Prognosis and Multidisciplinary Care

ALS is a rare degenerative disorder of motor neurons of the cerebral cortex, brainstem, and spinal cord that results in progressive wasting and paralysis of voluntary muscles. The median age of onset is 55, and the disease has a slight male predominance. Fifty percent of patients with ALS die within three years of symptoms onset; 90% of patients die within five years. Patients with bulbar-onset ALS are more likely to die sooner. Riluzole is the only FDA-approved disease-modifying therapy for patients with ALS. Studies have indicated that this drug extends median survival by two to three months.

In addition, data suggest that multidisciplinary care improves quality of life and survival in patients with ALS. Traynor et al found that survival increased by 7.5 months among all patients in multidisciplinary clinics; patients with bulbar onset lived 9.5 months longer.

Managing Muscle Cramps

Recent studies suggest that muscle cramps occur in 85% of patients with ALS. Cramps can vary in severity and can be debilitating, said Dr. Weiss. Some patients can have as many as 50 cramps per day. Few efficacious treatments for managing this symptom of ALS are available. A recent trial showed that patients who received either 300 mg or 900 mg of mexiletine experienced significant declines in cramping.

Spasticity

It is common for patients with ALS to develop spasticity. Several therapies that may reduce spasticity include baclofen, tizanidine, diazepam, and botulinum toxin injections. The baclofen pump might be more helpful than these therapies for patients who have upper motor neuron dominance.

Sialorrhea

Sialorrhea occurs when patients are unable to clear extra saliva due to weakness in the oropharyngeal muscles. Doses of 600 mg to 1,200 mg of guaifenesin twice per day may be beneficial in managing sialorrhea. Other drying agents such as atropine drops and glycopyrrolate may also be efficacious. These drying agents may cause urinary retention in older patients, Dr. Weiss cautioned.

Amitriptyline can also help manage sialorrhea. It also improves sleep and reduces depression. Hyoscyamine, the transdermal scopolamine patch, and botulinum toxin injections into the submandibular glands may also be beneficial for patients. A suction machine or a mechanical in-exsufflator can also help manage this symptom of ALS.

Emotional Incontinence and Depression

Pseudobulbar affect, also known as emotional incontinence, affects as much as 50% of patients with ALS and is more common in bulbar ALS. This condition causes patients to have uncontrollable episodes of laughing and crying that are inconsistent with the patients’ mood. A randomized controlled trial found that dextromethorphan–quinidine was beneficial in managing these emotional symptoms. Other treatments include tricyclic antidepressants and selective serotonin reuptake inhibitors.

Reactive clinical depression occurs in 9% to 11% of patients with ALS. Once the ALS diagnosis is confirmed, patients should be counseled about their prognosis; their spouses and family members should also be offered counseling. Antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors should be offered to all patients. These drugs may help to elevate mood, stimulate appetite, and improve sleep.

Respiratory Insufficiency and Falls

Respiratory insufficiency is one of the leading causes of death among patients with ALS. Patients with this condition may have morning headaches, vivid dreams and nightmares, frequent nocturnal arousals, fatigue, excessive daytime somnolence, and dyspnea on exertion. The American Academy of Neurology recommends that patients start noninvasive ventilation if their sniff nasal pressure is less than 40 cm, their maximal inspiratory pressure is less than –60 cm, or their forced vital capacity is less than 50%.

Bourke et al found that noninvasive ventilation was associated with improvement in quality of life and survival in patients with ALS. The median survival was increased by 205 days, and quality of life was maintained above 75% of baseline on the sleep apnea quality of life index score. In addition, patients who have a peak cough expiratory flow of less than 270 L/min should be offered a mechanical in-exsufflator suction device. If the patient does not tolerate noninvasive ventilation, then palliative medicine and hospice may be appropriate, said Dr. Weiss.

Evidence suggests that 2% of patients with ALS die from fall-related complications. Risk factors for falls in ALS include muscle weakness, deficits in gait or balance, and cognitive impairment. Assistive devices, wheelchairs, and physical therapy can help prevent falls. Some patients may need a brace to help stabilize their gait.

Managing Frontotemporal Dementia

Research suggests that 10% of patients with ALS develop frontotemporal dementia. Nearly 50% of these patients demonstrate behavioral changes such as apathy, disinhibition, and hostility. In addition, the incidence of frontotemporal dementia is higher in patients with familial ALS. The treatment of frontotemporal dementia remains symptomatic.

Observational studies have indicated that antidepressant medications, particularly serotonin reuptake inhibitors like sertraline, paroxetine, and trazadone, decrease disinhibition, anxiety, repetitive behaviors, and impulsivity. Although antipsychotic medications like quetiapine or olanzapine can limit agitation, they must be used cautiously, as they can cause extrapyramidal side effects. In addition, behavioral modification may also be helpful for problematic behavior. Finally, these patients require close supervision at all times to maintain their safety.

Dysphagia and Malnourishment

Between 16% and 55% of patients with ALS become malnourished because of dysphagia. This condition is characterized by difficulty with chewing and swallowing, nasal regurgitation, or coughing when drinking liquids. Nutritional status must be monitored every three months in patients with ALS, said Dr. Weiss. In addition, their BMI must be calculated and their weight measured. Paganoni et al found that the risk of death increased sevenfold in patients with ALS who had a BMI less than 18.5. Patients with ALS also need to be queried about the severity of choking, duration of meals, and caloric intake. A speech therapist should evaluate patients at every visit. Dietary changes might also be necessary and may include thickening liquids and preparing food that forms easily into a bolus.

As this disease progresses, patients may need a percutaneous gastrostomy (PEG) tube. According to the American Academy of Neurology practice guidelines, it is time to discuss PEG placement when a patient with ALS starts to lose weight. When a patient’s forced vital capacity is over 50%, the procedure can be done safely. When it is less than 50%, the procedure entails an increased risk of complications, including death.

Managing Dysarthria and Hospice

More than 95% of patients with ALS lose their ability to speak before they die. This condition, known as dysarthria, is difficult to treat. Almost all patients with bulbar-onset ALS and nearly 70% of patients with spinal-onset ALS develop dysarthria. Alternative augmentative communication devices and speech pathologists can be helpful. The Speakit application is a free speech-generating device available for the iPad, and a DynaVox device is a more costly augmentative and alternative communication tool. These devices help patients to communicate their needs and to stay connected to others.

As ALS advances, patients might require palliative medicine or hospice care. Before a patient reaches advanced stages of the disease, he or she should fill out a directive and Physician Orders for Life-Sustaining Treatment form, said Dr. Weiss. Patients must meet one of two criteria to receive Medicare reimbursement for hospice care. The first is a forced vital capacity of less than 30% with dyspnea at rest. The second is rapid progression of the disease with life-threatening complications (eg, infections) over 12 months or severe nutritional impairment over 12 months. Treatments for terminal dyspnea include morphine sulfate, oxygen, lorazepam, and chlorpromazine. These medications may depress respiratory drive, however, said Dr. Weiss.

Current Research and Recently Completed Trials

Smith et al found that dextromethorphan–quinidine may improve bulbar function. In addition, recent studies have found that diaphragmatic pacing, an FDA-approved technique, shortened the survival of patients with ALS by one year. An interanalysis found that patients using the diaphragmatic pacer died prematurely, compared with patients who had sham surgery in which electrodes were not implanted. Several phase II studies have suggested that tirasemtiv is substantially beneficial in decelerating slow vital capacity. Finally, a 24-week randomized controlled trial found that edaravone improved function in patients with definite or probable ALS. Edaravone was FDA-approved in May 2017.

—Erica Tricarico

Suggested Reading

Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;(3):CD001447.

Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-1226.

Paganoni S, Deng J, Jaffa M, et al. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve. 2011;44(1):20-24.

Shefner JM, Wolff AA, Meng L, et al. A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(5-6):426-435.

Smith R, Pioro E, Myers K, et al. Enhanced bulbar function in amyotrophic lateral sclerosis: The nuedexta treatment trial. Neurotherapeutics. 2017 Jan 9 [Epub ahead of print].

Traynor BJ, Alexander M, Corr B, et al. Effect of multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. J Neurol Neurosurg Psychiatry. 2003;74(9):1258-1261.

Weiss MD, Macklin EA, Simmons Z, et al. A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression. Neurology. 2016;86(16):1474-1481.

Prognosis and Multidisciplinary Care

ALS is a rare degenerative disorder of motor neurons of the cerebral cortex, brainstem, and spinal cord that results in progressive wasting and paralysis of voluntary muscles. The median age of onset is 55, and the disease has a slight male predominance. Fifty percent of patients with ALS die within three years of symptoms onset; 90% of patients die within five years. Patients with bulbar-onset ALS are more likely to die sooner. Riluzole is the only FDA-approved disease-modifying therapy for patients with ALS. Studies have indicated that this drug extends median survival by two to three months.

In addition, data suggest that multidisciplinary care improves quality of life and survival in patients with ALS. Traynor et al found that survival increased by 7.5 months among all patients in multidisciplinary clinics; patients with bulbar onset lived 9.5 months longer.

Managing Muscle Cramps

Recent studies suggest that muscle cramps occur in 85% of patients with ALS. Cramps can vary in severity and can be debilitating, said Dr. Weiss. Some patients can have as many as 50 cramps per day. Few efficacious treatments for managing this symptom of ALS are available. A recent trial showed that patients who received either 300 mg or 900 mg of mexiletine experienced significant declines in cramping.

Spasticity

It is common for patients with ALS to develop spasticity. Several therapies that may reduce spasticity include baclofen, tizanidine, diazepam, and botulinum toxin injections. The baclofen pump might be more helpful than these therapies for patients who have upper motor neuron dominance.

Sialorrhea

Sialorrhea occurs when patients are unable to clear extra saliva due to weakness in the oropharyngeal muscles. Doses of 600 mg to 1,200 mg of guaifenesin twice per day may be beneficial in managing sialorrhea. Other drying agents such as atropine drops and glycopyrrolate may also be efficacious. These drying agents may cause urinary retention in older patients, Dr. Weiss cautioned.

Amitriptyline can also help manage sialorrhea. It also improves sleep and reduces depression. Hyoscyamine, the transdermal scopolamine patch, and botulinum toxin injections into the submandibular glands may also be beneficial for patients. A suction machine or a mechanical in-exsufflator can also help manage this symptom of ALS.

Emotional Incontinence and Depression

Pseudobulbar affect, also known as emotional incontinence, affects as much as 50% of patients with ALS and is more common in bulbar ALS. This condition causes patients to have uncontrollable episodes of laughing and crying that are inconsistent with the patients’ mood. A randomized controlled trial found that dextromethorphan–quinidine was beneficial in managing these emotional symptoms. Other treatments include tricyclic antidepressants and selective serotonin reuptake inhibitors.

Reactive clinical depression occurs in 9% to 11% of patients with ALS. Once the ALS diagnosis is confirmed, patients should be counseled about their prognosis; their spouses and family members should also be offered counseling. Antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors should be offered to all patients. These drugs may help to elevate mood, stimulate appetite, and improve sleep.

Respiratory Insufficiency and Falls

Respiratory insufficiency is one of the leading causes of death among patients with ALS. Patients with this condition may have morning headaches, vivid dreams and nightmares, frequent nocturnal arousals, fatigue, excessive daytime somnolence, and dyspnea on exertion. The American Academy of Neurology recommends that patients start noninvasive ventilation if their sniff nasal pressure is less than 40 cm, their maximal inspiratory pressure is less than –60 cm, or their forced vital capacity is less than 50%.

Bourke et al found that noninvasive ventilation was associated with improvement in quality of life and survival in patients with ALS. The median survival was increased by 205 days, and quality of life was maintained above 75% of baseline on the sleep apnea quality of life index score. In addition, patients who have a peak cough expiratory flow of less than 270 L/min should be offered a mechanical in-exsufflator suction device. If the patient does not tolerate noninvasive ventilation, then palliative medicine and hospice may be appropriate, said Dr. Weiss.

Evidence suggests that 2% of patients with ALS die from fall-related complications. Risk factors for falls in ALS include muscle weakness, deficits in gait or balance, and cognitive impairment. Assistive devices, wheelchairs, and physical therapy can help prevent falls. Some patients may need a brace to help stabilize their gait.

Managing Frontotemporal Dementia

Research suggests that 10% of patients with ALS develop frontotemporal dementia. Nearly 50% of these patients demonstrate behavioral changes such as apathy, disinhibition, and hostility. In addition, the incidence of frontotemporal dementia is higher in patients with familial ALS. The treatment of frontotemporal dementia remains symptomatic.

Observational studies have indicated that antidepressant medications, particularly serotonin reuptake inhibitors like sertraline, paroxetine, and trazadone, decrease disinhibition, anxiety, repetitive behaviors, and impulsivity. Although antipsychotic medications like quetiapine or olanzapine can limit agitation, they must be used cautiously, as they can cause extrapyramidal side effects. In addition, behavioral modification may also be helpful for problematic behavior. Finally, these patients require close supervision at all times to maintain their safety.

Dysphagia and Malnourishment

Between 16% and 55% of patients with ALS become malnourished because of dysphagia. This condition is characterized by difficulty with chewing and swallowing, nasal regurgitation, or coughing when drinking liquids. Nutritional status must be monitored every three months in patients with ALS, said Dr. Weiss. In addition, their BMI must be calculated and their weight measured. Paganoni et al found that the risk of death increased sevenfold in patients with ALS who had a BMI less than 18.5. Patients with ALS also need to be queried about the severity of choking, duration of meals, and caloric intake. A speech therapist should evaluate patients at every visit. Dietary changes might also be necessary and may include thickening liquids and preparing food that forms easily into a bolus.

As this disease progresses, patients may need a percutaneous gastrostomy (PEG) tube. According to the American Academy of Neurology practice guidelines, it is time to discuss PEG placement when a patient with ALS starts to lose weight. When a patient’s forced vital capacity is over 50%, the procedure can be done safely. When it is less than 50%, the procedure entails an increased risk of complications, including death.

Managing Dysarthria and Hospice

More than 95% of patients with ALS lose their ability to speak before they die. This condition, known as dysarthria, is difficult to treat. Almost all patients with bulbar-onset ALS and nearly 70% of patients with spinal-onset ALS develop dysarthria. Alternative augmentative communication devices and speech pathologists can be helpful. The Speakit application is a free speech-generating device available for the iPad, and a DynaVox device is a more costly augmentative and alternative communication tool. These devices help patients to communicate their needs and to stay connected to others.

As ALS advances, patients might require palliative medicine or hospice care. Before a patient reaches advanced stages of the disease, he or she should fill out a directive and Physician Orders for Life-Sustaining Treatment form, said Dr. Weiss. Patients must meet one of two criteria to receive Medicare reimbursement for hospice care. The first is a forced vital capacity of less than 30% with dyspnea at rest. The second is rapid progression of the disease with life-threatening complications (eg, infections) over 12 months or severe nutritional impairment over 12 months. Treatments for terminal dyspnea include morphine sulfate, oxygen, lorazepam, and chlorpromazine. These medications may depress respiratory drive, however, said Dr. Weiss.

Current Research and Recently Completed Trials

Smith et al found that dextromethorphan–quinidine may improve bulbar function. In addition, recent studies have found that diaphragmatic pacing, an FDA-approved technique, shortened the survival of patients with ALS by one year. An interanalysis found that patients using the diaphragmatic pacer died prematurely, compared with patients who had sham surgery in which electrodes were not implanted. Several phase II studies have suggested that tirasemtiv is substantially beneficial in decelerating slow vital capacity. Finally, a 24-week randomized controlled trial found that edaravone improved function in patients with definite or probable ALS. Edaravone was FDA-approved in May 2017.

—Erica Tricarico

Suggested Reading

Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;(3):CD001447.

Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-1226.

Paganoni S, Deng J, Jaffa M, et al. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve. 2011;44(1):20-24.

Shefner JM, Wolff AA, Meng L, et al. A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(5-6):426-435.

Smith R, Pioro E, Myers K, et al. Enhanced bulbar function in amyotrophic lateral sclerosis: The nuedexta treatment trial. Neurotherapeutics. 2017 Jan 9 [Epub ahead of print].

