The Journal of Family Practice

Mention the word “botulinum toxin” and one’s mind is likely to go to the big business of cosmetic procedures. Among the 15.7 minimally invasive cosmetic procedures performed in 2017, botulinum toxin type A ­(BoNT-A) made up the largest share, with 7.23 million procedures.¹ However, botulinum toxin—which was first recognized for the ability to paralyze muscles through decreased release of acetylcholine—also has many pain-related and noncosmetic uses; some are approved by the US Food and Drug Administration (FDA) and others are off-label (see TABLE 1^2-31). This review provides an evidence-based look at these uses, from those that have good evidence to support them—including chronic migraine and overactive bladder—to those that have limited (or no) evidence to support them—such as chronic pelvic pain and cluster headache.

BoNT-A is 1 of 7 recognized serotypes derived from Clostridium botulinum.

But before we get into the evidence behind specific uses for botulinum toxin, let’s review the available options and the potential risks they pose.

Many options

Although botulinum toxin is produced by Clostridium botulinum, the synthetic process to produce pharmaceuticals is patented and branded. BoNT-A is 1 of 7 recognized serotypes derived from C botulinum; some examples of BoNT-A include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Clinically, the differences are minor, but they do allow for use of other brands if a patient becomes intolerant to the selected therapy. Treatment doses and costs for each brand vary.

Training. Primary care providers can obtain didactic training from pharmaceutical companies as well as skills training through workshops on botulinum toxin. Credentialed providers can perform some procedures in the primary care setting (TABLE 2).

Adverse effects also vary depending on the formulation and the sites injected. Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints. However, systemic events such as anaphylaxis and antibody development can occur. Depending on the formulation injected, the molecule can migrate and cause weakness in adjacent muscles, leading to undesired effects. Compensatory muscles can become strained, resulting in pain. Serious complications such as pneumonia and death have occurred with injection of botulinum toxin in or around the neck.

A note about pain management. In addition to muscle relaxation, analgesic properties are among the identified benefits of BoNT-A injections.^32,33 BoNT-A suppresses the release of norepinephrine, substance P, and glutamate, which reduces pain sensitization.³² However, the extent of ongoing research involving BoNT-A uses in pain management exceeds the scope of this article. Some pain-related indications will be discussed, but the focus will be on other noncosmetic uses.

Headache disorders

Chronic migraine affects 1.3% to 2.2% of the population and is defined as headaches occurring ≥ 15 days (≥ 8 migrainous days) per month.² To qualify for BoNT-A treatment, patients must have tried 2 prophylactic medications that failed to provide relief, and their headaches must last at least 4 hours. Injections every 12 weeks with 5 U in each of 31 prescribed sites is effective, as shown in the PREEMPT 2 study² with external verification.³ The 24-week, double-blind, placebo-­controlled study showed that BoNT-A treatment reduced headache days by 9 days (P < .001) and migraine days by 8.7 days (P < .001)² and, at 108 weeks, injections reduced headache days by 10.7 days (P < .0001).^4,5

Continue to: Episodic migraine, tension headache, and cluster headaches

Episodic migraine, tension headache, and cluster headaches. There is no significant BoNT-A-related pain reduction in episodic migraine (n = 1838; 0.05 headaches/mo; 95% CI, –0.26 to –0.36) or tension headaches (n = 675; –1.43 headaches/mo; 95% CI, –3.13 to –0.27).^5,6 For cluster headaches, a single prospective study with low enrollment showed no consistent benefit,⁷ while a pilot study showed some improvement, with reduction of attacks by 50% in half of subjects.⁸

Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints.

Occipital neuralgia and trigeminal neuralgia entail paroxysmal, brief, shock-like pain without associated deficits affecting the respective nerve distributions. Multiple prospective and double-blind placebo-­controlled studies with relatively low enrollment show consistent improvement in pain intensity, number of pain-free days, analgesic consumption, and headache frequency with BoNT-A added to nerve blocks.⁶

ENT disorders

Tinnitus by involuntary palatal tremor causes a discontinuous clicking noise. Palatal tremor can be treated with BoNT-A 15 U to tensor veli palatini and levator veli muscles to provide temporary relief for 2 to 6 months.⁹

Spasmodic dysphonia and voice tremor are the result of laryngeal hyperkinesis, and BoNT-A has been deemed the gold standard of treatment. BoNT-A is administered via bilateral injection of the thyroarytenoid muscles for patients with adductor-type spasmodic dysphonia and of the posterior cricoarytenoid muscles for those with the abductor type. A series of 1300 patients (predominantly with the adductor type) treated with BoNT-A showed a 100% improvement in symptoms for 6 to 15 weeks. Patients with abductor-type spasmodic dysphonia were found to have 89% improvement in Voice Related Quality of Life Index score.¹⁰

Secretory disorders

Primary axillary hyperhidrosis (PAH) is an idiopathic excessive production of sweat occurring for at least 6 months, typically with onset before age 25 years. PAH can cause significant psychosocial and physical impairment. Current treatments include topical aluminum chloride, systemic anticholinergics, and thoracic sympathectomy, which can provide temporary relief but are not well tolerated.

Continue to: BoNT-A treatment is efficacious...

Evaluation of BoNT-A as an adjunctive therapy in cerebral palsy has been extensive and conflicting.

BoNT-A treatment is efficacious, safe, and improves quality of life for PAH patients. A 52-week, multicenter, double-blind, randomized, placebo-controlled study showed significant reductions in symptom severity, decreased sweating at rest by gravimetric testing, and improvements in self-reported quality of life.¹¹ A 10-year retrospective study in patients ages 12 years and older showed a 75% to 100% improvement in hyperhidrosis, with a median treatment effect duration of 7 months.¹²

Sialorrhea, or hypersalivation, is typically associated with neurological conditions such as cerebral palsy, amyotrophic lateral sclerosis, Parkinson disease, and posttraumatic brain injuries. It typically is treated with anticholinergic drugs, surgery, and irradiation of salivary glands, which can have significant adverse effects and complications. In a randomized blinded study, BoNT-A injections in the parotid and submandibular glands resulted in a dramatic reduction of sialorrhea and were safe and well tolerated.¹³

Gastric disorders

Achalasia is a syndrome of aperistalsis and incomplete lower esophageal sphincter (LES) relaxation with a “bird beak” appearance on barium swallow. Patients who meet diagnostic criteria are treated with pneumatic dilation or myotomy; however, some patients demonstrate symptoms of achalasia but don’t meet the diagnostic criteria. In these patients, BoNT-A injection in the LES provides symptomatic relief. In a case series, LES BoNT-A injections 20 U were used as a decision tool in whether to proceed with definitive treatment.¹⁴

Gastroparesis is a disorder of impaired gastric motility without mechanical obstruction. Pyloric sphincter BoNT-A injections are useful in refractory patients. Multiple prospective, noncontrolled (4), retrospective (3), and randomized placebo-controlled (2), studies with limited enrollment showed benefit for 37.5% to 100% of patients receiving ­BoNT-A injections of 80 to 200 U.¹⁵

