Emergency Medicine

A 6-year-old girl was brought to a pediatric emergency department (ED) in Atlanta by her mother. The mother stated that during the previous hour, she had noticed that her daughter’s face seemed weaker on the right side.

The night before, the child had said, “I can’t blink my eye”; when her mother asked her to demonstrate, the child seemed to be able to blink both eyes appropriately, and she had no further complaints. The next morning, the child complained of the light being too bright and asked to wear her mother’s sunglasses. In the course of the day, she continued to complain of eye discomfort, which she described as “stinging” and “sore.” The mother could see nothing abnormal, but by late afternoon noticed that her daughter’s smile and facial movements were asymmetrical. She immediately took her to the pediatric ED.

The child had no significant medical history and no surgical history. Her vaccination schedule was current, and she denied any recent illnesses. The mother could recall no exposures to infections or tick bites, no rashes, and no trauma to the face or head. The mother and child were visiting Atlanta from northeastern Florida.

The review of systems was negative for headache, fever, chills, rash, earache, sore throat, cough, rhinorrhea, vision changes, weight loss, or change in appetite or disposition. The child was afebrile, and the other vital signs were within normal limits. 

Physical examination revealed an alert child who was calm and conversant. Her height was 45” and weight, 43 lb. Otoscopic exam showed normal ears and tympanic membranes with no sign of otitis media or ear pathology. No throat redness, tonsillar enlargement, or lymphadenopathies were noted. Breath sounds were clear, and heart rhythm and rate were regular without murmur. 

The patient’s left eye appeared normal, and the right eye was mildly erythematic without drainage or swelling; since corneal abrasion was not suspected, a slit lamp examination was not performed. Upon neurologic examination, right eye ptosis with incomplete lid closure, asymmetrical mouth movement with smile, and a diminished nasal labial fold crease were noted on the right side. When the child was asked to raise her eyebrows and wrinkle her forehead, asymmetrical forehead creases were apparent. All other cranial nerve functions were intact, and motor and sensory responses, including gait and reflexes, were assessed as normal. Unilateral dysfunction of right-sided cranial nerve VII (CN VII), including forehead involvement, was confirmed, consistent with a grade of III to IV on the House-Brackmann (maximum, VI)^1,2 facial nerve grading scale.

Based on the rapid onset of unilateral facial nerve paresis (FNP) and an otherwise normal exam, the patient was diagnosed with Bell’s palsy. No further testing was done, and the child was given a dose of oral prednisolone 40 mg in the ED, with a prescription for four more days of oral prednisolone at 15 mg bid. The need for eye protection and lubrication was emphasized to the mother, who was given lubricating eye drops to administer. The mother was also instructed to follow up with the child’s primary care practitioner upon their return to Florida. 

The child was seen by her pediatrician three days later. Her facial paresis had not worsened in the interim, and the pediatrician declined to extend the course of corticosteroids or to add an antiviral medication. At the mother’s request, the child was referred to a pediatric otolaryngologist, who saw her the following day and adjusted the treatment plan. The child was prescribed prednisolone elixir 20 mg bid for one week, followed by a tapering dose for the second week. In addition, she was prescribed oral acyclovir 400 mg qid for 10 days. Her mother was instructed to return with the child in one week for audiometry testing.  

Discussion
Idiopathic FNP, commonly referred to as Bell’s palsy, is defined as an acute unilateral paresis of the facial nerve without detectable underlying cause.^3,4 It most commonly occurs among persons ages 15 to 45, with a prevalence rate of 15 to 30 cases per 100,000 persons. The peak incidence of Bell’s palsy is in the fourth decade of life. Diabetic patients and pregnant women are disproportionately affected by idiopathic FNP.^2,5 About 8% to 10% of patients will experience a recurrence of Bell’s palsy within 10 years.^2,6

Pediatric FNP can be congenital or acquired. Congenital FNP is most often associated with birth trauma and occurs at a rate of 2.1 cases per 1,000 births. Rare genetic syndromes can also manifest with FNP and will most often present with other syndromic anomalies noted at birth.⁷

Acquired FNP is two to four times less common in children than adults, with an estimated prevalence of 2.7 per 100,000 patients younger than 10. Children account for only a small proportion of subjects in published studies that address diagnosis and management of FNP.³ While the presentation of FNP is much the same in adults and children, some notable differences in etiology exist.^2,3,7-9 Infectious, traumatic, or neoplastic causes of FNP are more common among children than adults and must be distinguished from idiopathic FNP.^7,9-11

Decisions regarding diagnostic testing, pharmacologic treatment, and referral must be guided by the history and physical exam, neurologic exam, and clinical judgment. Being able to identify or exclude alarming causes of FNP, such as neoplasm, will aid the primary care practitioner in treatment and referral practices for this condition.

Pathophysiology
CN VII, the facial nerve, has a broad scope of function that incorporates both sensory and motor pathways. The brachial nerve portion of CN VII controls the muscles of voluntary facial expression. CN VII also autonomically innervates the lacrimal gland and submandibular gland and governs sensation from part of the ear as well as taste from the anterior two-thirds of the tongue.⁴

The precise pathophysiology involved in FNP remains an area of continuing debate, but infectious, vascular, immunologic, and genetic causes have been hypothesized.^7,12 Inflammation and subsequent nerve damage along CN VII caused by an infectious process is thought to be the most likely explanation for the pathogenesis of acquired FNP in both adults and children.^5,13

Herpes simplex virus 1 (HSV-1) has been suggested as the virus most commonly linked to FNP in both adults and children, but it is unlikely to be the sole cause.^5,6,9 Data from a three-year prospective study of FNP cases in children support a relationship between pediatric FNP and HSV-1 infection.¹⁴ Other infectious causes implicated in pediatric FNP are Lyme disease, Epstein-Barr, varicella zoster virus, rubella, coxsackie virus, adenovirus, and otitis media.^4,7,9