Traynor BJ, Alexander M, Corr B, et al. Effect of multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. J Neurol Neurosurg Psychiatry. 2003;74(9):1258-1261.

Weiss MD, Macklin EA, Simmons Z, et al. A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression. Neurology. 2016;86(16):1474-1481.

Prognosis and Multidisciplinary Care

ALS is a rare degenerative disorder of motor neurons of the cerebral cortex, brainstem, and spinal cord that results in progressive wasting and paralysis of voluntary muscles. The median age of onset is 55, and the disease has a slight male predominance. Fifty percent of patients with ALS die within three years of symptoms onset; 90% of patients die within five years. Patients with bulbar-onset ALS are more likely to die sooner. Riluzole is the only FDA-approved disease-modifying therapy for patients with ALS. Studies have indicated that this drug extends median survival by two to three months.

In addition, data suggest that multidisciplinary care improves quality of life and survival in patients with ALS. Traynor et al found that survival increased by 7.5 months among all patients in multidisciplinary clinics; patients with bulbar onset lived 9.5 months longer.

Managing Muscle Cramps

Recent studies suggest that muscle cramps occur in 85% of patients with ALS. Cramps can vary in severity and can be debilitating, said Dr. Weiss. Some patients can have as many as 50 cramps per day. Few efficacious treatments for managing this symptom of ALS are available. A recent trial showed that patients who received either 300 mg or 900 mg of mexiletine experienced significant declines in cramping.

Spasticity

It is common for patients with ALS to develop spasticity. Several therapies that may reduce spasticity include baclofen, tizanidine, diazepam, and botulinum toxin injections. The baclofen pump might be more helpful than these therapies for patients who have upper motor neuron dominance.

Sialorrhea

Sialorrhea occurs when patients are unable to clear extra saliva due to weakness in the oropharyngeal muscles. Doses of 600 mg to 1,200 mg of guaifenesin twice per day may be beneficial in managing sialorrhea. Other drying agents such as atropine drops and glycopyrrolate may also be efficacious. These drying agents may cause urinary retention in older patients, Dr. Weiss cautioned.

Amitriptyline can also help manage sialorrhea. It also improves sleep and reduces depression. Hyoscyamine, the transdermal scopolamine patch, and botulinum toxin injections into the submandibular glands may also be beneficial for patients. A suction machine or a mechanical in-exsufflator can also help manage this symptom of ALS.

Emotional Incontinence and Depression

Pseudobulbar affect, also known as emotional incontinence, affects as much as 50% of patients with ALS and is more common in bulbar ALS. This condition causes patients to have uncontrollable episodes of laughing and crying that are inconsistent with the patients’ mood. A randomized controlled trial found that dextromethorphan–quinidine was beneficial in managing these emotional symptoms. Other treatments include tricyclic antidepressants and selective serotonin reuptake inhibitors.

Reactive clinical depression occurs in 9% to 11% of patients with ALS. Once the ALS diagnosis is confirmed, patients should be counseled about their prognosis; their spouses and family members should also be offered counseling. Antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors should be offered to all patients. These drugs may help to elevate mood, stimulate appetite, and improve sleep.

Respiratory Insufficiency and Falls

Respiratory insufficiency is one of the leading causes of death among patients with ALS. Patients with this condition may have morning headaches, vivid dreams and nightmares, frequent nocturnal arousals, fatigue, excessive daytime somnolence, and dyspnea on exertion. The American Academy of Neurology recommends that patients start noninvasive ventilation if their sniff nasal pressure is less than 40 cm, their maximal inspiratory pressure is less than –60 cm, or their forced vital capacity is less than 50%.

Bourke et al found that noninvasive ventilation was associated with improvement in quality of life and survival in patients with ALS. The median survival was increased by 205 days, and quality of life was maintained above 75% of baseline on the sleep apnea quality of life index score. In addition, patients who have a peak cough expiratory flow of less than 270 L/min should be offered a mechanical in-exsufflator suction device. If the patient does not tolerate noninvasive ventilation, then palliative medicine and hospice may be appropriate, said Dr. Weiss.

Evidence suggests that 2% of patients with ALS die from fall-related complications. Risk factors for falls in ALS include muscle weakness, deficits in gait or balance, and cognitive impairment. Assistive devices, wheelchairs, and physical therapy can help prevent falls. Some patients may need a brace to help stabilize their gait.

Managing Frontotemporal Dementia

Research suggests that 10% of patients with ALS develop frontotemporal dementia. Nearly 50% of these patients demonstrate behavioral changes such as apathy, disinhibition, and hostility. In addition, the incidence of frontotemporal dementia is higher in patients with familial ALS. The treatment of frontotemporal dementia remains symptomatic.

Observational studies have indicated that antidepressant medications, particularly serotonin reuptake inhibitors like sertraline, paroxetine, and trazadone, decrease disinhibition, anxiety, repetitive behaviors, and impulsivity. Although antipsychotic medications like quetiapine or olanzapine can limit agitation, they must be used cautiously, as they can cause extrapyramidal side effects. In addition, behavioral modification may also be helpful for problematic behavior. Finally, these patients require close supervision at all times to maintain their safety.

Dysphagia and Malnourishment

Between 16% and 55% of patients with ALS become malnourished because of dysphagia. This condition is characterized by difficulty with chewing and swallowing, nasal regurgitation, or coughing when drinking liquids. Nutritional status must be monitored every three months in patients with ALS, said Dr. Weiss. In addition, their BMI must be calculated and their weight measured. Paganoni et al found that the risk of death increased sevenfold in patients with ALS who had a BMI less than 18.5. Patients with ALS also need to be queried about the severity of choking, duration of meals, and caloric intake. A speech therapist should evaluate patients at every visit. Dietary changes might also be necessary and may include thickening liquids and preparing food that forms easily into a bolus.

As this disease progresses, patients may need a percutaneous gastrostomy (PEG) tube. According to the American Academy of Neurology practice guidelines, it is time to discuss PEG placement when a patient with ALS starts to lose weight. When a patient’s forced vital capacity is over 50%, the procedure can be done safely. When it is less than 50%, the procedure entails an increased risk of complications, including death.

Managing Dysarthria and Hospice

More than 95% of patients with ALS lose their ability to speak before they die. This condition, known as dysarthria, is difficult to treat. Almost all patients with bulbar-onset ALS and nearly 70% of patients with spinal-onset ALS develop dysarthria. Alternative augmentative communication devices and speech pathologists can be helpful. The Speakit application is a free speech-generating device available for the iPad, and a DynaVox device is a more costly augmentative and alternative communication tool. These devices help patients to communicate their needs and to stay connected to others.

As ALS advances, patients might require palliative medicine or hospice care. Before a patient reaches advanced stages of the disease, he or she should fill out a directive and Physician Orders for Life-Sustaining Treatment form, said Dr. Weiss. Patients must meet one of two criteria to receive Medicare reimbursement for hospice care. The first is a forced vital capacity of less than 30% with dyspnea at rest. The second is rapid progression of the disease with life-threatening complications (eg, infections) over 12 months or severe nutritional impairment over 12 months. Treatments for terminal dyspnea include morphine sulfate, oxygen, lorazepam, and chlorpromazine. These medications may depress respiratory drive, however, said Dr. Weiss.

Current Research and Recently Completed Trials

Smith et al found that dextromethorphan–quinidine may improve bulbar function. In addition, recent studies have found that diaphragmatic pacing, an FDA-approved technique, shortened the survival of patients with ALS by one year. An interanalysis found that patients using the diaphragmatic pacer died prematurely, compared with patients who had sham surgery in which electrodes were not implanted. Several phase II studies have suggested that tirasemtiv is substantially beneficial in decelerating slow vital capacity. Finally, a 24-week randomized controlled trial found that edaravone improved function in patients with definite or probable ALS. Edaravone was FDA-approved in May 2017.

—Erica Tricarico

Suggested Reading

Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;(3):CD001447.

Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-1226.

Paganoni S, Deng J, Jaffa M, et al. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve. 2011;44(1):20-24.

Shefner JM, Wolff AA, Meng L, et al. A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(5-6):426-435.

Smith R, Pioro E, Myers K, et al. Enhanced bulbar function in amyotrophic lateral sclerosis: The nuedexta treatment trial. Neurotherapeutics. 2017 Jan 9 [Epub ahead of print].

Traynor BJ, Alexander M, Corr B, et al. Effect of multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. J Neurol Neurosurg Psychiatry. 2003;74(9):1258-1261.

Weiss MD, Macklin EA, Simmons Z, et al. A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression. Neurology. 2016;86(16):1474-1481.

Sunscreens sold by two major retailers in the United States in 2017 are more adherent to the American Academy of Dermatology recommendations for sun protection than in 2014, but approximately 35% still do not meet the AAD criteria, according to results of a new study.

The results are based on data from a review of 472 products, available for sale on-line, a follow-up to a 2014 study that examined the proportion of sunscreen products that met three AAD recommendations: a sun protection factor of 30 or higher, broad-spectrum coverage, and 40-80 minutes of water resistance. In the 2014 study, almost 35% of sunscreens sold at Walmart and 41% of sunscreens sold at Walgreens met all three recommendations (J Am Acad Dermatol. 2014;71[5]:1011-2).

mark wragg/iStockphoto.com

Sunscreens sold by two major retailers in the United States in 2017 are more adherent to the American Academy of Dermatology recommendations for sun protection than in 2014, but approximately 35% still do not meet the AAD criteria, according to results of a new study.

The results are based on data from a review of 472 products, available for sale on-line, a follow-up to a 2014 study that examined the proportion of sunscreen products that met three AAD recommendations: a sun protection factor of 30 or higher, broad-spectrum coverage, and 40-80 minutes of water resistance. In the 2014 study, almost 35% of sunscreens sold at Walmart and 41% of sunscreens sold at Walgreens met all three recommendations (J Am Acad Dermatol. 2014;71[5]:1011-2).

mark wragg/iStockphoto.com

Sunscreens sold by two major retailers in the United States in 2017 are more adherent to the American Academy of Dermatology recommendations for sun protection than in 2014, but approximately 35% still do not meet the AAD criteria, according to results of a new study.

The results are based on data from a review of 472 products, available for sale on-line, a follow-up to a 2014 study that examined the proportion of sunscreen products that met three AAD recommendations: a sun protection factor of 30 or higher, broad-spectrum coverage, and 40-80 minutes of water resistance. In the 2014 study, almost 35% of sunscreens sold at Walmart and 41% of sunscreens sold at Walgreens met all three recommendations (J Am Acad Dermatol. 2014;71[5]:1011-2).

mark wragg/iStockphoto.com

In 1931, Lindberg¹ described a cutaneous variant of polyarteritis nodosa, which lacked visceral involvement and possessed a more favorable prognosis.² Cutaneous polyarteritis nodosa (CPAN) is a localized small- to medium-vessel vasculitis restricted to the skin. Both benign and chronic courses have been described, and systemic involvement does not occur.³ Diagnostic criteria proposed by Nakamura et al³ in 2009 included cutaneous nodules, livedo reticularis, purpura, or ulcers; histopathologic fibrinoid necrotizing vasculitis of small- to medium-sized vessels; and exclusion of systemic symptoms (eg, fever, hypertension, weight loss, renal failure, cerebral hemorrhage, neuropathy, myocardial infarction, ischemic heart disease, pericarditis, pleuritis, arthralgia/myalgia). Nodules occur in 30% to 50% of cases and can remain for years if left untreated. Ulcerations occur in up to 30% of patients. Myositis, arthritis, and weakness also have been reported with this condition.⁴ Cutaneous polyarteritis nodosa has been associated with abnormal antibody testing with elevations of antiphospholipid cofactor antibody, lupus anticoagulant, anticardiolipin antibody, and anti-β₂-glycoprotein I–dependent cardiolipin antibody, as well as elevated anti–phosphatidylserine-prothrombin complex antibody.⁵ These antibodies suggest increased risk for thrombosis and systemic diseases such as lupus or other autoimmune connective tissue disease. The distinction of this entity from systemic polyartertitis nodosa is key when determining treatment options and monitoring parameters.

Case Report

A 66-year-old woman was referred to our facility by an outside dermatologist with a mildly pruritic, blanchable, reticulated erythema on the chest and bilateral arms and legs of 3 months’ duration consistent with livedo reticularis (Figure 1). Prior systemic therapy included prednisone 10 mg 3 times daily, fexofenadine, loratadine, and hydroxyzine. When the systemic steroid was tapered, the patient developed an asymptomatic flare of her eruption. On presentation, the lesions had waxed and waned, and the patient was taking only vitamin B₁₂ and vitamin C. Her medical history was notable for an unknown-type lymphoma of the chest wall diagnosed at 46 years of age that was treated with an unknown chemotherapeutic agent, chronic pancreatitis that resulted in a duodenectomy at 61 years of age, chronic cholecystitis, and 1 first-trimester miscarriage. Outside laboratory tests, including a comprehensive metabolic panel, complete blood cell count, urinalysis, renal function, and liver function tests were within reference range, except for the finding of mild leukocytosis (11,000/µL)(reference range, 3800–10,800/µL), which resolved after steroids were discontinued, with otherwise normal results. Punch biopsy of a specimen from the right thigh revealed medium-vessel vasculitis consistent with polyarteritis nodosa (Figure 2). Laboratory workup by our facility including hepatitis panel, perinuclear antineutrophil cytoplasmic antibody, cytoplasmic antineutrophil cytoplasmic antibody, factor V Leiden, prothrombin time/international normalized ratio, anticardiolipin antibody, and proteins C and S were all within reference range. Abnormal values included a low positive but nondiagnostic antinuclear antibody screen with negative titers, and the lupus anticoagulant titer was mildly elevated at 44 IgG binding units (reference range, <40 IgG binding units). Serum protein electrophoresis (SPEP) and urine protein electrophoresis also were performed, and SPEP was low positive for elevated κ and γ light chains. The patient was referred to oncology, and further testing revealed no underlying malignancy. The patient was monitored and no treatment was initiated; her rash completely resolved within 3 months. Laboratory monitoring at 6 months including SPEP, urine protein electrophoresis, lupus anticoagulant, and clotting studies all were within reference range.

Comment

Although the treatment of systemic polyarteritis nodosa often is necessary and typically involves high-dose corticosteroids and cyclophosphamide, the treatment of CPAN initially is less aggressive. Of the options available for treatment of CPAN, each has associated risks and side effects. Chen⁶ classified CPAN into 3 groups: 1 (mild), 2 (severe with no systemic involvement), and 3 (severe with progression to systemic disease)(Table). The authors performed a review of all the published treatments and their respective side effects to evaluate if treatment should be instituted for asymptomatic (group 1) disease presenting with abnormal antibody findings as demonstrated in our case.

First-line treatment of CPAN includes nonsteroidal anti-inflammatory drugs (NSAIDS) and colchicine.⁷ Nonsteroidal anti-inflammatory drugs are preferred; however, they also have been associated with gastrointestinal tract upset and increased risk for peptic ulcer disease with long-term use. Although colchicine often is used in conjunction with NSAIDS⁸ for its anti-inflammatory activity, no studies have been performed on this drug as monotherapy, and the side effect of diarrhea often limits its use.

Other therapies include dapsone, which should be monitored carefully due to the risk for dapsone hypersensitivity syndrome.^8,9 Topical corticosteroids have been proven effective for mild cases of confluent erythema with remission occurring as early as 4 weeks.⁴ Some reports emphasize the role of streptococcal infections in CPAN, especially in children.^8,10-12 Consequently it is recommended that anti–streptolysin O titers should be included in the workup for CPAN. Long-term penicillin prophylaxis and tonsillectomy have been used to prevent disease flares with limited success.^8,10-12

For more severe disease, especially with neuromuscular involvement, oral methylprednisolone up to 1 mg/kg daily has been used and has proven effective in the control of acute exacerbations.^7,13 However, the many adverse effects of systemic steroids limit their use long-term, and taper will often result in flare of disease.^4,7 Medications used in conjunction with steroids include hydroxychloroquine, dapsone, azathioprine, cyclophosphamide, methotrexate, sulfapyridine, pentoxifylline, infliximab, etanercept, and intravenous immunoglobulin.^4,9,12-17

Low-dose methotrexate has shown some improvement in skin disease with CPAN, but other case reports suggest that complete remission is not achieved with this drug.^15,18 More studies are needed to assess the use of methotrexate for CPAN.