Musculoskeletal disorders

Cervical dystonia (CD) entails involuntary contractions of the neck and upper shoulder musculature, causing abnormal neck, shoulder, and head posturing. BoNT-A is first-line treatment for CD.⁵ BoNT-A is more efficacious than trihexyphenidyl based on multiple large, high-quality studies.¹⁶

Continue to: Chronic low back pain

Chronic low back pain (CLBP) is defined as back pain persisting ≥ 12 weeks. More than 80% of adults have had at least 1 episode of back pain in their lifetime. A 14-month open-label, pilot study evaluating the short- and long-term effects of paraspinal muscle ­BoNT-A injections for refractory CLBP showed reduced pain intensity, reduced number of pain days, and functional improvements.¹⁷

Myofascial pain syndrome (MPS) consists of myofascial trigger points (palpable, tender nodules that produce pain) with multiple pathophysiological etiologies that include dysfunctional acetylcholine activity, which releases nociceptive neurotransmitters. Studies have yielded inconsistent effects of BoNT-A on MPS.¹⁸

Spastic disorders

Cerebral palsy (CP) involves altered muscle tone, posture, and movement secondary to central motor dysfunction with spasticity. Evaluation of BoNT-A as an adjunctive therapy in CP has been extensive and conflicting. A prospective cohort study evaluating gastrocsoleus BoNT-A injections along with gait analysis in 37 children with CP showed no significant improvements.³⁰ In 60 children with CP who received BoNT-A injections, there was improvement in muscle tone and range of motion, while gait improved in patients up to (but not after) age 7 years.¹⁹ A multicenter Dutch study of 65 children compared BoNT-A injections in addition to a comprehensive rehabilitation program vs rehabilitation alone, with no difference identified.²⁰

Neonatal brachial plexus palsy (NBPP) is damage to the brachial plexus as a result of trauma during the perinatal period. It is typically self-resolving but can cause residual functional impairment. Surgery is recommended for serious injuries or if functional recovery is not achieved within 9 months. Off-label use of BoNT-A has been shown to be effective in relieving muscle contractures and imbalance, but data are limited and there have only been small studies performed.²¹ A retrospective cohort study of 59 patients with NBPP who received BoNT-A injections showed improved range of motion and function of the affected extremity. Moreover, surgical intervention was deferred, modified, or averted in patients who were under consideration for more invasive treatment.²¹

Post-stroke spasticity can be temporarily relieved with the use of BoNT-A injections. Several studies have examined the effect of BoNT-A coupled with rehabilitation programs vs injections alone in the treatment of post-stroke spasticity. Devier et al found that improvements in spasticity scores did not differ between groups; however, implementing rehabilitation after BoNT-A injections was associated with improved function compared to injection alone.³¹ A 2018 randomized, double-blind, placebo-controlled trial demonstrated improvements in both treatment groups: those who received ­BoNT-A plus targeted rehab regimen and those who received saline injection plus rehab.²² In this case, it appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.⁵

Continue to: Hemifacial spasm

Hemifacial spasm is an involuntary, brief, irregular unilateral (sometimes bilateral) spasm of the face in the distribution of the facial nerve. Injections with BoNT-A have been deemed effective by the American Academy of Neurology.²³ A 16-year retrospective study examined the efficacy and adverse effects of BoNT-A in the treatment of hemifacial spasm in 113 patients with a mean age of 63.1 years; it demonstrated high efficacy and mild temporary adverse effects.²⁴ The duration of improvement averaged 16 weeks; pretarsal injections had better results than preseptal injections; and there were no differences between the commercial brands.

Blepharospasm is a focal dystonia marked by excessive blinking and involuntary eye closures due to overexcitability of orbicularis oculi and periocular muscles, and BoNT-A is the treatment of choice.^5,25 A retrospective review of 19 patients with blepharospasm who were treated with BoNT-A for more than 5 years found that BoNT-A is a stable and effective treatment with an adverse event rate of 4%. Additionally, there were no differences found in clinical efficacy between the 4 BoNT-A brands on the market.²⁵

It appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.

Laryngeal tics can cause significant psychosocial distress for patients. This condition is characterized by involuntary, recurrent rhythmic sounds that are often preceded by premonitory urges that are relieved by the behavior. An open-label, uncontrolled, confirmatory study with 30 subjects showed that bilateral vocal cord BoNT-A injections resulted in 93% improvement in vocal tics.²⁶ A subsequent study highlighted case histories of 2 patients with laryngeal tics who received thyroarytenoid muscle BoNT-A injections and had marked reduction in symptoms and premonitory sensations.²⁷ Although these small studies have suggested possible effectiveness of BoNT-A for laryngeal tics, there is no high-quality evidence.

Urologic disorders

Overactive, idiopathic overactive, or neurogenic bladder causes increased urinary frequency, urgency, and nocturia without infectious etiology; they can be a result of neurologic dysregulation, detrusor overactivity, or idiopathic causes. Intravesical BoNT-A injection of 100 to 300 U has been found effective for symptoms refractory to anticholinergic and lifestyle therapy, with increased cystometric capacity (229.1 to 427 mL, P < .00001), decreased maximum detrusor pressure (60.7 to 26.1 cm H2O, P < .00001), and resolution of urgency in 87% of patients (P < .001).²⁸

Interstitial cystitis, also known as painful bladder syndrome, is characterized by reduced bladder emptying, urethral pressure, and residual urine pressure, with symptoms of increased urinary frequency without infection. Intravesicular BoNT-A injections have not consistently been effective in treatment of this condition.²⁸

Continue to: Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome

Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome involve urethral sphincter spasticity with difficulty passing urine and possibly retention. Urethral sphincter injections of 100 U ­BoNT-A improved flow rates and decreased residual volume. A randomized, double-blinded, ­placebo-controlled study showed a significantly improved International Prostate Symptom Score (IPSS), quality of life index, maximum flow rate, voided volume, and decreased detrusor voiding pressure at 1 month.²⁹

Intravesicular BoNT-A injections have not consistently been effective in the treatment of interstitial cystitis.

