hematologic malignancy, and bone pain as part of the focused physical exam.

Look for evidence of patellofemoral instability, pes planus, scoliosis, hallux deformities, decreased muscle tone, and muscular weakness. Check for cataracts and perform a thorough cardiovascular exam to assess for murmur or signs of chronic hypoxia, such as cyanosis. If a heart murmur is detected, refer the patient to a cardiologist.

Patients with Down syndrome are also at increased risk for atlantoaxial instability. A thorough neurologic evaluation to screen for this condition is indicated; however, routine radiologic screening is not needed.¹²

An annual complete blood cell count and thyroid-stimulating hormone test are recommended for all children with Down syndrome.¹³ For patients with Down syndrome who are 13 to 21 years of age, an echocardiogram also is recommended for concerning symptoms.¹³ Ferritin levels also should be assessed annually for patients who are younger than 13 years of age to check for iron-deficiency anemia.¹³ Consider high-risk screening strategies for patients with diabetes and metabolic syndrome.

Special considerations. Patients with Down syndrome were found to be injured more frequently than individuals with other disabilities during the Special Olympics.¹⁴ These patients may be hypersensitive to pain with prolonged pain responses, or unable to verbally communicate their pain or injury.¹⁵

Continue to: The complexity of pain assessment...

The complexity of pain assessment in patients with Down syndrome may increase the difficulty of accurately diagnosing an injury, leading to underdiagnosis or overdiagnosis. To increase accuracy of pain assessment in this setting, we recommend using the Wong-Baker FACES Pain Rating Scale or a numeric pain rating scale in verbal patients.¹⁵ In nonverbal patients, facial expressions are reliable indicators of pain.

Which exercise? Healthy patients with Down syndrome can participate in any sport. Aerobic exercise can help lower body fat, reduce oxidative stress, and improve blood flow.⁶ Muscle-strengthening exercises can lead to improved daily functioning and balance. Strength training and aerobic exercise benefit aging patients with Down syndrome who are struggling with obesity. Such exercise also helps increase bone mineral density and improve cardiovascular fitness, especially when initiated at a young age. Consistent exercise promotes positive health outcomes throughout the lifespan.¹⁶

Exercise recommendations for patients with cerebral palsy

Cerebral palsy, the most common motor disability in children, is associated with intellectual disability, seizures, respiratory insufficiency, scoliosis, osteoporosis, mood disorders, dysphagia, and speech and hearing impairment.¹⁷ The increasing survival of premature babies born with cerebral palsy and the growing prevalence of adults with the condition point to the importance of expanding one’s knowledge of how best to care for this population.¹⁸

Pre-participation exam. In addition to a complete sport physical exam, it’s important to further evaluate patients with cerebral palsy for epilepsy, joint contractures, muscle weakness, spinal deformities, and respiratory insufficiency. The Gross Motor Function Classification system, commonly used for patients with cerebral palsy, scores functional ability in 5 levels.¹⁸ Patients at Level I are the most mobile; patients at Level V need wheelchair transport in all settings.

Consider sports and exercise a vital therapeutic modality— something beyond a form of recreation.

Further evaluation of spinal deformities can be initiated with x-ray screening. Consider ordering dual x-ray absorptiometry scans to evaluate bone mass.¹⁷

Continue to: Special considerations

Special considerations. Patients with cerebral palsy have a heightened risk for depression and anxiety.¹⁹ Mental health can be assessed via the General Anxiety Disorder-7, the Patient Health ­Questionnaire-9, and the Ask Suicide-­Screening Questions tools, among others. Mental health screening may need to be adjusted depending on the patient’s level of cognition and ability to communicate. The patient’s caregiver also can provide supplemental information.

Consider screening vitamin D levels in patients with cerebral palsy. Approximately 50% of adults with cerebral palsy are vitamin D–deficient secondary to sedentary behavior and lack of sun exposure.^20-22

Optimal medical management has been shown to decrease muscle spasticity and may be beneficial before initiating an exercise program. For patients with moderate-to-­severe symptoms, referral for physical therapy to further improve gross motor function and spasticity may be required before initiating an exercise program.

Which exercise? Individuals with cerebral palsy spend 76% to 99% of their waking hours being sedentary.⁵   Consequently, they typically have decreased cardiorespiratory endurance and decreased muscle strength. Strength training may improve muscle spasticity, gross motor function, joint health, and respiratory insufficiency.⁵ Even in those who function at Level IV-V of the Gross Motor Function Classification system, exercise reduces vertebral fractures and improves time spent standing.²³ By improving endurance, spasticity, and strength with exercise, deconditioning can be mitigated.

Involvement in sports promotes peer interactions, personal interests, and positive self-identity. It can give a newfound passion for life. Additionally, families of children with disabilities who engage in leisure activities together have less caregiver burden.^24,25 Sporting activities offer a way to optimize psychosocial well-being for the patient and the entire family.

Continue to: Dance promotes functionality...

Dance promotes functionality and psychosocial adjustment.²⁶ Hippotherapy, defined as therapy and rehabilitation during which the patient interacts with horses, can diminish muscle spasticity.²⁷ Aquatic therapy also may increase muscle strength.²⁸

Sports for patients with autism spectrum disorder

Autism spectrum disorder is defined as persistent deficits in social communication and social interaction that are usually evident in the first 3 years of life.²⁹ Autism can manifest with or without intellectual or language impairment. Patients with autism commonly have difficulty processing sensory stimuli and can experience “sensory overload.” More than half have a coexisting mental health disorder, such as attention-deficit/hyperactivity disorder, anxiety, depression, schizophrenia, or bipolar disorder.³⁰

Vigorous exercise is associated with a reduction in stereotypic behaviors, hyperactivity, aggression, and self-injury in patients with autism spectrum disorder.

Aversions to foods and food selectivity, as well as adverse effects from medical treatment of autism-related agitation, result in a higher incidence of obesity in patients with autism.^31,32 

Pre-participation exam. In addition to a comprehensive pre-participation exam, the Autism Spectrum Syndrome Questionnaire (ASSQ) and Modified Checklist for Autism in Toddlers are tools to screen school-age children with normal cognition to mild intellectual disability.³³ These questionnaires have limitations, however. For example, ASSQ has limited ability to identify the female autistic phenotype.³⁴ As such, these are solely screening tools. Final diagnosis is based on clinical judgment.

Special considerations. Include screening for constipation or diarrhea, fiber intake, food aversions, and common mental health comorbidities using Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria.²⁹ Psychiatric referral may be necessary if certain previously undiagnosed condition(s) become apparent. The patient’s caregiver can provide supplemental information 

Continue to: During the physical exam...

During the physical exam, limit sensory stimuli as much as possible, including lights and sounds. Verbalize components of the exam before touching a patient with autism who is sensitive to physical touch.

Which exercise? Participation in sports is an effective therapy for autism and can help patients develop communication skills and promote socialization. Vigorous exercise is associated with a reduction in stereotypic behaviors, hyperactivity, aggression, and self-injury.³ Sports also can offer an alternative channel for social interaction. Children with autism may have impaired or delayed motor skills, and exercise can improve motor skill proficiency.⁴

The prevalence of feeding problems in children with autism spectrum disorder is estimated to be as high as 90%, and close to 70% are selective eaters.^31,35,36 For those with gastrointestinal disorders, exercise can exert positive effects on the microbiome-gut-brain axis.³⁷ Additionally, patients with autism are much more likely to be overweight or obese.³² Physical activity offers those with autism health benefits similar to those for the general population.³²

Children with autism spectrum disorder have similar odds of injury, including serious injury, relative to population controls.³⁸ Karate and swimming are among the most researched sports therapy options for patients with autism.^38-40 Both are shown to improve motor ability and reduce communication deficits. 

Summing up

The literature, although limited, demonstrates that exercise and sports improve the health and well-being of people with IDDs throughout the lifespan, especially if childhood exercise/­sports involvement is maintained.

Exercise participation increases based on the individual’s desire to be fit and active, skills practice, peer involvement, family support, accessible facilities, and skilled staff.

Encourage your patients to participate in sports, but be aware of factors that can limit (or facilitate) participation.⁴¹ Exercise participation increases based on, among other things, the individual’s desire to be fit and active, skills practice, peer involvement, family support, accessible facilities, and skilled staff.¹⁰

Additional resources that can help people with IDDs access sports and recreational activities include the Special Olympics; Paralympics; YMCA; after-school programs; The American College of Sports Medicine; The National Center on Health, Physical Activity, and Disability; and disability-certified inclusive fitness trainers.

CORRESPONDENCE 
Kristina Jones, BS, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612; kjones15@usf.edu

Approximately 6.5 million people in the United States have an intellectual disability, the most common type of developmental disability.¹ People with disabilities are 3 times more likely to have heart disease, stroke, or diabetes than adults without disabilities.²

Sports as a treatment modality are not used to full advantage to combat these conditions in people with intellectual/developmental disabilities (IDDs). Participation in sport activities can lead to weight loss, reduce risk for cardiovascular disease, and optimize physical health. Sports also can help enhance social and communication skills and improve quality of life for this patient population (TABLE).^3-6 

However, a 2014 report found that while inactive adults with disabilities (hearing, vision, cognition, mobility) were 50% more likely to report 1 or more chronic diseases than those who were physically active, only 44% of adults with disabilities who visited a health professional in the previous 12 months received a physical activity recommendation.⁷  In addition, more than 50% of adults with disabilities are not meeting US recommended exercise guidelines.^7-9

Family physicians may not feel they have adequate training to counsel patients with IDDs. Additional limiting factors include dependence on caregivers for exercise participation, expense, transportation difficulties, a lack of choice in sporting activities, and the patient’s level of motivation.¹⁰The guidance reviewed here details how to modify the pre-participation sports physical exam specifically for patients with IDDs. It also provides sport and exercise recommendations for patients with 3 disabilities: Down syndrome, cerebral palsy, and autism spectrum disorder.

Worth noting: As is true for adults without disabilities, those with IDDs should participate in at least 150 minutes of moderate-intensity, or 75 minutes of vigorous intensity, aerobic physical activity each week.⁹ Recommend muscle-­strengthening activities be performed at least 2 days each week.⁹

Exercise recommendations for patients with Down syndrome

One in every 700 babies receives a diagnosis of Down syndrome.¹¹ Among its many possible manifestations—which include intellectual disability, heart disease, and diabetes—Down syndrome is associated with an increased risk for obesity, which makes exercise an extremely important lifestyle modification for these patients. Obesity can lead to obstructive sleep apnea causing cor pulmonale and even premature death. Continuous positive airway pressure intervention can be difficult in terms of patient compliance. However, weight loss through exercise and sports is an effective intervention to mitigate these obesity-related health comorbidities. 

Pre-participation exam. A focused history and physical exam are often conducted before a patient engages in organized competitive or recreational sports. The pre-­participation sports physical exam typically focuses on cardiac, neurologic, hereditary, and musculoskeletal disorders. While we recommend including these baseline elements as part of the exam for patients with disabilities, we also recommend modifying the exam to include disability-specific screening for associated comorbidities.

Continue to: For patients with Down syndrome...

For patients with Down syndrome, a complete pre-participation sports physical exam is warranted. Inquire specifically about neck pain or dislocations, heart murmur, cardiac surgery, seizures, sleep issues, history of congenital abdominal defect, hematologic malignancy, and bone pain as part of the focused physical exam.

Look for evidence of patellofemoral instability, pes planus, scoliosis, hallux deformities, decreased muscle tone, and muscular weakness. Check for cataracts and perform a thorough cardiovascular exam to assess for murmur or signs of chronic hypoxia, such as cyanosis. If a heart murmur is detected, refer the patient to a cardiologist.

Patients with Down syndrome are also at increased risk for atlantoaxial instability. A thorough neurologic evaluation to screen for this condition is indicated; however, routine radiologic screening is not needed.¹²

An annual complete blood cell count and thyroid-stimulating hormone test are recommended for all children with Down syndrome.¹³ For patients with Down syndrome who are 13 to 21 years of age, an echocardiogram also is recommended for concerning symptoms.¹³ Ferritin levels also should be assessed annually for patients who are younger than 13 years of age to check for iron-deficiency anemia.¹³ Consider high-risk screening strategies for patients with diabetes and metabolic syndrome.

Special considerations. Patients with Down syndrome were found to be injured more frequently than individuals with other disabilities during the Special Olympics.¹⁴ These patients may be hypersensitive to pain with prolonged pain responses, or unable to verbally communicate their pain or injury.¹⁵

Continue to: The complexity of pain assessment...

The complexity of pain assessment in patients with Down syndrome may increase the difficulty of accurately diagnosing an injury, leading to underdiagnosis or overdiagnosis. To increase accuracy of pain assessment in this setting, we recommend using the Wong-Baker FACES Pain Rating Scale or a numeric pain rating scale in verbal patients.¹⁵ In nonverbal patients, facial expressions are reliable indicators of pain.

Which exercise? Healthy patients with Down syndrome can participate in any sport. Aerobic exercise can help lower body fat, reduce oxidative stress, and improve blood flow.⁶ Muscle-strengthening exercises can lead to improved daily functioning and balance. Strength training and aerobic exercise benefit aging patients with Down syndrome who are struggling with obesity. Such exercise also helps increase bone mineral density and improve cardiovascular fitness, especially when initiated at a young age. Consistent exercise promotes positive health outcomes throughout the lifespan.¹⁶

Exercise recommendations for patients with cerebral palsy

Cerebral palsy, the most common motor disability in children, is associated with intellectual disability, seizures, respiratory insufficiency, scoliosis, osteoporosis, mood disorders, dysphagia, and speech and hearing impairment.¹⁷ The increasing survival of premature babies born with cerebral palsy and the growing prevalence of adults with the condition point to the importance of expanding one’s knowledge of how best to care for this population.¹⁸

Pre-participation exam. In addition to a complete sport physical exam, it’s important to further evaluate patients with cerebral palsy for epilepsy, joint contractures, muscle weakness, spinal deformities, and respiratory insufficiency. The Gross Motor Function Classification system, commonly used for patients with cerebral palsy, scores functional ability in 5 levels.¹⁸ Patients at Level I are the most mobile; patients at Level V need wheelchair transport in all settings.

Consider sports and exercise a vital therapeutic modality— something beyond a form of recreation.

Further evaluation of spinal deformities can be initiated with x-ray screening. Consider ordering dual x-ray absorptiometry scans to evaluate bone mass.¹⁷

Continue to: Special considerations

Special considerations. Patients with cerebral palsy have a heightened risk for depression and anxiety.¹⁹ Mental health can be assessed via the General Anxiety Disorder-7, the Patient Health ­Questionnaire-9, and the Ask Suicide-­Screening Questions tools, among others. Mental health screening may need to be adjusted depending on the patient’s level of cognition and ability to communicate. The patient’s caregiver also can provide supplemental information.

Consider screening vitamin D levels in patients with cerebral palsy. Approximately 50% of adults with cerebral palsy are vitamin D–deficient secondary to sedentary behavior and lack of sun exposure.^20-22

Optimal medical management has been shown to decrease muscle spasticity and may be beneficial before initiating an exercise program. For patients with moderate-to-­severe symptoms, referral for physical therapy to further improve gross motor function and spasticity may be required before initiating an exercise program.

Which exercise? Individuals with cerebral palsy spend 76% to 99% of their waking hours being sedentary.⁵   Consequently, they typically have decreased cardiorespiratory endurance and decreased muscle strength. Strength training may improve muscle spasticity, gross motor function, joint health, and respiratory insufficiency.⁵ Even in those who function at Level IV-V of the Gross Motor Function Classification system, exercise reduces vertebral fractures and improves time spent standing.²³ By improving endurance, spasticity, and strength with exercise, deconditioning can be mitigated.

Involvement in sports promotes peer interactions, personal interests, and positive self-identity. It can give a newfound passion for life. Additionally, families of children with disabilities who engage in leisure activities together have less caregiver burden.^24,25 Sporting activities offer a way to optimize psychosocial well-being for the patient and the entire family.

Continue to: Dance promotes functionality...

Dance promotes functionality and psychosocial adjustment.²⁶ Hippotherapy, defined as therapy and rehabilitation during which the patient interacts with horses, can diminish muscle spasticity.²⁷ Aquatic therapy also may increase muscle strength.²⁸

Sports for patients with autism spectrum disorder

Autism spectrum disorder is defined as persistent deficits in social communication and social interaction that are usually evident in the first 3 years of life.²⁹ Autism can manifest with or without intellectual or language impairment. Patients with autism commonly have difficulty processing sensory stimuli and can experience “sensory overload.” More than half have a coexisting mental health disorder, such as attention-deficit/hyperactivity disorder, anxiety, depression, schizophrenia, or bipolar disorder.³⁰

Vigorous exercise is associated with a reduction in stereotypic behaviors, hyperactivity, aggression, and self-injury in patients with autism spectrum disorder.

Aversions to foods and food selectivity, as well as adverse effects from medical treatment of autism-related agitation, result in a higher incidence of obesity in patients with autism.^31,32 

Pre-participation exam. In addition to a comprehensive pre-participation exam, the Autism Spectrum Syndrome Questionnaire (ASSQ) and Modified Checklist for Autism in Toddlers are tools to screen school-age children with normal cognition to mild intellectual disability.³³ These questionnaires have limitations, however. For example, ASSQ has limited ability to identify the female autistic phenotype.³⁴ As such, these are solely screening tools. Final diagnosis is based on clinical judgment.

Special considerations. Include screening for constipation or diarrhea, fiber intake, food aversions, and common mental health comorbidities using Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria.²⁹ Psychiatric referral may be necessary if certain previously undiagnosed condition(s) become apparent. The patient’s caregiver can provide supplemental information 

Continue to: During the physical exam...