Immunomodulators have been used in multiple case reports with varying levels of success. Rogalski and Sticherling⁴ reported 3 cases that cleared with methylprednisolone plus azathioprine ranging from 4 weeks to 6 months; nausea limited tolerance of azathioprine in 1 case. Mycophenolate mofetil also was successfully used in 2 cases with clearance at 17 weeks and 6 months. In this series of cases, cyclosporine was ineffective for CPAN.⁴ Two case reports documented cutaneous clearance with cyclophosphamide in conjunction with prednisolone.^9,10 No prospective trials have been performed on these medications, and immunosuppressants should only be considered in steroid-resistant cases.

The use of intravenous immunoglobulin has been reported effective in prior cases that showed resistance to more conventional trials of steroids, azathioprine, and/or cyclophosphamide.^12,14 Intravenous immunoglobulin may be regarded as a treatment option for severe resistant disease. Several case reports also have documented success using tumor necrosis factor α blockers, particularly infliximab, as an adjunct to steroids and etanercept as both a steroid adjunct and monotherapy.^16,17,19 More studies are necessary to evaluate these treatments.

Additionally, single case reports have outlined the use of other therapeutic agents, including tamoxifen (10 mg twice daily increased to 20 mg twice daily during episodes of breakthrough lesions),²⁰ hyperbaric oxygen therapy (100% oxygen for 90 minutes 5 times weekly at 1.5 atm absolute followed by 2 weeks of 2 atm absolute),²¹ and granulocyte-macrophage colony-stimulating factor (300 µg injection in small portion to ulcer edges twice monthly for 2 months).²² All of these treatments show promise, but data are limited.

Because thrombosis is postulated to be a potential mechanism leading to CPAN, agents such as pentoxifylline, clopidogrel, and warfarin have been examined as treatment options. Pentoxifylline in combination with mycophenolate mofetil has been successful in treating a case that was resistant to other immunosuppressants.²³ Clopidogrel blocks the adenosine diphosphate pathway and impairs clot retraction. Clopidogrel was reported effective in an acute flare of CPAN for clearance of skin lesions and normalization of lupus anticoagulant.²⁴ It also was used successfully in recurrent CPAN after steroid treatments in a patient with neuromuscular symptoms. There was no recurrence in either of the patients in this case report series. Warfarin therapy at an international normalized ratio of 3.0 also has demonstrated success in halting disease progression and in facilitating the resolution of skin changes and normalization of anti–phosphatidylserine-prothrombin complex antibodies.²⁴ Our review of the literature did not reveal evidence of a standardized length of treatment following symptom resolution or if treatment is indicated in asymptomatic disease, or as in our case, with only mild elevations of antiphospholipid antibodies.

Conclusion

Multiple treatment options exist for CPAN, but the data on their efficacies is limited and based only on anecdotal evidence, not prospective analysis. We believe that it seems reasonable to initiate treatment only for symptomatic disease or cases in which the antibody titers suggest that the patient may be at high risk for thrombosis. Mild symptoms and mild cutaneous changes would suggest the likely choice of NSAIDs, colchicine, or dapsone as treatment options versus no treatment. In patients with antibody titers, pentoxifylline, clopidogrel, or warfarin may be considered first-line therapies. With severe ulcerative lesions and neuromuscular involvement, steroids, immunosuppressants, and other investigative agents should be contemplated. In our patient, the laboratory studies were repeated and normalized on complete resolution of her livedo eruption. She remained asymptomatic and clear for 8 months without any treatment. The incidence of this presentation of CPAN is unknown and is likely underreported, as we would not expect most patients to present to their physicians for the evaluation of otherwise asymptomatic livedo reticularis. In essence, our case report suggests that it may be prudent to simply monitor patients with asymptomatic CPAN.

In 1931, Lindberg¹ described a cutaneous variant of polyarteritis nodosa, which lacked visceral involvement and possessed a more favorable prognosis.² Cutaneous polyarteritis nodosa (CPAN) is a localized small- to medium-vessel vasculitis restricted to the skin. Both benign and chronic courses have been described, and systemic involvement does not occur.³ Diagnostic criteria proposed by Nakamura et al³ in 2009 included cutaneous nodules, livedo reticularis, purpura, or ulcers; histopathologic fibrinoid necrotizing vasculitis of small- to medium-sized vessels; and exclusion of systemic symptoms (eg, fever, hypertension, weight loss, renal failure, cerebral hemorrhage, neuropathy, myocardial infarction, ischemic heart disease, pericarditis, pleuritis, arthralgia/myalgia). Nodules occur in 30% to 50% of cases and can remain for years if left untreated. Ulcerations occur in up to 30% of patients. Myositis, arthritis, and weakness also have been reported with this condition.⁴ Cutaneous polyarteritis nodosa has been associated with abnormal antibody testing with elevations of antiphospholipid cofactor antibody, lupus anticoagulant, anticardiolipin antibody, and anti-β₂-glycoprotein I–dependent cardiolipin antibody, as well as elevated anti–phosphatidylserine-prothrombin complex antibody.⁵ These antibodies suggest increased risk for thrombosis and systemic diseases such as lupus or other autoimmune connective tissue disease. The distinction of this entity from systemic polyartertitis nodosa is key when determining treatment options and monitoring parameters.

Case Report

A 66-year-old woman was referred to our facility by an outside dermatologist with a mildly pruritic, blanchable, reticulated erythema on the chest and bilateral arms and legs of 3 months’ duration consistent with livedo reticularis (Figure 1). Prior systemic therapy included prednisone 10 mg 3 times daily, fexofenadine, loratadine, and hydroxyzine. When the systemic steroid was tapered, the patient developed an asymptomatic flare of her eruption. On presentation, the lesions had waxed and waned, and the patient was taking only vitamin B₁₂ and vitamin C. Her medical history was notable for an unknown-type lymphoma of the chest wall diagnosed at 46 years of age that was treated with an unknown chemotherapeutic agent, chronic pancreatitis that resulted in a duodenectomy at 61 years of age, chronic cholecystitis, and 1 first-trimester miscarriage. Outside laboratory tests, including a comprehensive metabolic panel, complete blood cell count, urinalysis, renal function, and liver function tests were within reference range, except for the finding of mild leukocytosis (11,000/µL)(reference range, 3800–10,800/µL), which resolved after steroids were discontinued, with otherwise normal results. Punch biopsy of a specimen from the right thigh revealed medium-vessel vasculitis consistent with polyarteritis nodosa (Figure 2). Laboratory workup by our facility including hepatitis panel, perinuclear antineutrophil cytoplasmic antibody, cytoplasmic antineutrophil cytoplasmic antibody, factor V Leiden, prothrombin time/international normalized ratio, anticardiolipin antibody, and proteins C and S were all within reference range. Abnormal values included a low positive but nondiagnostic antinuclear antibody screen with negative titers, and the lupus anticoagulant titer was mildly elevated at 44 IgG binding units (reference range, <40 IgG binding units). Serum protein electrophoresis (SPEP) and urine protein electrophoresis also were performed, and SPEP was low positive for elevated κ and γ light chains. The patient was referred to oncology, and further testing revealed no underlying malignancy. The patient was monitored and no treatment was initiated; her rash completely resolved within 3 months. Laboratory monitoring at 6 months including SPEP, urine protein electrophoresis, lupus anticoagulant, and clotting studies all were within reference range.

Comment

Although the treatment of systemic polyarteritis nodosa often is necessary and typically involves high-dose corticosteroids and cyclophosphamide, the treatment of CPAN initially is less aggressive. Of the options available for treatment of CPAN, each has associated risks and side effects. Chen⁶ classified CPAN into 3 groups: 1 (mild), 2 (severe with no systemic involvement), and 3 (severe with progression to systemic disease)(Table). The authors performed a review of all the published treatments and their respective side effects to evaluate if treatment should be instituted for asymptomatic (group 1) disease presenting with abnormal antibody findings as demonstrated in our case.

First-line treatment of CPAN includes nonsteroidal anti-inflammatory drugs (NSAIDS) and colchicine.⁷ Nonsteroidal anti-inflammatory drugs are preferred; however, they also have been associated with gastrointestinal tract upset and increased risk for peptic ulcer disease with long-term use. Although colchicine often is used in conjunction with NSAIDS⁸ for its anti-inflammatory activity, no studies have been performed on this drug as monotherapy, and the side effect of diarrhea often limits its use.

Other therapies include dapsone, which should be monitored carefully due to the risk for dapsone hypersensitivity syndrome.^8,9 Topical corticosteroids have been proven effective for mild cases of confluent erythema with remission occurring as early as 4 weeks.⁴ Some reports emphasize the role of streptococcal infections in CPAN, especially in children.^8,10-12 Consequently it is recommended that anti–streptolysin O titers should be included in the workup for CPAN. Long-term penicillin prophylaxis and tonsillectomy have been used to prevent disease flares with limited success.^8,10-12

For more severe disease, especially with neuromuscular involvement, oral methylprednisolone up to 1 mg/kg daily has been used and has proven effective in the control of acute exacerbations.^7,13 However, the many adverse effects of systemic steroids limit their use long-term, and taper will often result in flare of disease.^4,7 Medications used in conjunction with steroids include hydroxychloroquine, dapsone, azathioprine, cyclophosphamide, methotrexate, sulfapyridine, pentoxifylline, infliximab, etanercept, and intravenous immunoglobulin.^4,9,12-17

Low-dose methotrexate has shown some improvement in skin disease with CPAN, but other case reports suggest that complete remission is not achieved with this drug.^15,18 More studies are needed to assess the use of methotrexate for CPAN.

Immunomodulators have been used in multiple case reports with varying levels of success. Rogalski and Sticherling⁴ reported 3 cases that cleared with methylprednisolone plus azathioprine ranging from 4 weeks to 6 months; nausea limited tolerance of azathioprine in 1 case. Mycophenolate mofetil also was successfully used in 2 cases with clearance at 17 weeks and 6 months. In this series of cases, cyclosporine was ineffective for CPAN.⁴ Two case reports documented cutaneous clearance with cyclophosphamide in conjunction with prednisolone.^9,10 No prospective trials have been performed on these medications, and immunosuppressants should only be considered in steroid-resistant cases.

The use of intravenous immunoglobulin has been reported effective in prior cases that showed resistance to more conventional trials of steroids, azathioprine, and/or cyclophosphamide.^12,14 Intravenous immunoglobulin may be regarded as a treatment option for severe resistant disease. Several case reports also have documented success using tumor necrosis factor α blockers, particularly infliximab, as an adjunct to steroids and etanercept as both a steroid adjunct and monotherapy.^16,17,19 More studies are necessary to evaluate these treatments.

Additionally, single case reports have outlined the use of other therapeutic agents, including tamoxifen (10 mg twice daily increased to 20 mg twice daily during episodes of breakthrough lesions),²⁰ hyperbaric oxygen therapy (100% oxygen for 90 minutes 5 times weekly at 1.5 atm absolute followed by 2 weeks of 2 atm absolute),²¹ and granulocyte-macrophage colony-stimulating factor (300 µg injection in small portion to ulcer edges twice monthly for 2 months).²² All of these treatments show promise, but data are limited.

Because thrombosis is postulated to be a potential mechanism leading to CPAN, agents such as pentoxifylline, clopidogrel, and warfarin have been examined as treatment options. Pentoxifylline in combination with mycophenolate mofetil has been successful in treating a case that was resistant to other immunosuppressants.²³ Clopidogrel blocks the adenosine diphosphate pathway and impairs clot retraction. Clopidogrel was reported effective in an acute flare of CPAN for clearance of skin lesions and normalization of lupus anticoagulant.²⁴ It also was used successfully in recurrent CPAN after steroid treatments in a patient with neuromuscular symptoms. There was no recurrence in either of the patients in this case report series. Warfarin therapy at an international normalized ratio of 3.0 also has demonstrated success in halting disease progression and in facilitating the resolution of skin changes and normalization of anti–phosphatidylserine-prothrombin complex antibodies.²⁴ Our review of the literature did not reveal evidence of a standardized length of treatment following symptom resolution or if treatment is indicated in asymptomatic disease, or as in our case, with only mild elevations of antiphospholipid antibodies.

Conclusion

Multiple treatment options exist for CPAN, but the data on their efficacies is limited and based only on anecdotal evidence, not prospective analysis. We believe that it seems reasonable to initiate treatment only for symptomatic disease or cases in which the antibody titers suggest that the patient may be at high risk for thrombosis. Mild symptoms and mild cutaneous changes would suggest the likely choice of NSAIDs, colchicine, or dapsone as treatment options versus no treatment. In patients with antibody titers, pentoxifylline, clopidogrel, or warfarin may be considered first-line therapies. With severe ulcerative lesions and neuromuscular involvement, steroids, immunosuppressants, and other investigative agents should be contemplated. In our patient, the laboratory studies were repeated and normalized on complete resolution of her livedo eruption. She remained asymptomatic and clear for 8 months without any treatment. The incidence of this presentation of CPAN is unknown and is likely underreported, as we would not expect most patients to present to their physicians for the evaluation of otherwise asymptomatic livedo reticularis. In essence, our case report suggests that it may be prudent to simply monitor patients with asymptomatic CPAN.

In 1931, Lindberg¹ described a cutaneous variant of polyarteritis nodosa, which lacked visceral involvement and possessed a more favorable prognosis.² Cutaneous polyarteritis nodosa (CPAN) is a localized small- to medium-vessel vasculitis restricted to the skin. Both benign and chronic courses have been described, and systemic involvement does not occur.³ Diagnostic criteria proposed by Nakamura et al³ in 2009 included cutaneous nodules, livedo reticularis, purpura, or ulcers; histopathologic fibrinoid necrotizing vasculitis of small- to medium-sized vessels; and exclusion of systemic symptoms (eg, fever, hypertension, weight loss, renal failure, cerebral hemorrhage, neuropathy, myocardial infarction, ischemic heart disease, pericarditis, pleuritis, arthralgia/myalgia). Nodules occur in 30% to 50% of cases and can remain for years if left untreated. Ulcerations occur in up to 30% of patients. Myositis, arthritis, and weakness also have been reported with this condition.⁴ Cutaneous polyarteritis nodosa has been associated with abnormal antibody testing with elevations of antiphospholipid cofactor antibody, lupus anticoagulant, anticardiolipin antibody, and anti-β₂-glycoprotein I–dependent cardiolipin antibody, as well as elevated anti–phosphatidylserine-prothrombin complex antibody.⁵ These antibodies suggest increased risk for thrombosis and systemic diseases such as lupus or other autoimmune connective tissue disease. The distinction of this entity from systemic polyartertitis nodosa is key when determining treatment options and monitoring parameters.

Case Report

A 66-year-old woman was referred to our facility by an outside dermatologist with a mildly pruritic, blanchable, reticulated erythema on the chest and bilateral arms and legs of 3 months’ duration consistent with livedo reticularis (Figure 1). Prior systemic therapy included prednisone 10 mg 3 times daily, fexofenadine, loratadine, and hydroxyzine. When the systemic steroid was tapered, the patient developed an asymptomatic flare of her eruption. On presentation, the lesions had waxed and waned, and the patient was taking only vitamin B₁₂ and vitamin C. Her medical history was notable for an unknown-type lymphoma of the chest wall diagnosed at 46 years of age that was treated with an unknown chemotherapeutic agent, chronic pancreatitis that resulted in a duodenectomy at 61 years of age, chronic cholecystitis, and 1 first-trimester miscarriage. Outside laboratory tests, including a comprehensive metabolic panel, complete blood cell count, urinalysis, renal function, and liver function tests were within reference range, except for the finding of mild leukocytosis (11,000/µL)(reference range, 3800–10,800/µL), which resolved after steroids were discontinued, with otherwise normal results. Punch biopsy of a specimen from the right thigh revealed medium-vessel vasculitis consistent with polyarteritis nodosa (Figure 2). Laboratory workup by our facility including hepatitis panel, perinuclear antineutrophil cytoplasmic antibody, cytoplasmic antineutrophil cytoplasmic antibody, factor V Leiden, prothrombin time/international normalized ratio, anticardiolipin antibody, and proteins C and S were all within reference range. Abnormal values included a low positive but nondiagnostic antinuclear antibody screen with negative titers, and the lupus anticoagulant titer was mildly elevated at 44 IgG binding units (reference range, <40 IgG binding units). Serum protein electrophoresis (SPEP) and urine protein electrophoresis also were performed, and SPEP was low positive for elevated κ and γ light chains. The patient was referred to oncology, and further testing revealed no underlying malignancy. The patient was monitored and no treatment was initiated; her rash completely resolved within 3 months. Laboratory monitoring at 6 months including SPEP, urine protein electrophoresis, lupus anticoagulant, and clotting studies all were within reference range.