Benign prostatic hypertrophy (BPH) is a very common condition leading to outlet obstruction. The mainstays of treatment are 5-α-reductase inhibitors, α-adrenergic blockers, and surgical removal. Intraprostatic BoNT-A injections of 100 to 200 U were initially promising, and subsequent randomized, double-blind, placebo-controlled studies demonstrated patients with moderate-to-severe symptoms (IPSS ≥ 19) had improved IPSS, maximum flow rate, and post-void residual volume compared to placebo.²⁹

Gynecologic disorders

Vaginismus is the involuntary, recurrent, or persistent contraction of the perineal muscles surrounding the outer third of the vagina; it is classified by 4 progressively more severe degrees of intensity. Levator ani, bulbospongiosus, bulbocavernosus, pubococcygeus, and/or puborectalis muscle BoNT-A injections have shown benefits in decreasing resistance to vaginal exams (95.8%) and the ability to achieve satisfactory sexual intercourse after first injection (75%-100%). Effects were transient for up to 15.4% of patients requiring repeat injections.²⁸

Vulvodynia is vulvar pain and orgasmic difficulties and has been treated with bulbospongiosus muscle BoNT-A injections in retrospective studies. A single randomized, double-blinded, placebo-controlled study showed significantly improved pain scores after 1 to 2 injection series.²⁸

Chronic pelvic pain is a syndrome of somatic functional or regional pain, which can be caused by the spasm of the pelvic musculature with or without trigger points. Patients with pain refractory to treatment have been treated with levator ani injections. A retrospective cohort study found 79.3% of patients experienced pain relief and 20.7% reported improved symptoms. In a double-blind, randomized, placebo-controlled trial, pelvic floor muscles were injected with 80 U BoNT or saline, and symptoms were evaluated along with vaginal manometry. BoNT was associated with a reduction in some pain but not as much as placebo, while vaginal pressures decreased more with BoNT than with placebo.²⁸

CORRESPONDENCE
Blake Busey, DO, FAAFP, Texas Tech University of Health Sciences El Paso–Transmountain, 2000B Transmountain Road, Suite B400, El Paso, TX 79911; blake.busey@ttuhsc.edu

Mention the word “botulinum toxin” and one’s mind is likely to go to the big business of cosmetic procedures. Among the 15.7 minimally invasive cosmetic procedures performed in 2017, botulinum toxin type A ­(BoNT-A) made up the largest share, with 7.23 million procedures.¹ However, botulinum toxin—which was first recognized for the ability to paralyze muscles through decreased release of acetylcholine—also has many pain-related and noncosmetic uses; some are approved by the US Food and Drug Administration (FDA) and others are off-label (see TABLE 1^2-31). This review provides an evidence-based look at these uses, from those that have good evidence to support them—including chronic migraine and overactive bladder—to those that have limited (or no) evidence to support them—such as chronic pelvic pain and cluster headache.

BoNT-A is 1 of 7 recognized serotypes derived from Clostridium botulinum.

But before we get into the evidence behind specific uses for botulinum toxin, let’s review the available options and the potential risks they pose.

Many options

Although botulinum toxin is produced by Clostridium botulinum, the synthetic process to produce pharmaceuticals is patented and branded. BoNT-A is 1 of 7 recognized serotypes derived from C botulinum; some examples of BoNT-A include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Clinically, the differences are minor, but they do allow for use of other brands if a patient becomes intolerant to the selected therapy. Treatment doses and costs for each brand vary.

Training. Primary care providers can obtain didactic training from pharmaceutical companies as well as skills training through workshops on botulinum toxin. Credentialed providers can perform some procedures in the primary care setting (TABLE 2).

Adverse effects also vary depending on the formulation and the sites injected. Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints. However, systemic events such as anaphylaxis and antibody development can occur. Depending on the formulation injected, the molecule can migrate and cause weakness in adjacent muscles, leading to undesired effects. Compensatory muscles can become strained, resulting in pain. Serious complications such as pneumonia and death have occurred with injection of botulinum toxin in or around the neck.

A note about pain management. In addition to muscle relaxation, analgesic properties are among the identified benefits of BoNT-A injections.^32,33 BoNT-A suppresses the release of norepinephrine, substance P, and glutamate, which reduces pain sensitization.³² However, the extent of ongoing research involving BoNT-A uses in pain management exceeds the scope of this article. Some pain-related indications will be discussed, but the focus will be on other noncosmetic uses.

Headache disorders

Chronic migraine affects 1.3% to 2.2% of the population and is defined as headaches occurring ≥ 15 days (≥ 8 migrainous days) per month.² To qualify for BoNT-A treatment, patients must have tried 2 prophylactic medications that failed to provide relief, and their headaches must last at least 4 hours. Injections every 12 weeks with 5 U in each of 31 prescribed sites is effective, as shown in the PREEMPT 2 study² with external verification.³ The 24-week, double-blind, placebo-­controlled study showed that BoNT-A treatment reduced headache days by 9 days (P < .001) and migraine days by 8.7 days (P < .001)² and, at 108 weeks, injections reduced headache days by 10.7 days (P < .0001).^4,5

Continue to: Episodic migraine, tension headache, and cluster headaches

Episodic migraine, tension headache, and cluster headaches. There is no significant BoNT-A-related pain reduction in episodic migraine (n = 1838; 0.05 headaches/mo; 95% CI, –0.26 to –0.36) or tension headaches (n = 675; –1.43 headaches/mo; 95% CI, –3.13 to –0.27).^5,6 For cluster headaches, a single prospective study with low enrollment showed no consistent benefit,⁷ while a pilot study showed some improvement, with reduction of attacks by 50% in half of subjects.⁸

Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints.

Occipital neuralgia and trigeminal neuralgia entail paroxysmal, brief, shock-like pain without associated deficits affecting the respective nerve distributions. Multiple prospective and double-blind placebo-­controlled studies with relatively low enrollment show consistent improvement in pain intensity, number of pain-free days, analgesic consumption, and headache frequency with BoNT-A added to nerve blocks.⁶

ENT disorders

Tinnitus by involuntary palatal tremor causes a discontinuous clicking noise. Palatal tremor can be treated with BoNT-A 15 U to tensor veli palatini and levator veli muscles to provide temporary relief for 2 to 6 months.⁹

Spasmodic dysphonia and voice tremor are the result of laryngeal hyperkinesis, and BoNT-A has been deemed the gold standard of treatment. BoNT-A is administered via bilateral injection of the thyroarytenoid muscles for patients with adductor-type spasmodic dysphonia and of the posterior cricoarytenoid muscles for those with the abductor type. A series of 1300 patients (predominantly with the adductor type) treated with BoNT-A showed a 100% improvement in symptoms for 6 to 15 weeks. Patients with abductor-type spasmodic dysphonia were found to have 89% improvement in Voice Related Quality of Life Index score.¹⁰

Secretory disorders

Primary axillary hyperhidrosis (PAH) is an idiopathic excessive production of sweat occurring for at least 6 months, typically with onset before age 25 years. PAH can cause significant psychosocial and physical impairment. Current treatments include topical aluminum chloride, systemic anticholinergics, and thoracic sympathectomy, which can provide temporary relief but are not well tolerated.

Continue to: BoNT-A treatment is efficacious...

Evaluation of BoNT-A as an adjunctive therapy in cerebral palsy has been extensive and conflicting.