Presentation, History, and Physical Exam
Most children with idiopathic FNP will present with sudden-onset facial asymmetry and may have decreased tearing, loss of the conjunctival reflex (leading to difficulty closing the eye), an inability to hold the lips tightly together, and difficulty keeping food in the mouth. Complaints of otalgia, speech disturbances, hyperacusis, and altered sense of taste are common.^2,7 Recent occurrence of an upper respiratory infection is often reported in the history of a pediatric patient with FNP.^3,7,15,16

Idiopathic FNP is essentially a diagnosis of exclusion.^3,5 A meticulous history must be conducted, including any recent illnesses, trauma to the face or head, vaccines, rashes, and travel. Assessment of the head, eyes, ears, nose, and throat, and a careful neurologic history must be conducted to identify nonidiopathic causes of FNP (see Table 1^5-7,9). Facial weakness can progress from mild palsy to complete paralysis over one to two weeks⁵; therefore, a careful history of the progression of facial weakness should be ascertained and documented.^5,17 

A full neurologic exam is essential. Cranial nerves I through XII should be evaluated; any malfunction of a cranial nerve other than CN VII could be indicative of a tumor or process other than idiopathic FNP. Assessment of facial nerve function is imperative, as this factor is the most important for predicting recovery; it can also aid in formulating a prognosis and directing treatment.^5,9,17

The House-Brackmann facial nerve grading system^1,2 is considered the gold standard for grading severity of facial paresis⁹ (see Table 2^1,2 ). A clear distinction between paresis (partial or incomplete palsy) and paralysis (complete palsy) must be made. Pediatric patients with an incomplete palsy have an improved chance of full recovery.^17,18

Any abnormalities in the peripheral neurologic exam should prompt further testing. FNP not involving the forehead musculature, gradual progression of paresis, and weakness in any extremity could be indicative of a central lesion. FNP has been the presenting symptom in various neoplastic processes, including leukemia, cholesteatoma, and astrocytoma.^3,7,9

Otitis media is a frequent cause of FNP among children.^9-11 Thus, a thorough examination of the ear canal, tympanic membrane, and hearing should be performed. The throat and oropharynx should be inspected, and the parotid gland palpated. Any swelling or abnormalities warrant further investigation.

Lyme disease presenting with FNP is more common in children than adults. This may be related to the increased likelihood for children to be bitten by ticks in the head and neck areas. Frequently, FNP associated with Lyme disease is bilateral—as often as 25% of the time.¹⁹ Headache, onset of symptoms during peak Lyme season, or bilateral FNP should raise the clinician’s suspicion for Lyme disease.^7,9,19

An accurate assessment of blood pressure is essential, as severe hypertension may be implicated in FNP in children.^3,5,7 One literature review reported that hypertension was the origin of FNP in 3% to 17% of affected children.²⁰ Vascular hemorrhage induced by hypertension is thought to cause nerve compression and subsequent FNP.⁷

A bilateral eye exam is also important. Irritation is likely, and the patient with any suspected corneal abrasion or damage should be referred to an ophthalmologist.^6,18

Laboratory Testing and Imaging
Diagnostic testing that facilitates the exclusion of known causes of FNP should be considered, as there is no specific laboratory test to confirm the diagnosis. A complete blood count, Lyme titers, cerebrospinal fluid analysis, CT, and/or MRI may be warranted, based on the clinical presentation.^7-9 In children in whom Lyme disease is suspected (ie, those living in tick-endemic areas or with recent tick bites), serologic testing should be performed. Lumbar puncture and an evaluation of cerebrospinal fluid may be necessary in cases in which meningitis cannot be excluded.^7,9

Specialized diagnostic tests are not routinely recommended for patients with paresis that is improving. Audiometry and evaluation of the stapedial reflex may help guide treatment decisions for patients whose condition is not improving. In children, the presence or return of the stapedial reflex within three weeks of disease onset is predictive of complete recovery.⁵ In patients who experience complete paralysis or unimproved paresis, results of electrodiagnostic testing (in particular, evoked facial nerve electroneuronography) can help forecast recovery of facial nerve function.^5,17

Treatment and Management
Treatment for FNP in adults is controversial, and even more so for the pediatric patient. Treatment decisions consist of eye care, corticosteroids, antiviral medications, and appropriate referrals.

Eye care. Eye lubrication and protection should be implemented immediately. Protecting the cornea is paramount; thorough lubrication of the eye is the mainstay of treatment.¹⁸ Artificial tears should be used frequently during the day, and an ointment should be applied to the eye at night. Use of eye patches is controversial, as they may actually cause corneal injury.^7,9 Taping the eye shut at night may prevent trauma during sleep, but this option must be considered carefully.^9,18

Corticosteroids. Early initiation of corticosteroids should be considered for all patients with FNP, including children.^2,7,9,17 Studies are inconclusive as to whether steroid therapy is beneficial in children with idiopathic FNP. However, two 2010 reviews of pediatric FNP recommend early initiation of steroids for children with acute-onset FNP, particularly when facial paresis is evaluated at a House-Brackmann grade V or VI.^7,9 The American Academy of Family Physicians (AAFP) recommends a tapering course of prednisone for all patients, begun as soon as possible.⁶ The prednisone dosage for pediatric patients is usually 1.0 mg/kg/d, split into two doses, for six days, followed by a tapering dose for four days.⁵