Comment

Although the treatment of systemic polyarteritis nodosa often is necessary and typically involves high-dose corticosteroids and cyclophosphamide, the treatment of CPAN initially is less aggressive. Of the options available for treatment of CPAN, each has associated risks and side effects. Chen⁶ classified CPAN into 3 groups: 1 (mild), 2 (severe with no systemic involvement), and 3 (severe with progression to systemic disease)(Table). The authors performed a review of all the published treatments and their respective side effects to evaluate if treatment should be instituted for asymptomatic (group 1) disease presenting with abnormal antibody findings as demonstrated in our case.

First-line treatment of CPAN includes nonsteroidal anti-inflammatory drugs (NSAIDS) and colchicine.⁷ Nonsteroidal anti-inflammatory drugs are preferred; however, they also have been associated with gastrointestinal tract upset and increased risk for peptic ulcer disease with long-term use. Although colchicine often is used in conjunction with NSAIDS⁸ for its anti-inflammatory activity, no studies have been performed on this drug as monotherapy, and the side effect of diarrhea often limits its use.

Other therapies include dapsone, which should be monitored carefully due to the risk for dapsone hypersensitivity syndrome.^8,9 Topical corticosteroids have been proven effective for mild cases of confluent erythema with remission occurring as early as 4 weeks.⁴ Some reports emphasize the role of streptococcal infections in CPAN, especially in children.^8,10-12 Consequently it is recommended that anti–streptolysin O titers should be included in the workup for CPAN. Long-term penicillin prophylaxis and tonsillectomy have been used to prevent disease flares with limited success.^8,10-12

For more severe disease, especially with neuromuscular involvement, oral methylprednisolone up to 1 mg/kg daily has been used and has proven effective in the control of acute exacerbations.^7,13 However, the many adverse effects of systemic steroids limit their use long-term, and taper will often result in flare of disease.^4,7 Medications used in conjunction with steroids include hydroxychloroquine, dapsone, azathioprine, cyclophosphamide, methotrexate, sulfapyridine, pentoxifylline, infliximab, etanercept, and intravenous immunoglobulin.^4,9,12-17

Low-dose methotrexate has shown some improvement in skin disease with CPAN, but other case reports suggest that complete remission is not achieved with this drug.^15,18 More studies are needed to assess the use of methotrexate for CPAN.

Immunomodulators have been used in multiple case reports with varying levels of success. Rogalski and Sticherling⁴ reported 3 cases that cleared with methylprednisolone plus azathioprine ranging from 4 weeks to 6 months; nausea limited tolerance of azathioprine in 1 case. Mycophenolate mofetil also was successfully used in 2 cases with clearance at 17 weeks and 6 months. In this series of cases, cyclosporine was ineffective for CPAN.⁴ Two case reports documented cutaneous clearance with cyclophosphamide in conjunction with prednisolone.^9,10 No prospective trials have been performed on these medications, and immunosuppressants should only be considered in steroid-resistant cases.

The use of intravenous immunoglobulin has been reported effective in prior cases that showed resistance to more conventional trials of steroids, azathioprine, and/or cyclophosphamide.^12,14 Intravenous immunoglobulin may be regarded as a treatment option for severe resistant disease. Several case reports also have documented success using tumor necrosis factor α blockers, particularly infliximab, as an adjunct to steroids and etanercept as both a steroid adjunct and monotherapy.^16,17,19 More studies are necessary to evaluate these treatments.

Additionally, single case reports have outlined the use of other therapeutic agents, including tamoxifen (10 mg twice daily increased to 20 mg twice daily during episodes of breakthrough lesions),²⁰ hyperbaric oxygen therapy (100% oxygen for 90 minutes 5 times weekly at 1.5 atm absolute followed by 2 weeks of 2 atm absolute),²¹ and granulocyte-macrophage colony-stimulating factor (300 µg injection in small portion to ulcer edges twice monthly for 2 months).²² All of these treatments show promise, but data are limited.

Because thrombosis is postulated to be a potential mechanism leading to CPAN, agents such as pentoxifylline, clopidogrel, and warfarin have been examined as treatment options. Pentoxifylline in combination with mycophenolate mofetil has been successful in treating a case that was resistant to other immunosuppressants.²³ Clopidogrel blocks the adenosine diphosphate pathway and impairs clot retraction. Clopidogrel was reported effective in an acute flare of CPAN for clearance of skin lesions and normalization of lupus anticoagulant.²⁴ It also was used successfully in recurrent CPAN after steroid treatments in a patient with neuromuscular symptoms. There was no recurrence in either of the patients in this case report series. Warfarin therapy at an international normalized ratio of 3.0 also has demonstrated success in halting disease progression and in facilitating the resolution of skin changes and normalization of anti–phosphatidylserine-prothrombin complex antibodies.²⁴ Our review of the literature did not reveal evidence of a standardized length of treatment following symptom resolution or if treatment is indicated in asymptomatic disease, or as in our case, with only mild elevations of antiphospholipid antibodies.

Conclusion

Multiple treatment options exist for CPAN, but the data on their efficacies is limited and based only on anecdotal evidence, not prospective analysis. We believe that it seems reasonable to initiate treatment only for symptomatic disease or cases in which the antibody titers suggest that the patient may be at high risk for thrombosis. Mild symptoms and mild cutaneous changes would suggest the likely choice of NSAIDs, colchicine, or dapsone as treatment options versus no treatment. In patients with antibody titers, pentoxifylline, clopidogrel, or warfarin may be considered first-line therapies. With severe ulcerative lesions and neuromuscular involvement, steroids, immunosuppressants, and other investigative agents should be contemplated. In our patient, the laboratory studies were repeated and normalized on complete resolution of her livedo eruption. She remained asymptomatic and clear for 8 months without any treatment. The incidence of this presentation of CPAN is unknown and is likely underreported, as we would not expect most patients to present to their physicians for the evaluation of otherwise asymptomatic livedo reticularis. In essence, our case report suggests that it may be prudent to simply monitor patients with asymptomatic CPAN.

NASHVILLE, TENN. – A panel of experts discussed highlights from the 2017 AHA Kawasaki Guidelines at Pediatric Hospital Medicine, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

Session

Kawasaki Disease Reconsidered: New AHA Guidelines
 

Presenters

John Darby, MD, Marietta DeGuzman, MD, Kristen Sexson, MD, PhD, MPH, Stanford Shulman, MD, Nisha Tamaskar, MD
 

Session summary

For the second year in a row, the session highlighting American Heart Association updates on Kawasaki disease did not disappoint and again attracted a large crowd of community and academic pediatric hospitalists. The newly-revised 2017 AHA Kawasaki Guidelines hot off the press by McCrindle et al. was reviewed in detail.

Pathophysiology

• Cause is likely to be a common ubiquitous agent that in genetically inclined children will lead to a particular inflammatory response that manifests clinically as KD.

• A new theory about how the “ubiquitous agent” is spread by wind patterns.
 

Diagnosis

• Confirmed that infants younger than 1 year of age are more difficult to diagnose because they don’t present classically so it must be on the differential.

• The new algorithm makes it clearer that infants with fever for 7 days without symptoms should get lab screening tests for KD.

• Those who have classic symptoms and lab abnormalities consistent with KD but in whom fever is still at 3-4 days may be diagnosed with KD prior to the “5 days of fever rule” because these tend to be a sicker cohort of patients with higher rate of complications. Pretest probability and suspicion for KD must be high to treat before 5 days.

• Importance of the Z-score when evaluating an echocardiogram completed on a patient with suspected KD was stressed with a score greater than or equal to 2.5 reaching a level of significance for the patient’s body size.
 

Management

• It is still agreed that IVIG is first line therapy.

• For refractory KD (not responsive within 36 hours of first dose IVIG), management is more controversial. Experts on the panel agreed that they would likely provide a second dose of IVIG before thinking about steroids.

• Moderate dose aspirin is just as effective as high dose aspirin in the acute phase of KD.

• For more detailed information regarding the role of corticosteroids in KD, refer to Dr. Carl Galloway’s article in The Hospitalist July 2017 issue.

• A certain subset of patients may benefit from steroids if given early in the disease course, including those who present in shock syndrome. Steroids would still be in conjunction with IVIG treatment.

• Even though the new guidelines recommend a longer course of steroids for those refractory cases of KD in high-risk patients, panel experts are still unsure about evidence behind the claim.



The RAISE study was referenced and indicates there are significantly different outcomes for patients with severe disease placed on steroid therapy in combination with IVIG. In this group of patients, the incidence of coronary artery aneurysms was 23% in the IVIG-only group compared to 3% in the IVIG + steroid group (P less than .0001). This study and a recent Cochrane review that supported use of steroids in KD were completed in a homogeneous population of Japanese children and may not be generalizable to children in the United States.

Hyponatremia has been used as a diagnostic criterion for severe KD in Japanese children and was referenced as an indicator for addition of steroid therapy. Also, studies investigating the necessity of ASA at 80-100 mg/kg/d, a common practice for patients with KD treated in the United States, were compared to medium-dose ASA (30-50 mg/kg/d). There was no clinically significant difference in patient outcome or development of aneurysm formation between these two dosing regimens.
 

Key takeaways for Pediatric HM

• Diagnosis of classic KD remains unchanged and includes 5 or more days of fever and at least four clinical features (extremity changes, rash, conjunctivitis, oral changes, and cervical lymphadenopathy).

• Infants with fever of 7 days or more without other explanation should be evaluated for KD.

• Echocardiographic findings should be adjusted for body surface area and are significant if Z-score greater than or equal to 2.5.

• Moderate- to high-dose ASA is appropriate as an adjunct to IVIG until the patient is afebrile.

• Steroid therapy (for a total of 14 days) should be considered for high-risk patients.
 

Dr. King is associate program director, University of Minnesota Pediatric Residency Program. Dr. Hopkins is assistant professor of pediatrics, Johns Hopkins All Children’s Hospital.

NASHVILLE, TENN. – A panel of experts discussed highlights from the 2017 AHA Kawasaki Guidelines at Pediatric Hospital Medicine, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

Session

Kawasaki Disease Reconsidered: New AHA Guidelines
 

Presenters

John Darby, MD, Marietta DeGuzman, MD, Kristen Sexson, MD, PhD, MPH, Stanford Shulman, MD, Nisha Tamaskar, MD
 

Session summary

For the second year in a row, the session highlighting American Heart Association updates on Kawasaki disease did not disappoint and again attracted a large crowd of community and academic pediatric hospitalists. The newly-revised 2017 AHA Kawasaki Guidelines hot off the press by McCrindle et al. was reviewed in detail.

Pathophysiology

• Cause is likely to be a common ubiquitous agent that in genetically inclined children will lead to a particular inflammatory response that manifests clinically as KD.

• A new theory about how the “ubiquitous agent” is spread by wind patterns.
 

Diagnosis

• Confirmed that infants younger than 1 year of age are more difficult to diagnose because they don’t present classically so it must be on the differential.

• The new algorithm makes it clearer that infants with fever for 7 days without symptoms should get lab screening tests for KD.

• Those who have classic symptoms and lab abnormalities consistent with KD but in whom fever is still at 3-4 days may be diagnosed with KD prior to the “5 days of fever rule” because these tend to be a sicker cohort of patients with higher rate of complications. Pretest probability and suspicion for KD must be high to treat before 5 days.

• Importance of the Z-score when evaluating an echocardiogram completed on a patient with suspected KD was stressed with a score greater than or equal to 2.5 reaching a level of significance for the patient’s body size.
 

Management

• It is still agreed that IVIG is first line therapy.

• For refractory KD (not responsive within 36 hours of first dose IVIG), management is more controversial. Experts on the panel agreed that they would likely provide a second dose of IVIG before thinking about steroids.

• Moderate dose aspirin is just as effective as high dose aspirin in the acute phase of KD.

• For more detailed information regarding the role of corticosteroids in KD, refer to Dr. Carl Galloway’s article in The Hospitalist July 2017 issue.

• A certain subset of patients may benefit from steroids if given early in the disease course, including those who present in shock syndrome. Steroids would still be in conjunction with IVIG treatment.

• Even though the new guidelines recommend a longer course of steroids for those refractory cases of KD in high-risk patients, panel experts are still unsure about evidence behind the claim.



The RAISE study was referenced and indicates there are significantly different outcomes for patients with severe disease placed on steroid therapy in combination with IVIG. In this group of patients, the incidence of coronary artery aneurysms was 23% in the IVIG-only group compared to 3% in the IVIG + steroid group (P less than .0001). This study and a recent Cochrane review that supported use of steroids in KD were completed in a homogeneous population of Japanese children and may not be generalizable to children in the United States.

Hyponatremia has been used as a diagnostic criterion for severe KD in Japanese children and was referenced as an indicator for addition of steroid therapy. Also, studies investigating the necessity of ASA at 80-100 mg/kg/d, a common practice for patients with KD treated in the United States, were compared to medium-dose ASA (30-50 mg/kg/d). There was no clinically significant difference in patient outcome or development of aneurysm formation between these two dosing regimens.
 

Key takeaways for Pediatric HM

• Diagnosis of classic KD remains unchanged and includes 5 or more days of fever and at least four clinical features (extremity changes, rash, conjunctivitis, oral changes, and cervical lymphadenopathy).

• Infants with fever of 7 days or more without other explanation should be evaluated for KD.

• Echocardiographic findings should be adjusted for body surface area and are significant if Z-score greater than or equal to 2.5.

• Moderate- to high-dose ASA is appropriate as an adjunct to IVIG until the patient is afebrile.

• Steroid therapy (for a total of 14 days) should be considered for high-risk patients.
 

Dr. King is associate program director, University of Minnesota Pediatric Residency Program. Dr. Hopkins is assistant professor of pediatrics, Johns Hopkins All Children’s Hospital.

NASHVILLE, TENN. – A panel of experts discussed highlights from the 2017 AHA Kawasaki Guidelines at Pediatric Hospital Medicine, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

Session

Kawasaki Disease Reconsidered: New AHA Guidelines
 

Presenters

John Darby, MD, Marietta DeGuzman, MD, Kristen Sexson, MD, PhD, MPH, Stanford Shulman, MD, Nisha Tamaskar, MD
 

Session summary

For the second year in a row, the session highlighting American Heart Association updates on Kawasaki disease did not disappoint and again attracted a large crowd of community and academic pediatric hospitalists. The newly-revised 2017 AHA Kawasaki Guidelines hot off the press by McCrindle et al. was reviewed in detail.

Pathophysiology

• Cause is likely to be a common ubiquitous agent that in genetically inclined children will lead to a particular inflammatory response that manifests clinically as KD.

• A new theory about how the “ubiquitous agent” is spread by wind patterns.
 

Diagnosis

• Confirmed that infants younger than 1 year of age are more difficult to diagnose because they don’t present classically so it must be on the differential.

• The new algorithm makes it clearer that infants with fever for 7 days without symptoms should get lab screening tests for KD.

• Those who have classic symptoms and lab abnormalities consistent with KD but in whom fever is still at 3-4 days may be diagnosed with KD prior to the “5 days of fever rule” because these tend to be a sicker cohort of patients with higher rate of complications. Pretest probability and suspicion for KD must be high to treat before 5 days.

• Importance of the Z-score when evaluating an echocardiogram completed on a patient with suspected KD was stressed with a score greater than or equal to 2.5 reaching a level of significance for the patient’s body size.
 

Management

• It is still agreed that IVIG is first line therapy.