BoNT-A treatment is efficacious, safe, and improves quality of life for PAH patients. A 52-week, multicenter, double-blind, randomized, placebo-controlled study showed significant reductions in symptom severity, decreased sweating at rest by gravimetric testing, and improvements in self-reported quality of life.¹¹ A 10-year retrospective study in patients ages 12 years and older showed a 75% to 100% improvement in hyperhidrosis, with a median treatment effect duration of 7 months.¹²

Sialorrhea, or hypersalivation, is typically associated with neurological conditions such as cerebral palsy, amyotrophic lateral sclerosis, Parkinson disease, and posttraumatic brain injuries. It typically is treated with anticholinergic drugs, surgery, and irradiation of salivary glands, which can have significant adverse effects and complications. In a randomized blinded study, BoNT-A injections in the parotid and submandibular glands resulted in a dramatic reduction of sialorrhea and were safe and well tolerated.¹³

Gastric disorders

Achalasia is a syndrome of aperistalsis and incomplete lower esophageal sphincter (LES) relaxation with a “bird beak” appearance on barium swallow. Patients who meet diagnostic criteria are treated with pneumatic dilation or myotomy; however, some patients demonstrate symptoms of achalasia but don’t meet the diagnostic criteria. In these patients, BoNT-A injection in the LES provides symptomatic relief. In a case series, LES BoNT-A injections 20 U were used as a decision tool in whether to proceed with definitive treatment.¹⁴

Gastroparesis is a disorder of impaired gastric motility without mechanical obstruction. Pyloric sphincter BoNT-A injections are useful in refractory patients. Multiple prospective, noncontrolled (4), retrospective (3), and randomized placebo-controlled (2), studies with limited enrollment showed benefit for 37.5% to 100% of patients receiving ­BoNT-A injections of 80 to 200 U.¹⁵

Musculoskeletal disorders

Cervical dystonia (CD) entails involuntary contractions of the neck and upper shoulder musculature, causing abnormal neck, shoulder, and head posturing. BoNT-A is first-line treatment for CD.⁵ BoNT-A is more efficacious than trihexyphenidyl based on multiple large, high-quality studies.¹⁶

Continue to: Chronic low back pain

Chronic low back pain (CLBP) is defined as back pain persisting ≥ 12 weeks. More than 80% of adults have had at least 1 episode of back pain in their lifetime. A 14-month open-label, pilot study evaluating the short- and long-term effects of paraspinal muscle ­BoNT-A injections for refractory CLBP showed reduced pain intensity, reduced number of pain days, and functional improvements.¹⁷

Myofascial pain syndrome (MPS) consists of myofascial trigger points (palpable, tender nodules that produce pain) with multiple pathophysiological etiologies that include dysfunctional acetylcholine activity, which releases nociceptive neurotransmitters. Studies have yielded inconsistent effects of BoNT-A on MPS.¹⁸

Spastic disorders

Cerebral palsy (CP) involves altered muscle tone, posture, and movement secondary to central motor dysfunction with spasticity. Evaluation of BoNT-A as an adjunctive therapy in CP has been extensive and conflicting. A prospective cohort study evaluating gastrocsoleus BoNT-A injections along with gait analysis in 37 children with CP showed no significant improvements.³⁰ In 60 children with CP who received BoNT-A injections, there was improvement in muscle tone and range of motion, while gait improved in patients up to (but not after) age 7 years.¹⁹ A multicenter Dutch study of 65 children compared BoNT-A injections in addition to a comprehensive rehabilitation program vs rehabilitation alone, with no difference identified.²⁰

Neonatal brachial plexus palsy (NBPP) is damage to the brachial plexus as a result of trauma during the perinatal period. It is typically self-resolving but can cause residual functional impairment. Surgery is recommended for serious injuries or if functional recovery is not achieved within 9 months. Off-label use of BoNT-A has been shown to be effective in relieving muscle contractures and imbalance, but data are limited and there have only been small studies performed.²¹ A retrospective cohort study of 59 patients with NBPP who received BoNT-A injections showed improved range of motion and function of the affected extremity. Moreover, surgical intervention was deferred, modified, or averted in patients who were under consideration for more invasive treatment.²¹

Post-stroke spasticity can be temporarily relieved with the use of BoNT-A injections. Several studies have examined the effect of BoNT-A coupled with rehabilitation programs vs injections alone in the treatment of post-stroke spasticity. Devier et al found that improvements in spasticity scores did not differ between groups; however, implementing rehabilitation after BoNT-A injections was associated with improved function compared to injection alone.³¹ A 2018 randomized, double-blind, placebo-controlled trial demonstrated improvements in both treatment groups: those who received ­BoNT-A plus targeted rehab regimen and those who received saline injection plus rehab.²² In this case, it appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.⁵

Continue to: Hemifacial spasm

Hemifacial spasm is an involuntary, brief, irregular unilateral (sometimes bilateral) spasm of the face in the distribution of the facial nerve. Injections with BoNT-A have been deemed effective by the American Academy of Neurology.²³ A 16-year retrospective study examined the efficacy and adverse effects of BoNT-A in the treatment of hemifacial spasm in 113 patients with a mean age of 63.1 years; it demonstrated high efficacy and mild temporary adverse effects.²⁴ The duration of improvement averaged 16 weeks; pretarsal injections had better results than preseptal injections; and there were no differences between the commercial brands.

Blepharospasm is a focal dystonia marked by excessive blinking and involuntary eye closures due to overexcitability of orbicularis oculi and periocular muscles, and BoNT-A is the treatment of choice.^5,25 A retrospective review of 19 patients with blepharospasm who were treated with BoNT-A for more than 5 years found that BoNT-A is a stable and effective treatment with an adverse event rate of 4%. Additionally, there were no differences found in clinical efficacy between the 4 BoNT-A brands on the market.²⁵

It appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.

Laryngeal tics can cause significant psychosocial distress for patients. This condition is characterized by involuntary, recurrent rhythmic sounds that are often preceded by premonitory urges that are relieved by the behavior. An open-label, uncontrolled, confirmatory study with 30 subjects showed that bilateral vocal cord BoNT-A injections resulted in 93% improvement in vocal tics.²⁶ A subsequent study highlighted case histories of 2 patients with laryngeal tics who received thyroarytenoid muscle BoNT-A injections and had marked reduction in symptoms and premonitory sensations.²⁷ Although these small studies have suggested possible effectiveness of BoNT-A for laryngeal tics, there is no high-quality evidence.

Urologic disorders

Overactive, idiopathic overactive, or neurogenic bladder causes increased urinary frequency, urgency, and nocturia without infectious etiology; they can be a result of neurologic dysregulation, detrusor overactivity, or idiopathic causes. Intravesical BoNT-A injection of 100 to 300 U has been found effective for symptoms refractory to anticholinergic and lifestyle therapy, with increased cystometric capacity (229.1 to 427 mL, P < .00001), decreased maximum detrusor pressure (60.7 to 26.1 cm H2O, P < .00001), and resolution of urgency in 87% of patients (P < .001).²⁸

Interstitial cystitis, also known as painful bladder syndrome, is characterized by reduced bladder emptying, urethral pressure, and residual urine pressure, with symptoms of increased urinary frequency without infection. Intravesicular BoNT-A injections have not consistently been effective in treatment of this condition.²⁸

Continue to: Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome

Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome involve urethral sphincter spasticity with difficulty passing urine and possibly retention. Urethral sphincter injections of 100 U ­BoNT-A improved flow rates and decreased residual volume. A randomized, double-blinded, ­placebo-controlled study showed a significantly improved International Prostate Symptom Score (IPSS), quality of life index, maximum flow rate, voided volume, and decreased detrusor voiding pressure at 1 month.²⁹

Intravesicular BoNT-A injections have not consistently been effective in the treatment of interstitial cystitis.