Antivirals and antibiotic therapy. When an infectious cause of FNP is known, appropriate antibiotic or antiviral therapy should begin. If the patient lives in or has traveled to an area endemic for Lyme disease, empiric treatment may be appropriate. When Ramsay Hunt syndrome is diagnosed or herpetic lesions are visible, antiviral treatment should be initiated.⁷

Antiviral therapy for idiopathic FNP is the most controversial of the treatment decisions. In 2001, the American Academy of Neurology concluded that no clear benefit from acyclovir could be ascertained, although it might be effective.¹³ This was affirmed in a recently updated Cochrane review of antiviral therapy for idiopathic FNP.¹² Antiviral therapy alone showed no benefit, compared with placebo; however, combined antiviral and corticosteroid therapy was more effective than placebo alone in recovery outcomes. Antivirals may benefit pediatric patients and should be considered early when the cause of FNP is viral or idiopathic.^7,9

Referrals. Initial presentation and course of paresis should guide referral patterns for the pediatric patient presenting with FNP. The American Academy of Pediatrics (AAP) recommends referral to an otolaryngologist for any infant or child with FNP.²¹ The AAFP recommends referral to a specialist for any patient who does not show improvement within two weeks.⁶

In patients with complete paralysis, early surgical intervention may be considered, and referral should be made promptly for electrodiagnostic testing and surgical consult. In cases in which otitis media causes FNP, myringotomy and tube insertion are indicated, and appropriate referral should be made.^7,9

Outcomes
|The prognosis in children with FNP is good, and most will recover completely.^2,9-11,22 Idiopathic and infectious etiologies of FNP seem to have the greatest likelihood for complete recovery.^10,11,16,17 Recovery appears to be affected by etiology, degree of paresis, and treatment. How these factors coalesce is not fully understood, and up to 20% of children may have mild to moderate residual facial nerve dysfunction.^10,11,19,22

The Case Patient
The child’s facial nerve function gradually returned over a three-week period, with no residual deficit (see Figures 1a, 1b, and 1c). Results of the audiometry screening on day 10 were normal, showing a positive stapedial reflex. An MRI, performed four months after the initial paralysis to rule out any tumors, yielded normal results. 

This case highlights the differing management of pediatric Bell’s palsy among emergency, pediatric, and specialized providers. This child was managed more aggressively under the care of an otolaryngologist with a two-week course of steroids, antiviral medication for 10 days, and a follow-up MRI to rule out any evidence of a tumor. The need for further research to guide practice in the pediatric patient with Bell’s palsy is apparent.

Conclusion
FNP in the pediatric population is rare and more likely to have an identifiable cause than among adults. Careful examination should reveal differential diagnoses that warrant treatment and referrals. The main causes of FNP that should not be missed are otitis media, hypertension, varicella zoster virus (Ramsay Hunt syndrome), neoplastic processes, and Lyme disease.

Practitioners should have a high index of suspicion for nonidiopathic causes of FNP when a child has a neurologic exam that includes facial paresis of gradual onset, abnormal function of other cranial nerves, lack of forehead muscle weakness, or peripheral abnormalities. In addition to the history and exam, blood work and radiologic imaging can aid the practitioner in ruling in or out nonidiopathic causes of FNP. 

Grading of facial palsy severity using the House-Brackmann scale helps guide prognosis and referral choices. Referral to a specialist in otolaryngology is appropriate and recommended by the AAP. Referral should be made to an ophthalmologist if any suspicion of corneal abrasion exists. 

Treatment in children should consist of eye care and steroids. Antiviral therapy should be considered on an individualized basis and when evidence of HSV or varicella exists. Parents should be advised about the importance of eye care in a child with FNP (see Table 3^{5-7,9,17,18,22}).

The emotional stress associated with FNP can be significant for both children and adults; fear of lifelong facial deformity can be psychologically debilitating. Yet a favorable prognosis for recovery of facial nerve function can be relayed to anxious parents.

A 6-year-old girl was brought to a pediatric emergency department (ED) in Atlanta by her mother. The mother stated that during the previous hour, she had noticed that her daughter’s face seemed weaker on the right side.

The night before, the child had said, “I can’t blink my eye”; when her mother asked her to demonstrate, the child seemed to be able to blink both eyes appropriately, and she had no further complaints. The next morning, the child complained of the light being too bright and asked to wear her mother’s sunglasses. In the course of the day, she continued to complain of eye discomfort, which she described as “stinging” and “sore.” The mother could see nothing abnormal, but by late afternoon noticed that her daughter’s smile and facial movements were asymmetrical. She immediately took her to the pediatric ED.

The child had no significant medical history and no surgical history. Her vaccination schedule was current, and she denied any recent illnesses. The mother could recall no exposures to infections or tick bites, no rashes, and no trauma to the face or head. The mother and child were visiting Atlanta from northeastern Florida.

The review of systems was negative for headache, fever, chills, rash, earache, sore throat, cough, rhinorrhea, vision changes, weight loss, or change in appetite or disposition. The child was afebrile, and the other vital signs were within normal limits. 

Physical examination revealed an alert child who was calm and conversant. Her height was 45” and weight, 43 lb. Otoscopic exam showed normal ears and tympanic membranes with no sign of otitis media or ear pathology. No throat redness, tonsillar enlargement, or lymphadenopathies were noted. Breath sounds were clear, and heart rhythm and rate were regular without murmur. 

The patient’s left eye appeared normal, and the right eye was mildly erythematic without drainage or swelling; since corneal abrasion was not suspected, a slit lamp examination was not performed. Upon neurologic examination, right eye ptosis with incomplete lid closure, asymmetrical mouth movement with smile, and a diminished nasal labial fold crease were noted on the right side. When the child was asked to raise her eyebrows and wrinkle her forehead, asymmetrical forehead creases were apparent. All other cranial nerve functions were intact, and motor and sensory responses, including gait and reflexes, were assessed as normal. Unilateral dysfunction of right-sided cranial nerve VII (CN VII), including forehead involvement, was confirmed, consistent with a grade of III to IV on the House-Brackmann (maximum, VI)^1,2 facial nerve grading scale.