During the physical exam, limit sensory stimuli as much as possible, including lights and sounds. Verbalize components of the exam before touching a patient with autism who is sensitive to physical touch.

Which exercise? Participation in sports is an effective therapy for autism and can help patients develop communication skills and promote socialization. Vigorous exercise is associated with a reduction in stereotypic behaviors, hyperactivity, aggression, and self-injury.³ Sports also can offer an alternative channel for social interaction. Children with autism may have impaired or delayed motor skills, and exercise can improve motor skill proficiency.⁴

The prevalence of feeding problems in children with autism spectrum disorder is estimated to be as high as 90%, and close to 70% are selective eaters.^31,35,36 For those with gastrointestinal disorders, exercise can exert positive effects on the microbiome-gut-brain axis.³⁷ Additionally, patients with autism are much more likely to be overweight or obese.³² Physical activity offers those with autism health benefits similar to those for the general population.³²

Children with autism spectrum disorder have similar odds of injury, including serious injury, relative to population controls.³⁸ Karate and swimming are among the most researched sports therapy options for patients with autism.^38-40 Both are shown to improve motor ability and reduce communication deficits. 

Summing up

The literature, although limited, demonstrates that exercise and sports improve the health and well-being of people with IDDs throughout the lifespan, especially if childhood exercise/­sports involvement is maintained.

Exercise participation increases based on the individual’s desire to be fit and active, skills practice, peer involvement, family support, accessible facilities, and skilled staff.

Encourage your patients to participate in sports, but be aware of factors that can limit (or facilitate) participation.⁴¹ Exercise participation increases based on, among other things, the individual’s desire to be fit and active, skills practice, peer involvement, family support, accessible facilities, and skilled staff.¹⁰

Additional resources that can help people with IDDs access sports and recreational activities include the Special Olympics; Paralympics; YMCA; after-school programs; The American College of Sports Medicine; The National Center on Health, Physical Activity, and Disability; and disability-certified inclusive fitness trainers.

CORRESPONDENCE 
Kristina Jones, BS, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612; kjones15@usf.edu

THE CASE

Janice M* presented to the emergency department (ED) with worsening slurred speech. The 55-year-old patient’s history was significant for diabetes; hypertension; depression; sleep apnea; multiple transient ischemic attacks (TIAs) thought to be stress related; and left lower-extremity weakness secondary to prior infarct. Ms. M had been to the hospital multiple times in the previous 2 to 3 years for similar symptoms. Her most recent visit to the ED had been 2 months earlier.

In the ED, the patient’s NIH stroke score was 1 for the presence of dysarthria, and a code for emergency stroke management was initiated. Ms. M was alert and oriented x 3, with no focal motor or sensory deficits noted. Computed tomography (CT) and CT angiography were negative for any acute abnormality. Throughout the course of the ED visit, her NIH score improved to 0. Ms. M exhibited staccato/stuttering speech, but it was believed that this would likely improve over the next few days.

According to the hospital neurologist, the ED work-up suggested either a TIA, stress-induced psychiatric speech disorder, or conversion disorder. The patient was discharged home in stable condition and was asked to follow up with the outpatient neurologist in 1 week.

Ms. M was seen approximately 2 weeks later in the outpatient neurology stroke ­clinic. Her symptoms had resolved, and she did not report any new or worsening symptoms. An outpatient stroke work-up was initiated, including magnetic resonance imaging (MRI) of the brain, echocardiography, and measurement of low-density lipoprotein and hemoglobin A1C; all results were unremarkable. Given the timeline for symptom improvement and results of the work-up, the patient was given a diagnosis of conversion disorder. Ms. M was encouraged to follow up with her primary care physician (PCP) for further medical management.

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

 

 

What is conversion disorder, and how common is it?

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, text revision, conversion disorder (also known as functional neurological symptom disorder) is characterized as a somatic symptom and related disorder.¹ The prominent feature shared among disorders in this category is the presence of somatic symptoms that are associated with distress and impairment.

In conversion disorder, the focus is on symptoms that are neurologic in nature but are not due to underlying neurologic disease and are incongruent with typical patterns of presentation for any neurologic condition. Patients with conversion disorder may present with motor symptoms (eg, weakness, paralysis, tremor, dystonia), altered sensory or cognitive function, seizure-like symptoms, alterations in speech, or changes in swallowing.^1,2

For a diagnosis of conversion disorder, the following criteria must be met¹:

• The patient has 1 or more symptoms of altered voluntary motor or sensory function.
• Symptom presentation is incongruent with recognized neurologic or medical disease or conditions.
• Symptoms are not better explained by another medical or mental health condition.
• There is significant distress or impairment in functioning due to symptoms or the deficit.

The etiology of conversion disorder has not been firmly established. While the literature suggests that psychological stressors play a role,^3,4 an effort also has been made to better understand the underlying neural and biological basis. Specifically, studies have utilized brain imaging to explore brain pathways and mechanisms that could account for symptom presentation.^5,6

Prevalence rates for conversion disorder vary depending on the population studied. While it is estimated that 5% of patients in a general hospital setting meet full criteria for conversion disorder,⁷ higher rates may exist in specialty settings; 1 study found that 30% of patients in a neurology specialty clinic exhibited symptoms that were medically unexplained.⁸

Continue to: In primary care...

One study indicated that physicians identified medically unexplained symptoms as the main presenting problem for nearly 20% of patients in a primary care setting.

In primary care, prevalence of conversion disorder can be difficult to pinpoint; however, 1 study indicated that physicians identified medically unexplained symptoms as the main presenting problem for nearly 20% of patients in a primary care setting.⁹ Therefore, it is important for family physicians (FPs) to be familiar with the assessment and treatment of conversion disorder (and other disorders in which medically unexplained symptoms may be at the core of the patient presentation).

The differential: Neurologic and psychiatric conditions

Patients with conversion disorder may present with a variety of neurologic symptoms that can mimic those of organic disease. This can pose a diagnostic challenge, increase the chance of misdiagnosis, and delay treatment.

Motor symptoms may include paralysis, gait disturbance, dysphagia, or aphasia. Patients also may have sensory symptoms, such as blindness, deafness, or anesthesia.^10,11 As a result, it is important to rule out both urgent neurologic presentations, such as TIA, acute stroke, and brain tumor, and other chronic neurologic conditions, including multiple sclerosis, myasthenia gravis, and epilepsy.^11,12

Multiple sclerosis will demonstrate characteristic lesions on MRI that differentiate it from conversion disorder.

Myasthenia gravis is distinguished by positive findings on autoantibodies testing and on electrophysiologic studies.

Continue to: Epilepsy

Epilepsy. Patients with conversion disorder may present with unresponsiveness and abnormal movements, such as generalized limb shaking and hip thrusting, that mimic an epileptic seizure. In contrast to epileptic seizures, psychogenic nonepileptic seizures may last longer, symptoms may wax and wane, and patients generally do not have bowel or bladder incontinence or sustain injury as they would during an actual seizure.¹²

There are several psychiatric/­psychosocial conditions that also should be considered in the differential diagnosis of conversion disorder.

Somatic symptom disorder, like conversion disorder, produces somatic symptoms that can cause significant distress for patients. The difference in the 2 conditions is that symptoms of somatic symptom disorder may be compatible with a recognized neurologic or general medical condition, whereas in conversion disorder, the symptoms are not consistent with a recognized disease.^1,12

Factitious disorder, similar to conversion disorder, can involve neurologic symptoms that are not attributed to disease. However, patients with factitious disorder deliberately simulate symptoms to receive medical care. A thorough clinical interview and physical exam can help to distinguish conversion disorder from factitious disorder.

Malingering is not a psychiatric condition but a behavior that involves intentionally feigning symptoms for the purpose of personal or financial gain. There is no evidence that patients with conversion disorder simulate their symptoms.^12,13

Continue to: Negative results and positive signs point to the Dx

Negative results and positive signs point to the Dx

Conversion disorder is not a diagnosis of exclusion. Diagnosis requires detailed history taking and a thorough neurologic exam. Laboratory testing and neuroimaging are also important, and results will have to be negative to support the diagnosis.

Conversion disorder is not a diagnosis of exclusion; diagnosis requires detailed history taking and a thorough neurologic exam.

Neurologic deficits with conversion disorder do not follow a known neurologic insult.¹⁴ There are many tests that can be used to distinguish functional symptoms vs organic symptoms. Two of the most well-known tests are the Hoover sign and the abductor sign, which will be positive in conversion disorder. Both can be performed easily in an outpatient setting.

The Hoover sign is considered positive when there is weakness of voluntary hip extension in the presence of normal involuntary hip extension during contralateral hip flexion against resistance. According to a meta-­analysis of multiple studies of patients with conversion disorder, the overall estimated sensitivity of this test is 94% and the specificity, 99%.¹⁵

The abductor sign follows the same principle as the Hoover sign: When the patient abducts the nonparetic leg, both the nonparetic and “paretic” leg are strong. When the patient abducts just the “paretic” leg, both legs become weak.¹⁶

Other symptom evaluations. For patients who have functional seizures, video electroencephalography is helpful to distinguish functional seizures from “true” seizures.^17,18 In conversion disorder, functional dysarthria normally resembles a stutter or speech that is extremely slow with long hesitations that are hard to interrupt.¹⁸ Dysphonia and functional dysphagia are also very common functional symptoms. Usually after extensive work-up, no organic cause of the patient’s symptoms is ever found.¹⁸

Continue to: Treatment requires an integrated team approach

 

 

Treatment requires an integrated team approach

Treatment for conversion disorder can be difficult due to the complex and not fully understood etiology of the condition. Due to its multifaceted nature, an integrated team approach can be beneficial at each stage, including assessment and intervention.

Explain the diagnosis clearly. An essential initial step in the treatment of conversion disorder is careful explanation of the diagnosis. Clear explanation of the terminology and presentation of conversion disorder may prevent the patient from misinterpreting their diagnosis as a suggestion that they are feigning or malingering symptoms or feeling that their symptoms or concerns are being dismissed.² Understanding the condition can help improve the likelihood of the patient accepting the treatment plan and help decrease the likelihood of unnecessary testing, health care visits, and consultations. Developing a strong rapport with the patient is key when explaining the diagnosis.

Recommend cognitive behavioral therapy (CBT). In a meta-analysis of 15 randomized controlled trials, CBT significantly reduced somatic, anxious, and depressive symptoms and improved physical functioning in patients with somatoform disorders and medically unexplained symptoms.¹⁹ Another study, utilizing a case series, demonstrated significant improvement in social, emotional, and behavioral functioning in children and adolescents with functional neurologic symptoms (conversion disorder) post–CBT intervention.²⁰

Given that research supports CBT’s effectiveness in the management of conversion disorder, it is beneficial to engage a behavioral health professional as a part of the treatment team to focus on factors such as stress management, development of coping skills, and treatment of underlying psychiatric conditions.

Consider these other options. The addition of medication management can be considered for patients with comorbid psychiatric disorders. Evidence suggests that physical therapy is helpful in the treatment of motor and gait dysfunction seen in conversion disorder.^21,22 The role of hypnosis in the management of conversion disorder has also been studied, but more randomized clinical trials are needed to further explore this treatment.^2,23,24

Continue to: The FP's role in coordination of care

The FP’s role in coordination of care

Conversion disorder can be challenging to diagnose and often involves a multidisciplinary approach. Patients with conversion disorder may see multiple clinicians as they undergo evaluation for their symptoms, but they usually are referred back to their PCP for management and coordination of care. Thus, the FP’s understanding of how the condition is diagnosed and appropriately managed is beneficial.

The prognosis of conversion disorder is associated with symptom duration; thus, consultation between FPs and mental health providers is essential.

Open and effective communication among all members of the health care team can ensure consistency in treatment, a strong patient–provider relationship, favorable prognosis, and prevention of symptom relapse. FPs, by establishing a good rapport with patients, can help them understand the condition and the mind-body connection. Once other diagnoses have been ruled out, the FP can provide reassurance to patients and minimize further diagnostic testing.

The prognosis of conversion disorder is associated with symptom duration²⁵; thus, consultation between FPs and mental health providers is essential. The FP also can be integral in the recognition of psychiatric comorbidities, such as anxiety and depression, helping to ensure that these conditions also are treated appropriately.^25,26

THE CASE

Ms. M was referred to a neuropsychologist for further assessment, and the diagnosis of conversion disorder was confirmed. She was then referred to a family medicine behavioral health psychologist for CBT. The initial consult indicated that psychological stressors were contributing to symptoms, and Ms. M was diagnosed with depression and anxiety as well as conversion disorder.

Treatment started with patient education. The treatment framework was carefully explained to Ms. M, with a focus on identifying possible symptom triggers, helping her build a more effective stress response, increasing skills to more effectively manage stressors, and managing underlying psychiatric disorders (ie, depression, anxiety).

Ms. M continued regular visits with the family medicine behavioral health psychologist for CBT and followed up with her PCP as needed to manage chronic health conditions and stroke risk factors. The patient was able to implement skills discussed in treatment sessions, including identifying triggers and implementing coping skills (eg, managing negative thoughts that contribute to symptoms, setting boundaries) to manage stressors.

Her depressive and anxious symptoms improved, as indicated by symptom measurement tools and self-report. The frequency and severity of episodes of slurred speech and muscle weakness decreased, and the patient reported only 1 ED visit related to speech difficulties in the 2 years while following up with the behavioral health psychologist.

CORRESPONDENCE
Kristen J. Alston, PhD, University of Mississippi Medical Center, 2400 North State Street, Jackson, MS 39216; kalston@umc.edu

THE CASE

Janice M* presented to the emergency department (ED) with worsening slurred speech. The 55-year-old patient’s history was significant for diabetes; hypertension; depression; sleep apnea; multiple transient ischemic attacks (TIAs) thought to be stress related; and left lower-extremity weakness secondary to prior infarct. Ms. M had been to the hospital multiple times in the previous 2 to 3 years for similar symptoms. Her most recent visit to the ED had been 2 months earlier.

In the ED, the patient’s NIH stroke score was 1 for the presence of dysarthria, and a code for emergency stroke management was initiated. Ms. M was alert and oriented x 3, with no focal motor or sensory deficits noted. Computed tomography (CT) and CT angiography were negative for any acute abnormality. Throughout the course of the ED visit, her NIH score improved to 0. Ms. M exhibited staccato/stuttering speech, but it was believed that this would likely improve over the next few days.

According to the hospital neurologist, the ED work-up suggested either a TIA, stress-induced psychiatric speech disorder, or conversion disorder. The patient was discharged home in stable condition and was asked to follow up with the outpatient neurologist in 1 week.

Ms. M was seen approximately 2 weeks later in the outpatient neurology stroke ­clinic. Her symptoms had resolved, and she did not report any new or worsening symptoms. An outpatient stroke work-up was initiated, including magnetic resonance imaging (MRI) of the brain, echocardiography, and measurement of low-density lipoprotein and hemoglobin A1C; all results were unremarkable. Given the timeline for symptom improvement and results of the work-up, the patient was given a diagnosis of conversion disorder. Ms. M was encouraged to follow up with her primary care physician (PCP) for further medical management.

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

 

 

What is conversion disorder, and how common is it?

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, text revision, conversion disorder (also known as functional neurological symptom disorder) is characterized as a somatic symptom and related disorder.¹ The prominent feature shared among disorders in this category is the presence of somatic symptoms that are associated with distress and impairment.

In conversion disorder, the focus is on symptoms that are neurologic in nature but are not due to underlying neurologic disease and are incongruent with typical patterns of presentation for any neurologic condition. Patients with conversion disorder may present with motor symptoms (eg, weakness, paralysis, tremor, dystonia), altered sensory or cognitive function, seizure-like symptoms, alterations in speech, or changes in swallowing.^1,2

For a diagnosis of conversion disorder, the following criteria must be met¹:

• The patient has 1 or more symptoms of altered voluntary motor or sensory function.
• Symptom presentation is incongruent with recognized neurologic or medical disease or conditions.
• Symptoms are not better explained by another medical or mental health condition.
• There is significant distress or impairment in functioning due to symptoms or the deficit.

The etiology of conversion disorder has not been firmly established. While the literature suggests that psychological stressors play a role,^3,4 an effort also has been made to better understand the underlying neural and biological basis. Specifically, studies have utilized brain imaging to explore brain pathways and mechanisms that could account for symptom presentation.^5,6

Prevalence rates for conversion disorder vary depending on the population studied. While it is estimated that 5% of patients in a general hospital setting meet full criteria for conversion disorder,⁷ higher rates may exist in specialty settings; 1 study found that 30% of patients in a neurology specialty clinic exhibited symptoms that were medically unexplained.⁸

Continue to: In primary care...

One study indicated that physicians identified medically unexplained symptoms as the main presenting problem for nearly 20% of patients in a primary care setting.

In primary care, prevalence of conversion disorder can be difficult to pinpoint; however, 1 study indicated that physicians identified medically unexplained symptoms as the main presenting problem for nearly 20% of patients in a primary care setting.⁹ Therefore, it is important for family physicians (FPs) to be familiar with the assessment and treatment of conversion disorder (and other disorders in which medically unexplained symptoms may be at the core of the patient presentation).

The differential: Neurologic and psychiatric conditions

Patients with conversion disorder may present with a variety of neurologic symptoms that can mimic those of organic disease. This can pose a diagnostic challenge, increase the chance of misdiagnosis, and delay treatment.

Motor symptoms may include paralysis, gait disturbance, dysphagia, or aphasia. Patients also may have sensory symptoms, such as blindness, deafness, or anesthesia.^10,11 As a result, it is important to rule out both urgent neurologic presentations, such as TIA, acute stroke, and brain tumor, and other chronic neurologic conditions, including multiple sclerosis, myasthenia gravis, and epilepsy.^11,12

Multiple sclerosis will demonstrate characteristic lesions on MRI that differentiate it from conversion disorder.