Benign prostatic hypertrophy (BPH) is a very common condition leading to outlet obstruction. The mainstays of treatment are 5-α-reductase inhibitors, α-adrenergic blockers, and surgical removal. Intraprostatic BoNT-A injections of 100 to 200 U were initially promising, and subsequent randomized, double-blind, placebo-controlled studies demonstrated patients with moderate-to-severe symptoms (IPSS ≥ 19) had improved IPSS, maximum flow rate, and post-void residual volume compared to placebo.²⁹

Gynecologic disorders

Vaginismus is the involuntary, recurrent, or persistent contraction of the perineal muscles surrounding the outer third of the vagina; it is classified by 4 progressively more severe degrees of intensity. Levator ani, bulbospongiosus, bulbocavernosus, pubococcygeus, and/or puborectalis muscle BoNT-A injections have shown benefits in decreasing resistance to vaginal exams (95.8%) and the ability to achieve satisfactory sexual intercourse after first injection (75%-100%). Effects were transient for up to 15.4% of patients requiring repeat injections.²⁸

Vulvodynia is vulvar pain and orgasmic difficulties and has been treated with bulbospongiosus muscle BoNT-A injections in retrospective studies. A single randomized, double-blinded, placebo-controlled study showed significantly improved pain scores after 1 to 2 injection series.²⁸

Chronic pelvic pain is a syndrome of somatic functional or regional pain, which can be caused by the spasm of the pelvic musculature with or without trigger points. Patients with pain refractory to treatment have been treated with levator ani injections. A retrospective cohort study found 79.3% of patients experienced pain relief and 20.7% reported improved symptoms. In a double-blind, randomized, placebo-controlled trial, pelvic floor muscles were injected with 80 U BoNT or saline, and symptoms were evaluated along with vaginal manometry. BoNT was associated with a reduction in some pain but not as much as placebo, while vaginal pressures decreased more with BoNT than with placebo.²⁸

CORRESPONDENCE
Blake Busey, DO, FAAFP, Texas Tech University of Health Sciences El Paso–Transmountain, 2000B Transmountain Road, Suite B400, El Paso, TX 79911; blake.busey@ttuhsc.edu

Mention the word “botulinum toxin” and one’s mind is likely to go to the big business of cosmetic procedures. Among the 15.7 minimally invasive cosmetic procedures performed in 2017, botulinum toxin type A ­(BoNT-A) made up the largest share, with 7.23 million procedures.¹ However, botulinum toxin—which was first recognized for the ability to paralyze muscles through decreased release of acetylcholine—also has many pain-related and noncosmetic uses; some are approved by the US Food and Drug Administration (FDA) and others are off-label (see TABLE 1^2-31). This review provides an evidence-based look at these uses, from those that have good evidence to support them—including chronic migraine and overactive bladder—to those that have limited (or no) evidence to support them—such as chronic pelvic pain and cluster headache.

BoNT-A is 1 of 7 recognized serotypes derived from Clostridium botulinum.

But before we get into the evidence behind specific uses for botulinum toxin, let’s review the available options and the potential risks they pose.

Many options

Although botulinum toxin is produced by Clostridium botulinum, the synthetic process to produce pharmaceuticals is patented and branded. BoNT-A is 1 of 7 recognized serotypes derived from C botulinum; some examples of BoNT-A include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Clinically, the differences are minor, but they do allow for use of other brands if a patient becomes intolerant to the selected therapy. Treatment doses and costs for each brand vary.

Training. Primary care providers can obtain didactic training from pharmaceutical companies as well as skills training through workshops on botulinum toxin. Credentialed providers can perform some procedures in the primary care setting (TABLE 2).

Adverse effects also vary depending on the formulation and the sites injected. Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints. However, systemic events such as anaphylaxis and antibody development can occur. Depending on the formulation injected, the molecule can migrate and cause weakness in adjacent muscles, leading to undesired effects. Compensatory muscles can become strained, resulting in pain. Serious complications such as pneumonia and death have occurred with injection of botulinum toxin in or around the neck.

A note about pain management. In addition to muscle relaxation, analgesic properties are among the identified benefits of BoNT-A injections.^32,33 BoNT-A suppresses the release of norepinephrine, substance P, and glutamate, which reduces pain sensitization.³² However, the extent of ongoing research involving BoNT-A uses in pain management exceeds the scope of this article. Some pain-related indications will be discussed, but the focus will be on other noncosmetic uses.

Headache disorders

Chronic migraine affects 1.3% to 2.2% of the population and is defined as headaches occurring ≥ 15 days (≥ 8 migrainous days) per month.² To qualify for BoNT-A treatment, patients must have tried 2 prophylactic medications that failed to provide relief, and their headaches must last at least 4 hours. Injections every 12 weeks with 5 U in each of 31 prescribed sites is effective, as shown in the PREEMPT 2 study² with external verification.³ The 24-week, double-blind, placebo-­controlled study showed that BoNT-A treatment reduced headache days by 9 days (P < .001) and migraine days by 8.7 days (P < .001)² and, at 108 weeks, injections reduced headache days by 10.7 days (P < .0001).^4,5

Continue to: Episodic migraine, tension headache, and cluster headaches

Episodic migraine, tension headache, and cluster headaches. There is no significant BoNT-A-related pain reduction in episodic migraine (n = 1838; 0.05 headaches/mo; 95% CI, –0.26 to –0.36) or tension headaches (n = 675; –1.43 headaches/mo; 95% CI, –3.13 to –0.27).^5,6 For cluster headaches, a single prospective study with low enrollment showed no consistent benefit,⁷ while a pilot study showed some improvement, with reduction of attacks by 50% in half of subjects.⁸

Patients generally tolerate the procedure well, with discomfort from injections and localized bleeding as the major complaints.

Occipital neuralgia and trigeminal neuralgia entail paroxysmal, brief, shock-like pain without associated deficits affecting the respective nerve distributions. Multiple prospective and double-blind placebo-­controlled studies with relatively low enrollment show consistent improvement in pain intensity, number of pain-free days, analgesic consumption, and headache frequency with BoNT-A added to nerve blocks.⁶

ENT disorders

Tinnitus by involuntary palatal tremor causes a discontinuous clicking noise. Palatal tremor can be treated with BoNT-A 15 U to tensor veli palatini and levator veli muscles to provide temporary relief for 2 to 6 months.⁹

Spasmodic dysphonia and voice tremor are the result of laryngeal hyperkinesis, and BoNT-A has been deemed the gold standard of treatment. BoNT-A is administered via bilateral injection of the thyroarytenoid muscles for patients with adductor-type spasmodic dysphonia and of the posterior cricoarytenoid muscles for those with the abductor type. A series of 1300 patients (predominantly with the adductor type) treated with BoNT-A showed a 100% improvement in symptoms for 6 to 15 weeks. Patients with abductor-type spasmodic dysphonia were found to have 89% improvement in Voice Related Quality of Life Index score.¹⁰

Secretory disorders

Primary axillary hyperhidrosis (PAH) is an idiopathic excessive production of sweat occurring for at least 6 months, typically with onset before age 25 years. PAH can cause significant psychosocial and physical impairment. Current treatments include topical aluminum chloride, systemic anticholinergics, and thoracic sympathectomy, which can provide temporary relief but are not well tolerated.