Based on the rapid onset of unilateral facial nerve paresis (FNP) and an otherwise normal exam, the patient was diagnosed with Bell’s palsy. No further testing was done, and the child was given a dose of oral prednisolone 40 mg in the ED, with a prescription for four more days of oral prednisolone at 15 mg bid. The need for eye protection and lubrication was emphasized to the mother, who was given lubricating eye drops to administer. The mother was also instructed to follow up with the child’s primary care practitioner upon their return to Florida. 

The child was seen by her pediatrician three days later. Her facial paresis had not worsened in the interim, and the pediatrician declined to extend the course of corticosteroids or to add an antiviral medication. At the mother’s request, the child was referred to a pediatric otolaryngologist, who saw her the following day and adjusted the treatment plan. The child was prescribed prednisolone elixir 20 mg bid for one week, followed by a tapering dose for the second week. In addition, she was prescribed oral acyclovir 400 mg qid for 10 days. Her mother was instructed to return with the child in one week for audiometry testing.  

Discussion
Idiopathic FNP, commonly referred to as Bell’s palsy, is defined as an acute unilateral paresis of the facial nerve without detectable underlying cause.^3,4 It most commonly occurs among persons ages 15 to 45, with a prevalence rate of 15 to 30 cases per 100,000 persons. The peak incidence of Bell’s palsy is in the fourth decade of life. Diabetic patients and pregnant women are disproportionately affected by idiopathic FNP.^2,5 About 8% to 10% of patients will experience a recurrence of Bell’s palsy within 10 years.^2,6

Pediatric FNP can be congenital or acquired. Congenital FNP is most often associated with birth trauma and occurs at a rate of 2.1 cases per 1,000 births. Rare genetic syndromes can also manifest with FNP and will most often present with other syndromic anomalies noted at birth.⁷

Acquired FNP is two to four times less common in children than adults, with an estimated prevalence of 2.7 per 100,000 patients younger than 10. Children account for only a small proportion of subjects in published studies that address diagnosis and management of FNP.³ While the presentation of FNP is much the same in adults and children, some notable differences in etiology exist.^2,3,7-9 Infectious, traumatic, or neoplastic causes of FNP are more common among children than adults and must be distinguished from idiopathic FNP.^7,9-11

Decisions regarding diagnostic testing, pharmacologic treatment, and referral must be guided by the history and physical exam, neurologic exam, and clinical judgment. Being able to identify or exclude alarming causes of FNP, such as neoplasm, will aid the primary care practitioner in treatment and referral practices for this condition.

Pathophysiology
CN VII, the facial nerve, has a broad scope of function that incorporates both sensory and motor pathways. The brachial nerve portion of CN VII controls the muscles of voluntary facial expression. CN VII also autonomically innervates the lacrimal gland and submandibular gland and governs sensation from part of the ear as well as taste from the anterior two-thirds of the tongue.⁴

The precise pathophysiology involved in FNP remains an area of continuing debate, but infectious, vascular, immunologic, and genetic causes have been hypothesized.^7,12 Inflammation and subsequent nerve damage along CN VII caused by an infectious process is thought to be the most likely explanation for the pathogenesis of acquired FNP in both adults and children.^5,13

Herpes simplex virus 1 (HSV-1) has been suggested as the virus most commonly linked to FNP in both adults and children, but it is unlikely to be the sole cause.^5,6,9 Data from a three-year prospective study of FNP cases in children support a relationship between pediatric FNP and HSV-1 infection.¹⁴ Other infectious causes implicated in pediatric FNP are Lyme disease, Epstein-Barr, varicella zoster virus, rubella, coxsackie virus, adenovirus, and otitis media.^4,7,9

Presentation, History, and Physical Exam
Most children with idiopathic FNP will present with sudden-onset facial asymmetry and may have decreased tearing, loss of the conjunctival reflex (leading to difficulty closing the eye), an inability to hold the lips tightly together, and difficulty keeping food in the mouth. Complaints of otalgia, speech disturbances, hyperacusis, and altered sense of taste are common.^2,7 Recent occurrence of an upper respiratory infection is often reported in the history of a pediatric patient with FNP.^3,7,15,16

Idiopathic FNP is essentially a diagnosis of exclusion.^3,5 A meticulous history must be conducted, including any recent illnesses, trauma to the face or head, vaccines, rashes, and travel. Assessment of the head, eyes, ears, nose, and throat, and a careful neurologic history must be conducted to identify nonidiopathic causes of FNP (see Table 1^5-7,9). Facial weakness can progress from mild palsy to complete paralysis over one to two weeks⁵; therefore, a careful history of the progression of facial weakness should be ascertained and documented.^5,17 

A full neurologic exam is essential. Cranial nerves I through XII should be evaluated; any malfunction of a cranial nerve other than CN VII could be indicative of a tumor or process other than idiopathic FNP. Assessment of facial nerve function is imperative, as this factor is the most important for predicting recovery; it can also aid in formulating a prognosis and directing treatment.^5,9,17

The House-Brackmann facial nerve grading system^1,2 is considered the gold standard for grading severity of facial paresis⁹ (see Table 2^1,2 ). A clear distinction between paresis (partial or incomplete palsy) and paralysis (complete palsy) must be made. Pediatric patients with an incomplete palsy have an improved chance of full recovery.^17,18

Any abnormalities in the peripheral neurologic exam should prompt further testing. FNP not involving the forehead musculature, gradual progression of paresis, and weakness in any extremity could be indicative of a central lesion. FNP has been the presenting symptom in various neoplastic processes, including leukemia, cholesteatoma, and astrocytoma.^3,7,9

Otitis media is a frequent cause of FNP among children.^9-11 Thus, a thorough examination of the ear canal, tympanic membrane, and hearing should be performed. The throat and oropharynx should be inspected, and the parotid gland palpated. Any swelling or abnormalities warrant further investigation.