• For refractory KD (not responsive within 36 hours of first dose IVIG), management is more controversial. Experts on the panel agreed that they would likely provide a second dose of IVIG before thinking about steroids.

• Moderate dose aspirin is just as effective as high dose aspirin in the acute phase of KD.

• For more detailed information regarding the role of corticosteroids in KD, refer to Dr. Carl Galloway’s article in The Hospitalist July 2017 issue.

• A certain subset of patients may benefit from steroids if given early in the disease course, including those who present in shock syndrome. Steroids would still be in conjunction with IVIG treatment.

• Even though the new guidelines recommend a longer course of steroids for those refractory cases of KD in high-risk patients, panel experts are still unsure about evidence behind the claim.



The RAISE study was referenced and indicates there are significantly different outcomes for patients with severe disease placed on steroid therapy in combination with IVIG. In this group of patients, the incidence of coronary artery aneurysms was 23% in the IVIG-only group compared to 3% in the IVIG + steroid group (P less than .0001). This study and a recent Cochrane review that supported use of steroids in KD were completed in a homogeneous population of Japanese children and may not be generalizable to children in the United States.

Hyponatremia has been used as a diagnostic criterion for severe KD in Japanese children and was referenced as an indicator for addition of steroid therapy. Also, studies investigating the necessity of ASA at 80-100 mg/kg/d, a common practice for patients with KD treated in the United States, were compared to medium-dose ASA (30-50 mg/kg/d). There was no clinically significant difference in patient outcome or development of aneurysm formation between these two dosing regimens.
 

Key takeaways for Pediatric HM

• Diagnosis of classic KD remains unchanged and includes 5 or more days of fever and at least four clinical features (extremity changes, rash, conjunctivitis, oral changes, and cervical lymphadenopathy).

• Infants with fever of 7 days or more without other explanation should be evaluated for KD.

• Echocardiographic findings should be adjusted for body surface area and are significant if Z-score greater than or equal to 2.5.

• Moderate- to high-dose ASA is appropriate as an adjunct to IVIG until the patient is afebrile.

• Steroid therapy (for a total of 14 days) should be considered for high-risk patients.
 

Dr. King is associate program director, University of Minnesota Pediatric Residency Program. Dr. Hopkins is assistant professor of pediatrics, Johns Hopkins All Children’s Hospital.

The Diagnosis: Disseminated Cryptococcosis

Histopathologic examination of a 3-mm punch biopsy showed a diffuse dermal neutrophilic infiltrate with necrosis and subcutaneous tissue with round yeast surrounded by a prominent halo staining bright red with mucicarmine, representing a thick mucinous capsule (Figure). Grocott-Gomori methenamine-silver and periodic acid-Schiff stains also demonstrated fungal spores morphologically. Cerebrospinal fluid culture grew Cryptococcus neoformans, and cryptococcal antigen titers were positive in both serum and cerebrospinal fluid samples (>1:4096). The patient had autolytic debridement of the ulcer after completing a 4-week induction course of intravenous liposomal amphotericin B with oral flucytosine. He was transitioned to oral fluconazole for the consolidation phase of treatment.

Cryptococcus is an opportunistic basidiomycetous yeast with worldwide distribution and 2 primary pathogenic species in humans: C neoformans and Cryptococcus gattii. It is associated with bird feces, composted food, and decayed wood.^1,2 A predilection toward an immunosuppressed host is recognized in 70% to 90% of the infections caused by C neoformans; however, C gattii commonly affects individuals with apparently intact immune systems.^1,3 Risk factors for infection include advanced human immunodeficiency virus infection, solid organ transplantation, chronic liver disease, autoimmune disease, hematological malignancy, and underlying genetic susceptibility.^1,2

Initial exposure is through the respiratory tract with formation of latent reservoirs in the pulmonary lymph nodes with subsequent reactivation that can result in hematogenous dissemination.^1,2 Cutaneous involvement was described in 108 patients (5%) in a large review of 1974 cases in France.⁴ Among those with cutaneous involvement, disseminated disease was diagnosed in 80 cases (74%), and 28 cases (26%) were considered primary cutaneous cryptococcosis. Primary cutaneous cryptococcosis typically presents as a single lesion, predominantly on the hand, with whitlow and more rarely with extensive cellulitis or necrotizing fasciitis.⁴ In disseminated cutaneous disease, there is no pathognomonic single lesion; however, it is commonly associated with multiple cutaneous lesions predominantly involving the head and neck. Plaques, abscesses, nodules, and pustular or umbilicated papules have been reported.^1,5 There are few case reports that describe a single isolated necrotic ulcer with disseminated disease similar to our presented case, and more typically the necrotic ulcer is seen in transplanted patients.⁶ The differential diagnosis of a necrotic thigh ulcer includes pseudomonal ecthyma gangrenosum, cutaneous anthrax and aspergillosis, fusariosis, and a bite from the brown recluse spider.⁷ Our patient had an increased susceptibility to infection from his ongoing chemotherapy, a risk previously described in oncology patients with cell-mediated immunosuppression.⁸

Management for disseminated cryptococcosis is a 3-phase therapy including induction with intravenous amphotericin B and oral flucytosine for a minimum of 2 weeks, with consolidation and maintenance phases both with oral fluconazole for a length depending on underlying immunosuppression.⁹

The Diagnosis: Disseminated Cryptococcosis

Histopathologic examination of a 3-mm punch biopsy showed a diffuse dermal neutrophilic infiltrate with necrosis and subcutaneous tissue with round yeast surrounded by a prominent halo staining bright red with mucicarmine, representing a thick mucinous capsule (Figure). Grocott-Gomori methenamine-silver and periodic acid-Schiff stains also demonstrated fungal spores morphologically. Cerebrospinal fluid culture grew Cryptococcus neoformans, and cryptococcal antigen titers were positive in both serum and cerebrospinal fluid samples (>1:4096). The patient had autolytic debridement of the ulcer after completing a 4-week induction course of intravenous liposomal amphotericin B with oral flucytosine. He was transitioned to oral fluconazole for the consolidation phase of treatment.

Cryptococcus is an opportunistic basidiomycetous yeast with worldwide distribution and 2 primary pathogenic species in humans: C neoformans and Cryptococcus gattii. It is associated with bird feces, composted food, and decayed wood.^1,2 A predilection toward an immunosuppressed host is recognized in 70% to 90% of the infections caused by C neoformans; however, C gattii commonly affects individuals with apparently intact immune systems.^1,3 Risk factors for infection include advanced human immunodeficiency virus infection, solid organ transplantation, chronic liver disease, autoimmune disease, hematological malignancy, and underlying genetic susceptibility.^1,2

Initial exposure is through the respiratory tract with formation of latent reservoirs in the pulmonary lymph nodes with subsequent reactivation that can result in hematogenous dissemination.^1,2 Cutaneous involvement was described in 108 patients (5%) in a large review of 1974 cases in France.⁴ Among those with cutaneous involvement, disseminated disease was diagnosed in 80 cases (74%), and 28 cases (26%) were considered primary cutaneous cryptococcosis. Primary cutaneous cryptococcosis typically presents as a single lesion, predominantly on the hand, with whitlow and more rarely with extensive cellulitis or necrotizing fasciitis.⁴ In disseminated cutaneous disease, there is no pathognomonic single lesion; however, it is commonly associated with multiple cutaneous lesions predominantly involving the head and neck. Plaques, abscesses, nodules, and pustular or umbilicated papules have been reported.^1,5 There are few case reports that describe a single isolated necrotic ulcer with disseminated disease similar to our presented case, and more typically the necrotic ulcer is seen in transplanted patients.⁶ The differential diagnosis of a necrotic thigh ulcer includes pseudomonal ecthyma gangrenosum, cutaneous anthrax and aspergillosis, fusariosis, and a bite from the brown recluse spider.⁷ Our patient had an increased susceptibility to infection from his ongoing chemotherapy, a risk previously described in oncology patients with cell-mediated immunosuppression.⁸

Management for disseminated cryptococcosis is a 3-phase therapy including induction with intravenous amphotericin B and oral flucytosine for a minimum of 2 weeks, with consolidation and maintenance phases both with oral fluconazole for a length depending on underlying immunosuppression.⁹

The Diagnosis: Disseminated Cryptococcosis

Histopathologic examination of a 3-mm punch biopsy showed a diffuse dermal neutrophilic infiltrate with necrosis and subcutaneous tissue with round yeast surrounded by a prominent halo staining bright red with mucicarmine, representing a thick mucinous capsule (Figure). Grocott-Gomori methenamine-silver and periodic acid-Schiff stains also demonstrated fungal spores morphologically. Cerebrospinal fluid culture grew Cryptococcus neoformans, and cryptococcal antigen titers were positive in both serum and cerebrospinal fluid samples (>1:4096). The patient had autolytic debridement of the ulcer after completing a 4-week induction course of intravenous liposomal amphotericin B with oral flucytosine. He was transitioned to oral fluconazole for the consolidation phase of treatment.

Cryptococcus is an opportunistic basidiomycetous yeast with worldwide distribution and 2 primary pathogenic species in humans: C neoformans and Cryptococcus gattii. It is associated with bird feces, composted food, and decayed wood.^1,2 A predilection toward an immunosuppressed host is recognized in 70% to 90% of the infections caused by C neoformans; however, C gattii commonly affects individuals with apparently intact immune systems.^1,3 Risk factors for infection include advanced human immunodeficiency virus infection, solid organ transplantation, chronic liver disease, autoimmune disease, hematological malignancy, and underlying genetic susceptibility.^1,2

Initial exposure is through the respiratory tract with formation of latent reservoirs in the pulmonary lymph nodes with subsequent reactivation that can result in hematogenous dissemination.^1,2 Cutaneous involvement was described in 108 patients (5%) in a large review of 1974 cases in France.⁴ Among those with cutaneous involvement, disseminated disease was diagnosed in 80 cases (74%), and 28 cases (26%) were considered primary cutaneous cryptococcosis. Primary cutaneous cryptococcosis typically presents as a single lesion, predominantly on the hand, with whitlow and more rarely with extensive cellulitis or necrotizing fasciitis.⁴ In disseminated cutaneous disease, there is no pathognomonic single lesion; however, it is commonly associated with multiple cutaneous lesions predominantly involving the head and neck. Plaques, abscesses, nodules, and pustular or umbilicated papules have been reported.^1,5 There are few case reports that describe a single isolated necrotic ulcer with disseminated disease similar to our presented case, and more typically the necrotic ulcer is seen in transplanted patients.⁶ The differential diagnosis of a necrotic thigh ulcer includes pseudomonal ecthyma gangrenosum, cutaneous anthrax and aspergillosis, fusariosis, and a bite from the brown recluse spider.⁷ Our patient had an increased susceptibility to infection from his ongoing chemotherapy, a risk previously described in oncology patients with cell-mediated immunosuppression.⁸

Management for disseminated cryptococcosis is a 3-phase therapy including induction with intravenous amphotericin B and oral flucytosine for a minimum of 2 weeks, with consolidation and maintenance phases both with oral fluconazole for a length depending on underlying immunosuppression.⁹

Click Here to Read the Supplement.

Topics include:

• Overview of HE
• Early Identification and Management
• An Option for HE Management

Dr. William Ford, MD, SFHM

Regional Medical Director

Clinical Associate Professor

of Medicine

Abington, Jefferson Health

Philadelphia, PA

Click Here to Read the Supplement.
XIF.0129.USA.17

Click Here to Read the Supplement.

Topics include:

• Overview of HE
• Early Identification and Management
• An Option for HE Management

Dr. William Ford, MD, SFHM

Regional Medical Director

Clinical Associate Professor

of Medicine

Abington, Jefferson Health

Philadelphia, PA

Click Here to Read the Supplement.
XIF.0129.USA.17

Click Here to Read the Supplement.

Topics include:

• Overview of HE
• Early Identification and Management
• An Option for HE Management

Dr. William Ford, MD, SFHM

Regional Medical Director

Clinical Associate Professor

of Medicine

Abington, Jefferson Health

Philadelphia, PA

Click Here to Read the Supplement.
XIF.0129.USA.17

Mobile health devices enable patients and clinicians to monitor the type, quantity, and quality of everyday activities and hold the promise of improving patient health and health care practices.¹ In 2013, 75% of surveyed consumers in the United States owned a fitness technology product, either a dedicated fitness device, application, or portable blood pressure monitor.² Ownership of dedicated wearable fitness devices among consumers in the United States increased from 3% in 2012 to 9% in 2013. The immense popularity of wearable fitness devices is evident in the trajectory of their reported sales, which increased from $43 million in 2009 to $854 million in 2013.² Recognizing that “widespread adoption and use of mobile technologies is opening new and innovative ways to improve health,”³ the US Food and Drug Administration (FDA) ruled that “[technologies] that can pose a greater risk to patients will require FDA review.” One popular class of mobile technologies—activity and sleep sensors—falls outside the FDA’s regulatory guidance. To enable continuous monitoring, these sensors often are embedded into wearable devices.

Reports in the media have documented skin rashes arising in conjunction with use of one type of device,⁴ which may be related to nickel contact allergy, and the manufacturer has reported that the metal housing consists of surgical stainless steel that is known to contain nickel. We report a complication related to continuous use of an unregulated, commercially available, watchlike wearable sensor that was linked not to nickel but to an acrylate-containing component.

Case Report

An otherwise healthy 52-year-old woman with no history of contact allergy presented with an intensely itchy eruption involving the left wrist arising 4 days after continuous use of a new watchlike wearable fitness sensor. By day 11, the eruption evolved into a well-demarcated, erythematous, scaly plaque at the location where the device’s rechargeable battery metal housing came into contact with skin (Figure 1).

Dimethylglyoxime testing of the metal housing and clips was negative, but testing of contacts within the housing was positive for nickel (Figure 2). Epicutaneous patch testing of the patient using a modified North American Contact Dermatitis Group patch test series (Table) demonstrated no reaction to nickel, instead showing a strong positive (2+) reaction at 48 and 72 hours to methyl methacrylate 2% and a positive (1+) reaction at 96 hours to ethyl acrylate 0.1% (Figure 3).

Comment

Acrylates are used as adhesives to bond metal to plastic and as part of lithium ion polymer batteries, presumably similar to the one used in this device.⁵ Our patient had a history of using acrylic nail polish, which may have been a source of prior sensitization. Exposure to sweat or other moisture could theoretically dissolve such a water-soluble polymer,⁶ allowing for skin contact. Other acrylate polymers have been reported to break down slowly in contact with water, leading to contact sensitization to the monomer.⁷ The manufacturer of the device was contacted for additional information but declined to provide specific details regarding the device’s composition (personal communication, January 2014).

Although not considered toxic,⁸ acrylate was named Allergen of the Year in 2012 by the American Contact Dermatitis Society.^9-11 Nickel might be a source of allergy for some other patients who wear mobile health devices, but we concluded that this particular patient developed allergic contact dermatitis from prolonged exposure to low levels of methyl methacrylate or another acrylate due to gradual breakdown of the acrylate polymer used in the rechargeable battery housing for this wearable health device.

Given the FDA’s tailored risk approach to regulation, many wearable sensors that may contain potential contact allergens such as nickel and acrylates do not fall under the FDA regulatory framework. This case should alert physicians to the lack of regulatory oversight for many mobile technologies. They should consider a screening history for contact allergens before recommending wearable sensors and broader testing for contact allergens should exposed patients develop reactions. Future wearable sensor materials and designs should minimize exposure to allergens given prolonged contact with continuous use. In the absence of regulation, manufacturers of these devices should consider due care testing prior to commercialization.

Acknowledgment

We are indebted to Alexander S. Rattner, PhD (State College, Pennsylvania), who provided his engineering expertise and insight during conversations with the authors.

Mobile health devices enable patients and clinicians to monitor the type, quantity, and quality of everyday activities and hold the promise of improving patient health and health care practices.¹ In 2013, 75% of surveyed consumers in the United States owned a fitness technology product, either a dedicated fitness device, application, or portable blood pressure monitor.² Ownership of dedicated wearable fitness devices among consumers in the United States increased from 3% in 2012 to 9% in 2013. The immense popularity of wearable fitness devices is evident in the trajectory of their reported sales, which increased from $43 million in 2009 to $854 million in 2013.² Recognizing that “widespread adoption and use of mobile technologies is opening new and innovative ways to improve health,”³ the US Food and Drug Administration (FDA) ruled that “[technologies] that can pose a greater risk to patients will require FDA review.” One popular class of mobile technologies—activity and sleep sensors—falls outside the FDA’s regulatory guidance. To enable continuous monitoring, these sensors often are embedded into wearable devices.