Myasthenia gravis is distinguished by positive findings on autoantibodies testing and on electrophysiologic studies.

Continue to: Epilepsy

Epilepsy. Patients with conversion disorder may present with unresponsiveness and abnormal movements, such as generalized limb shaking and hip thrusting, that mimic an epileptic seizure. In contrast to epileptic seizures, psychogenic nonepileptic seizures may last longer, symptoms may wax and wane, and patients generally do not have bowel or bladder incontinence or sustain injury as they would during an actual seizure.¹²

There are several psychiatric/­psychosocial conditions that also should be considered in the differential diagnosis of conversion disorder.

Somatic symptom disorder, like conversion disorder, produces somatic symptoms that can cause significant distress for patients. The difference in the 2 conditions is that symptoms of somatic symptom disorder may be compatible with a recognized neurologic or general medical condition, whereas in conversion disorder, the symptoms are not consistent with a recognized disease.^1,12

Factitious disorder, similar to conversion disorder, can involve neurologic symptoms that are not attributed to disease. However, patients with factitious disorder deliberately simulate symptoms to receive medical care. A thorough clinical interview and physical exam can help to distinguish conversion disorder from factitious disorder.

Malingering is not a psychiatric condition but a behavior that involves intentionally feigning symptoms for the purpose of personal or financial gain. There is no evidence that patients with conversion disorder simulate their symptoms.^12,13

Continue to: Negative results and positive signs point to the Dx

Negative results and positive signs point to the Dx

Conversion disorder is not a diagnosis of exclusion. Diagnosis requires detailed history taking and a thorough neurologic exam. Laboratory testing and neuroimaging are also important, and results will have to be negative to support the diagnosis.

Conversion disorder is not a diagnosis of exclusion; diagnosis requires detailed history taking and a thorough neurologic exam.

Neurologic deficits with conversion disorder do not follow a known neurologic insult.¹⁴ There are many tests that can be used to distinguish functional symptoms vs organic symptoms. Two of the most well-known tests are the Hoover sign and the abductor sign, which will be positive in conversion disorder. Both can be performed easily in an outpatient setting.

The Hoover sign is considered positive when there is weakness of voluntary hip extension in the presence of normal involuntary hip extension during contralateral hip flexion against resistance. According to a meta-­analysis of multiple studies of patients with conversion disorder, the overall estimated sensitivity of this test is 94% and the specificity, 99%.¹⁵

The abductor sign follows the same principle as the Hoover sign: When the patient abducts the nonparetic leg, both the nonparetic and “paretic” leg are strong. When the patient abducts just the “paretic” leg, both legs become weak.¹⁶

Other symptom evaluations. For patients who have functional seizures, video electroencephalography is helpful to distinguish functional seizures from “true” seizures.^17,18 In conversion disorder, functional dysarthria normally resembles a stutter or speech that is extremely slow with long hesitations that are hard to interrupt.¹⁸ Dysphonia and functional dysphagia are also very common functional symptoms. Usually after extensive work-up, no organic cause of the patient’s symptoms is ever found.¹⁸

Continue to: Treatment requires an integrated team approach

 

 

Treatment requires an integrated team approach

Treatment for conversion disorder can be difficult due to the complex and not fully understood etiology of the condition. Due to its multifaceted nature, an integrated team approach can be beneficial at each stage, including assessment and intervention.

Explain the diagnosis clearly. An essential initial step in the treatment of conversion disorder is careful explanation of the diagnosis. Clear explanation of the terminology and presentation of conversion disorder may prevent the patient from misinterpreting their diagnosis as a suggestion that they are feigning or malingering symptoms or feeling that their symptoms or concerns are being dismissed.² Understanding the condition can help improve the likelihood of the patient accepting the treatment plan and help decrease the likelihood of unnecessary testing, health care visits, and consultations. Developing a strong rapport with the patient is key when explaining the diagnosis.

Recommend cognitive behavioral therapy (CBT). In a meta-analysis of 15 randomized controlled trials, CBT significantly reduced somatic, anxious, and depressive symptoms and improved physical functioning in patients with somatoform disorders and medically unexplained symptoms.¹⁹ Another study, utilizing a case series, demonstrated significant improvement in social, emotional, and behavioral functioning in children and adolescents with functional neurologic symptoms (conversion disorder) post–CBT intervention.²⁰

Given that research supports CBT’s effectiveness in the management of conversion disorder, it is beneficial to engage a behavioral health professional as a part of the treatment team to focus on factors such as stress management, development of coping skills, and treatment of underlying psychiatric conditions.

Consider these other options. The addition of medication management can be considered for patients with comorbid psychiatric disorders. Evidence suggests that physical therapy is helpful in the treatment of motor and gait dysfunction seen in conversion disorder.^21,22 The role of hypnosis in the management of conversion disorder has also been studied, but more randomized clinical trials are needed to further explore this treatment.^2,23,24

Continue to: The FP's role in coordination of care

The FP’s role in coordination of care

Conversion disorder can be challenging to diagnose and often involves a multidisciplinary approach. Patients with conversion disorder may see multiple clinicians as they undergo evaluation for their symptoms, but they usually are referred back to their PCP for management and coordination of care. Thus, the FP’s understanding of how the condition is diagnosed and appropriately managed is beneficial.

The prognosis of conversion disorder is associated with symptom duration; thus, consultation between FPs and mental health providers is essential.

Open and effective communication among all members of the health care team can ensure consistency in treatment, a strong patient–provider relationship, favorable prognosis, and prevention of symptom relapse. FPs, by establishing a good rapport with patients, can help them understand the condition and the mind-body connection. Once other diagnoses have been ruled out, the FP can provide reassurance to patients and minimize further diagnostic testing.

The prognosis of conversion disorder is associated with symptom duration²⁵; thus, consultation between FPs and mental health providers is essential. The FP also can be integral in the recognition of psychiatric comorbidities, such as anxiety and depression, helping to ensure that these conditions also are treated appropriately.^25,26

THE CASE

Ms. M was referred to a neuropsychologist for further assessment, and the diagnosis of conversion disorder was confirmed. She was then referred to a family medicine behavioral health psychologist for CBT. The initial consult indicated that psychological stressors were contributing to symptoms, and Ms. M was diagnosed with depression and anxiety as well as conversion disorder.

Treatment started with patient education. The treatment framework was carefully explained to Ms. M, with a focus on identifying possible symptom triggers, helping her build a more effective stress response, increasing skills to more effectively manage stressors, and managing underlying psychiatric disorders (ie, depression, anxiety).

Ms. M continued regular visits with the family medicine behavioral health psychologist for CBT and followed up with her PCP as needed to manage chronic health conditions and stroke risk factors. The patient was able to implement skills discussed in treatment sessions, including identifying triggers and implementing coping skills (eg, managing negative thoughts that contribute to symptoms, setting boundaries) to manage stressors.

Her depressive and anxious symptoms improved, as indicated by symptom measurement tools and self-report. The frequency and severity of episodes of slurred speech and muscle weakness decreased, and the patient reported only 1 ED visit related to speech difficulties in the 2 years while following up with the behavioral health psychologist.

CORRESPONDENCE
Kristen J. Alston, PhD, University of Mississippi Medical Center, 2400 North State Street, Jackson, MS 39216; kalston@umc.edu

THE CASE

Janice M* presented to the emergency department (ED) with worsening slurred speech. The 55-year-old patient’s history was significant for diabetes; hypertension; depression; sleep apnea; multiple transient ischemic attacks (TIAs) thought to be stress related; and left lower-extremity weakness secondary to prior infarct. Ms. M had been to the hospital multiple times in the previous 2 to 3 years for similar symptoms. Her most recent visit to the ED had been 2 months earlier.

In the ED, the patient’s NIH stroke score was 1 for the presence of dysarthria, and a code for emergency stroke management was initiated. Ms. M was alert and oriented x 3, with no focal motor or sensory deficits noted. Computed tomography (CT) and CT angiography were negative for any acute abnormality. Throughout the course of the ED visit, her NIH score improved to 0. Ms. M exhibited staccato/stuttering speech, but it was believed that this would likely improve over the next few days.

According to the hospital neurologist, the ED work-up suggested either a TIA, stress-induced psychiatric speech disorder, or conversion disorder. The patient was discharged home in stable condition and was asked to follow up with the outpatient neurologist in 1 week.

Ms. M was seen approximately 2 weeks later in the outpatient neurology stroke ­clinic. Her symptoms had resolved, and she did not report any new or worsening symptoms. An outpatient stroke work-up was initiated, including magnetic resonance imaging (MRI) of the brain, echocardiography, and measurement of low-density lipoprotein and hemoglobin A1C; all results were unremarkable. Given the timeline for symptom improvement and results of the work-up, the patient was given a diagnosis of conversion disorder. Ms. M was encouraged to follow up with her primary care physician (PCP) for further medical management.

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

 

 

What is conversion disorder, and how common is it?

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, text revision, conversion disorder (also known as functional neurological symptom disorder) is characterized as a somatic symptom and related disorder.¹ The prominent feature shared among disorders in this category is the presence of somatic symptoms that are associated with distress and impairment.

In conversion disorder, the focus is on symptoms that are neurologic in nature but are not due to underlying neurologic disease and are incongruent with typical patterns of presentation for any neurologic condition. Patients with conversion disorder may present with motor symptoms (eg, weakness, paralysis, tremor, dystonia), altered sensory or cognitive function, seizure-like symptoms, alterations in speech, or changes in swallowing.^1,2

For a diagnosis of conversion disorder, the following criteria must be met¹:

• The patient has 1 or more symptoms of altered voluntary motor or sensory function.
• Symptom presentation is incongruent with recognized neurologic or medical disease or conditions.
• Symptoms are not better explained by another medical or mental health condition.
• There is significant distress or impairment in functioning due to symptoms or the deficit.

The etiology of conversion disorder has not been firmly established. While the literature suggests that psychological stressors play a role,^3,4 an effort also has been made to better understand the underlying neural and biological basis. Specifically, studies have utilized brain imaging to explore brain pathways and mechanisms that could account for symptom presentation.^5,6

Prevalence rates for conversion disorder vary depending on the population studied. While it is estimated that 5% of patients in a general hospital setting meet full criteria for conversion disorder,⁷ higher rates may exist in specialty settings; 1 study found that 30% of patients in a neurology specialty clinic exhibited symptoms that were medically unexplained.⁸

Continue to: In primary care...

One study indicated that physicians identified medically unexplained symptoms as the main presenting problem for nearly 20% of patients in a primary care setting.

In primary care, prevalence of conversion disorder can be difficult to pinpoint; however, 1 study indicated that physicians identified medically unexplained symptoms as the main presenting problem for nearly 20% of patients in a primary care setting.⁹ Therefore, it is important for family physicians (FPs) to be familiar with the assessment and treatment of conversion disorder (and other disorders in which medically unexplained symptoms may be at the core of the patient presentation).

The differential: Neurologic and psychiatric conditions

Patients with conversion disorder may present with a variety of neurologic symptoms that can mimic those of organic disease. This can pose a diagnostic challenge, increase the chance of misdiagnosis, and delay treatment.

Motor symptoms may include paralysis, gait disturbance, dysphagia, or aphasia. Patients also may have sensory symptoms, such as blindness, deafness, or anesthesia.^10,11 As a result, it is important to rule out both urgent neurologic presentations, such as TIA, acute stroke, and brain tumor, and other chronic neurologic conditions, including multiple sclerosis, myasthenia gravis, and epilepsy.^11,12

Multiple sclerosis will demonstrate characteristic lesions on MRI that differentiate it from conversion disorder.

Myasthenia gravis is distinguished by positive findings on autoantibodies testing and on electrophysiologic studies.

Continue to: Epilepsy

Epilepsy. Patients with conversion disorder may present with unresponsiveness and abnormal movements, such as generalized limb shaking and hip thrusting, that mimic an epileptic seizure. In contrast to epileptic seizures, psychogenic nonepileptic seizures may last longer, symptoms may wax and wane, and patients generally do not have bowel or bladder incontinence or sustain injury as they would during an actual seizure.¹²

There are several psychiatric/­psychosocial conditions that also should be considered in the differential diagnosis of conversion disorder.

Somatic symptom disorder, like conversion disorder, produces somatic symptoms that can cause significant distress for patients. The difference in the 2 conditions is that symptoms of somatic symptom disorder may be compatible with a recognized neurologic or general medical condition, whereas in conversion disorder, the symptoms are not consistent with a recognized disease.^1,12

Factitious disorder, similar to conversion disorder, can involve neurologic symptoms that are not attributed to disease. However, patients with factitious disorder deliberately simulate symptoms to receive medical care. A thorough clinical interview and physical exam can help to distinguish conversion disorder from factitious disorder.

Malingering is not a psychiatric condition but a behavior that involves intentionally feigning symptoms for the purpose of personal or financial gain. There is no evidence that patients with conversion disorder simulate their symptoms.^12,13

Continue to: Negative results and positive signs point to the Dx

Negative results and positive signs point to the Dx

Conversion disorder is not a diagnosis of exclusion. Diagnosis requires detailed history taking and a thorough neurologic exam. Laboratory testing and neuroimaging are also important, and results will have to be negative to support the diagnosis.

Conversion disorder is not a diagnosis of exclusion; diagnosis requires detailed history taking and a thorough neurologic exam.

Neurologic deficits with conversion disorder do not follow a known neurologic insult.¹⁴ There are many tests that can be used to distinguish functional symptoms vs organic symptoms. Two of the most well-known tests are the Hoover sign and the abductor sign, which will be positive in conversion disorder. Both can be performed easily in an outpatient setting.

The Hoover sign is considered positive when there is weakness of voluntary hip extension in the presence of normal involuntary hip extension during contralateral hip flexion against resistance. According to a meta-­analysis of multiple studies of patients with conversion disorder, the overall estimated sensitivity of this test is 94% and the specificity, 99%.¹⁵

The abductor sign follows the same principle as the Hoover sign: When the patient abducts the nonparetic leg, both the nonparetic and “paretic” leg are strong. When the patient abducts just the “paretic” leg, both legs become weak.¹⁶

Other symptom evaluations. For patients who have functional seizures, video electroencephalography is helpful to distinguish functional seizures from “true” seizures.^17,18 In conversion disorder, functional dysarthria normally resembles a stutter or speech that is extremely slow with long hesitations that are hard to interrupt.¹⁸ Dysphonia and functional dysphagia are also very common functional symptoms. Usually after extensive work-up, no organic cause of the patient’s symptoms is ever found.¹⁸

Continue to: Treatment requires an integrated team approach

 

 

Treatment requires an integrated team approach

Treatment for conversion disorder can be difficult due to the complex and not fully understood etiology of the condition. Due to its multifaceted nature, an integrated team approach can be beneficial at each stage, including assessment and intervention.

Explain the diagnosis clearly. An essential initial step in the treatment of conversion disorder is careful explanation of the diagnosis. Clear explanation of the terminology and presentation of conversion disorder may prevent the patient from misinterpreting their diagnosis as a suggestion that they are feigning or malingering symptoms or feeling that their symptoms or concerns are being dismissed.² Understanding the condition can help improve the likelihood of the patient accepting the treatment plan and help decrease the likelihood of unnecessary testing, health care visits, and consultations. Developing a strong rapport with the patient is key when explaining the diagnosis.

Recommend cognitive behavioral therapy (CBT). In a meta-analysis of 15 randomized controlled trials, CBT significantly reduced somatic, anxious, and depressive symptoms and improved physical functioning in patients with somatoform disorders and medically unexplained symptoms.¹⁹ Another study, utilizing a case series, demonstrated significant improvement in social, emotional, and behavioral functioning in children and adolescents with functional neurologic symptoms (conversion disorder) post–CBT intervention.²⁰

Given that research supports CBT’s effectiveness in the management of conversion disorder, it is beneficial to engage a behavioral health professional as a part of the treatment team to focus on factors such as stress management, development of coping skills, and treatment of underlying psychiatric conditions.

Consider these other options. The addition of medication management can be considered for patients with comorbid psychiatric disorders. Evidence suggests that physical therapy is helpful in the treatment of motor and gait dysfunction seen in conversion disorder.^21,22 The role of hypnosis in the management of conversion disorder has also been studied, but more randomized clinical trials are needed to further explore this treatment.^2,23,24

Continue to: The FP's role in coordination of care

The FP’s role in coordination of care

Conversion disorder can be challenging to diagnose and often involves a multidisciplinary approach. Patients with conversion disorder may see multiple clinicians as they undergo evaluation for their symptoms, but they usually are referred back to their PCP for management and coordination of care. Thus, the FP’s understanding of how the condition is diagnosed and appropriately managed is beneficial.

The prognosis of conversion disorder is associated with symptom duration; thus, consultation between FPs and mental health providers is essential.

Open and effective communication among all members of the health care team can ensure consistency in treatment, a strong patient–provider relationship, favorable prognosis, and prevention of symptom relapse. FPs, by establishing a good rapport with patients, can help them understand the condition and the mind-body connection. Once other diagnoses have been ruled out, the FP can provide reassurance to patients and minimize further diagnostic testing.

The prognosis of conversion disorder is associated with symptom duration²⁵; thus, consultation between FPs and mental health providers is essential. The FP also can be integral in the recognition of psychiatric comorbidities, such as anxiety and depression, helping to ensure that these conditions also are treated appropriately.^25,26

THE CASE

Ms. M was referred to a neuropsychologist for further assessment, and the diagnosis of conversion disorder was confirmed. She was then referred to a family medicine behavioral health psychologist for CBT. The initial consult indicated that psychological stressors were contributing to symptoms, and Ms. M was diagnosed with depression and anxiety as well as conversion disorder.