Lyme disease presenting with FNP is more common in children than adults. This may be related to the increased likelihood for children to be bitten by ticks in the head and neck areas. Frequently, FNP associated with Lyme disease is bilateral—as often as 25% of the time.¹⁹ Headache, onset of symptoms during peak Lyme season, or bilateral FNP should raise the clinician’s suspicion for Lyme disease.^7,9,19

An accurate assessment of blood pressure is essential, as severe hypertension may be implicated in FNP in children.^3,5,7 One literature review reported that hypertension was the origin of FNP in 3% to 17% of affected children.²⁰ Vascular hemorrhage induced by hypertension is thought to cause nerve compression and subsequent FNP.⁷

A bilateral eye exam is also important. Irritation is likely, and the patient with any suspected corneal abrasion or damage should be referred to an ophthalmologist.^6,18

Laboratory Testing and Imaging
Diagnostic testing that facilitates the exclusion of known causes of FNP should be considered, as there is no specific laboratory test to confirm the diagnosis. A complete blood count, Lyme titers, cerebrospinal fluid analysis, CT, and/or MRI may be warranted, based on the clinical presentation.^7-9 In children in whom Lyme disease is suspected (ie, those living in tick-endemic areas or with recent tick bites), serologic testing should be performed. Lumbar puncture and an evaluation of cerebrospinal fluid may be necessary in cases in which meningitis cannot be excluded.^7,9

Specialized diagnostic tests are not routinely recommended for patients with paresis that is improving. Audiometry and evaluation of the stapedial reflex may help guide treatment decisions for patients whose condition is not improving. In children, the presence or return of the stapedial reflex within three weeks of disease onset is predictive of complete recovery.⁵ In patients who experience complete paralysis or unimproved paresis, results of electrodiagnostic testing (in particular, evoked facial nerve electroneuronography) can help forecast recovery of facial nerve function.^5,17

Treatment and Management
Treatment for FNP in adults is controversial, and even more so for the pediatric patient. Treatment decisions consist of eye care, corticosteroids, antiviral medications, and appropriate referrals.

Eye care. Eye lubrication and protection should be implemented immediately. Protecting the cornea is paramount; thorough lubrication of the eye is the mainstay of treatment.¹⁸ Artificial tears should be used frequently during the day, and an ointment should be applied to the eye at night. Use of eye patches is controversial, as they may actually cause corneal injury.^7,9 Taping the eye shut at night may prevent trauma during sleep, but this option must be considered carefully.^9,18

Corticosteroids. Early initiation of corticosteroids should be considered for all patients with FNP, including children.^2,7,9,17 Studies are inconclusive as to whether steroid therapy is beneficial in children with idiopathic FNP. However, two 2010 reviews of pediatric FNP recommend early initiation of steroids for children with acute-onset FNP, particularly when facial paresis is evaluated at a House-Brackmann grade V or VI.^7,9 The American Academy of Family Physicians (AAFP) recommends a tapering course of prednisone for all patients, begun as soon as possible.⁶ The prednisone dosage for pediatric patients is usually 1.0 mg/kg/d, split into two doses, for six days, followed by a tapering dose for four days.⁵

Antivirals and antibiotic therapy. When an infectious cause of FNP is known, appropriate antibiotic or antiviral therapy should begin. If the patient lives in or has traveled to an area endemic for Lyme disease, empiric treatment may be appropriate. When Ramsay Hunt syndrome is diagnosed or herpetic lesions are visible, antiviral treatment should be initiated.⁷

Antiviral therapy for idiopathic FNP is the most controversial of the treatment decisions. In 2001, the American Academy of Neurology concluded that no clear benefit from acyclovir could be ascertained, although it might be effective.¹³ This was affirmed in a recently updated Cochrane review of antiviral therapy for idiopathic FNP.¹² Antiviral therapy alone showed no benefit, compared with placebo; however, combined antiviral and corticosteroid therapy was more effective than placebo alone in recovery outcomes. Antivirals may benefit pediatric patients and should be considered early when the cause of FNP is viral or idiopathic.^7,9

Referrals. Initial presentation and course of paresis should guide referral patterns for the pediatric patient presenting with FNP. The American Academy of Pediatrics (AAP) recommends referral to an otolaryngologist for any infant or child with FNP.²¹ The AAFP recommends referral to a specialist for any patient who does not show improvement within two weeks.⁶

In patients with complete paralysis, early surgical intervention may be considered, and referral should be made promptly for electrodiagnostic testing and surgical consult. In cases in which otitis media causes FNP, myringotomy and tube insertion are indicated, and appropriate referral should be made.^7,9

Outcomes
|The prognosis in children with FNP is good, and most will recover completely.^2,9-11,22 Idiopathic and infectious etiologies of FNP seem to have the greatest likelihood for complete recovery.^10,11,16,17 Recovery appears to be affected by etiology, degree of paresis, and treatment. How these factors coalesce is not fully understood, and up to 20% of children may have mild to moderate residual facial nerve dysfunction.^10,11,19,22

The Case Patient
The child’s facial nerve function gradually returned over a three-week period, with no residual deficit (see Figures 1a, 1b, and 1c). Results of the audiometry screening on day 10 were normal, showing a positive stapedial reflex. An MRI, performed four months after the initial paralysis to rule out any tumors, yielded normal results. 