Continue to: BoNT-A treatment is efficacious...

Evaluation of BoNT-A as an adjunctive therapy in cerebral palsy has been extensive and conflicting.

BoNT-A treatment is efficacious, safe, and improves quality of life for PAH patients. A 52-week, multicenter, double-blind, randomized, placebo-controlled study showed significant reductions in symptom severity, decreased sweating at rest by gravimetric testing, and improvements in self-reported quality of life.¹¹ A 10-year retrospective study in patients ages 12 years and older showed a 75% to 100% improvement in hyperhidrosis, with a median treatment effect duration of 7 months.¹²

Sialorrhea, or hypersalivation, is typically associated with neurological conditions such as cerebral palsy, amyotrophic lateral sclerosis, Parkinson disease, and posttraumatic brain injuries. It typically is treated with anticholinergic drugs, surgery, and irradiation of salivary glands, which can have significant adverse effects and complications. In a randomized blinded study, BoNT-A injections in the parotid and submandibular glands resulted in a dramatic reduction of sialorrhea and were safe and well tolerated.¹³

Gastric disorders

Achalasia is a syndrome of aperistalsis and incomplete lower esophageal sphincter (LES) relaxation with a “bird beak” appearance on barium swallow. Patients who meet diagnostic criteria are treated with pneumatic dilation or myotomy; however, some patients demonstrate symptoms of achalasia but don’t meet the diagnostic criteria. In these patients, BoNT-A injection in the LES provides symptomatic relief. In a case series, LES BoNT-A injections 20 U were used as a decision tool in whether to proceed with definitive treatment.¹⁴

Gastroparesis is a disorder of impaired gastric motility without mechanical obstruction. Pyloric sphincter BoNT-A injections are useful in refractory patients. Multiple prospective, noncontrolled (4), retrospective (3), and randomized placebo-controlled (2), studies with limited enrollment showed benefit for 37.5% to 100% of patients receiving ­BoNT-A injections of 80 to 200 U.¹⁵

Musculoskeletal disorders

Cervical dystonia (CD) entails involuntary contractions of the neck and upper shoulder musculature, causing abnormal neck, shoulder, and head posturing. BoNT-A is first-line treatment for CD.⁵ BoNT-A is more efficacious than trihexyphenidyl based on multiple large, high-quality studies.¹⁶

Continue to: Chronic low back pain

Chronic low back pain (CLBP) is defined as back pain persisting ≥ 12 weeks. More than 80% of adults have had at least 1 episode of back pain in their lifetime. A 14-month open-label, pilot study evaluating the short- and long-term effects of paraspinal muscle ­BoNT-A injections for refractory CLBP showed reduced pain intensity, reduced number of pain days, and functional improvements.¹⁷

Myofascial pain syndrome (MPS) consists of myofascial trigger points (palpable, tender nodules that produce pain) with multiple pathophysiological etiologies that include dysfunctional acetylcholine activity, which releases nociceptive neurotransmitters. Studies have yielded inconsistent effects of BoNT-A on MPS.¹⁸

Spastic disorders

Cerebral palsy (CP) involves altered muscle tone, posture, and movement secondary to central motor dysfunction with spasticity. Evaluation of BoNT-A as an adjunctive therapy in CP has been extensive and conflicting. A prospective cohort study evaluating gastrocsoleus BoNT-A injections along with gait analysis in 37 children with CP showed no significant improvements.³⁰ In 60 children with CP who received BoNT-A injections, there was improvement in muscle tone and range of motion, while gait improved in patients up to (but not after) age 7 years.¹⁹ A multicenter Dutch study of 65 children compared BoNT-A injections in addition to a comprehensive rehabilitation program vs rehabilitation alone, with no difference identified.²⁰

Neonatal brachial plexus palsy (NBPP) is damage to the brachial plexus as a result of trauma during the perinatal period. It is typically self-resolving but can cause residual functional impairment. Surgery is recommended for serious injuries or if functional recovery is not achieved within 9 months. Off-label use of BoNT-A has been shown to be effective in relieving muscle contractures and imbalance, but data are limited and there have only been small studies performed.²¹ A retrospective cohort study of 59 patients with NBPP who received BoNT-A injections showed improved range of motion and function of the affected extremity. Moreover, surgical intervention was deferred, modified, or averted in patients who were under consideration for more invasive treatment.²¹

Post-stroke spasticity can be temporarily relieved with the use of BoNT-A injections. Several studies have examined the effect of BoNT-A coupled with rehabilitation programs vs injections alone in the treatment of post-stroke spasticity. Devier et al found that improvements in spasticity scores did not differ between groups; however, implementing rehabilitation after BoNT-A injections was associated with improved function compared to injection alone.³¹ A 2018 randomized, double-blind, placebo-controlled trial demonstrated improvements in both treatment groups: those who received ­BoNT-A plus targeted rehab regimen and those who received saline injection plus rehab.²² In this case, it appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.⁵

Continue to: Hemifacial spasm

Hemifacial spasm is an involuntary, brief, irregular unilateral (sometimes bilateral) spasm of the face in the distribution of the facial nerve. Injections with BoNT-A have been deemed effective by the American Academy of Neurology.²³ A 16-year retrospective study examined the efficacy and adverse effects of BoNT-A in the treatment of hemifacial spasm in 113 patients with a mean age of 63.1 years; it demonstrated high efficacy and mild temporary adverse effects.²⁴ The duration of improvement averaged 16 weeks; pretarsal injections had better results than preseptal injections; and there were no differences between the commercial brands.

Blepharospasm is a focal dystonia marked by excessive blinking and involuntary eye closures due to overexcitability of orbicularis oculi and periocular muscles, and BoNT-A is the treatment of choice.^5,25 A retrospective review of 19 patients with blepharospasm who were treated with BoNT-A for more than 5 years found that BoNT-A is a stable and effective treatment with an adverse event rate of 4%. Additionally, there were no differences found in clinical efficacy between the 4 BoNT-A brands on the market.²⁵

It appears BoNT-A acts as more of an adjunct to physical therapy in the treatment of post-stroke spasticity.