Treatment started with patient education. The treatment framework was carefully explained to Ms. M, with a focus on identifying possible symptom triggers, helping her build a more effective stress response, increasing skills to more effectively manage stressors, and managing underlying psychiatric disorders (ie, depression, anxiety).

Ms. M continued regular visits with the family medicine behavioral health psychologist for CBT and followed up with her PCP as needed to manage chronic health conditions and stroke risk factors. The patient was able to implement skills discussed in treatment sessions, including identifying triggers and implementing coping skills (eg, managing negative thoughts that contribute to symptoms, setting boundaries) to manage stressors.

Her depressive and anxious symptoms improved, as indicated by symptom measurement tools and self-report. The frequency and severity of episodes of slurred speech and muscle weakness decreased, and the patient reported only 1 ED visit related to speech difficulties in the 2 years while following up with the behavioral health psychologist.

CORRESPONDENCE
Kristen J. Alston, PhD, University of Mississippi Medical Center, 2400 North State Street, Jackson, MS 39216; kalston@umc.edu

ILLUSTRATIVE CASE

A healthy 33-year-old woman presents to your office with a 3-month history of depressed mood. She reports difficulty concentrating, insomnia, decreased appetite, and generalized fatigue. She denies suicidal or homicidal ideation, substance misuse, or history consistent with manic episodes. Her vital signs are normal and overall her physical examination is unremarkable, although the patient is tearful when discussing her mood. Using shared decision-making, you and the patient determine it is appropriate to initiate pharmacotherapy. Is there a role for combination pharmacotherapy to treat this patient’s acute depression?

Unipolar depression is a highly prevalent condition, estimated to affect 21% of US adults at some point in their lifetime.² It is the second leading cause of disability in the United States, with an ­estimated economic impact of more than $200 billion annually.³

The diagnosis of unipolar depression is based on the criteria set forth in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and commonly includes depressed mood, anhedonia, sleep disturbance, appetite changes, fatigue, feelings of worthlessness or guilt, decreased ability to concentrate, and psychomotor symptoms occurring over at least a 2-week period.⁴ Symptoms represent a decrease in functioning from previous levels that are not attributable to another medical condition or substance, and must not include a history of past manic or hypomanic episodes. Thoughts of death and suicidal ideation are common.

Several systematic reviews and meta-analyses have shown that a combination of psychotherapy and pharmacotherapy is more efficacious for treatment of unipolar depression than either therapy alone.^5-7 As for which medication is most effective and tolerable, multiple systematic reviews and meta-analyses have not demonstrated superiority of 1 second-generation antidepressant (eg, SSRIs, SNRIs) over another.^7,8

General practice guidelines support titration of the dose or a switch in monotherapy medications until treatment response is achieved, prior to initiation of a second agent. When an adjunctive medication is considered, there are several options: a ­second-generation antipsychotic, a second antidepressant from a different class, thyroid hormone, and lithium. Special consideration is given to the adverse effect profile and potential tolerability; higher adverse effect profiles are observed with second-generation antipsychotics and lithium.⁹

This study suggests that combination pharmacotherapy is superior to monotherapy, both at the time of treatment initiation and in patients with previous inadequate pharmacologic response.

It is not common practice to initiate 2 antidepressants for a new diagnosis of acute depression. The systematic review and meta-analysis conducted by Henssler et al¹ attempted to provide evidence to support the efficacy and tolerability of specific antidepressants when used in combination for initial treatment of acute depression. Of note, a 2008 national survey showed that a majority of psychotropic medications in the United States are prescribed by primary care physicians (73.6%) rather than psychiatrists, making this analysis relevant to family physicians.¹⁰

STUDY SUMMARY

Combination pharmacotherapy yields superior efficacy in acute depression

This 2022 systematic review and meta-­analysis (39 randomized clinical trials [RCTs]; N = 6751) compared the efficacy and tolerability of monotherapy to combination therapy in the treatment of patients with acute depression.¹ The study also aimed to address which specific combination therapies were superior.

Continue to: Selected RCTs included...

Selected RCTs included an intervention group using a combination of 2 antidepressants, regardless of dosage, and a control group of patients taking antidepressant monotherapy. Studies evaluated both patients being treated for the first time and those with a previously inadequate response to medical treatment. All participants were ages 18 years or older (mean age not reported) and had received a diagnosis of depressive disorder according to standard operationalized criteria; patients with multiple psychiatric comorbidities were not excluded.

Studies used various standardized questionnaires—most frequently, the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS)—to determine the severity of depression at baseline and following treatment. The HDRS is a 17-item depression scale and the MADRS is a 10-item depression scale; for both, higher scores indicate worsening depression. Follow-up time ranged from 2 to 12 weeks.

The primary outcome was treatment efficacy measured as the standardized mean difference (SMD). Secondary outcomes included remission (normal-range scores) and response to treatment (eg, ≥ 50% reduction in scores), as defined by the study authors.

Combination therapy was determined to have superior efficacy relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44; P < .001). Combinations with a presynaptic α2-autoreceptor antagonist (eg, mirtazapine, trazodone, or mianserin [the last of which is not approved by the US Food and Drug Administration for use in the United States]) and a monoamine reuptake inhibitor (eg, an SSRI, SNRI, or TCA) were superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Combinations that included bupropion were not superior to monotherapy (SMD = 0.10; 95% CI, –0.07 to 0.27).

Secondary outcomes revealed combination therapy to be superior to monotherapy with respect to remission (odds ratio [OR] = 1.52; 95% CI, 1.20-1.92) and response (OR = 1.40; 95% CI, 1.15-1.69). Subgroup analyses showed that combinations with presynaptic α2-autoreceptor antagonists led to improved remission (OR = 1.42; 95% CI, 1.01-2.01) and response (OR = 1.49; 95% CI, 1.18-1.87) compared with monotherapy, whereas combinations that included bupropion were not superior to monotherapy. For patients who dropped out of treatment for any reason, including adverse drug events, results for combination pharmacotherapy and monotherapy were similar.

Continue to: WHAT'S NEW

 

 

WHAT’S NEW

One combination proved more effective than others

Current clinical guidelines indicate the suitability of trialing pharmacologic monotherapy during the acute phase of depression treatment prior to initiating an adjunctive medication.⁹ All classes of medication investigated in this meta-analysis are generally regarded as first-line therapies, although they are rarely started in combination. This study’s findings suggest that combination pharmacotherapy, especially with a presynaptic α2-autoreceptor antagonist (eg, mirtazapine, trazodone) and a monoamine reuptake inhibitor (eg, an SSRI, SNRI, or a TCA), is superior to monotherapy, both at the time of treatment initiation and in patients with previous inadequate pharmacologic response.

CAVEATS

Potential limitations due to publication bias

Concerns about publication bias and significant study heterogeneity may limit the generalizability of these findings. However, conclusions were robust in a subgroup analysis that was restricted to publications with low risk for bias.

CHALLENGES TO IMPLEMENTATION

None to report

There are no major challenges to implementing this combination treatment. Importantly, there were no differences in tolerability between monotherapy and combination treatment. 

ILLUSTRATIVE CASE

A healthy 33-year-old woman presents to your office with a 3-month history of depressed mood. She reports difficulty concentrating, insomnia, decreased appetite, and generalized fatigue. She denies suicidal or homicidal ideation, substance misuse, or history consistent with manic episodes. Her vital signs are normal and overall her physical examination is unremarkable, although the patient is tearful when discussing her mood. Using shared decision-making, you and the patient determine it is appropriate to initiate pharmacotherapy. Is there a role for combination pharmacotherapy to treat this patient’s acute depression?

Unipolar depression is a highly prevalent condition, estimated to affect 21% of US adults at some point in their lifetime.² It is the second leading cause of disability in the United States, with an ­estimated economic impact of more than $200 billion annually.³

The diagnosis of unipolar depression is based on the criteria set forth in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and commonly includes depressed mood, anhedonia, sleep disturbance, appetite changes, fatigue, feelings of worthlessness or guilt, decreased ability to concentrate, and psychomotor symptoms occurring over at least a 2-week period.⁴ Symptoms represent a decrease in functioning from previous levels that are not attributable to another medical condition or substance, and must not include a history of past manic or hypomanic episodes. Thoughts of death and suicidal ideation are common.

Several systematic reviews and meta-analyses have shown that a combination of psychotherapy and pharmacotherapy is more efficacious for treatment of unipolar depression than either therapy alone.^5-7 As for which medication is most effective and tolerable, multiple systematic reviews and meta-analyses have not demonstrated superiority of 1 second-generation antidepressant (eg, SSRIs, SNRIs) over another.^7,8

General practice guidelines support titration of the dose or a switch in monotherapy medications until treatment response is achieved, prior to initiation of a second agent. When an adjunctive medication is considered, there are several options: a ­second-generation antipsychotic, a second antidepressant from a different class, thyroid hormone, and lithium. Special consideration is given to the adverse effect profile and potential tolerability; higher adverse effect profiles are observed with second-generation antipsychotics and lithium.⁹

This study suggests that combination pharmacotherapy is superior to monotherapy, both at the time of treatment initiation and in patients with previous inadequate pharmacologic response.

It is not common practice to initiate 2 antidepressants for a new diagnosis of acute depression. The systematic review and meta-analysis conducted by Henssler et al¹ attempted to provide evidence to support the efficacy and tolerability of specific antidepressants when used in combination for initial treatment of acute depression. Of note, a 2008 national survey showed that a majority of psychotropic medications in the United States are prescribed by primary care physicians (73.6%) rather than psychiatrists, making this analysis relevant to family physicians.¹⁰

STUDY SUMMARY

Combination pharmacotherapy yields superior efficacy in acute depression

This 2022 systematic review and meta-­analysis (39 randomized clinical trials [RCTs]; N = 6751) compared the efficacy and tolerability of monotherapy to combination therapy in the treatment of patients with acute depression.¹ The study also aimed to address which specific combination therapies were superior.

Continue to: Selected RCTs included...

Selected RCTs included an intervention group using a combination of 2 antidepressants, regardless of dosage, and a control group of patients taking antidepressant monotherapy. Studies evaluated both patients being treated for the first time and those with a previously inadequate response to medical treatment. All participants were ages 18 years or older (mean age not reported) and had received a diagnosis of depressive disorder according to standard operationalized criteria; patients with multiple psychiatric comorbidities were not excluded.

Studies used various standardized questionnaires—most frequently, the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS)—to determine the severity of depression at baseline and following treatment. The HDRS is a 17-item depression scale and the MADRS is a 10-item depression scale; for both, higher scores indicate worsening depression. Follow-up time ranged from 2 to 12 weeks.

The primary outcome was treatment efficacy measured as the standardized mean difference (SMD). Secondary outcomes included remission (normal-range scores) and response to treatment (eg, ≥ 50% reduction in scores), as defined by the study authors.

Combination therapy was determined to have superior efficacy relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44; P < .001). Combinations with a presynaptic α2-autoreceptor antagonist (eg, mirtazapine, trazodone, or mianserin [the last of which is not approved by the US Food and Drug Administration for use in the United States]) and a monoamine reuptake inhibitor (eg, an SSRI, SNRI, or TCA) were superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Combinations that included bupropion were not superior to monotherapy (SMD = 0.10; 95% CI, –0.07 to 0.27).

Secondary outcomes revealed combination therapy to be superior to monotherapy with respect to remission (odds ratio [OR] = 1.52; 95% CI, 1.20-1.92) and response (OR = 1.40; 95% CI, 1.15-1.69). Subgroup analyses showed that combinations with presynaptic α2-autoreceptor antagonists led to improved remission (OR = 1.42; 95% CI, 1.01-2.01) and response (OR = 1.49; 95% CI, 1.18-1.87) compared with monotherapy, whereas combinations that included bupropion were not superior to monotherapy. For patients who dropped out of treatment for any reason, including adverse drug events, results for combination pharmacotherapy and monotherapy were similar.

Continue to: WHAT'S NEW

 

 

WHAT’S NEW

One combination proved more effective than others

Current clinical guidelines indicate the suitability of trialing pharmacologic monotherapy during the acute phase of depression treatment prior to initiating an adjunctive medication.⁹ All classes of medication investigated in this meta-analysis are generally regarded as first-line therapies, although they are rarely started in combination. This study’s findings suggest that combination pharmacotherapy, especially with a presynaptic α2-autoreceptor antagonist (eg, mirtazapine, trazodone) and a monoamine reuptake inhibitor (eg, an SSRI, SNRI, or a TCA), is superior to monotherapy, both at the time of treatment initiation and in patients with previous inadequate pharmacologic response.

CAVEATS

Potential limitations due to publication bias

Concerns about publication bias and significant study heterogeneity may limit the generalizability of these findings. However, conclusions were robust in a subgroup analysis that was restricted to publications with low risk for bias.

CHALLENGES TO IMPLEMENTATION

None to report

There are no major challenges to implementing this combination treatment. Importantly, there were no differences in tolerability between monotherapy and combination treatment. 

ILLUSTRATIVE CASE

A healthy 33-year-old woman presents to your office with a 3-month history of depressed mood. She reports difficulty concentrating, insomnia, decreased appetite, and generalized fatigue. She denies suicidal or homicidal ideation, substance misuse, or history consistent with manic episodes. Her vital signs are normal and overall her physical examination is unremarkable, although the patient is tearful when discussing her mood. Using shared decision-making, you and the patient determine it is appropriate to initiate pharmacotherapy. Is there a role for combination pharmacotherapy to treat this patient’s acute depression?

Unipolar depression is a highly prevalent condition, estimated to affect 21% of US adults at some point in their lifetime.² It is the second leading cause of disability in the United States, with an ­estimated economic impact of more than $200 billion annually.³

The diagnosis of unipolar depression is based on the criteria set forth in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and commonly includes depressed mood, anhedonia, sleep disturbance, appetite changes, fatigue, feelings of worthlessness or guilt, decreased ability to concentrate, and psychomotor symptoms occurring over at least a 2-week period.⁴ Symptoms represent a decrease in functioning from previous levels that are not attributable to another medical condition or substance, and must not include a history of past manic or hypomanic episodes. Thoughts of death and suicidal ideation are common.

Several systematic reviews and meta-analyses have shown that a combination of psychotherapy and pharmacotherapy is more efficacious for treatment of unipolar depression than either therapy alone.^5-7 As for which medication is most effective and tolerable, multiple systematic reviews and meta-analyses have not demonstrated superiority of 1 second-generation antidepressant (eg, SSRIs, SNRIs) over another.^7,8

General practice guidelines support titration of the dose or a switch in monotherapy medications until treatment response is achieved, prior to initiation of a second agent. When an adjunctive medication is considered, there are several options: a ­second-generation antipsychotic, a second antidepressant from a different class, thyroid hormone, and lithium. Special consideration is given to the adverse effect profile and potential tolerability; higher adverse effect profiles are observed with second-generation antipsychotics and lithium.⁹

This study suggests that combination pharmacotherapy is superior to monotherapy, both at the time of treatment initiation and in patients with previous inadequate pharmacologic response.

It is not common practice to initiate 2 antidepressants for a new diagnosis of acute depression. The systematic review and meta-analysis conducted by Henssler et al¹ attempted to provide evidence to support the efficacy and tolerability of specific antidepressants when used in combination for initial treatment of acute depression. Of note, a 2008 national survey showed that a majority of psychotropic medications in the United States are prescribed by primary care physicians (73.6%) rather than psychiatrists, making this analysis relevant to family physicians.¹⁰

STUDY SUMMARY

Combination pharmacotherapy yields superior efficacy in acute depression

This 2022 systematic review and meta-­analysis (39 randomized clinical trials [RCTs]; N = 6751) compared the efficacy and tolerability of monotherapy to combination therapy in the treatment of patients with acute depression.¹ The study also aimed to address which specific combination therapies were superior.

Continue to: Selected RCTs included...

Selected RCTs included an intervention group using a combination of 2 antidepressants, regardless of dosage, and a control group of patients taking antidepressant monotherapy. Studies evaluated both patients being treated for the first time and those with a previously inadequate response to medical treatment. All participants were ages 18 years or older (mean age not reported) and had received a diagnosis of depressive disorder according to standard operationalized criteria; patients with multiple psychiatric comorbidities were not excluded.

Studies used various standardized questionnaires—most frequently, the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS)—to determine the severity of depression at baseline and following treatment. The HDRS is a 17-item depression scale and the MADRS is a 10-item depression scale; for both, higher scores indicate worsening depression. Follow-up time ranged from 2 to 12 weeks.

The primary outcome was treatment efficacy measured as the standardized mean difference (SMD). Secondary outcomes included remission (normal-range scores) and response to treatment (eg, ≥ 50% reduction in scores), as defined by the study authors.

Combination therapy was determined to have superior efficacy relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44; P < .001). Combinations with a presynaptic α2-autoreceptor antagonist (eg, mirtazapine, trazodone, or mianserin [the last of which is not approved by the US Food and Drug Administration for use in the United States]) and a monoamine reuptake inhibitor (eg, an SSRI, SNRI, or TCA) were superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Combinations that included bupropion were not superior to monotherapy (SMD = 0.10; 95% CI, –0.07 to 0.27).

Secondary outcomes revealed combination therapy to be superior to monotherapy with respect to remission (odds ratio [OR] = 1.52; 95% CI, 1.20-1.92) and response (OR = 1.40; 95% CI, 1.15-1.69). Subgroup analyses showed that combinations with presynaptic α2-autoreceptor antagonists led to improved remission (OR = 1.42; 95% CI, 1.01-2.01) and response (OR = 1.49; 95% CI, 1.18-1.87) compared with monotherapy, whereas combinations that included bupropion were not superior to monotherapy. For patients who dropped out of treatment for any reason, including adverse drug events, results for combination pharmacotherapy and monotherapy were similar.