This case highlights the differing management of pediatric Bell’s palsy among emergency, pediatric, and specialized providers. This child was managed more aggressively under the care of an otolaryngologist with a two-week course of steroids, antiviral medication for 10 days, and a follow-up MRI to rule out any evidence of a tumor. The need for further research to guide practice in the pediatric patient with Bell’s palsy is apparent.

Conclusion
FNP in the pediatric population is rare and more likely to have an identifiable cause than among adults. Careful examination should reveal differential diagnoses that warrant treatment and referrals. The main causes of FNP that should not be missed are otitis media, hypertension, varicella zoster virus (Ramsay Hunt syndrome), neoplastic processes, and Lyme disease.

Practitioners should have a high index of suspicion for nonidiopathic causes of FNP when a child has a neurologic exam that includes facial paresis of gradual onset, abnormal function of other cranial nerves, lack of forehead muscle weakness, or peripheral abnormalities. In addition to the history and exam, blood work and radiologic imaging can aid the practitioner in ruling in or out nonidiopathic causes of FNP. 

Grading of facial palsy severity using the House-Brackmann scale helps guide prognosis and referral choices. Referral to a specialist in otolaryngology is appropriate and recommended by the AAP. Referral should be made to an ophthalmologist if any suspicion of corneal abrasion exists. 

Treatment in children should consist of eye care and steroids. Antiviral therapy should be considered on an individualized basis and when evidence of HSV or varicella exists. Parents should be advised about the importance of eye care in a child with FNP (see Table 3^{5-7,9,17,18,22}).

The emotional stress associated with FNP can be significant for both children and adults; fear of lifelong facial deformity can be psychologically debilitating. Yet a favorable prognosis for recovery of facial nerve function can be relayed to anxious parents.

A 6-year-old girl was brought to a pediatric emergency department (ED) in Atlanta by her mother. The mother stated that during the previous hour, she had noticed that her daughter’s face seemed weaker on the right side.

The night before, the child had said, “I can’t blink my eye”; when her mother asked her to demonstrate, the child seemed to be able to blink both eyes appropriately, and she had no further complaints. The next morning, the child complained of the light being too bright and asked to wear her mother’s sunglasses. In the course of the day, she continued to complain of eye discomfort, which she described as “stinging” and “sore.” The mother could see nothing abnormal, but by late afternoon noticed that her daughter’s smile and facial movements were asymmetrical. She immediately took her to the pediatric ED.

The child had no significant medical history and no surgical history. Her vaccination schedule was current, and she denied any recent illnesses. The mother could recall no exposures to infections or tick bites, no rashes, and no trauma to the face or head. The mother and child were visiting Atlanta from northeastern Florida.

The review of systems was negative for headache, fever, chills, rash, earache, sore throat, cough, rhinorrhea, vision changes, weight loss, or change in appetite or disposition. The child was afebrile, and the other vital signs were within normal limits. 

Physical examination revealed an alert child who was calm and conversant. Her height was 45” and weight, 43 lb. Otoscopic exam showed normal ears and tympanic membranes with no sign of otitis media or ear pathology. No throat redness, tonsillar enlargement, or lymphadenopathies were noted. Breath sounds were clear, and heart rhythm and rate were regular without murmur. 

The patient’s left eye appeared normal, and the right eye was mildly erythematic without drainage or swelling; since corneal abrasion was not suspected, a slit lamp examination was not performed. Upon neurologic examination, right eye ptosis with incomplete lid closure, asymmetrical mouth movement with smile, and a diminished nasal labial fold crease were noted on the right side. When the child was asked to raise her eyebrows and wrinkle her forehead, asymmetrical forehead creases were apparent. All other cranial nerve functions were intact, and motor and sensory responses, including gait and reflexes, were assessed as normal. Unilateral dysfunction of right-sided cranial nerve VII (CN VII), including forehead involvement, was confirmed, consistent with a grade of III to IV on the House-Brackmann (maximum, VI)^1,2 facial nerve grading scale.

Based on the rapid onset of unilateral facial nerve paresis (FNP) and an otherwise normal exam, the patient was diagnosed with Bell’s palsy. No further testing was done, and the child was given a dose of oral prednisolone 40 mg in the ED, with a prescription for four more days of oral prednisolone at 15 mg bid. The need for eye protection and lubrication was emphasized to the mother, who was given lubricating eye drops to administer. The mother was also instructed to follow up with the child’s primary care practitioner upon their return to Florida. 

The child was seen by her pediatrician three days later. Her facial paresis had not worsened in the interim, and the pediatrician declined to extend the course of corticosteroids or to add an antiviral medication. At the mother’s request, the child was referred to a pediatric otolaryngologist, who saw her the following day and adjusted the treatment plan. The child was prescribed prednisolone elixir 20 mg bid for one week, followed by a tapering dose for the second week. In addition, she was prescribed oral acyclovir 400 mg qid for 10 days. Her mother was instructed to return with the child in one week for audiometry testing.  