Laryngeal tics can cause significant psychosocial distress for patients. This condition is characterized by involuntary, recurrent rhythmic sounds that are often preceded by premonitory urges that are relieved by the behavior. An open-label, uncontrolled, confirmatory study with 30 subjects showed that bilateral vocal cord BoNT-A injections resulted in 93% improvement in vocal tics.²⁶ A subsequent study highlighted case histories of 2 patients with laryngeal tics who received thyroarytenoid muscle BoNT-A injections and had marked reduction in symptoms and premonitory sensations.²⁷ Although these small studies have suggested possible effectiveness of BoNT-A for laryngeal tics, there is no high-quality evidence.

Urologic disorders

Overactive, idiopathic overactive, or neurogenic bladder causes increased urinary frequency, urgency, and nocturia without infectious etiology; they can be a result of neurologic dysregulation, detrusor overactivity, or idiopathic causes. Intravesical BoNT-A injection of 100 to 300 U has been found effective for symptoms refractory to anticholinergic and lifestyle therapy, with increased cystometric capacity (229.1 to 427 mL, P < .00001), decreased maximum detrusor pressure (60.7 to 26.1 cm H2O, P < .00001), and resolution of urgency in 87% of patients (P < .001).²⁸

Interstitial cystitis, also known as painful bladder syndrome, is characterized by reduced bladder emptying, urethral pressure, and residual urine pressure, with symptoms of increased urinary frequency without infection. Intravesicular BoNT-A injections have not consistently been effective in treatment of this condition.²⁸

Continue to: Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome

Dysfunctional voiding, urethral sphincter overactivity, and Fowler syndrome involve urethral sphincter spasticity with difficulty passing urine and possibly retention. Urethral sphincter injections of 100 U ­BoNT-A improved flow rates and decreased residual volume. A randomized, double-blinded, ­placebo-controlled study showed a significantly improved International Prostate Symptom Score (IPSS), quality of life index, maximum flow rate, voided volume, and decreased detrusor voiding pressure at 1 month.²⁹

Intravesicular BoNT-A injections have not consistently been effective in the treatment of interstitial cystitis.

Benign prostatic hypertrophy (BPH) is a very common condition leading to outlet obstruction. The mainstays of treatment are 5-α-reductase inhibitors, α-adrenergic blockers, and surgical removal. Intraprostatic BoNT-A injections of 100 to 200 U were initially promising, and subsequent randomized, double-blind, placebo-controlled studies demonstrated patients with moderate-to-severe symptoms (IPSS ≥ 19) had improved IPSS, maximum flow rate, and post-void residual volume compared to placebo.²⁹

Gynecologic disorders

Vaginismus is the involuntary, recurrent, or persistent contraction of the perineal muscles surrounding the outer third of the vagina; it is classified by 4 progressively more severe degrees of intensity. Levator ani, bulbospongiosus, bulbocavernosus, pubococcygeus, and/or puborectalis muscle BoNT-A injections have shown benefits in decreasing resistance to vaginal exams (95.8%) and the ability to achieve satisfactory sexual intercourse after first injection (75%-100%). Effects were transient for up to 15.4% of patients requiring repeat injections.²⁸

Vulvodynia is vulvar pain and orgasmic difficulties and has been treated with bulbospongiosus muscle BoNT-A injections in retrospective studies. A single randomized, double-blinded, placebo-controlled study showed significantly improved pain scores after 1 to 2 injection series.²⁸

Chronic pelvic pain is a syndrome of somatic functional or regional pain, which can be caused by the spasm of the pelvic musculature with or without trigger points. Patients with pain refractory to treatment have been treated with levator ani injections. A retrospective cohort study found 79.3% of patients experienced pain relief and 20.7% reported improved symptoms. In a double-blind, randomized, placebo-controlled trial, pelvic floor muscles were injected with 80 U BoNT or saline, and symptoms were evaluated along with vaginal manometry. BoNT was associated with a reduction in some pain but not as much as placebo, while vaginal pressures decreased more with BoNT than with placebo.²⁸

CORRESPONDENCE
Blake Busey, DO, FAAFP, Texas Tech University of Health Sciences El Paso–Transmountain, 2000B Transmountain Road, Suite B400, El Paso, TX 79911; blake.busey@ttuhsc.edu

Stroke ranks second behind heart disease as the leading cause of mortality worldwide, accounting for 1 of every 19 deaths,¹ and remains a serious cause of morbidity. Best practices in stroke diagnosis and management can seem elusive to front-line clinicians, for 2 reasons: the rate of proliferation and nuance in stroke medicine and the fact that the typical scope of primary care practice exists apart from much of the diagnostic tools and management schema provided in stroke centers.² In this article, we describe and update the diagnosis of stroke and review imaging modalities, their nuances, and their application in practice.

Diagnosis of acute stroke

Acute stroke is diagnosed upon observation of new neurologic deficits and congruent neuroimaging. Some updated definitions favor a silent form of cerebral ischemia manifested by imaging pathology only; this form is not discussed in this article. Although there are several characteristically distinct stroke syndromes, there is no way to clinically distinguish ischemic pathology from hemorrhagic pathology.

Some common symptoms that should prompt evaluation for stroke are part of the American Stroke Association FAST mnemonic designed to promote public health awareness^3-5:

• face drooping
• arm weakness
• speech difficulty
• time to call 911.

There are several characteristically distinct stroke syndromes, but no way to differentiate ischemic and hemorrhagic pathologies clinically.

Other commonly reported stroke symptoms include unilateral weakness or numbness, confusion, word-finding difficulty, visual problems, difficulty ambulating, dizziness, loss of balance or coordination, and thunderclap headache. A stroke should also be considered in the presence of any new focal neurologic deficit.^3,4

Stroke patients should be triaged by emergency medical services using a stroke screening scale, such as BE-FAST⁵ (a modification of FAST that adds balance and eye assessments); the Los Angeles Prehospital Stroke Screen (LAPSS)^6,7; the Rapid Arterial oCclusion Evaluation (RACE)⁸; and the Cincinnati Prehospital Stroke Severity Scale (CP-SSS)^9,10 (see “Stroke screening scales for early identification and triage"). Studies have not found that any single prehospital stroke scale is superior to the others for reliably predicting large-vessel occlusion; therefore, prehospital assessment is typically based on practice patterns in a given locale.¹¹ A patient (or family member or caregiver) who seeks your care for stroke symptoms should be told to call 911 and get emergency transport to a health care facility that can capably administer intravenous (IV) thrombolysis.^a

First responders should elicit “last-known-normal” time; this critical information can aid in diagnosis and drive therapeutic options, especially if patients are unaccompanied at time of transport to a higher echelon of care. A point-of-care blood glucose test should be performed by emergency medical staff, with dextrose administered for a level < 45 mg/dL. Establishing IV access for fluids, medications, and contrast can be considered if it does not delay transport. A 12-lead electrocardiogram can also be considered, again, as long as it does not delay transport to a facility capable of providing definitive therapy. Notification by emergency services staff before arrival and transport of the patient to such a facility is the essential element of prehospital care, and should be prioritized above ancillary testing beyond the stroke assessment.¹⁴

Guidelines recommend use of the National Institutes of Health Stroke Scale ­(NIHSS; www.stroke.nih.gov/resources/scale.htm) for clinical evaluation upon arrival at the ED.¹⁵ Although no scale has been identified that can reliably predict large-vessel occlusion amenable to endovascular therapy (EVT), no other score has been found to outperform the NIHSS in achieving meaningful patient outcomes.¹⁶ Furthermore, NIHSS has been validated to track clinical changes in response to therapy, is widely utilized, and is free.