Continue to: WHAT'S NEW

 

 

WHAT’S NEW

One combination proved more effective than others

Current clinical guidelines indicate the suitability of trialing pharmacologic monotherapy during the acute phase of depression treatment prior to initiating an adjunctive medication.⁹ All classes of medication investigated in this meta-analysis are generally regarded as first-line therapies, although they are rarely started in combination. This study’s findings suggest that combination pharmacotherapy, especially with a presynaptic α2-autoreceptor antagonist (eg, mirtazapine, trazodone) and a monoamine reuptake inhibitor (eg, an SSRI, SNRI, or a TCA), is superior to monotherapy, both at the time of treatment initiation and in patients with previous inadequate pharmacologic response.

CAVEATS

Potential limitations due to publication bias

Concerns about publication bias and significant study heterogeneity may limit the generalizability of these findings. However, conclusions were robust in a subgroup analysis that was restricted to publications with low risk for bias.

CHALLENGES TO IMPLEMENTATION

None to report

There are no major challenges to implementing this combination treatment. Importantly, there were no differences in tolerability between monotherapy and combination treatment. 

The Diagnosis: Type I Cryoglobulinemia

Retiform purpura with overlying necrosis subsequently developed over the course of a week following presentation (Figure 1). A skin biopsy showed fibrin thrombi and congestion of small- and medium-sized blood vessels, consistent with vasculopathy (Figure 2). Urinalysis revealed hematuria and proteinuria. A renal biopsy performed due to a continually elevated serum creatinine level revealed glomerulonephritis with numerous IgG1 lambda–restricted glomerular capillary hyaline thrombi, compatible with a lymphoproliferative disorder–associated type I cryoglobulinemia. A serum cryoglobulin immunofixation test confirmed type I cryoglobulinemia involving monoclonal IgG lambda. The combination of cutaneous, renal, and hematologic findings was consistent with type I cryoglobulinemia. A subsequent bone marrow biopsy demonstrated a CD20+ lambda–restricted plasma cell neoplasm. Initial treatment with high-dose corticosteroids followed by targeted treatment of the underlying hematologic condition with bortezomib, rituximab, and dexamethasone improved the skin disease.

Cryoglobulins are abnormal immunoglobulins that precipitate at temperatures below 37 °C. The persistent presence of cryoglobulins in the serum is termed cryoglobulinemia.¹ Type I cryoglobulinemia is distinguished from mixed cryoglobulinemia—types II and III—by the presence of a single monoclonal immunoglobulin, typically IgM or IgG. It is associated with lymphoproliferative disorders, most commonly monoclonal gammopathy of undetermined significance and B-cell malignancies such as Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. Histopathology shows occlusion of small vessel lumina with homogenous eosinophilic material containing the monoclonal cryoprecipitate.² Disease manifestations are caused by small vessel occlusion, which leads to ischemia and tissue damage.

Retiform purpura, livedo reticularis/racemosa, and necrosis leading to ulcers are the most common cutaneous clinical findings. Extracutaneous signs include peripheral neuropathy, arthralgia, Raynaud phenomenon, and acrocyanosis. Renal involvement, most commonly glomerulonephritis with associated proteinuria, is noted in 14% to 20% of cases.^3,4 An elevated cryocrit can lead to symptoms of hyperviscosity syndrome.²

Treatment is difficult and primarily is focused on addressing the underlying hematologic condition, which is responsible for synthesis of the cryoglobulin. Decreasing cryoglobulin production leads to decreased occlusion of blood vessels, thus alleviating the ischemia and skin damage. Monoclonal gammopathy of undetermined significance–related type I cryoglobulinemia initially is treated with corticosteroids followed by rituximab if a CD20+ B-cell clone is identified.² Bortezomib is recommended for cases associated with Waldenström macroglobulinemia and cases associated with multiple myeloma with concurrent renal failure. In patients with neuropathy, a lenalidomide-based treatment can be employed. Patients should be instructed to keep extremities warm.² Diabetic foot care guidelines should be followed to prevent wound complications. The differential diagnosis for type I cryoglobulinemia includes other causes of retiform purpura–like angioinvasive fungal infection, antiphospholipid antibody syndrome, calciphylaxis, and livedoid vasculopathy.⁵ Angioinvasive fungal infections are caused by Candida, Aspergillus, and Mucorales species, as well as other hyaline molds. They typically occur in immunocompromised patients and invade the blood vessels via direct inoculation or dissemination.⁶ Patients present with retiform purpura but typically will be acutely ill with fevers and vital sign abnormalities. Histopathology with special stains often will identify the fungal organisms in the dermis or inside blood vessel walls with vessel wall destruction and hemorrhage.⁷ Accurate diagnosis is essential to selecting appropriate antifungal agents. If angioinvasive fungal infection is clinically suspected, treatment should begin before culture and histopathologic data are available.⁷

Antiphospholipid antibody syndrome is an autoimmune thrombophilia that can occur as primary disease or in association with other autoimmune conditions, most commonly systemic lupus erythematosus. Diagnosis requires the presence of antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibody, anti–β2-glycoprotein-1 antibody, with arterial or venous thrombosis and/or recurrent pregnancy loss. Paraproteinemia is not seen. The most common cutaneous finding is livedo reticularis, with livedo racemosa being a more distinctive finding.8 Small vessel thrombosis is seen histopathologically. Treatment includes antiplatelet and anticoagulant medications. Patients with refractory disease may benefit from additional therapy with hydroxychloroquine or intravenous immunoglobulins.⁸

Calciphylaxis is a rare depositional vasculopathy that often occurs in patients with end-stage renal disease on dialysis. Patients present with painful and poor-healing skin lesions including indurated nodules, violaceous plaques, and retiform purpura that typically affect areas of high adiposity such as the thighs, abdomen, and buttocks.⁹ Ulceration and superimposed infections are common complications. Histopathologically, small dermal and subcutaneous vessels demonstrate calcification, microthrombosis, and fibrointimal hyperplasia.⁹ Wound management is critically important in patients with calciphylaxis. Treatment with intravenous sodium thiosulfate is typical, but prognosis remains poor. Although livedoid vasculopathy may present with retiform purpura in the ankles, paraproteinemia is not seen and patients frequently present with punched-out ulcerations that tend to heal into atrophie blanche.¹⁰ Livedoid vasculopathy has been associated with underlying hypercoagulable states, connective tissue diseases, and chronic venous hypertension. Hypercoagulability and endothelial cell damage contribute to the formation of fibrin thrombi in the superficial dermal blood vessels. Histopathology demonstrates thickening of vessel walls and intraluminal hyaline thrombi. Successful treatment in most cases is achieved with anticoagulation therapy, typically rivaroxaban, especially in patients with underlying hypercoagulability. Antiplatelet therapy also may be considered, while anabolic agents have been shown to be helpful in patients with connective tissue disease.¹⁰

The Diagnosis: Type I Cryoglobulinemia

Retiform purpura with overlying necrosis subsequently developed over the course of a week following presentation (Figure 1). A skin biopsy showed fibrin thrombi and congestion of small- and medium-sized blood vessels, consistent with vasculopathy (Figure 2). Urinalysis revealed hematuria and proteinuria. A renal biopsy performed due to a continually elevated serum creatinine level revealed glomerulonephritis with numerous IgG1 lambda–restricted glomerular capillary hyaline thrombi, compatible with a lymphoproliferative disorder–associated type I cryoglobulinemia. A serum cryoglobulin immunofixation test confirmed type I cryoglobulinemia involving monoclonal IgG lambda. The combination of cutaneous, renal, and hematologic findings was consistent with type I cryoglobulinemia. A subsequent bone marrow biopsy demonstrated a CD20+ lambda–restricted plasma cell neoplasm. Initial treatment with high-dose corticosteroids followed by targeted treatment of the underlying hematologic condition with bortezomib, rituximab, and dexamethasone improved the skin disease.

Cryoglobulins are abnormal immunoglobulins that precipitate at temperatures below 37 °C. The persistent presence of cryoglobulins in the serum is termed cryoglobulinemia.¹ Type I cryoglobulinemia is distinguished from mixed cryoglobulinemia—types II and III—by the presence of a single monoclonal immunoglobulin, typically IgM or IgG. It is associated with lymphoproliferative disorders, most commonly monoclonal gammopathy of undetermined significance and B-cell malignancies such as Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. Histopathology shows occlusion of small vessel lumina with homogenous eosinophilic material containing the monoclonal cryoprecipitate.² Disease manifestations are caused by small vessel occlusion, which leads to ischemia and tissue damage.

Retiform purpura, livedo reticularis/racemosa, and necrosis leading to ulcers are the most common cutaneous clinical findings. Extracutaneous signs include peripheral neuropathy, arthralgia, Raynaud phenomenon, and acrocyanosis. Renal involvement, most commonly glomerulonephritis with associated proteinuria, is noted in 14% to 20% of cases.^3,4 An elevated cryocrit can lead to symptoms of hyperviscosity syndrome.²

Treatment is difficult and primarily is focused on addressing the underlying hematologic condition, which is responsible for synthesis of the cryoglobulin. Decreasing cryoglobulin production leads to decreased occlusion of blood vessels, thus alleviating the ischemia and skin damage. Monoclonal gammopathy of undetermined significance–related type I cryoglobulinemia initially is treated with corticosteroids followed by rituximab if a CD20+ B-cell clone is identified.² Bortezomib is recommended for cases associated with Waldenström macroglobulinemia and cases associated with multiple myeloma with concurrent renal failure. In patients with neuropathy, a lenalidomide-based treatment can be employed. Patients should be instructed to keep extremities warm.² Diabetic foot care guidelines should be followed to prevent wound complications. The differential diagnosis for type I cryoglobulinemia includes other causes of retiform purpura–like angioinvasive fungal infection, antiphospholipid antibody syndrome, calciphylaxis, and livedoid vasculopathy.⁵ Angioinvasive fungal infections are caused by Candida, Aspergillus, and Mucorales species, as well as other hyaline molds. They typically occur in immunocompromised patients and invade the blood vessels via direct inoculation or dissemination.⁶ Patients present with retiform purpura but typically will be acutely ill with fevers and vital sign abnormalities. Histopathology with special stains often will identify the fungal organisms in the dermis or inside blood vessel walls with vessel wall destruction and hemorrhage.⁷ Accurate diagnosis is essential to selecting appropriate antifungal agents. If angioinvasive fungal infection is clinically suspected, treatment should begin before culture and histopathologic data are available.⁷

Antiphospholipid antibody syndrome is an autoimmune thrombophilia that can occur as primary disease or in association with other autoimmune conditions, most commonly systemic lupus erythematosus. Diagnosis requires the presence of antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibody, anti–β2-glycoprotein-1 antibody, with arterial or venous thrombosis and/or recurrent pregnancy loss. Paraproteinemia is not seen. The most common cutaneous finding is livedo reticularis, with livedo racemosa being a more distinctive finding.8 Small vessel thrombosis is seen histopathologically. Treatment includes antiplatelet and anticoagulant medications. Patients with refractory disease may benefit from additional therapy with hydroxychloroquine or intravenous immunoglobulins.⁸

Calciphylaxis is a rare depositional vasculopathy that often occurs in patients with end-stage renal disease on dialysis. Patients present with painful and poor-healing skin lesions including indurated nodules, violaceous plaques, and retiform purpura that typically affect areas of high adiposity such as the thighs, abdomen, and buttocks.⁹ Ulceration and superimposed infections are common complications. Histopathologically, small dermal and subcutaneous vessels demonstrate calcification, microthrombosis, and fibrointimal hyperplasia.⁹ Wound management is critically important in patients with calciphylaxis. Treatment with intravenous sodium thiosulfate is typical, but prognosis remains poor. Although livedoid vasculopathy may present with retiform purpura in the ankles, paraproteinemia is not seen and patients frequently present with punched-out ulcerations that tend to heal into atrophie blanche.¹⁰ Livedoid vasculopathy has been associated with underlying hypercoagulable states, connective tissue diseases, and chronic venous hypertension. Hypercoagulability and endothelial cell damage contribute to the formation of fibrin thrombi in the superficial dermal blood vessels. Histopathology demonstrates thickening of vessel walls and intraluminal hyaline thrombi. Successful treatment in most cases is achieved with anticoagulation therapy, typically rivaroxaban, especially in patients with underlying hypercoagulability. Antiplatelet therapy also may be considered, while anabolic agents have been shown to be helpful in patients with connective tissue disease.¹⁰

The Diagnosis: Type I Cryoglobulinemia

Retiform purpura with overlying necrosis subsequently developed over the course of a week following presentation (Figure 1). A skin biopsy showed fibrin thrombi and congestion of small- and medium-sized blood vessels, consistent with vasculopathy (Figure 2). Urinalysis revealed hematuria and proteinuria. A renal biopsy performed due to a continually elevated serum creatinine level revealed glomerulonephritis with numerous IgG1 lambda–restricted glomerular capillary hyaline thrombi, compatible with a lymphoproliferative disorder–associated type I cryoglobulinemia. A serum cryoglobulin immunofixation test confirmed type I cryoglobulinemia involving monoclonal IgG lambda. The combination of cutaneous, renal, and hematologic findings was consistent with type I cryoglobulinemia. A subsequent bone marrow biopsy demonstrated a CD20+ lambda–restricted plasma cell neoplasm. Initial treatment with high-dose corticosteroids followed by targeted treatment of the underlying hematologic condition with bortezomib, rituximab, and dexamethasone improved the skin disease.

Cryoglobulins are abnormal immunoglobulins that precipitate at temperatures below 37 °C. The persistent presence of cryoglobulins in the serum is termed cryoglobulinemia.¹ Type I cryoglobulinemia is distinguished from mixed cryoglobulinemia—types II and III—by the presence of a single monoclonal immunoglobulin, typically IgM or IgG. It is associated with lymphoproliferative disorders, most commonly monoclonal gammopathy of undetermined significance and B-cell malignancies such as Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. Histopathology shows occlusion of small vessel lumina with homogenous eosinophilic material containing the monoclonal cryoprecipitate.² Disease manifestations are caused by small vessel occlusion, which leads to ischemia and tissue damage.

Retiform purpura, livedo reticularis/racemosa, and necrosis leading to ulcers are the most common cutaneous clinical findings. Extracutaneous signs include peripheral neuropathy, arthralgia, Raynaud phenomenon, and acrocyanosis. Renal involvement, most commonly glomerulonephritis with associated proteinuria, is noted in 14% to 20% of cases.^3,4 An elevated cryocrit can lead to symptoms of hyperviscosity syndrome.²

Treatment is difficult and primarily is focused on addressing the underlying hematologic condition, which is responsible for synthesis of the cryoglobulin. Decreasing cryoglobulin production leads to decreased occlusion of blood vessels, thus alleviating the ischemia and skin damage. Monoclonal gammopathy of undetermined significance–related type I cryoglobulinemia initially is treated with corticosteroids followed by rituximab if a CD20+ B-cell clone is identified.² Bortezomib is recommended for cases associated with Waldenström macroglobulinemia and cases associated with multiple myeloma with concurrent renal failure. In patients with neuropathy, a lenalidomide-based treatment can be employed. Patients should be instructed to keep extremities warm.² Diabetic foot care guidelines should be followed to prevent wound complications. The differential diagnosis for type I cryoglobulinemia includes other causes of retiform purpura–like angioinvasive fungal infection, antiphospholipid antibody syndrome, calciphylaxis, and livedoid vasculopathy.⁵ Angioinvasive fungal infections are caused by Candida, Aspergillus, and Mucorales species, as well as other hyaline molds. They typically occur in immunocompromised patients and invade the blood vessels via direct inoculation or dissemination.⁶ Patients present with retiform purpura but typically will be acutely ill with fevers and vital sign abnormalities. Histopathology with special stains often will identify the fungal organisms in the dermis or inside blood vessel walls with vessel wall destruction and hemorrhage.⁷ Accurate diagnosis is essential to selecting appropriate antifungal agents. If angioinvasive fungal infection is clinically suspected, treatment should begin before culture and histopathologic data are available.⁷

Antiphospholipid antibody syndrome is an autoimmune thrombophilia that can occur as primary disease or in association with other autoimmune conditions, most commonly systemic lupus erythematosus. Diagnosis requires the presence of antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibody, anti–β2-glycoprotein-1 antibody, with arterial or venous thrombosis and/or recurrent pregnancy loss. Paraproteinemia is not seen. The most common cutaneous finding is livedo reticularis, with livedo racemosa being a more distinctive finding.8 Small vessel thrombosis is seen histopathologically. Treatment includes antiplatelet and anticoagulant medications. Patients with refractory disease may benefit from additional therapy with hydroxychloroquine or intravenous immunoglobulins.⁸

Calciphylaxis is a rare depositional vasculopathy that often occurs in patients with end-stage renal disease on dialysis. Patients present with painful and poor-healing skin lesions including indurated nodules, violaceous plaques, and retiform purpura that typically affect areas of high adiposity such as the thighs, abdomen, and buttocks.⁹ Ulceration and superimposed infections are common complications. Histopathologically, small dermal and subcutaneous vessels demonstrate calcification, microthrombosis, and fibrointimal hyperplasia.⁹ Wound management is critically important in patients with calciphylaxis. Treatment with intravenous sodium thiosulfate is typical, but prognosis remains poor. Although livedoid vasculopathy may present with retiform purpura in the ankles, paraproteinemia is not seen and patients frequently present with punched-out ulcerations that tend to heal into atrophie blanche.¹⁰ Livedoid vasculopathy has been associated with underlying hypercoagulable states, connective tissue diseases, and chronic venous hypertension. Hypercoagulability and endothelial cell damage contribute to the formation of fibrin thrombi in the superficial dermal blood vessels. Histopathology demonstrates thickening of vessel walls and intraluminal hyaline thrombi. Successful treatment in most cases is achieved with anticoagulation therapy, typically rivaroxaban, especially in patients with underlying hypercoagulability. Antiplatelet therapy also may be considered, while anabolic agents have been shown to be helpful in patients with connective tissue disease.¹⁰

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that results in progressive deterioration of motor neurons in the ventral horn of the spinal cord, which results in loss of voluntary muscle movements.¹ Eventually, typical daily tasks become difficult to perform, and as the disease progresses, the ability to eat and breathe is impaired.² Reports from 2015 show the annual incidence of ALS is 5 cases per 100,000 people, with the total number of cases reported at more than 16,000 in the United States.³ In clinical practice, disease progression is routinely assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Typical decline is 1 point per month.⁴

Unfortunately, at this time, ALS care focuses on symptom management, including prevention of weight loss; implementation of communication strategies; and management of pain, constipation, excess secretions, cramping, and breathing. Despite copious research into treatment options, few exist. Riluzole is an oral medication administered twice daily and has been on the market since 1995.^5-7 Efficacy was demonstrated in a study showing statistically significant survival at 12 months compared with controls (74% vs 58%, respectively; P = .014).⁶ Since its approval, riluzole has become part of standard-of-care ALS management.