Reports in the media have documented skin rashes arising in conjunction with use of one type of device,⁴ which may be related to nickel contact allergy, and the manufacturer has reported that the metal housing consists of surgical stainless steel that is known to contain nickel. We report a complication related to continuous use of an unregulated, commercially available, watchlike wearable sensor that was linked not to nickel but to an acrylate-containing component.

Case Report

An otherwise healthy 52-year-old woman with no history of contact allergy presented with an intensely itchy eruption involving the left wrist arising 4 days after continuous use of a new watchlike wearable fitness sensor. By day 11, the eruption evolved into a well-demarcated, erythematous, scaly plaque at the location where the device’s rechargeable battery metal housing came into contact with skin (Figure 1).

Dimethylglyoxime testing of the metal housing and clips was negative, but testing of contacts within the housing was positive for nickel (Figure 2). Epicutaneous patch testing of the patient using a modified North American Contact Dermatitis Group patch test series (Table) demonstrated no reaction to nickel, instead showing a strong positive (2+) reaction at 48 and 72 hours to methyl methacrylate 2% and a positive (1+) reaction at 96 hours to ethyl acrylate 0.1% (Figure 3).

Comment

Acrylates are used as adhesives to bond metal to plastic and as part of lithium ion polymer batteries, presumably similar to the one used in this device.⁵ Our patient had a history of using acrylic nail polish, which may have been a source of prior sensitization. Exposure to sweat or other moisture could theoretically dissolve such a water-soluble polymer,⁶ allowing for skin contact. Other acrylate polymers have been reported to break down slowly in contact with water, leading to contact sensitization to the monomer.⁷ The manufacturer of the device was contacted for additional information but declined to provide specific details regarding the device’s composition (personal communication, January 2014).

Although not considered toxic,⁸ acrylate was named Allergen of the Year in 2012 by the American Contact Dermatitis Society.^9-11 Nickel might be a source of allergy for some other patients who wear mobile health devices, but we concluded that this particular patient developed allergic contact dermatitis from prolonged exposure to low levels of methyl methacrylate or another acrylate due to gradual breakdown of the acrylate polymer used in the rechargeable battery housing for this wearable health device.

Given the FDA’s tailored risk approach to regulation, many wearable sensors that may contain potential contact allergens such as nickel and acrylates do not fall under the FDA regulatory framework. This case should alert physicians to the lack of regulatory oversight for many mobile technologies. They should consider a screening history for contact allergens before recommending wearable sensors and broader testing for contact allergens should exposed patients develop reactions. Future wearable sensor materials and designs should minimize exposure to allergens given prolonged contact with continuous use. In the absence of regulation, manufacturers of these devices should consider due care testing prior to commercialization.

Acknowledgment

We are indebted to Alexander S. Rattner, PhD (State College, Pennsylvania), who provided his engineering expertise and insight during conversations with the authors.

Mobile health devices enable patients and clinicians to monitor the type, quantity, and quality of everyday activities and hold the promise of improving patient health and health care practices.¹ In 2013, 75% of surveyed consumers in the United States owned a fitness technology product, either a dedicated fitness device, application, or portable blood pressure monitor.² Ownership of dedicated wearable fitness devices among consumers in the United States increased from 3% in 2012 to 9% in 2013. The immense popularity of wearable fitness devices is evident in the trajectory of their reported sales, which increased from $43 million in 2009 to $854 million in 2013.² Recognizing that “widespread adoption and use of mobile technologies is opening new and innovative ways to improve health,”³ the US Food and Drug Administration (FDA) ruled that “[technologies] that can pose a greater risk to patients will require FDA review.” One popular class of mobile technologies—activity and sleep sensors—falls outside the FDA’s regulatory guidance. To enable continuous monitoring, these sensors often are embedded into wearable devices.

Reports in the media have documented skin rashes arising in conjunction with use of one type of device,⁴ which may be related to nickel contact allergy, and the manufacturer has reported that the metal housing consists of surgical stainless steel that is known to contain nickel. We report a complication related to continuous use of an unregulated, commercially available, watchlike wearable sensor that was linked not to nickel but to an acrylate-containing component.

Case Report

An otherwise healthy 52-year-old woman with no history of contact allergy presented with an intensely itchy eruption involving the left wrist arising 4 days after continuous use of a new watchlike wearable fitness sensor. By day 11, the eruption evolved into a well-demarcated, erythematous, scaly plaque at the location where the device’s rechargeable battery metal housing came into contact with skin (Figure 1).

Dimethylglyoxime testing of the metal housing and clips was negative, but testing of contacts within the housing was positive for nickel (Figure 2). Epicutaneous patch testing of the patient using a modified North American Contact Dermatitis Group patch test series (Table) demonstrated no reaction to nickel, instead showing a strong positive (2+) reaction at 48 and 72 hours to methyl methacrylate 2% and a positive (1+) reaction at 96 hours to ethyl acrylate 0.1% (Figure 3).

Comment

Acrylates are used as adhesives to bond metal to plastic and as part of lithium ion polymer batteries, presumably similar to the one used in this device.⁵ Our patient had a history of using acrylic nail polish, which may have been a source of prior sensitization. Exposure to sweat or other moisture could theoretically dissolve such a water-soluble polymer,⁶ allowing for skin contact. Other acrylate polymers have been reported to break down slowly in contact with water, leading to contact sensitization to the monomer.⁷ The manufacturer of the device was contacted for additional information but declined to provide specific details regarding the device’s composition (personal communication, January 2014).

Although not considered toxic,⁸ acrylate was named Allergen of the Year in 2012 by the American Contact Dermatitis Society.^9-11 Nickel might be a source of allergy for some other patients who wear mobile health devices, but we concluded that this particular patient developed allergic contact dermatitis from prolonged exposure to low levels of methyl methacrylate or another acrylate due to gradual breakdown of the acrylate polymer used in the rechargeable battery housing for this wearable health device.

Given the FDA’s tailored risk approach to regulation, many wearable sensors that may contain potential contact allergens such as nickel and acrylates do not fall under the FDA regulatory framework. This case should alert physicians to the lack of regulatory oversight for many mobile technologies. They should consider a screening history for contact allergens before recommending wearable sensors and broader testing for contact allergens should exposed patients develop reactions. Future wearable sensor materials and designs should minimize exposure to allergens given prolonged contact with continuous use. In the absence of regulation, manufacturers of these devices should consider due care testing prior to commercialization.

Acknowledgment

We are indebted to Alexander S. Rattner, PhD (State College, Pennsylvania), who provided his engineering expertise and insight during conversations with the authors.

Delusional infestation is the fixed false belief of skin infestation with a pathogen. Patients will often bring “proof” of their infestation to their visit to a physician. The presentation of a specimen was previously referred to by several names that reflected the receptacle that the patient utilized to bring the specimen (eg, a baggie or matchbox), but now the more encompassing term specimen sign is employed.¹ Establishing rapport with the patient is critically important in the treatment of delusional infestation. Examining the specimen samples brought by the patient is a simple manner of communicating to a patient that the clinician is empathetic to and respectful of his/her concerns.^2,3 The specimens often consist of dirt, dust, debris, fibers, and skin flakes and fragments, but they also have been reported to contain flies and insect parts.^4,5 In our case, the patient captured a minute brown scavenger beetle with adhesive tape.

Case Report

A woman in her mid-30s with a history of generalized anxiety disorder presented to the dermatology clinic with a concern of bugs infesting her skin. The symptoms occurred just after she moved into a new home with her family approximately 4 months prior to presentation. She felt the home was not cleaned properly, but they could not afford to move. She reported a crawling sensation that she identified as bugs biting her all over her body. Prior to presentation in the dermatology clinic, she and her family were treated by primary care for scabies 3 times with permethrin cream, and she was prescribed 1 course of oral ivermectin. She reported seeing bugs all over her house, which led her to clean her home and clothing many times. She was more concerned now because she thought her 2 children also were starting to be affected.

Physical examination revealed pressured speech, and the patient became tearful several times. The skin demonstrated several excoriations in various stages of healing on the breasts, legs, and upper back, as well as small scars in the same distribution. She brought several specimens stuck to clear tape to the visit. Examination of the specimens revealed fabric fibers; various debris; and a small, brown, 6-legged beetle with punctate indentations in rows along the wing covers (Figure). The head was narrower than the thorax, which was narrower than the abdomen.

We diagnosed the patient with a delusional infestation and discussed the beetle that we saw when examining the specimen the patient brought to the clinic. We provided reassurance that the minute brown scavenger beetle is not pathogenic and was present incidentally. Thus far, the patient has been resistant to initiating specific therapy for the delusional infestation, such as risperidone, olanzapine, or pimozide. We continue regular follow-up appointments with the patient to continue building the therapeutic relationship and revisiting the subject of treatment.

Comment

Minute brown scavenger beetles are arthropod members of the family Latridiidae. They also are commonly referred to as plaster or mold beetles. They are small (0.8–3.0 mm) and can be found in moist environments such as dead and rotting foliage, bird’s nests, debris, moist wallpaper/plaster, and stored products. They feed exclusively on fungus, such as mold and mildew, and pose no threat to humans.⁶ It is important for clinicians to recognize the appearance of the minute brown scavenger beetle so as not to mistake it for a pathogenic arthropod in patients presenting with delusional parasitosis.

Delusional infestation is the fixed false belief of skin infestation with a pathogen. Patients will often bring “proof” of their infestation to their visit to a physician. The presentation of a specimen was previously referred to by several names that reflected the receptacle that the patient utilized to bring the specimen (eg, a baggie or matchbox), but now the more encompassing term specimen sign is employed.¹ Establishing rapport with the patient is critically important in the treatment of delusional infestation. Examining the specimen samples brought by the patient is a simple manner of communicating to a patient that the clinician is empathetic to and respectful of his/her concerns.^2,3 The specimens often consist of dirt, dust, debris, fibers, and skin flakes and fragments, but they also have been reported to contain flies and insect parts.^4,5 In our case, the patient captured a minute brown scavenger beetle with adhesive tape.

Case Report

A woman in her mid-30s with a history of generalized anxiety disorder presented to the dermatology clinic with a concern of bugs infesting her skin. The symptoms occurred just after she moved into a new home with her family approximately 4 months prior to presentation. She felt the home was not cleaned properly, but they could not afford to move. She reported a crawling sensation that she identified as bugs biting her all over her body. Prior to presentation in the dermatology clinic, she and her family were treated by primary care for scabies 3 times with permethrin cream, and she was prescribed 1 course of oral ivermectin. She reported seeing bugs all over her house, which led her to clean her home and clothing many times. She was more concerned now because she thought her 2 children also were starting to be affected.

Physical examination revealed pressured speech, and the patient became tearful several times. The skin demonstrated several excoriations in various stages of healing on the breasts, legs, and upper back, as well as small scars in the same distribution. She brought several specimens stuck to clear tape to the visit. Examination of the specimens revealed fabric fibers; various debris; and a small, brown, 6-legged beetle with punctate indentations in rows along the wing covers (Figure). The head was narrower than the thorax, which was narrower than the abdomen.

We diagnosed the patient with a delusional infestation and discussed the beetle that we saw when examining the specimen the patient brought to the clinic. We provided reassurance that the minute brown scavenger beetle is not pathogenic and was present incidentally. Thus far, the patient has been resistant to initiating specific therapy for the delusional infestation, such as risperidone, olanzapine, or pimozide. We continue regular follow-up appointments with the patient to continue building the therapeutic relationship and revisiting the subject of treatment.

Comment

Minute brown scavenger beetles are arthropod members of the family Latridiidae. They also are commonly referred to as plaster or mold beetles. They are small (0.8–3.0 mm) and can be found in moist environments such as dead and rotting foliage, bird’s nests, debris, moist wallpaper/plaster, and stored products. They feed exclusively on fungus, such as mold and mildew, and pose no threat to humans.⁶ It is important for clinicians to recognize the appearance of the minute brown scavenger beetle so as not to mistake it for a pathogenic arthropod in patients presenting with delusional parasitosis.

Delusional infestation is the fixed false belief of skin infestation with a pathogen. Patients will often bring “proof” of their infestation to their visit to a physician. The presentation of a specimen was previously referred to by several names that reflected the receptacle that the patient utilized to bring the specimen (eg, a baggie or matchbox), but now the more encompassing term specimen sign is employed.¹ Establishing rapport with the patient is critically important in the treatment of delusional infestation. Examining the specimen samples brought by the patient is a simple manner of communicating to a patient that the clinician is empathetic to and respectful of his/her concerns.^2,3 The specimens often consist of dirt, dust, debris, fibers, and skin flakes and fragments, but they also have been reported to contain flies and insect parts.^4,5 In our case, the patient captured a minute brown scavenger beetle with adhesive tape.

Case Report

A woman in her mid-30s with a history of generalized anxiety disorder presented to the dermatology clinic with a concern of bugs infesting her skin. The symptoms occurred just after she moved into a new home with her family approximately 4 months prior to presentation. She felt the home was not cleaned properly, but they could not afford to move. She reported a crawling sensation that she identified as bugs biting her all over her body. Prior to presentation in the dermatology clinic, she and her family were treated by primary care for scabies 3 times with permethrin cream, and she was prescribed 1 course of oral ivermectin. She reported seeing bugs all over her house, which led her to clean her home and clothing many times. She was more concerned now because she thought her 2 children also were starting to be affected.

Physical examination revealed pressured speech, and the patient became tearful several times. The skin demonstrated several excoriations in various stages of healing on the breasts, legs, and upper back, as well as small scars in the same distribution. She brought several specimens stuck to clear tape to the visit. Examination of the specimens revealed fabric fibers; various debris; and a small, brown, 6-legged beetle with punctate indentations in rows along the wing covers (Figure). The head was narrower than the thorax, which was narrower than the abdomen.

We diagnosed the patient with a delusional infestation and discussed the beetle that we saw when examining the specimen the patient brought to the clinic. We provided reassurance that the minute brown scavenger beetle is not pathogenic and was present incidentally. Thus far, the patient has been resistant to initiating specific therapy for the delusional infestation, such as risperidone, olanzapine, or pimozide. We continue regular follow-up appointments with the patient to continue building the therapeutic relationship and revisiting the subject of treatment.

Comment

Minute brown scavenger beetles are arthropod members of the family Latridiidae. They also are commonly referred to as plaster or mold beetles. They are small (0.8–3.0 mm) and can be found in moist environments such as dead and rotting foliage, bird’s nests, debris, moist wallpaper/plaster, and stored products. They feed exclusively on fungus, such as mold and mildew, and pose no threat to humans.⁶ It is important for clinicians to recognize the appearance of the minute brown scavenger beetle so as not to mistake it for a pathogenic arthropod in patients presenting with delusional parasitosis.

Title: Inpatient rehabilitation does not improve mobility after total knee arthroplasty versus a monitored home-based program.

Clinical Question: Does initial treatment in an inpatient rehabilitation facility offer greater improvements in mobility when added to a monitored home-based program after undergoing total knee arthroplasty?

Background: Total knee arthroplasty (TKA) is common and postsurgical care varies. No randomized controlled trials have compared inpatient rehabilitation to monitored home-based programs.

Study Design: Multicenter, two intervention groups in parallel, randomized controlled trial with a third observational group.

Dr. Burns is assistant professor in the division of hospital medicine at the University of New Mexico.

Title: Inpatient rehabilitation does not improve mobility after total knee arthroplasty versus a monitored home-based program.

Clinical Question: Does initial treatment in an inpatient rehabilitation facility offer greater improvements in mobility when added to a monitored home-based program after undergoing total knee arthroplasty?

Background: Total knee arthroplasty (TKA) is common and postsurgical care varies. No randomized controlled trials have compared inpatient rehabilitation to monitored home-based programs.