Discussion
Idiopathic FNP, commonly referred to as Bell’s palsy, is defined as an acute unilateral paresis of the facial nerve without detectable underlying cause.^3,4 It most commonly occurs among persons ages 15 to 45, with a prevalence rate of 15 to 30 cases per 100,000 persons. The peak incidence of Bell’s palsy is in the fourth decade of life. Diabetic patients and pregnant women are disproportionately affected by idiopathic FNP.^2,5 About 8% to 10% of patients will experience a recurrence of Bell’s palsy within 10 years.^2,6

Pediatric FNP can be congenital or acquired. Congenital FNP is most often associated with birth trauma and occurs at a rate of 2.1 cases per 1,000 births. Rare genetic syndromes can also manifest with FNP and will most often present with other syndromic anomalies noted at birth.⁷

Acquired FNP is two to four times less common in children than adults, with an estimated prevalence of 2.7 per 100,000 patients younger than 10. Children account for only a small proportion of subjects in published studies that address diagnosis and management of FNP.³ While the presentation of FNP is much the same in adults and children, some notable differences in etiology exist.^2,3,7-9 Infectious, traumatic, or neoplastic causes of FNP are more common among children than adults and must be distinguished from idiopathic FNP.^7,9-11

Decisions regarding diagnostic testing, pharmacologic treatment, and referral must be guided by the history and physical exam, neurologic exam, and clinical judgment. Being able to identify or exclude alarming causes of FNP, such as neoplasm, will aid the primary care practitioner in treatment and referral practices for this condition.

Pathophysiology
CN VII, the facial nerve, has a broad scope of function that incorporates both sensory and motor pathways. The brachial nerve portion of CN VII controls the muscles of voluntary facial expression. CN VII also autonomically innervates the lacrimal gland and submandibular gland and governs sensation from part of the ear as well as taste from the anterior two-thirds of the tongue.⁴

The precise pathophysiology involved in FNP remains an area of continuing debate, but infectious, vascular, immunologic, and genetic causes have been hypothesized.^7,12 Inflammation and subsequent nerve damage along CN VII caused by an infectious process is thought to be the most likely explanation for the pathogenesis of acquired FNP in both adults and children.^5,13

Herpes simplex virus 1 (HSV-1) has been suggested as the virus most commonly linked to FNP in both adults and children, but it is unlikely to be the sole cause.^5,6,9 Data from a three-year prospective study of FNP cases in children support a relationship between pediatric FNP and HSV-1 infection.¹⁴ Other infectious causes implicated in pediatric FNP are Lyme disease, Epstein-Barr, varicella zoster virus, rubella, coxsackie virus, adenovirus, and otitis media.^4,7,9

Presentation, History, and Physical Exam
Most children with idiopathic FNP will present with sudden-onset facial asymmetry and may have decreased tearing, loss of the conjunctival reflex (leading to difficulty closing the eye), an inability to hold the lips tightly together, and difficulty keeping food in the mouth. Complaints of otalgia, speech disturbances, hyperacusis, and altered sense of taste are common.^2,7 Recent occurrence of an upper respiratory infection is often reported in the history of a pediatric patient with FNP.^3,7,15,16

Idiopathic FNP is essentially a diagnosis of exclusion.^3,5 A meticulous history must be conducted, including any recent illnesses, trauma to the face or head, vaccines, rashes, and travel. Assessment of the head, eyes, ears, nose, and throat, and a careful neurologic history must be conducted to identify nonidiopathic causes of FNP (see Table 1^5-7,9). Facial weakness can progress from mild palsy to complete paralysis over one to two weeks⁵; therefore, a careful history of the progression of facial weakness should be ascertained and documented.^5,17 

A full neurologic exam is essential. Cranial nerves I through XII should be evaluated; any malfunction of a cranial nerve other than CN VII could be indicative of a tumor or process other than idiopathic FNP. Assessment of facial nerve function is imperative, as this factor is the most important for predicting recovery; it can also aid in formulating a prognosis and directing treatment.^5,9,17

The House-Brackmann facial nerve grading system^1,2 is considered the gold standard for grading severity of facial paresis⁹ (see Table 2^1,2 ). A clear distinction between paresis (partial or incomplete palsy) and paralysis (complete palsy) must be made. Pediatric patients with an incomplete palsy have an improved chance of full recovery.^17,18

Any abnormalities in the peripheral neurologic exam should prompt further testing. FNP not involving the forehead musculature, gradual progression of paresis, and weakness in any extremity could be indicative of a central lesion. FNP has been the presenting symptom in various neoplastic processes, including leukemia, cholesteatoma, and astrocytoma.^3,7,9

Otitis media is a frequent cause of FNP among children.^9-11 Thus, a thorough examination of the ear canal, tympanic membrane, and hearing should be performed. The throat and oropharynx should be inspected, and the parotid gland palpated. Any swelling or abnormalities warrant further investigation.

Lyme disease presenting with FNP is more common in children than adults. This may be related to the increased likelihood for children to be bitten by ticks in the head and neck areas. Frequently, FNP associated with Lyme disease is bilateral—as often as 25% of the time.¹⁹ Headache, onset of symptoms during peak Lyme season, or bilateral FNP should raise the clinician’s suspicion for Lyme disease.^7,9,19

An accurate assessment of blood pressure is essential, as severe hypertension may be implicated in FNP in children.^3,5,7 One literature review reported that hypertension was the origin of FNP in 3% to 17% of affected children.²⁰ Vascular hemorrhage induced by hypertension is thought to cause nerve compression and subsequent FNP.⁷

A bilateral eye exam is also important. Irritation is likely, and the patient with any suspected corneal abrasion or damage should be referred to an ophthalmologist.^6,18

Laboratory Testing and Imaging
Diagnostic testing that facilitates the exclusion of known causes of FNP should be considered, as there is no specific laboratory test to confirm the diagnosis. A complete blood count, Lyme titers, cerebrospinal fluid analysis, CT, and/or MRI may be warranted, based on the clinical presentation.^7-9 In children in whom Lyme disease is suspected (ie, those living in tick-endemic areas or with recent tick bites), serologic testing should be performed. Lumbar puncture and an evaluation of cerebrospinal fluid may be necessary in cases in which meningitis cannot be excluded.^7,9

Specialized diagnostic tests are not routinely recommended for patients with paresis that is improving. Audiometry and evaluation of the stapedial reflex may help guide treatment decisions for patients whose condition is not improving. In children, the presence or return of the stapedial reflex within three weeks of disease onset is predictive of complete recovery.⁵ In patients who experience complete paralysis or unimproved paresis, results of electrodiagnostic testing (in particular, evoked facial nerve electroneuronography) can help forecast recovery of facial nerve function.^5,17

Treatment and Management
Treatment for FNP in adults is controversial, and even more so for the pediatric patient. Treatment decisions consist of eye care, corticosteroids, antiviral medications, and appropriate referrals.