In 2017, the US Food and Drug Administration (FDA) approved edaravone, an IV medication that was found to slow the progression of ALS in some patients.^8-12 Oxidative stress caused by free radicals is hypothesized to increase the progression of ALS by motor neuron degradation.¹³ Edaravone works as a free radical and peroxynitrite scavenger and has been shown to eliminate lipid peroxides and hydroxyl radicals known to damage endothelial and neuronal cells.¹²

Given the mechanism of action of edaravone, it seemed to be a promising option to slow the progression of ALS. A 2019 systematic review analyzed 3 randomized studies with 367 patients and found a statistically significant difference in change in ALSFRS-R scores between patients treated with edaravone for 24 weeks compared with patients treated with the placebo (mean difference, 1.63; 95% CI, 0.26-3.00; P = .02).¹² Secondary endpoints evaluated included percent forced vital capacity (%FVC), grip strength, and pinch strength: All showing no significant difference when comparing IV edaravone with placebo.

A 2022 postmarketing study of 324 patients with ALS evaluated the safety and efficacy of long-term edaravone treatment. IV edaravone therapy for > 24 weeks was well tolerated, although it was not associated with any disease-modifying benefit when comparing ALSFRS-R scores with patients not receiving edaravone over a median 13.9 months (ALSFRS-R points/month, -0.91 vs -0.85; P = .37).¹³ A third ALS treatment medication, sodium phenylbutyrate/taurursodiol was approved in 2022 but not available during our study period and not included here.^14,15

Studies have shown an increased incidence of ALS in the veteran population. Veterans serving in the Gulf War were nearly twice as likely to develop ALS as those not serving in the Gulf.¹⁶ However, existing literature regarding the effectiveness of edaravone does not specifically examine the effect on this unique population. The objective of this study was to assess the effect of IV edaravone on ALS progression in veterans compared with veterans who received standard of care.

Methods

This study was conducted at a large, academic US Department of Veterans Affairs (VA) medical center. Patients with ALS are followed by a multidisciplinary clinic composed of a neurologist, pulmonologist, clinical pharmacist, social worker, speech therapist, physical therapist, occupational therapist, dietician, clinical psychologist, wheelchair clinic representative, and benefits representative. Patients are typically seen for a half-day appointment about every 3 months. During these visits, a comprehensive review of disease progression is performed. This review entails completion of the ALSFRS-R, physical examination, and pulmonary function testing. Speech intelligibility stage (SIS) is assessed by a speech therapist as well. SIS is scored from 1 (no detectable speech disorder) to 5 (no functional speech). All patients followed in this multidisciplinary ALS clinic receive standard-of-care treatment. This includes the discussion of treatment options that if appropriate are provided to help manage a wide range of complications associated with this disease (eg, pain, cramping, constipation, excessive secretions, weight loss, dysphagia). As a part of these personal discussions, treatment with riluzole is also offered as a standard-of-care pharmacologic option.

Study Design

This retrospective case-control study was conducted using electronic health record data to compare ALS progression in patients on IV edaravone therapy with standard of care. The Indiana University/Purdue University, Indianapolis Institutional Review Board and the VA Research and Development Committee approved the study. The control cohort received the standard of care. Patients in the case cohort received standard of care and edaravone 60 mg infusions daily for an initial cycle of 14 days on treatment, followed by 14 days off. All subsequent cycles were 10 of 14 days on treatment followed by 14 days off. The initial 2 doses were administered in the outpatient infusion clinic to monitor for a hypersensitivity reaction. Patients then had a peripherally inserted central catheter line placed and received doses on days 3 through 14 at home. A port was placed for subsequent cycles, which were also completed at home. Appropriateness of edaravone therapy was assessed by the neurologist at each follow-up appointment. Therapy was then discontinued if warranted based on disease progression or patient preference.

Study Population

Patients included were aged 18 to 75 years with diagnosed ALS. Patients with complications that might influence evaluation of medication efficacy (eg, Parkinson disease, schizophrenia, significant dementia, other major medical morbidity) were excluded. Patients were also excluded if they were on continuous bilevel positive airway pressure and/or had a total score of ≤ 3 points on ALSFRS-R items for dyspnea, orthopnea, or respiratory insufficiency. Due to our small sample size, patients were excluded if treatment was < 6 months, which is the gold standard of therapy duration established by clinical trials.^9,11,12

The standard-of-care cohort included patients enrolled in the multidisciplinary clinic September 1, 2014 to August 31, 2017. These patients were compared in a 2:1 ratio with patients who received IV edaravone. The edaravone cohort included patients who initiated treatment with IV edaravone between September 1, 2017, and August 31, 2020. This date range prior to the approval of edaravone was chosen to compare patients at similar stages of disease progression and to have the largest sample size possible.

Data Collection

Data were obtained for eligible patients using the VA Computerized Patient Record System. Demographic data gathered for each patient included age, sex, weight, height, body mass index (BMI), race, and riluzole use.

The primary endpoint was the change in ALSFRS-R score after 6 months of IV edaravone compared with standard-of-care ALS management. Secondary outcomes included change in ALSFRS-R scores 3, 12, 18, and 24 months after therapy initiation, change in %FVC and SIS 3, 6, 12, 18, and 24 months after therapy initiation, duration of edaravone completed (months), time to death (months), and adverse events.

Statistical Analysis

Comparisons between the edaravone and control groups for differences in patient characteristics were made using χ² and 2-sample t tests for categorical and continuous variables, respectively. Comparisons between the 2 groups for differences in study outcomes (ALSFRS-R scores, %FVC, SIS) at each time point were evaluated using 2-sample t tests. Adverse events and adverse drug reactions were compared between groups using χ² tests. Statistical significance was set at 0.05.

We estimated that a sample size of 21 subjects in the edaravone (case) group and 42 in the standard-of-care (control) group would be needed to achieve 80% power to detect a difference of 6.5 between the 2 groups for the change in ALSFRS-R scores. This 80% power was calculated based on a 2-sample t test, and assuming a 2-sided 5% significance level and a within-group SD of 8.5.⁹ Statistical analysis was conducted using Microsoft Excel.

Results

Of the 96 patients, 10 met exclusion criteria. From the remaining 86, 42 were randomly selected for the standard-of-care group. A total of 27 patients seen in multidisciplinary ALS clinic between September 1, 2017, and August 31, 2020, received at least 1 dose of IV edaravone. Of the 27 edaravone patients, 6 were excluded for not completing a total of 6 months of edaravone. Two of the 6 excluded developed a rash, which resolved within 1 week after discontinuing edaravone. The other 4 discontinued edaravone before 6 months because of disease progression.

Baseline Characteristics

Efficacy

Discussion

This 24-month, case-control retrospective study assessed efficacy and safety of IV edaravone for the management of ALS. Although the landmark edaravone study showed slowed progression of ALS at 6 and 12 months, the effectiveness of edaravone outside the clinical trial setting has been less compelling.^9-11,13 A later study showed no difference in change in ALSFRS-R score at 6 months compared with that of the placebo group.⁷ In our study, no statistically significant difference was found for change in ALSFRS-R scores at 6 months.

Our study was unique given we evaluated a veteran population. The link between the military and ALS is largely unknown, although studies have shown increased incidence of ALS in people with a military history compared with that of the general population.^16-18 Our study was also unique because it was single-centered in design and allowed for outcome assessments, including ALSFRS-R scores, SIS, and %FVC measurements, to all be conducted by the same practitioner to limit variability. Unfortunately, our sample size resulted in a cohort that was underpowered at 12, 18, and 24 months. In addition, there was a lack of data on chart review for SIS and %FVC measurements at 24 months. As ALS progresses toward end stage, SIS and %FVC measurements can become difficult and burdensome on the patient to obtain, and the ALS multidisciplinary team may decide not to gather these data points as ALS progresses. As a result, change in SIS and %FVC measurements were unable to be reported due to lack of gathering this information at the 24-month mark in the edaravone group. Due to the cost and administration burden associated with edaravone, it is important that assessment of disease progression is performed regularly to assess benefit and appropriateness of continued therapy. The oral formulation of edaravone was approved in 2022, shortly after the completion of data collection for this study.^19,20 Although our study did not analyze oral edaravone, the administration burden of treatment would be reduced with the oral formulation, and we hypothesize there will be increased patient interest in ALS management with oral vs IV edaravone. Evaluation of long-term treatment for efficacy and safety beyond 24 months has not been evaluated. Future studies should continue to evaluate edaravone use in a larger veteran population.

Limitations

One limitation for our study alluded to earlier in the discussion was sample size. Although this study met power at the 6-month mark, it was limited by the number of patients who received more than 6 months of edaravone (n = 21). As a result, statistical analyses between treatment groups were underpowered at 12, 18, and 24 months. Our study had 80% power to detect a difference of 6.5 between the groups for the change in ALSFRS-R scores. Previous studies detected a statistically significant difference in ALSFRS-R scores, with a difference in ALSFRS-R scores of 2.49 between groups.⁸ Future studies should evaluate a larger sample size of patients who are prescribed edaravone.

Another limitation was that the edaravone and standard-of-care group data were gathered from different time periods. Two different time frames were selected to increase sample size by gathering data over a longer period and to account for patients who may have qualified for IV edaravone but could not receive it as it was not yet available on the market. There were no known changes to the standard of care between the time periods that would affect results. As noted previously, the standard-of-care group had fewer patients taking riluzole compared with the edaravone group, which may have confounded our results. We concluded patients opting for edaravone were more likely to trial riluzole, taken by mouth twice daily, before starting edaravone, a once-daily IV infusion.

Conclusions

No difference in the rate of ALS progression was noted between patients who received IV edaravone vs standard of care at 6 months. In addition, no difference was noted in other objective measures of disease progression, including %FVC, SIS, and time to death. As a result, the decision to initiate and continue edaravone therapy should be made on an individualized basis according to a prescriber’s clinical judgment and a patient’s goals. Edaravone therapy should be discontinued when disease progression occurs or when medication administration becomes a burden.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at Veteran Health Indiana.

Horner syndrome is a rare condition that has no sex or race predilection and is characterized by the clinical triad of a miosis, anhidrosis, and small, unilateral ptosis. The prompt diagnosis and determination of the etiology of Horner syndrome are of utmost importance, as the condition can result from many life-threatening systemic complications. Horner syndrome is often asymptomatic but can have distinct, easily identified characteristics seen with an ophthalmic examination. This report describes a patient who presented with Horner syndrome resulting from an internal carotid artery dissection.

Case Presentation

A 61-year-old woman presented with periorbital pain with onset 3 days prior. The patient described the pain as 7 of 10 that had been worsening and was localized around and behind the right eye. She reported new-onset headaches on the right side over the past week with associated intermittent vision blurriness in the right eye. She had a history of mobility issues and had fallen backward about 1 week before, hitting the back of her head on the floor without direct trauma to the eye. She was symptomatic for light sensitivity, syncope, and dizziness, with reports of a recent history of transient ischemic attacks (TIAs) of unknown etiology, which had occurred in the months preceding her examination. She reported no jaw claudication, scalp tenderness, and neck or shoulder pain. She was unaware of any changes in her perspiration pattern on the right side of her face but mentioned that she had noticed her right upper eyelid drooping while looking in the mirror.

This patient had a routine eye examination 2 months before, which was remarkable for stable, nonfoveal involving adult-onset vitelliform dystrophy in the left eye and nuclear sclerotic cataracts and mild refractive error in both eyes. No iris heterochromia was noted, and her pupils were equal, round, and reactive to light. Her history was remarkable for chest pain, obesity, bipolar disorder, vertigo, transient cerebral ischemia, hypertension, hypercholesterolemia, alcohol use disorder, cocaine use disorder, and asthma. A carotid ultrasound had been performed 1 month before the onset of symptoms due to her history of TIAs, which showed no hemodynamically significant stenosis (> 50% stenosis) of either carotid artery. Her medications included oxybutynin chloride, amlodipine, acetaminophen, sertraline hydrochloride, lidocaine, albuterol, risperidone, hydroxyzine hydrochloride, lisinopril, omeprazole, once-daily baby aspirin, atorvastatin, and calcium.

At the time of presentation, an ophthalmic examination revealed no decrease in visual acuity with a best-corrected visual acuity of 20/20 in the right and left eyes. The patient’s pupil sizes were unequal, with a smaller, more miotic right pupil with a greater difference between the pupil sizes in dim illumination (Figure 1).

CTA revealed a focal linear filling defect in the right midinternal carotid artery, likely related to an internal carotid artery vascular flap. There was no evidence of proximal intracranial occlusive disease. MRI revealed a linear area of high-intensity signal projecting over the mid and distal right internal carotid artery lumen (Figure 2A).

Discussion

Anisocoria is defined as a difference in pupil sizes between the eyes.¹ This difference can be physiologic with no underlying pathology as an etiology of the condition. If underlying pathology causes anisocoria, it can result in dysfunction with mydriasis, leading to a more miotic pupil, or it can result from issues with miosis, leading to a more mydriatic pupil.¹

To determine whether anisocoria is physiologic or pathologic, one must assess the patient’s pupil sizes in dim and bright illumination. If the difference in the pupil size is the same in both room illuminations (ie, the anisocoria is 2 mm in both bright and dim illumination, pupillary constriction and dilation are functioning normally), then the patient has physiologic anisocoria.¹ If anisocoria is different in bright and dim illumination (ie, the anisocoria is 1 mm in bright and 3 mm in dim settings or 3 mm in bright and 1 mm in dim settings), the condition is related to pathology. To determine the underlying pathology of anisocoria in cases that are not physiologic, it is important to first determine whether the anisocoria is related to miotic or mydriatic dysfunction.¹

If the anisocoria is greater in dim illumination, this suggests mydriatic dysfunction and could be a result of damage to the sympathetic pupillary pathway.¹ The smaller or more miotic pupil in this instance is the pathologic pupil. If the anisocoria is greater in bright illumination, this suggests miotic dysfunction and could be a result of damage to the parasympathetic pathway.¹ The larger or more mydriatic pupil in this instance is the pathologic pupil. Congenital abnormalities, such as iris colobomas, aniridia, and ectopic pupils, can result in a wide range of pupil sizes and shapes, including miotic or mydriatic pupils.¹

Pathologic Mydriasis

Pathologic mydriatic pupils can result from dysfunction in the parasympathetic nervous system, which results in a pupil that is not sufficiently able to dilate with the removal of a light stimulus. Mydriatic pupils can be related to Adie tonic pupil, Argyll-Robertson pupil, third nerve palsy, trauma, surgeries, or pharmacologic mydriasis.² The conditions that cause mydriasis can be readily differentiated from one another based on clinical examination.