Study Design: Multicenter, two intervention groups in parallel, randomized controlled trial with a third observational group.

Dr. Burns is assistant professor in the division of hospital medicine at the University of New Mexico.

Title: Inpatient rehabilitation does not improve mobility after total knee arthroplasty versus a monitored home-based program.

Clinical Question: Does initial treatment in an inpatient rehabilitation facility offer greater improvements in mobility when added to a monitored home-based program after undergoing total knee arthroplasty?

Background: Total knee arthroplasty (TKA) is common and postsurgical care varies. No randomized controlled trials have compared inpatient rehabilitation to monitored home-based programs.

Study Design: Multicenter, two intervention groups in parallel, randomized controlled trial with a third observational group.

Dr. Burns is assistant professor in the division of hospital medicine at the University of New Mexico.

The gold standard for diagnosing dermatophytosis is the use of direct microscopic examination together with fungal culture.¹ However, in the last 2 decades, molecular techniques that currently are available worldwide have improved the diagnosis procedure.^2,3 In the practice of dermatology, potassium hydroxide (KOH) testing is a commonly used method for the diagnosis of superficial fungal infections.⁴ The sensitivity and specificity of KOH testing in patients with tinea pedis have been reported as 73.3% and 42.5%, respectively.⁵ Repetition of this test after an initial negative test result is recommended if the clinical picture strongly suggests a fungal infection.^6,7 Alternatively, several repetitions of direct microscopic examinations also have been proposed for detecting other microorganisms. For example, 3 negative sputum smears traditionally are recommended to exclude a diagnosis of pulmonary tuberculosis.⁸ However, after numerous investigations in various regions of the world, the World Health Organization reduced the recommended number of these specimens from 3 to 2 in 2007.⁹

The literature suggests that successive mycological tests, both with direct microscopy and fungal cultures, improve the diagnosis of onychomycosis.^1,10,11 Therefore, if such investigations are increased in number, recommendations for successive mycological tests may be more reliable. In the current study, we aimed to investigate the value of successive KOH testing in the management of patients with clinically suspected tinea pedis.

Methods

Patients and Clinical Evaluation
One hundred thirty-five consecutive patients (63 male; 72 female) with clinical symptoms suggestive of intertriginous, vesiculobullous, and/or moccasin-type tinea pedis were enrolled in this prospective study. The mean age (SD) of patients was 45.9 (14.7) years (range, 11–77 years). Almost exclusively, the clinical symptoms suggestive of tinea pedis were desquamation or maceration in the toe webs, blistering lesions on the soles, and diffuse or patchy scaling or keratosis on the soles. A single dermatologist (B.F.K.) clinically evaluated the patients and found only 1 region showing different patterns suggestive of tinea pedis in 72 patients, 2 regions in 61 patients, and 3 regions in 2 patients. Therefore, 200 lesions from the 135 patients were chosen for the KOH test. The dermatologist recorded her level of suspicion for a fungal infection as low or high for each lesion, depending on the absence or presence of signs (eg, unilateral involvement, a well-defined border). None of the patients had used topical or systemic antifungal therapy for at least 1 month prior to the study.¹²

Clinical Sampling and Direct Microscopic Examination
The dermatologist took 3 samples of skin scrapings from each of the 200 lesions. All 3 samples from a given lesion were obtained from sites with the same clinical symptoms in a single session. Special attention was paid to samples from the active advancing borders of the lesions and the roofs of blisters if they were present.¹³ Upon completion of every 15 samples from every 5 lesions, the dermatologist randomized the order of the samples (https://www.random.org/). She then gave the samples, without the identities of the patients or any clinical information, to an experienced laboratory technician for direct microscopic examination. The technician prepared and examined the samples as described elsewhere^5,7,14 and recorded the results as positive if hyphal elements were present or negative if they were not. The study was reviewed and approved by the Çukurova University Faculty of Medicine Ethics Committee (Adana, Turkey). Informed consent was obtained from each patient or from his/her guardian(s) prior to initiating the study.

Statistical Analysis
Statistical analysis was conducted using the χ² test in the SPSS software version 20.0. McNemar test was used for analysis of the paired data.

Results

Among the 135 patients, lesions were suggestive of the intertriginous type of tinea pedis in 24 patients, moccasin type in 50 patients, and both intertriginous and moccasin type in 58 patients. Among the remaining 3 patients, 1 had lesions suggestive of the vesiculobullous type, and another patient had both the vesiculobullous and intertriginous types; the last patient demonstrated lesions that were inconsistent with any of these 3 subtypes of tinea pedis, and a well-defined eczematous plaque was observed on the dorsal surface of the patient’s left foot.

Among the 200 lesions from which skin scrapings were taken for KOH testing, 83 were in the toe webs, 110 were on the soles, and 7 were on the dorsal surfaces of the feet. Of these 7 dorsal lesions, 6 were extensions from lesions on the toe webs or soles and 1 was inconsistent with the 3 subtypes of tinea pedis. Among the 200 lesions, the main clinical symptom was maceration in 38 lesions, desquamation or scaling in 132 lesions, keratosis in 28 lesions, and blistering in 2 lesions. The dermatologist recorded the level of suspicion for tinea pedis as low in 68 lesions and high in 132.

According to the order in which the dermatologist took the 3 samples from each lesion, the KOH test was positive in 95 of the first set of 200 samples, 94 of the second set, and 86 of the third set; however, from the second set, the incremental yield (ie, the number of lesions in which the first KOH test was negative and the second was positive) was 10. The number of lesions in which the first and the second tests were negative and the third was positive was only 4. Therefore, the number of lesions with a positive KOH test was significantly increased from 95 to 105 by performing the second KOH test (P=.002). This number again increased from 105 to 109 when a third test was performed; however, this increase was not statistically significant (P=.125)(Table 1).

According to an evaluation that was not stratified by the dermatologist’s order of sampling, 72 lesions (36.0%) showed KOH test positivity in all 3 samples, 22 (11.0%) were positive in 2 samples, 15 (7.5%) were positive in only 1 sample, and 91 (45.5%) were positive in none of the samples (Table 2). When the data were subdivided based on the sites of the lesions, the toe web lesions (n=83) showed rates of 41.0%, 9.6%, and 4.8% for 3, 2, and 1 positive KOH tests, respectively. For the sole lesions (n=110), the rates were somewhat different at 31.8%, 11.8%, and 10.0%, respectively, but the difference was not statistically significant (P=.395).

For the subgroups based on the main clinical symptoms, the percentage of lesions having at least 1 positive KOH test from the 3 samples was 35.7% for the keratotic lesions (n=28). This rate was lower than macerated lesions (n=38) and desquamating or scaling lesions (n=132), which were 52.6% and 59.1%, respectively (Table 2). On the other hand, the percentage of lesions that produced only 1 or 2 positive KOH tests from the 3 samples was 25.0% for the keratotic lesions, which was higher than the rates for the macerated lesions and the desquamating or scaling lesions (13.1% and 18.9%, respectively). In particular, the difference between the keratotic lesions and the desquamating or scaling lesions in the distribution of the rates of 0, 1, 2, and 3 positive KOH tests was statistically significant (P=.019). The macerated, desquamating or scaling, keratotic, and blistering lesions are presented in the Figure.

Comment

In the current study, we aimed to investigate if successive KOH tests provide an incremental diagnostic yield in the management of patients with clinically suspected tinea pedis and if these results differ among the subgroups of patients. Both in the evaluation taking into account the order of sampling and in the evaluation disregarding this order, we found that the second sample was necessary for all subgroups, and even the third sample was necessary for patients with keratotic lesions. The main limitation of the study was that we lacked a gold-standard technique (eg, a molecular-based technique); therefore, we are unable to comment on the false-negative and false-positive results of the successive KOH testing.

Summerbell et al¹¹ found in their study that in initial specimens of toenails with apparent lesions taken from 473 patients, the KOH test was 73.8% sensitive for dermatophytes, and this rate was only somewhat higher for cultures (74.6%). Arabatzis et al² investigated 92 skin, nail, and hair specimens from 67 patients with suspected dermatophytosis and found that the KOH test was superior to culture for the detection of dermatophytes (43% vs 33%). Moreover and more importantly, they noted that a real-time polymerase chain reaction (PCR) assay yielded a higher detection rate (51%).² In another study, Wisselink et al³ examined 1437 clinical samples and demonstrated a great increase in the detection of dermatophytes using a real-time PCR assay (48.5%) compared to culture (26.9%). However, PCR may not reflect active disease and could lead to false-positive results.^2,3 Therefore, the aforementioned weakness of our study will be overcome in further studies investigating the benefit of successive KOH testing compared to a molecular-based assay, such as the real-time PCR assay.

In this study, repeating the KOH test provided better results for achieving the diagnosis of tinea pedis in a large number of samples from clinically suspected lesions. Additionally, the distribution of 3, 2, or 1 positive results on the 3 KOH tests was different among the subgroups of lesions. Overall, positivity was less frequent in the keratotic lesions compared to the macerated or desquamating or scaling lesions. Moreover, positivity on all 3 tests also was less frequent in the keratotic lesions. Inversely, the frequency of samples with only 1 or 2 positive results was higher in this subgroup. The necessity for the second, even the third, tests was greater in this subgroup.

Our findings were consistent with the results of the studies performed with successive mycological tests on the nail specimens. Meireles et al¹ repeated 156 mycological nail tests 3 times and found the rate of positivity in the first test to be 19.9%. When the results of the first and second tests were combined, this rate increased to 28.2%, and when the results of all 3 tests were combined, it increased to 37.8%.¹ Gupta¹⁰ demonstrated that even a fourth culture provided an incremental diagnostic yield in the diagnosis of onychomycosis, yet 4 cultures may not be clinically practical. Furthermore, periodic acid–Schiff staining is a more effective measure of positivity in onychomycosis.¹⁵

Although the overall rate of positivity on the 3 tests in our study was unsurprisingly higher in lesions rated highly suspicious for a fungal infection, the rate of only 1 or 2 positive tests was surprisingly somewhat higher in low-suspicion lesions, which suggested that repeating the KOH test would be beneficial, even if the clinical suspicion for tinea pedis was low. The novel contribution of this study includes the finding that mycological information was markedly improved in highly suspicious tinea pedis lesions regardless of the infection site (Table 1) by using 3 successive KOH tests; the percentage of lesions with 1, 2, or 3 positive KOH tests was 5.3%, 12.1%, and 47.0%, respectively (Table 2). A single physician from a single geographical location introduces a limitation to the study for a variety of reasons, including bias in the cases chosen and possible overrepresentation of the causative organism due to region-specific incidence. It is unknown how different causative organisms affect KOH results. The lack of fungal culture results limits the value of this information.

Conclusion

In this study, we investigated the benefit of successive KOH testing in the laboratory diagnosis of tinea pedis and found that the use of second samples in particular provided a substantial increase in diagnostic yield. In other words, the utilization of successive KOH testing remarkably improved the diagnosis of tinea pedis. Therefore, we suggest that at least 2 samples of skin scrapings should be taken for the diagnosis of tinea pedis and that the number of samples should be at least 3 for keratotic lesions. However, further study by using a gold-standard method such as a molecular-based assay as well as taking the samples in daily or weekly intervals is recommended to achieve a more reliable result.

Acknowledgment

The authors would like to thank Gökçen Şahin (Adana, Turkey) for providing technical support in direct microscopic examination.

The gold standard for diagnosing dermatophytosis is the use of direct microscopic examination together with fungal culture.¹ However, in the last 2 decades, molecular techniques that currently are available worldwide have improved the diagnosis procedure.^2,3 In the practice of dermatology, potassium hydroxide (KOH) testing is a commonly used method for the diagnosis of superficial fungal infections.⁴ The sensitivity and specificity of KOH testing in patients with tinea pedis have been reported as 73.3% and 42.5%, respectively.⁵ Repetition of this test after an initial negative test result is recommended if the clinical picture strongly suggests a fungal infection.^6,7 Alternatively, several repetitions of direct microscopic examinations also have been proposed for detecting other microorganisms. For example, 3 negative sputum smears traditionally are recommended to exclude a diagnosis of pulmonary tuberculosis.⁸ However, after numerous investigations in various regions of the world, the World Health Organization reduced the recommended number of these specimens from 3 to 2 in 2007.⁹

The literature suggests that successive mycological tests, both with direct microscopy and fungal cultures, improve the diagnosis of onychomycosis.^1,10,11 Therefore, if such investigations are increased in number, recommendations for successive mycological tests may be more reliable. In the current study, we aimed to investigate the value of successive KOH testing in the management of patients with clinically suspected tinea pedis.

Methods

Patients and Clinical Evaluation
One hundred thirty-five consecutive patients (63 male; 72 female) with clinical symptoms suggestive of intertriginous, vesiculobullous, and/or moccasin-type tinea pedis were enrolled in this prospective study. The mean age (SD) of patients was 45.9 (14.7) years (range, 11–77 years). Almost exclusively, the clinical symptoms suggestive of tinea pedis were desquamation or maceration in the toe webs, blistering lesions on the soles, and diffuse or patchy scaling or keratosis on the soles. A single dermatologist (B.F.K.) clinically evaluated the patients and found only 1 region showing different patterns suggestive of tinea pedis in 72 patients, 2 regions in 61 patients, and 3 regions in 2 patients. Therefore, 200 lesions from the 135 patients were chosen for the KOH test. The dermatologist recorded her level of suspicion for a fungal infection as low or high for each lesion, depending on the absence or presence of signs (eg, unilateral involvement, a well-defined border). None of the patients had used topical or systemic antifungal therapy for at least 1 month prior to the study.¹²

Clinical Sampling and Direct Microscopic Examination
The dermatologist took 3 samples of skin scrapings from each of the 200 lesions. All 3 samples from a given lesion were obtained from sites with the same clinical symptoms in a single session. Special attention was paid to samples from the active advancing borders of the lesions and the roofs of blisters if they were present.¹³ Upon completion of every 15 samples from every 5 lesions, the dermatologist randomized the order of the samples (https://www.random.org/). She then gave the samples, without the identities of the patients or any clinical information, to an experienced laboratory technician for direct microscopic examination. The technician prepared and examined the samples as described elsewhere^5,7,14 and recorded the results as positive if hyphal elements were present or negative if they were not. The study was reviewed and approved by the Çukurova University Faculty of Medicine Ethics Committee (Adana, Turkey). Informed consent was obtained from each patient or from his/her guardian(s) prior to initiating the study.

Statistical Analysis
Statistical analysis was conducted using the χ² test in the SPSS software version 20.0. McNemar test was used for analysis of the paired data.

Results

Among the 135 patients, lesions were suggestive of the intertriginous type of tinea pedis in 24 patients, moccasin type in 50 patients, and both intertriginous and moccasin type in 58 patients. Among the remaining 3 patients, 1 had lesions suggestive of the vesiculobullous type, and another patient had both the vesiculobullous and intertriginous types; the last patient demonstrated lesions that were inconsistent with any of these 3 subtypes of tinea pedis, and a well-defined eczematous plaque was observed on the dorsal surface of the patient’s left foot.

Among the 200 lesions from which skin scrapings were taken for KOH testing, 83 were in the toe webs, 110 were on the soles, and 7 were on the dorsal surfaces of the feet. Of these 7 dorsal lesions, 6 were extensions from lesions on the toe webs or soles and 1 was inconsistent with the 3 subtypes of tinea pedis. Among the 200 lesions, the main clinical symptom was maceration in 38 lesions, desquamation or scaling in 132 lesions, keratosis in 28 lesions, and blistering in 2 lesions. The dermatologist recorded the level of suspicion for tinea pedis as low in 68 lesions and high in 132.

According to the order in which the dermatologist took the 3 samples from each lesion, the KOH test was positive in 95 of the first set of 200 samples, 94 of the second set, and 86 of the third set; however, from the second set, the incremental yield (ie, the number of lesions in which the first KOH test was negative and the second was positive) was 10. The number of lesions in which the first and the second tests were negative and the third was positive was only 4. Therefore, the number of lesions with a positive KOH test was significantly increased from 95 to 105 by performing the second KOH test (P=.002). This number again increased from 105 to 109 when a third test was performed; however, this increase was not statistically significant (P=.125)(Table 1).