Eye care. Eye lubrication and protection should be implemented immediately. Protecting the cornea is paramount; thorough lubrication of the eye is the mainstay of treatment.¹⁸ Artificial tears should be used frequently during the day, and an ointment should be applied to the eye at night. Use of eye patches is controversial, as they may actually cause corneal injury.^7,9 Taping the eye shut at night may prevent trauma during sleep, but this option must be considered carefully.^9,18

Corticosteroids. Early initiation of corticosteroids should be considered for all patients with FNP, including children.^2,7,9,17 Studies are inconclusive as to whether steroid therapy is beneficial in children with idiopathic FNP. However, two 2010 reviews of pediatric FNP recommend early initiation of steroids for children with acute-onset FNP, particularly when facial paresis is evaluated at a House-Brackmann grade V or VI.^7,9 The American Academy of Family Physicians (AAFP) recommends a tapering course of prednisone for all patients, begun as soon as possible.⁶ The prednisone dosage for pediatric patients is usually 1.0 mg/kg/d, split into two doses, for six days, followed by a tapering dose for four days.⁵

Antivirals and antibiotic therapy. When an infectious cause of FNP is known, appropriate antibiotic or antiviral therapy should begin. If the patient lives in or has traveled to an area endemic for Lyme disease, empiric treatment may be appropriate. When Ramsay Hunt syndrome is diagnosed or herpetic lesions are visible, antiviral treatment should be initiated.⁷

Antiviral therapy for idiopathic FNP is the most controversial of the treatment decisions. In 2001, the American Academy of Neurology concluded that no clear benefit from acyclovir could be ascertained, although it might be effective.¹³ This was affirmed in a recently updated Cochrane review of antiviral therapy for idiopathic FNP.¹² Antiviral therapy alone showed no benefit, compared with placebo; however, combined antiviral and corticosteroid therapy was more effective than placebo alone in recovery outcomes. Antivirals may benefit pediatric patients and should be considered early when the cause of FNP is viral or idiopathic.^7,9

Referrals. Initial presentation and course of paresis should guide referral patterns for the pediatric patient presenting with FNP. The American Academy of Pediatrics (AAP) recommends referral to an otolaryngologist for any infant or child with FNP.²¹ The AAFP recommends referral to a specialist for any patient who does not show improvement within two weeks.⁶

In patients with complete paralysis, early surgical intervention may be considered, and referral should be made promptly for electrodiagnostic testing and surgical consult. In cases in which otitis media causes FNP, myringotomy and tube insertion are indicated, and appropriate referral should be made.^7,9

Outcomes
|The prognosis in children with FNP is good, and most will recover completely.^2,9-11,22 Idiopathic and infectious etiologies of FNP seem to have the greatest likelihood for complete recovery.^10,11,16,17 Recovery appears to be affected by etiology, degree of paresis, and treatment. How these factors coalesce is not fully understood, and up to 20% of children may have mild to moderate residual facial nerve dysfunction.^10,11,19,22

The Case Patient
The child’s facial nerve function gradually returned over a three-week period, with no residual deficit (see Figures 1a, 1b, and 1c). Results of the audiometry screening on day 10 were normal, showing a positive stapedial reflex. An MRI, performed four months after the initial paralysis to rule out any tumors, yielded normal results. 

This case highlights the differing management of pediatric Bell’s palsy among emergency, pediatric, and specialized providers. This child was managed more aggressively under the care of an otolaryngologist with a two-week course of steroids, antiviral medication for 10 days, and a follow-up MRI to rule out any evidence of a tumor. The need for further research to guide practice in the pediatric patient with Bell’s palsy is apparent.

Conclusion
FNP in the pediatric population is rare and more likely to have an identifiable cause than among adults. Careful examination should reveal differential diagnoses that warrant treatment and referrals. The main causes of FNP that should not be missed are otitis media, hypertension, varicella zoster virus (Ramsay Hunt syndrome), neoplastic processes, and Lyme disease.

Practitioners should have a high index of suspicion for nonidiopathic causes of FNP when a child has a neurologic exam that includes facial paresis of gradual onset, abnormal function of other cranial nerves, lack of forehead muscle weakness, or peripheral abnormalities. In addition to the history and exam, blood work and radiologic imaging can aid the practitioner in ruling in or out nonidiopathic causes of FNP. 

Grading of facial palsy severity using the House-Brackmann scale helps guide prognosis and referral choices. Referral to a specialist in otolaryngology is appropriate and recommended by the AAP. Referral should be made to an ophthalmologist if any suspicion of corneal abrasion exists. 

Treatment in children should consist of eye care and steroids. Antiviral therapy should be considered on an individualized basis and when evidence of HSV or varicella exists. Parents should be advised about the importance of eye care in a child with FNP (see Table 3^{5-7,9,17,18,22}).

The emotional stress associated with FNP can be significant for both children and adults; fear of lifelong facial deformity can be psychologically debilitating. Yet a favorable prognosis for recovery of facial nerve function can be relayed to anxious parents.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.