Adie tonic pupil results from damage to the ciliary ganglion.² While pupillary constriction in response to light will be absent or sluggish in an Adie pupil, the patient will have an intact but sluggish accommodative pupillary response; therefore, the pupil will still constrict with accommodation and convergence to focus on near objects, although slowly. This is known as light-near dissociation.²

Argyll-Robertson pupils are caused by damage to the Edinger-Westphal nucleus in the rostral midbrain.³ Lesions to this area of the brain are typically associated with neurosyphilis but also can be a result of Lyme disease, multiple sclerosis, encephalitis, neurosarcoidosis, herpes zoster, diabetes mellitus, and chronic alcohol misuse.³ Argyll Robertson pupils can appear very similar to a tonic pupil in that this condition will also have a dilated pupil and light-near dissociation.³ These pupils will differ in that they also tend to have an irregular shape (dyscoria), and the pupils will constrict briskly when focusing on near objects and dilate briskly when focusing on distant objects, not sluggishly, as in Adie tonic pupil.³

Mydriasis due to a third nerve palsy will present with ptosis and extraocular muscle dysfunction (including deficits to the superior rectus, medial rectus, inferior oblique, and inferior rectus), with the classic presentation of a completed palsy with the eye positioned “down and out” or the patient’s inability to look medially and superiorly with the affected eye.²

As in cases of pathologic mydriasis, a thorough and in-depth history can help determine traumatic, surgical and pharmacologic etiologies of a mydriatic pupil. It should be determined whether the patient has had any previous trauma or surgeries to the eye or has been in contact with any of the following: acetylcholine receptor antagonists (atropine, scopolamine, homatropine, cyclopentolate, and tropicamide), motion sickness patches (scopolamine), nasal vasoconstrictors, glycopyrrolate deodorants, and/or various plants (Jimson weed or plants belonging to the digitalis family, such as foxglove).²

Pathologic Miosis

Pathologic miotic pupils can result from dysfunction in the sympathetic nervous system and can be related to blunt or penetrating trauma to the orbit, Horner syndrome, and pharmacologic miosis.² Horner syndrome will be accompanied by a slight ptosis and sometimes anhidrosis on the ipsilateral side of the face. To differentiate between traumatic and pharmacologic miosis, a detailed history should be obtained, paying close attention to injuries to the eyes or head and/or possible exposure to chemical or pharmaceutical agents, including prostaglandins, pilocarpine, organophosphates, and opiates.²

Horner Syndrome

Horner syndrome is a neurologic condition that results from damage to the oculosympathetic pathway.⁴ The oculosympathetic pathway is a 3-neuron pathway that begins in the hypothalamus and follows a circuitous route to ultimately innervate the facial sweat glands, the smooth muscles of the blood vessels in the orbit and face, the iris dilator muscle, and the Müller muscles of the superior and inferior eyelids.^1,5 Therefore, this pathway’s functions include vasoconstriction of facial blood vessels, facial diaphoresis (sweating), pupillary dilation, and maintaining an open position of the eyelids.¹

Oculosympathetic pathway anatomy. To understand the findings associated with Horner syndrome, it is necessary to understand the anatomy of this 3-neuron pathway.⁵ First-order neurons, or central neurons, arise in the posterolateral aspect of the hypothalamus, where they then descend through the midbrain, pons, medulla, and cervical spinal cord via the intermediolateral gray column.⁶ The fibers then synapse in the ciliospinal center of Budge at the level of cervical vertebra C8 to thoracic vertebra T2, which give rise to the preganglionic, or second-order neurons.⁶

Second-order neurons begin at the ciliospinal center of Budge and exit the spinal cord via the central roots, most at the level of thoracic vertebra T1, with the remainder leaving at the levels of cervical vertebra C8 and thoracic vertebra T2.⁷ After exiting the spinal cord, the second-order neurons loop around the subclavian artery, where they then ascend close to the apex of the lung to synapse with the cell bodies of the third-order neurons at the superior cervical ganglion near cervical vertebrae C2 and C3.⁷

After arising at the superior cervical ganglion, third-order neurons diverge to follow 2 different courses.⁷ A portion of the neurons travels along the external carotid artery to ultimately innervate the facial sweat glands, while the other portion of the neurons combines with the carotid plexus and travels within the walls of the internal carotid artery and through the cavernous sinus.⁷ The fibers then briefly join the abducens nerve before anastomosing with the ophthalmic division of the trigeminal nerve.⁷ After coursing through the superior orbital fissure, the fibers innervate the iris dilator and Müller muscles via the long ciliary nerves.⁷

Symptoms and signs. Patients with Horner syndrome can present with a variety of symptoms and signs. Patients may be largely asymptomatic or they may complain of a droopy eyelid and blurry vision. The full Horner syndrome triad consists of ipsilateral miosis, anhidrosis of the face, and mild ptosis of the upper eyelid with reverse ptosis of the lower eyelid.⁸ The difference in pupil size is greatest 4 to 5 seconds after switching from bright to dim room illumination due to dilation lag in the miotic pupil from poor innervation.¹

Although the classical triad of ptosis, miosis, and anhidrosis is emphasized in the literature, the full triad may not always be present.⁴ This variation is due to the anatomy of the oculosympathetic pathway with branches of the nerve system separating at the superior cervical ganglion and following different pathways along the internal and external carotid arteries, resulting in anhidrosis only in Horner syndrome caused by lesions to the first- or second-order neurons.^4,5 Because of this deviation of the nerve fibers in the pathway, the presence of miosis and a slight ptosis in the absence of anhidrosis should still strongly suggest Horner syndrome.

In addition to the classic triad, Horner syndrome can present with other ophthalmic findings, including conjunctival injection, changes in accommodation, and a small decrease in intraocular pressure usually by no more than 1 to 2 mm Hg.⁴ Congenital Horner syndrome is unique in that it can result in iris heterochromia, with the lighter eye being the affected eye.⁴

Due to the long and circuitous nature of the oculosympathetic pathway, damage can occur due to a wide variety of conditions (Table) and can present with many neurologic findings.⁷

Localization of lesions. In Horner syndrome, 13% of lesions were present at first-order neurons, 44% at second-order neurons, and 43% at third-order neurons.⁷ While all these lesions have similar clinical presentations that can be difficult to differentiate, localization of the lesion within the oculosympathetic pathway is important to determine the underlying cause. This determination can be readily achieved in office with pharmacologic pupil testing (Figure 3).

In this patient’s case, an immediate neurologic evaluation was appropriate due to the acute and painful nature of her presentation. Ultimately, her Horner syndrome was determined to result from an internal carotid artery dissection. As indicated by Schievink, all acute Horner syndrome cases should be considered a result of a carotid artery dissection until proven otherwise, despite the presence or absence of any other signs or symptoms.¹¹ This consideration is not only because of the potentially life-threatening sequelae associated with carotid dissections, but also because dissections have been shown to be the most common cause of ischemic strokes in young and middle-aged patients, accounting for 10% to 25% of all ischemic strokes.^4,11

Carotid Artery Dissection

An artery dissection is typically the result of a tear of the tunica intima of the arterial wall, which leads to a leakage of blood into the potential space between the artery’s walls.^12,13 As the arterial blood pressure forces blood through the tear, an intramural hematoma, or false lumen, is formed within the layers of the tunica media.¹⁴ The hematoma can form as a subintimal dissection, which tends to result in arterial lumen stenosis, or a subadventitial dissection, leading to aneurysmal dilation resulting in partial or complete blockage of the affected artery.¹⁴ Additional complications resulting from carotid artery dissections can include complete vascular occlusion or thrombus formation, resulting in a cerebrovascular accident. Additionally, subarachnoid hemorrhages may result if the carotid artery ruptures due to compromised vessel wall integrity.¹¹

There are many causes of carotid artery dissections, such as structural defects of the arterial wall, fibromuscular dysplasia, cystic medial necrosis, and connective tissue disorders, including Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I.¹³ Many environmental factors also can induce a carotid artery dissection, such as a history of anesthesia use, resuscitation with classic cardiopulmonary resuscitation techniques, head or neck trauma, chiropractic manipulation of the neck, and hyperextension or rotation of the neck, which can occur in activities such as yoga, painting a ceiling, coughing, vomiting, or sneezing.¹¹

Patients with an internal carotid artery dissection typically present with pain on one side of the neck, face, or head, which can be accompanied by a partial Horner syndrome that results from damage to the oculosympathetic neurons traveling with the carotid plexus in the internal carotid artery wall.^9,10 Unilateral facial or orbital pain has been noted to be present in half of patients and is typically accompanied by an ipsilateral headache.⁹ These symptoms are typically followed by cerebral or retinal ischemia within hours or days of onset and other ophthalmic conditions that can cause blindness, such as ischemic optic neuropathy or retinal artery occlusions, although these are rare.⁹

Conclusions

Due to the potential life-threatening complications that can arise from conditions resulting in Horner syndrome, it is imperative that clinicians have a thorough understanding of the condition and its appropriate treatment and management modalities. Understanding the need for immediate testing to determine the underlying etiology of Horner syndrome can help prevent a decrease in a patient’s vision or quality of life, and in some cases, prevent death.

Acknowledgments

The author recognizes and thanks Kyle Stuard for his invaluable assistance in the editing of this manuscript

Horner syndrome is a rare condition that has no sex or race predilection and is characterized by the clinical triad of a miosis, anhidrosis, and small, unilateral ptosis. The prompt diagnosis and determination of the etiology of Horner syndrome are of utmost importance, as the condition can result from many life-threatening systemic complications. Horner syndrome is often asymptomatic but can have distinct, easily identified characteristics seen with an ophthalmic examination. This report describes a patient who presented with Horner syndrome resulting from an internal carotid artery dissection.

Case Presentation

A 61-year-old woman presented with periorbital pain with onset 3 days prior. The patient described the pain as 7 of 10 that had been worsening and was localized around and behind the right eye. She reported new-onset headaches on the right side over the past week with associated intermittent vision blurriness in the right eye. She had a history of mobility issues and had fallen backward about 1 week before, hitting the back of her head on the floor without direct trauma to the eye. She was symptomatic for light sensitivity, syncope, and dizziness, with reports of a recent history of transient ischemic attacks (TIAs) of unknown etiology, which had occurred in the months preceding her examination. She reported no jaw claudication, scalp tenderness, and neck or shoulder pain. She was unaware of any changes in her perspiration pattern on the right side of her face but mentioned that she had noticed her right upper eyelid drooping while looking in the mirror.

This patient had a routine eye examination 2 months before, which was remarkable for stable, nonfoveal involving adult-onset vitelliform dystrophy in the left eye and nuclear sclerotic cataracts and mild refractive error in both eyes. No iris heterochromia was noted, and her pupils were equal, round, and reactive to light. Her history was remarkable for chest pain, obesity, bipolar disorder, vertigo, transient cerebral ischemia, hypertension, hypercholesterolemia, alcohol use disorder, cocaine use disorder, and asthma. A carotid ultrasound had been performed 1 month before the onset of symptoms due to her history of TIAs, which showed no hemodynamically significant stenosis (> 50% stenosis) of either carotid artery. Her medications included oxybutynin chloride, amlodipine, acetaminophen, sertraline hydrochloride, lidocaine, albuterol, risperidone, hydroxyzine hydrochloride, lisinopril, omeprazole, once-daily baby aspirin, atorvastatin, and calcium.

At the time of presentation, an ophthalmic examination revealed no decrease in visual acuity with a best-corrected visual acuity of 20/20 in the right and left eyes. The patient’s pupil sizes were unequal, with a smaller, more miotic right pupil with a greater difference between the pupil sizes in dim illumination (Figure 1).

CTA revealed a focal linear filling defect in the right midinternal carotid artery, likely related to an internal carotid artery vascular flap. There was no evidence of proximal intracranial occlusive disease. MRI revealed a linear area of high-intensity signal projecting over the mid and distal right internal carotid artery lumen (Figure 2A).

Discussion

Anisocoria is defined as a difference in pupil sizes between the eyes.¹ This difference can be physiologic with no underlying pathology as an etiology of the condition. If underlying pathology causes anisocoria, it can result in dysfunction with mydriasis, leading to a more miotic pupil, or it can result from issues with miosis, leading to a more mydriatic pupil.¹

To determine whether anisocoria is physiologic or pathologic, one must assess the patient’s pupil sizes in dim and bright illumination. If the difference in the pupil size is the same in both room illuminations (ie, the anisocoria is 2 mm in both bright and dim illumination, pupillary constriction and dilation are functioning normally), then the patient has physiologic anisocoria.¹ If anisocoria is different in bright and dim illumination (ie, the anisocoria is 1 mm in bright and 3 mm in dim settings or 3 mm in bright and 1 mm in dim settings), the condition is related to pathology. To determine the underlying pathology of anisocoria in cases that are not physiologic, it is important to first determine whether the anisocoria is related to miotic or mydriatic dysfunction.¹

If the anisocoria is greater in dim illumination, this suggests mydriatic dysfunction and could be a result of damage to the sympathetic pupillary pathway.¹ The smaller or more miotic pupil in this instance is the pathologic pupil. If the anisocoria is greater in bright illumination, this suggests miotic dysfunction and could be a result of damage to the parasympathetic pathway.¹ The larger or more mydriatic pupil in this instance is the pathologic pupil. Congenital abnormalities, such as iris colobomas, aniridia, and ectopic pupils, can result in a wide range of pupil sizes and shapes, including miotic or mydriatic pupils.¹

Pathologic Mydriasis

Pathologic mydriatic pupils can result from dysfunction in the parasympathetic nervous system, which results in a pupil that is not sufficiently able to dilate with the removal of a light stimulus. Mydriatic pupils can be related to Adie tonic pupil, Argyll-Robertson pupil, third nerve palsy, trauma, surgeries, or pharmacologic mydriasis.² The conditions that cause mydriasis can be readily differentiated from one another based on clinical examination.

Adie tonic pupil results from damage to the ciliary ganglion.² While pupillary constriction in response to light will be absent or sluggish in an Adie pupil, the patient will have an intact but sluggish accommodative pupillary response; therefore, the pupil will still constrict with accommodation and convergence to focus on near objects, although slowly. This is known as light-near dissociation.²

Argyll-Robertson pupils are caused by damage to the Edinger-Westphal nucleus in the rostral midbrain.³ Lesions to this area of the brain are typically associated with neurosyphilis but also can be a result of Lyme disease, multiple sclerosis, encephalitis, neurosarcoidosis, herpes zoster, diabetes mellitus, and chronic alcohol misuse.³ Argyll Robertson pupils can appear very similar to a tonic pupil in that this condition will also have a dilated pupil and light-near dissociation.³ These pupils will differ in that they also tend to have an irregular shape (dyscoria), and the pupils will constrict briskly when focusing on near objects and dilate briskly when focusing on distant objects, not sluggishly, as in Adie tonic pupil.³

Mydriasis due to a third nerve palsy will present with ptosis and extraocular muscle dysfunction (including deficits to the superior rectus, medial rectus, inferior oblique, and inferior rectus), with the classic presentation of a completed palsy with the eye positioned “down and out” or the patient’s inability to look medially and superiorly with the affected eye.²

As in cases of pathologic mydriasis, a thorough and in-depth history can help determine traumatic, surgical and pharmacologic etiologies of a mydriatic pupil. It should be determined whether the patient has had any previous trauma or surgeries to the eye or has been in contact with any of the following: acetylcholine receptor antagonists (atropine, scopolamine, homatropine, cyclopentolate, and tropicamide), motion sickness patches (scopolamine), nasal vasoconstrictors, glycopyrrolate deodorants, and/or various plants (Jimson weed or plants belonging to the digitalis family, such as foxglove).²

Pathologic Miosis

Pathologic miotic pupils can result from dysfunction in the sympathetic nervous system and can be related to blunt or penetrating trauma to the orbit, Horner syndrome, and pharmacologic miosis.² Horner syndrome will be accompanied by a slight ptosis and sometimes anhidrosis on the ipsilateral side of the face. To differentiate between traumatic and pharmacologic miosis, a detailed history should be obtained, paying close attention to injuries to the eyes or head and/or possible exposure to chemical or pharmaceutical agents, including prostaglandins, pilocarpine, organophosphates, and opiates.²

Horner Syndrome

Horner syndrome is a neurologic condition that results from damage to the oculosympathetic pathway.⁴ The oculosympathetic pathway is a 3-neuron pathway that begins in the hypothalamus and follows a circuitous route to ultimately innervate the facial sweat glands, the smooth muscles of the blood vessels in the orbit and face, the iris dilator muscle, and the Müller muscles of the superior and inferior eyelids.^1,5 Therefore, this pathway’s functions include vasoconstriction of facial blood vessels, facial diaphoresis (sweating), pupillary dilation, and maintaining an open position of the eyelids.¹

Oculosympathetic pathway anatomy. To understand the findings associated with Horner syndrome, it is necessary to understand the anatomy of this 3-neuron pathway.⁵ First-order neurons, or central neurons, arise in the posterolateral aspect of the hypothalamus, where they then descend through the midbrain, pons, medulla, and cervical spinal cord via the intermediolateral gray column.⁶ The fibers then synapse in the ciliospinal center of Budge at the level of cervical vertebra C8 to thoracic vertebra T2, which give rise to the preganglionic, or second-order neurons.⁶

Second-order neurons begin at the ciliospinal center of Budge and exit the spinal cord via the central roots, most at the level of thoracic vertebra T1, with the remainder leaving at the levels of cervical vertebra C8 and thoracic vertebra T2.⁷ After exiting the spinal cord, the second-order neurons loop around the subclavian artery, where they then ascend close to the apex of the lung to synapse with the cell bodies of the third-order neurons at the superior cervical ganglion near cervical vertebrae C2 and C3.⁷

After arising at the superior cervical ganglion, third-order neurons diverge to follow 2 different courses.⁷ A portion of the neurons travels along the external carotid artery to ultimately innervate the facial sweat glands, while the other portion of the neurons combines with the carotid plexus and travels within the walls of the internal carotid artery and through the cavernous sinus.⁷ The fibers then briefly join the abducens nerve before anastomosing with the ophthalmic division of the trigeminal nerve.⁷ After coursing through the superior orbital fissure, the fibers innervate the iris dilator and Müller muscles via the long ciliary nerves.⁷

Symptoms and signs. Patients with Horner syndrome can present with a variety of symptoms and signs. Patients may be largely asymptomatic or they may complain of a droopy eyelid and blurry vision. The full Horner syndrome triad consists of ipsilateral miosis, anhidrosis of the face, and mild ptosis of the upper eyelid with reverse ptosis of the lower eyelid.⁸ The difference in pupil size is greatest 4 to 5 seconds after switching from bright to dim room illumination due to dilation lag in the miotic pupil from poor innervation.¹

Although the classical triad of ptosis, miosis, and anhidrosis is emphasized in the literature, the full triad may not always be present.⁴ This variation is due to the anatomy of the oculosympathetic pathway with branches of the nerve system separating at the superior cervical ganglion and following different pathways along the internal and external carotid arteries, resulting in anhidrosis only in Horner syndrome caused by lesions to the first- or second-order neurons.^4,5 Because of this deviation of the nerve fibers in the pathway, the presence of miosis and a slight ptosis in the absence of anhidrosis should still strongly suggest Horner syndrome.