According to an evaluation that was not stratified by the dermatologist’s order of sampling, 72 lesions (36.0%) showed KOH test positivity in all 3 samples, 22 (11.0%) were positive in 2 samples, 15 (7.5%) were positive in only 1 sample, and 91 (45.5%) were positive in none of the samples (Table 2). When the data were subdivided based on the sites of the lesions, the toe web lesions (n=83) showed rates of 41.0%, 9.6%, and 4.8% for 3, 2, and 1 positive KOH tests, respectively. For the sole lesions (n=110), the rates were somewhat different at 31.8%, 11.8%, and 10.0%, respectively, but the difference was not statistically significant (P=.395).

For the subgroups based on the main clinical symptoms, the percentage of lesions having at least 1 positive KOH test from the 3 samples was 35.7% for the keratotic lesions (n=28). This rate was lower than macerated lesions (n=38) and desquamating or scaling lesions (n=132), which were 52.6% and 59.1%, respectively (Table 2). On the other hand, the percentage of lesions that produced only 1 or 2 positive KOH tests from the 3 samples was 25.0% for the keratotic lesions, which was higher than the rates for the macerated lesions and the desquamating or scaling lesions (13.1% and 18.9%, respectively). In particular, the difference between the keratotic lesions and the desquamating or scaling lesions in the distribution of the rates of 0, 1, 2, and 3 positive KOH tests was statistically significant (P=.019). The macerated, desquamating or scaling, keratotic, and blistering lesions are presented in the Figure.

Comment

In the current study, we aimed to investigate if successive KOH tests provide an incremental diagnostic yield in the management of patients with clinically suspected tinea pedis and if these results differ among the subgroups of patients. Both in the evaluation taking into account the order of sampling and in the evaluation disregarding this order, we found that the second sample was necessary for all subgroups, and even the third sample was necessary for patients with keratotic lesions. The main limitation of the study was that we lacked a gold-standard technique (eg, a molecular-based technique); therefore, we are unable to comment on the false-negative and false-positive results of the successive KOH testing.

Summerbell et al¹¹ found in their study that in initial specimens of toenails with apparent lesions taken from 473 patients, the KOH test was 73.8% sensitive for dermatophytes, and this rate was only somewhat higher for cultures (74.6%). Arabatzis et al² investigated 92 skin, nail, and hair specimens from 67 patients with suspected dermatophytosis and found that the KOH test was superior to culture for the detection of dermatophytes (43% vs 33%). Moreover and more importantly, they noted that a real-time polymerase chain reaction (PCR) assay yielded a higher detection rate (51%).² In another study, Wisselink et al³ examined 1437 clinical samples and demonstrated a great increase in the detection of dermatophytes using a real-time PCR assay (48.5%) compared to culture (26.9%). However, PCR may not reflect active disease and could lead to false-positive results.^2,3 Therefore, the aforementioned weakness of our study will be overcome in further studies investigating the benefit of successive KOH testing compared to a molecular-based assay, such as the real-time PCR assay.

In this study, repeating the KOH test provided better results for achieving the diagnosis of tinea pedis in a large number of samples from clinically suspected lesions. Additionally, the distribution of 3, 2, or 1 positive results on the 3 KOH tests was different among the subgroups of lesions. Overall, positivity was less frequent in the keratotic lesions compared to the macerated or desquamating or scaling lesions. Moreover, positivity on all 3 tests also was less frequent in the keratotic lesions. Inversely, the frequency of samples with only 1 or 2 positive results was higher in this subgroup. The necessity for the second, even the third, tests was greater in this subgroup.

Our findings were consistent with the results of the studies performed with successive mycological tests on the nail specimens. Meireles et al¹ repeated 156 mycological nail tests 3 times and found the rate of positivity in the first test to be 19.9%. When the results of the first and second tests were combined, this rate increased to 28.2%, and when the results of all 3 tests were combined, it increased to 37.8%.¹ Gupta¹⁰ demonstrated that even a fourth culture provided an incremental diagnostic yield in the diagnosis of onychomycosis, yet 4 cultures may not be clinically practical. Furthermore, periodic acid–Schiff staining is a more effective measure of positivity in onychomycosis.¹⁵

Although the overall rate of positivity on the 3 tests in our study was unsurprisingly higher in lesions rated highly suspicious for a fungal infection, the rate of only 1 or 2 positive tests was surprisingly somewhat higher in low-suspicion lesions, which suggested that repeating the KOH test would be beneficial, even if the clinical suspicion for tinea pedis was low. The novel contribution of this study includes the finding that mycological information was markedly improved in highly suspicious tinea pedis lesions regardless of the infection site (Table 1) by using 3 successive KOH tests; the percentage of lesions with 1, 2, or 3 positive KOH tests was 5.3%, 12.1%, and 47.0%, respectively (Table 2). A single physician from a single geographical location introduces a limitation to the study for a variety of reasons, including bias in the cases chosen and possible overrepresentation of the causative organism due to region-specific incidence. It is unknown how different causative organisms affect KOH results. The lack of fungal culture results limits the value of this information.

Conclusion

In this study, we investigated the benefit of successive KOH testing in the laboratory diagnosis of tinea pedis and found that the use of second samples in particular provided a substantial increase in diagnostic yield. In other words, the utilization of successive KOH testing remarkably improved the diagnosis of tinea pedis. Therefore, we suggest that at least 2 samples of skin scrapings should be taken for the diagnosis of tinea pedis and that the number of samples should be at least 3 for keratotic lesions. However, further study by using a gold-standard method such as a molecular-based assay as well as taking the samples in daily or weekly intervals is recommended to achieve a more reliable result.

Acknowledgment

The authors would like to thank Gökçen Şahin (Adana, Turkey) for providing technical support in direct microscopic examination.

The gold standard for diagnosing dermatophytosis is the use of direct microscopic examination together with fungal culture.¹ However, in the last 2 decades, molecular techniques that currently are available worldwide have improved the diagnosis procedure.^2,3 In the practice of dermatology, potassium hydroxide (KOH) testing is a commonly used method for the diagnosis of superficial fungal infections.⁴ The sensitivity and specificity of KOH testing in patients with tinea pedis have been reported as 73.3% and 42.5%, respectively.⁵ Repetition of this test after an initial negative test result is recommended if the clinical picture strongly suggests a fungal infection.^6,7 Alternatively, several repetitions of direct microscopic examinations also have been proposed for detecting other microorganisms. For example, 3 negative sputum smears traditionally are recommended to exclude a diagnosis of pulmonary tuberculosis.⁸ However, after numerous investigations in various regions of the world, the World Health Organization reduced the recommended number of these specimens from 3 to 2 in 2007.⁹

The literature suggests that successive mycological tests, both with direct microscopy and fungal cultures, improve the diagnosis of onychomycosis.^1,10,11 Therefore, if such investigations are increased in number, recommendations for successive mycological tests may be more reliable. In the current study, we aimed to investigate the value of successive KOH testing in the management of patients with clinically suspected tinea pedis.

Methods

Patients and Clinical Evaluation
One hundred thirty-five consecutive patients (63 male; 72 female) with clinical symptoms suggestive of intertriginous, vesiculobullous, and/or moccasin-type tinea pedis were enrolled in this prospective study. The mean age (SD) of patients was 45.9 (14.7) years (range, 11–77 years). Almost exclusively, the clinical symptoms suggestive of tinea pedis were desquamation or maceration in the toe webs, blistering lesions on the soles, and diffuse or patchy scaling or keratosis on the soles. A single dermatologist (B.F.K.) clinically evaluated the patients and found only 1 region showing different patterns suggestive of tinea pedis in 72 patients, 2 regions in 61 patients, and 3 regions in 2 patients. Therefore, 200 lesions from the 135 patients were chosen for the KOH test. The dermatologist recorded her level of suspicion for a fungal infection as low or high for each lesion, depending on the absence or presence of signs (eg, unilateral involvement, a well-defined border). None of the patients had used topical or systemic antifungal therapy for at least 1 month prior to the study.¹²

Clinical Sampling and Direct Microscopic Examination
The dermatologist took 3 samples of skin scrapings from each of the 200 lesions. All 3 samples from a given lesion were obtained from sites with the same clinical symptoms in a single session. Special attention was paid to samples from the active advancing borders of the lesions and the roofs of blisters if they were present.¹³ Upon completion of every 15 samples from every 5 lesions, the dermatologist randomized the order of the samples (https://www.random.org/). She then gave the samples, without the identities of the patients or any clinical information, to an experienced laboratory technician for direct microscopic examination. The technician prepared and examined the samples as described elsewhere^5,7,14 and recorded the results as positive if hyphal elements were present or negative if they were not. The study was reviewed and approved by the Çukurova University Faculty of Medicine Ethics Committee (Adana, Turkey). Informed consent was obtained from each patient or from his/her guardian(s) prior to initiating the study.

Statistical Analysis
Statistical analysis was conducted using the χ² test in the SPSS software version 20.0. McNemar test was used for analysis of the paired data.

Results

Among the 135 patients, lesions were suggestive of the intertriginous type of tinea pedis in 24 patients, moccasin type in 50 patients, and both intertriginous and moccasin type in 58 patients. Among the remaining 3 patients, 1 had lesions suggestive of the vesiculobullous type, and another patient had both the vesiculobullous and intertriginous types; the last patient demonstrated lesions that were inconsistent with any of these 3 subtypes of tinea pedis, and a well-defined eczematous plaque was observed on the dorsal surface of the patient’s left foot.

Among the 200 lesions from which skin scrapings were taken for KOH testing, 83 were in the toe webs, 110 were on the soles, and 7 were on the dorsal surfaces of the feet. Of these 7 dorsal lesions, 6 were extensions from lesions on the toe webs or soles and 1 was inconsistent with the 3 subtypes of tinea pedis. Among the 200 lesions, the main clinical symptom was maceration in 38 lesions, desquamation or scaling in 132 lesions, keratosis in 28 lesions, and blistering in 2 lesions. The dermatologist recorded the level of suspicion for tinea pedis as low in 68 lesions and high in 132.

According to the order in which the dermatologist took the 3 samples from each lesion, the KOH test was positive in 95 of the first set of 200 samples, 94 of the second set, and 86 of the third set; however, from the second set, the incremental yield (ie, the number of lesions in which the first KOH test was negative and the second was positive) was 10. The number of lesions in which the first and the second tests were negative and the third was positive was only 4. Therefore, the number of lesions with a positive KOH test was significantly increased from 95 to 105 by performing the second KOH test (P=.002). This number again increased from 105 to 109 when a third test was performed; however, this increase was not statistically significant (P=.125)(Table 1).

According to an evaluation that was not stratified by the dermatologist’s order of sampling, 72 lesions (36.0%) showed KOH test positivity in all 3 samples, 22 (11.0%) were positive in 2 samples, 15 (7.5%) were positive in only 1 sample, and 91 (45.5%) were positive in none of the samples (Table 2). When the data were subdivided based on the sites of the lesions, the toe web lesions (n=83) showed rates of 41.0%, 9.6%, and 4.8% for 3, 2, and 1 positive KOH tests, respectively. For the sole lesions (n=110), the rates were somewhat different at 31.8%, 11.8%, and 10.0%, respectively, but the difference was not statistically significant (P=.395).

For the subgroups based on the main clinical symptoms, the percentage of lesions having at least 1 positive KOH test from the 3 samples was 35.7% for the keratotic lesions (n=28). This rate was lower than macerated lesions (n=38) and desquamating or scaling lesions (n=132), which were 52.6% and 59.1%, respectively (Table 2). On the other hand, the percentage of lesions that produced only 1 or 2 positive KOH tests from the 3 samples was 25.0% for the keratotic lesions, which was higher than the rates for the macerated lesions and the desquamating or scaling lesions (13.1% and 18.9%, respectively). In particular, the difference between the keratotic lesions and the desquamating or scaling lesions in the distribution of the rates of 0, 1, 2, and 3 positive KOH tests was statistically significant (P=.019). The macerated, desquamating or scaling, keratotic, and blistering lesions are presented in the Figure.

Comment

In the current study, we aimed to investigate if successive KOH tests provide an incremental diagnostic yield in the management of patients with clinically suspected tinea pedis and if these results differ among the subgroups of patients. Both in the evaluation taking into account the order of sampling and in the evaluation disregarding this order, we found that the second sample was necessary for all subgroups, and even the third sample was necessary for patients with keratotic lesions. The main limitation of the study was that we lacked a gold-standard technique (eg, a molecular-based technique); therefore, we are unable to comment on the false-negative and false-positive results of the successive KOH testing.

Summerbell et al¹¹ found in their study that in initial specimens of toenails with apparent lesions taken from 473 patients, the KOH test was 73.8% sensitive for dermatophytes, and this rate was only somewhat higher for cultures (74.6%). Arabatzis et al² investigated 92 skin, nail, and hair specimens from 67 patients with suspected dermatophytosis and found that the KOH test was superior to culture for the detection of dermatophytes (43% vs 33%). Moreover and more importantly, they noted that a real-time polymerase chain reaction (PCR) assay yielded a higher detection rate (51%).² In another study, Wisselink et al³ examined 1437 clinical samples and demonstrated a great increase in the detection of dermatophytes using a real-time PCR assay (48.5%) compared to culture (26.9%). However, PCR may not reflect active disease and could lead to false-positive results.^2,3 Therefore, the aforementioned weakness of our study will be overcome in further studies investigating the benefit of successive KOH testing compared to a molecular-based assay, such as the real-time PCR assay.

In this study, repeating the KOH test provided better results for achieving the diagnosis of tinea pedis in a large number of samples from clinically suspected lesions. Additionally, the distribution of 3, 2, or 1 positive results on the 3 KOH tests was different among the subgroups of lesions. Overall, positivity was less frequent in the keratotic lesions compared to the macerated or desquamating or scaling lesions. Moreover, positivity on all 3 tests also was less frequent in the keratotic lesions. Inversely, the frequency of samples with only 1 or 2 positive results was higher in this subgroup. The necessity for the second, even the third, tests was greater in this subgroup.

Our findings were consistent with the results of the studies performed with successive mycological tests on the nail specimens. Meireles et al¹ repeated 156 mycological nail tests 3 times and found the rate of positivity in the first test to be 19.9%. When the results of the first and second tests were combined, this rate increased to 28.2%, and when the results of all 3 tests were combined, it increased to 37.8%.¹ Gupta¹⁰ demonstrated that even a fourth culture provided an incremental diagnostic yield in the diagnosis of onychomycosis, yet 4 cultures may not be clinically practical. Furthermore, periodic acid–Schiff staining is a more effective measure of positivity in onychomycosis.¹⁵

Although the overall rate of positivity on the 3 tests in our study was unsurprisingly higher in lesions rated highly suspicious for a fungal infection, the rate of only 1 or 2 positive tests was surprisingly somewhat higher in low-suspicion lesions, which suggested that repeating the KOH test would be beneficial, even if the clinical suspicion for tinea pedis was low. The novel contribution of this study includes the finding that mycological information was markedly improved in highly suspicious tinea pedis lesions regardless of the infection site (Table 1) by using 3 successive KOH tests; the percentage of lesions with 1, 2, or 3 positive KOH tests was 5.3%, 12.1%, and 47.0%, respectively (Table 2). A single physician from a single geographical location introduces a limitation to the study for a variety of reasons, including bias in the cases chosen and possible overrepresentation of the causative organism due to region-specific incidence. It is unknown how different causative organisms affect KOH results. The lack of fungal culture results limits the value of this information.

Conclusion

In this study, we investigated the benefit of successive KOH testing in the laboratory diagnosis of tinea pedis and found that the use of second samples in particular provided a substantial increase in diagnostic yield. In other words, the utilization of successive KOH testing remarkably improved the diagnosis of tinea pedis. Therefore, we suggest that at least 2 samples of skin scrapings should be taken for the diagnosis of tinea pedis and that the number of samples should be at least 3 for keratotic lesions. However, further study by using a gold-standard method such as a molecular-based assay as well as taking the samples in daily or weekly intervals is recommended to achieve a more reliable result.

Acknowledgment

The authors would like to thank Gökçen Şahin (Adana, Turkey) for providing technical support in direct microscopic examination.