In addition to the classic triad, Horner syndrome can present with other ophthalmic findings, including conjunctival injection, changes in accommodation, and a small decrease in intraocular pressure usually by no more than 1 to 2 mm Hg.⁴ Congenital Horner syndrome is unique in that it can result in iris heterochromia, with the lighter eye being the affected eye.⁴

Due to the long and circuitous nature of the oculosympathetic pathway, damage can occur due to a wide variety of conditions (Table) and can present with many neurologic findings.⁷

Localization of lesions. In Horner syndrome, 13% of lesions were present at first-order neurons, 44% at second-order neurons, and 43% at third-order neurons.⁷ While all these lesions have similar clinical presentations that can be difficult to differentiate, localization of the lesion within the oculosympathetic pathway is important to determine the underlying cause. This determination can be readily achieved in office with pharmacologic pupil testing (Figure 3).

In this patient’s case, an immediate neurologic evaluation was appropriate due to the acute and painful nature of her presentation. Ultimately, her Horner syndrome was determined to result from an internal carotid artery dissection. As indicated by Schievink, all acute Horner syndrome cases should be considered a result of a carotid artery dissection until proven otherwise, despite the presence or absence of any other signs or symptoms.¹¹ This consideration is not only because of the potentially life-threatening sequelae associated with carotid dissections, but also because dissections have been shown to be the most common cause of ischemic strokes in young and middle-aged patients, accounting for 10% to 25% of all ischemic strokes.^4,11

Carotid Artery Dissection

An artery dissection is typically the result of a tear of the tunica intima of the arterial wall, which leads to a leakage of blood into the potential space between the artery’s walls.^12,13 As the arterial blood pressure forces blood through the tear, an intramural hematoma, or false lumen, is formed within the layers of the tunica media.¹⁴ The hematoma can form as a subintimal dissection, which tends to result in arterial lumen stenosis, or a subadventitial dissection, leading to aneurysmal dilation resulting in partial or complete blockage of the affected artery.¹⁴ Additional complications resulting from carotid artery dissections can include complete vascular occlusion or thrombus formation, resulting in a cerebrovascular accident. Additionally, subarachnoid hemorrhages may result if the carotid artery ruptures due to compromised vessel wall integrity.¹¹

There are many causes of carotid artery dissections, such as structural defects of the arterial wall, fibromuscular dysplasia, cystic medial necrosis, and connective tissue disorders, including Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I.¹³ Many environmental factors also can induce a carotid artery dissection, such as a history of anesthesia use, resuscitation with classic cardiopulmonary resuscitation techniques, head or neck trauma, chiropractic manipulation of the neck, and hyperextension or rotation of the neck, which can occur in activities such as yoga, painting a ceiling, coughing, vomiting, or sneezing.¹¹

Patients with an internal carotid artery dissection typically present with pain on one side of the neck, face, or head, which can be accompanied by a partial Horner syndrome that results from damage to the oculosympathetic neurons traveling with the carotid plexus in the internal carotid artery wall.^9,10 Unilateral facial or orbital pain has been noted to be present in half of patients and is typically accompanied by an ipsilateral headache.⁹ These symptoms are typically followed by cerebral or retinal ischemia within hours or days of onset and other ophthalmic conditions that can cause blindness, such as ischemic optic neuropathy or retinal artery occlusions, although these are rare.⁹

Conclusions

Due to the potential life-threatening complications that can arise from conditions resulting in Horner syndrome, it is imperative that clinicians have a thorough understanding of the condition and its appropriate treatment and management modalities. Understanding the need for immediate testing to determine the underlying etiology of Horner syndrome can help prevent a decrease in a patient’s vision or quality of life, and in some cases, prevent death.

Acknowledgments

The author recognizes and thanks Kyle Stuard for his invaluable assistance in the editing of this manuscript

Horner syndrome is a rare condition that has no sex or race predilection and is characterized by the clinical triad of a miosis, anhidrosis, and small, unilateral ptosis. The prompt diagnosis and determination of the etiology of Horner syndrome are of utmost importance, as the condition can result from many life-threatening systemic complications. Horner syndrome is often asymptomatic but can have distinct, easily identified characteristics seen with an ophthalmic examination. This report describes a patient who presented with Horner syndrome resulting from an internal carotid artery dissection.

Case Presentation

A 61-year-old woman presented with periorbital pain with onset 3 days prior. The patient described the pain as 7 of 10 that had been worsening and was localized around and behind the right eye. She reported new-onset headaches on the right side over the past week with associated intermittent vision blurriness in the right eye. She had a history of mobility issues and had fallen backward about 1 week before, hitting the back of her head on the floor without direct trauma to the eye. She was symptomatic for light sensitivity, syncope, and dizziness, with reports of a recent history of transient ischemic attacks (TIAs) of unknown etiology, which had occurred in the months preceding her examination. She reported no jaw claudication, scalp tenderness, and neck or shoulder pain. She was unaware of any changes in her perspiration pattern on the right side of her face but mentioned that she had noticed her right upper eyelid drooping while looking in the mirror.

This patient had a routine eye examination 2 months before, which was remarkable for stable, nonfoveal involving adult-onset vitelliform dystrophy in the left eye and nuclear sclerotic cataracts and mild refractive error in both eyes. No iris heterochromia was noted, and her pupils were equal, round, and reactive to light. Her history was remarkable for chest pain, obesity, bipolar disorder, vertigo, transient cerebral ischemia, hypertension, hypercholesterolemia, alcohol use disorder, cocaine use disorder, and asthma. A carotid ultrasound had been performed 1 month before the onset of symptoms due to her history of TIAs, which showed no hemodynamically significant stenosis (> 50% stenosis) of either carotid artery. Her medications included oxybutynin chloride, amlodipine, acetaminophen, sertraline hydrochloride, lidocaine, albuterol, risperidone, hydroxyzine hydrochloride, lisinopril, omeprazole, once-daily baby aspirin, atorvastatin, and calcium.

At the time of presentation, an ophthalmic examination revealed no decrease in visual acuity with a best-corrected visual acuity of 20/20 in the right and left eyes. The patient’s pupil sizes were unequal, with a smaller, more miotic right pupil with a greater difference between the pupil sizes in dim illumination (Figure 1).

CTA revealed a focal linear filling defect in the right midinternal carotid artery, likely related to an internal carotid artery vascular flap. There was no evidence of proximal intracranial occlusive disease. MRI revealed a linear area of high-intensity signal projecting over the mid and distal right internal carotid artery lumen (Figure 2A).

Discussion

Anisocoria is defined as a difference in pupil sizes between the eyes.¹ This difference can be physiologic with no underlying pathology as an etiology of the condition. If underlying pathology causes anisocoria, it can result in dysfunction with mydriasis, leading to a more miotic pupil, or it can result from issues with miosis, leading to a more mydriatic pupil.¹

To determine whether anisocoria is physiologic or pathologic, one must assess the patient’s pupil sizes in dim and bright illumination. If the difference in the pupil size is the same in both room illuminations (ie, the anisocoria is 2 mm in both bright and dim illumination, pupillary constriction and dilation are functioning normally), then the patient has physiologic anisocoria.¹ If anisocoria is different in bright and dim illumination (ie, the anisocoria is 1 mm in bright and 3 mm in dim settings or 3 mm in bright and 1 mm in dim settings), the condition is related to pathology. To determine the underlying pathology of anisocoria in cases that are not physiologic, it is important to first determine whether the anisocoria is related to miotic or mydriatic dysfunction.¹

If the anisocoria is greater in dim illumination, this suggests mydriatic dysfunction and could be a result of damage to the sympathetic pupillary pathway.¹ The smaller or more miotic pupil in this instance is the pathologic pupil. If the anisocoria is greater in bright illumination, this suggests miotic dysfunction and could be a result of damage to the parasympathetic pathway.¹ The larger or more mydriatic pupil in this instance is the pathologic pupil. Congenital abnormalities, such as iris colobomas, aniridia, and ectopic pupils, can result in a wide range of pupil sizes and shapes, including miotic or mydriatic pupils.¹

Pathologic Mydriasis

Pathologic mydriatic pupils can result from dysfunction in the parasympathetic nervous system, which results in a pupil that is not sufficiently able to dilate with the removal of a light stimulus. Mydriatic pupils can be related to Adie tonic pupil, Argyll-Robertson pupil, third nerve palsy, trauma, surgeries, or pharmacologic mydriasis.² The conditions that cause mydriasis can be readily differentiated from one another based on clinical examination.

Adie tonic pupil results from damage to the ciliary ganglion.² While pupillary constriction in response to light will be absent or sluggish in an Adie pupil, the patient will have an intact but sluggish accommodative pupillary response; therefore, the pupil will still constrict with accommodation and convergence to focus on near objects, although slowly. This is known as light-near dissociation.²

Argyll-Robertson pupils are caused by damage to the Edinger-Westphal nucleus in the rostral midbrain.³ Lesions to this area of the brain are typically associated with neurosyphilis but also can be a result of Lyme disease, multiple sclerosis, encephalitis, neurosarcoidosis, herpes zoster, diabetes mellitus, and chronic alcohol misuse.³ Argyll Robertson pupils can appear very similar to a tonic pupil in that this condition will also have a dilated pupil and light-near dissociation.³ These pupils will differ in that they also tend to have an irregular shape (dyscoria), and the pupils will constrict briskly when focusing on near objects and dilate briskly when focusing on distant objects, not sluggishly, as in Adie tonic pupil.³

Mydriasis due to a third nerve palsy will present with ptosis and extraocular muscle dysfunction (including deficits to the superior rectus, medial rectus, inferior oblique, and inferior rectus), with the classic presentation of a completed palsy with the eye positioned “down and out” or the patient’s inability to look medially and superiorly with the affected eye.²

As in cases of pathologic mydriasis, a thorough and in-depth history can help determine traumatic, surgical and pharmacologic etiologies of a mydriatic pupil. It should be determined whether the patient has had any previous trauma or surgeries to the eye or has been in contact with any of the following: acetylcholine receptor antagonists (atropine, scopolamine, homatropine, cyclopentolate, and tropicamide), motion sickness patches (scopolamine), nasal vasoconstrictors, glycopyrrolate deodorants, and/or various plants (Jimson weed or plants belonging to the digitalis family, such as foxglove).²

Pathologic Miosis

Pathologic miotic pupils can result from dysfunction in the sympathetic nervous system and can be related to blunt or penetrating trauma to the orbit, Horner syndrome, and pharmacologic miosis.² Horner syndrome will be accompanied by a slight ptosis and sometimes anhidrosis on the ipsilateral side of the face. To differentiate between traumatic and pharmacologic miosis, a detailed history should be obtained, paying close attention to injuries to the eyes or head and/or possible exposure to chemical or pharmaceutical agents, including prostaglandins, pilocarpine, organophosphates, and opiates.²

Horner Syndrome

Horner syndrome is a neurologic condition that results from damage to the oculosympathetic pathway.⁴ The oculosympathetic pathway is a 3-neuron pathway that begins in the hypothalamus and follows a circuitous route to ultimately innervate the facial sweat glands, the smooth muscles of the blood vessels in the orbit and face, the iris dilator muscle, and the Müller muscles of the superior and inferior eyelids.^1,5 Therefore, this pathway’s functions include vasoconstriction of facial blood vessels, facial diaphoresis (sweating), pupillary dilation, and maintaining an open position of the eyelids.¹

Oculosympathetic pathway anatomy. To understand the findings associated with Horner syndrome, it is necessary to understand the anatomy of this 3-neuron pathway.⁵ First-order neurons, or central neurons, arise in the posterolateral aspect of the hypothalamus, where they then descend through the midbrain, pons, medulla, and cervical spinal cord via the intermediolateral gray column.⁶ The fibers then synapse in the ciliospinal center of Budge at the level of cervical vertebra C8 to thoracic vertebra T2, which give rise to the preganglionic, or second-order neurons.⁶

Second-order neurons begin at the ciliospinal center of Budge and exit the spinal cord via the central roots, most at the level of thoracic vertebra T1, with the remainder leaving at the levels of cervical vertebra C8 and thoracic vertebra T2.⁷ After exiting the spinal cord, the second-order neurons loop around the subclavian artery, where they then ascend close to the apex of the lung to synapse with the cell bodies of the third-order neurons at the superior cervical ganglion near cervical vertebrae C2 and C3.⁷

After arising at the superior cervical ganglion, third-order neurons diverge to follow 2 different courses.⁷ A portion of the neurons travels along the external carotid artery to ultimately innervate the facial sweat glands, while the other portion of the neurons combines with the carotid plexus and travels within the walls of the internal carotid artery and through the cavernous sinus.⁷ The fibers then briefly join the abducens nerve before anastomosing with the ophthalmic division of the trigeminal nerve.⁷ After coursing through the superior orbital fissure, the fibers innervate the iris dilator and Müller muscles via the long ciliary nerves.⁷

Symptoms and signs. Patients with Horner syndrome can present with a variety of symptoms and signs. Patients may be largely asymptomatic or they may complain of a droopy eyelid and blurry vision. The full Horner syndrome triad consists of ipsilateral miosis, anhidrosis of the face, and mild ptosis of the upper eyelid with reverse ptosis of the lower eyelid.⁸ The difference in pupil size is greatest 4 to 5 seconds after switching from bright to dim room illumination due to dilation lag in the miotic pupil from poor innervation.¹

Although the classical triad of ptosis, miosis, and anhidrosis is emphasized in the literature, the full triad may not always be present.⁴ This variation is due to the anatomy of the oculosympathetic pathway with branches of the nerve system separating at the superior cervical ganglion and following different pathways along the internal and external carotid arteries, resulting in anhidrosis only in Horner syndrome caused by lesions to the first- or second-order neurons.^4,5 Because of this deviation of the nerve fibers in the pathway, the presence of miosis and a slight ptosis in the absence of anhidrosis should still strongly suggest Horner syndrome.

In addition to the classic triad, Horner syndrome can present with other ophthalmic findings, including conjunctival injection, changes in accommodation, and a small decrease in intraocular pressure usually by no more than 1 to 2 mm Hg.⁴ Congenital Horner syndrome is unique in that it can result in iris heterochromia, with the lighter eye being the affected eye.⁴

Due to the long and circuitous nature of the oculosympathetic pathway, damage can occur due to a wide variety of conditions (Table) and can present with many neurologic findings.⁷

Localization of lesions. In Horner syndrome, 13% of lesions were present at first-order neurons, 44% at second-order neurons, and 43% at third-order neurons.⁷ While all these lesions have similar clinical presentations that can be difficult to differentiate, localization of the lesion within the oculosympathetic pathway is important to determine the underlying cause. This determination can be readily achieved in office with pharmacologic pupil testing (Figure 3).

In this patient’s case, an immediate neurologic evaluation was appropriate due to the acute and painful nature of her presentation. Ultimately, her Horner syndrome was determined to result from an internal carotid artery dissection. As indicated by Schievink, all acute Horner syndrome cases should be considered a result of a carotid artery dissection until proven otherwise, despite the presence or absence of any other signs or symptoms.¹¹ This consideration is not only because of the potentially life-threatening sequelae associated with carotid dissections, but also because dissections have been shown to be the most common cause of ischemic strokes in young and middle-aged patients, accounting for 10% to 25% of all ischemic strokes.^4,11

Carotid Artery Dissection

An artery dissection is typically the result of a tear of the tunica intima of the arterial wall, which leads to a leakage of blood into the potential space between the artery’s walls.^12,13 As the arterial blood pressure forces blood through the tear, an intramural hematoma, or false lumen, is formed within the layers of the tunica media.¹⁴ The hematoma can form as a subintimal dissection, which tends to result in arterial lumen stenosis, or a subadventitial dissection, leading to aneurysmal dilation resulting in partial or complete blockage of the affected artery.¹⁴ Additional complications resulting from carotid artery dissections can include complete vascular occlusion or thrombus formation, resulting in a cerebrovascular accident. Additionally, subarachnoid hemorrhages may result if the carotid artery ruptures due to compromised vessel wall integrity.¹¹

There are many causes of carotid artery dissections, such as structural defects of the arterial wall, fibromuscular dysplasia, cystic medial necrosis, and connective tissue disorders, including Ehlers-Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I.¹³ Many environmental factors also can induce a carotid artery dissection, such as a history of anesthesia use, resuscitation with classic cardiopulmonary resuscitation techniques, head or neck trauma, chiropractic manipulation of the neck, and hyperextension or rotation of the neck, which can occur in activities such as yoga, painting a ceiling, coughing, vomiting, or sneezing.¹¹

Patients with an internal carotid artery dissection typically present with pain on one side of the neck, face, or head, which can be accompanied by a partial Horner syndrome that results from damage to the oculosympathetic neurons traveling with the carotid plexus in the internal carotid artery wall.^9,10 Unilateral facial or orbital pain has been noted to be present in half of patients and is typically accompanied by an ipsilateral headache.⁹ These symptoms are typically followed by cerebral or retinal ischemia within hours or days of onset and other ophthalmic conditions that can cause blindness, such as ischemic optic neuropathy or retinal artery occlusions, although these are rare.⁹

Conclusions

Due to the potential life-threatening complications that can arise from conditions resulting in Horner syndrome, it is imperative that clinicians have a thorough understanding of the condition and its appropriate treatment and management modalities. Understanding the need for immediate testing to determine the underlying etiology of Horner syndrome can help prevent a decrease in a patient’s vision or quality of life, and in some cases, prevent death.

Acknowledgments

The author recognizes and thanks Kyle Stuard for his invaluable assistance in the editing of this manuscript