Continue to: A criticism of the NIHSS...

A criticism of the NIHSS is its bias toward left-hemispheric ischemic pathology.¹⁷ NIHSS includes 11 questions on a scale of 0 to 42; typically, a score < 4 is associated with a higher chance of a positive clinical outcome.¹⁸ There is no minimum or maximum NIHSS score that precludes treatment with thrombolysis or EVT.

Other commonly used scores in acute stroke include disability assessments. The modified Rankin scale, which is used most often, features a score of 0 (symptom-free) to 6 (death). A modified Rankin scale score of 0 or 1 is considered an indication of a favorable outcome after stroke.¹⁹ Note that these functional scores are not always part of an acute assessment but can be done early in the clinical course to gauge the response to treatment, and are collected for stroke-center certification.

Imaging modalities

Imaging is recommended within 20 minutes of arrival in the ED in a stroke patient who might be a candidate for thrombolysis or thrombectomy.³ There, imaging modalities commonly performed are noncontrast-enhanced head computed tomography (NCHCT); computed tomography (CT) angiography, with or without perfusion; and diffusion-weighted magnetic resonance imaging (MRI).^20,21 In addition, more highly specialized imaging modalities are available for the evaluation of the stroke patient in specific, often limited, circumstances. All these modalities are described below and compared in the TABLE,^20,21 using the ACR Appropriateness Criteria (of the American College of Radiology),²¹ which are guidelines for appropriate imaging of stroke, based on a clinical complaint. Separate recommendations and appraisals are offered by the most recent American Heart Association/American Stroke Association (AHA/ASA) guideline.³

NCHCT. This study should be performed within 20 minutes after arrival at the ED because it provides rapid assessment of intracerebral hemorrhage, can effectively corroborate the diagnosis of some stroke mimickers, and identifies some candidates for EVT or thrombolysis^3,21,22 (typically, the decision to proceed with EVT is based on adjunct imaging studies discussed in a bit). Evaluation for intracerebral hemorrhage is required prior to administering thrombolysis. Ischemic changes can be seen with variable specificity and sensitivity on NCHCT, depending on how much time has passed since the original insult. In all historical trials, CT was the only imaging modality used in the diagnosis of acute ischemic stroke (AIS) that suggested benefit from IV thrombolysis.^23-25

Acute, subacute, and chronic changes can be seen on NCHCT, although the modality has limited sensitivity for identifying AIS (ie, approximately 75% within 6 hours after the original insult):

• Acute findings on NCHCT include intracellular edema, which causes loss of the gray matter–white matter interface and effacement of the cortical sulci. This occurs as a result of increased cellular uptake of water in response to ischemia and cell death, resulting in a decreased density of tissue (hypoattenuation) in affected areas.
• Subacute changes appear in the 2- to 5-day window, including vasogenic edema with greater mass effect, hypoattenuation, and well-defined margins.^3,20,21
• Chronic vascular findings on NCHCT include loss of brain tissue and hypoattenuation.

Continue to: NCHCT is typically performed...

NCHCT is typically performed in advance of other adjunct imaging modalities.^3,20,21 Baseline NCHCT can be performed on patients with advanced kidney disease and those who have an indwelling metallic device.

CT angiography is performed with timed contrast, providing a 3-dimensional representation of the cerebral vasculature; the entire intracranial and extracranial vasculature, including the aortic arch, can be mapped in approximately 60 seconds. CT angiography is sensitive in identifying areas of stenosis > 50% and identifies clinically significant areas of stenosis up to approximately 90% of the time.²⁶ For this reason, it is particularly helpful in identifying candidates for an interventional strategy beyond pharmacotherapeutic thrombolysis. In addition, CT angiography can visualize aneurysmal dilation and dissection, and help with the planning of interventions—specifically, the confident administration of thrombolysis or more specific planning for target lesions and EVT.

Commonly used scoring systems in acute stroke include disability assessments— not always part of the acute assessment but undertaken early in the clinical course to gauge response to treatment.

It also can help identify a host of vascular phenomena, such as arteriovenous malformations, Moyamoya disease (progressive arterial blockage within the basal ganglia and compensatory microvascularization), and some vasculopathies.^20,27 In intracranial hemorrhage, CT with angiography can help evaluate for structural malformations and identify patients at risk of hematoma expansion.²²

CT perfusion. Many stroke centers will perform a CT perfusion study,²⁸ which encompasses as many as 3 different CT sequences:

• NCHCT
• vertex-to-arch angiography with contrast bolus
• administration of contrast and capture of a dynamic sequence through 1 or 2 slabs of tissue, allowing for the generation of maps of cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) of the entire cerebral vasculature.

The interplay of these 3 sequences drives characterization of lesions (ie, CBF = CBV/MTT). An infarct is characterized by low CBF, low CBV, and elevated MTT. In penumbral tissue, MTT is elevated but CBF is slightly decreased and CBV is normal or increased. Using CT perfusion, areas throughout the ischemic penumbra can be surveyed for favorable interventional characteristics.^20,29

Continue to: A CT perfusion study adds...

A CT perfusion study adds at least 60 seconds to NCHCT. This modality can be useful in planning interventions and for stratifying appropriateness of reperfusion strategies in strokes of unknown duration.^3,30 CT perfusion can be performed on any multidetector CT scan but (1) requires specialized software and expertise to interpret and (2) subjects the patient to a significant radiation dose, which, if incorrectly administered, can be considerably higher than intended.^20,26,27

Diffusion-weighted MRI. This is the most sensitive study for demonstrating early ischemic changes; however, limitations include lack of availability, contraindication in patients with metallic indwelling implants, and duration of the study—although, at some stroke centers, diffusion-weighted MRI can be performed in ≤ 10 minutes.

MRI and NCHCT have comparable sensitivity in detecting intracranial hemorrhage. MRI is likely more sensitive in identifying areas of microhemorrhage: In diffusion-weighted MRI, the sensitivity of stroke detection increases to > 95%.³¹ The modality relies on the comparable movement of water through damaged vs normal neuronal tissue. Diffusion-weighted MRI does not require administration of concomitant contrast, which can be a benefit in patients who are allergic to gadolinium-based contrast agents or have advanced kidney disease that precludes the use of contrast. It typically does not result in adequate characterization of extracranial vasculature.

Other MRI modalities. These MRI extensions include magnetic resonance (MR) perfusion and MR angiography. Whereas diffusion-weighted MRI (discussed above) offers the most rapid and sensitive evaluation for ischemia, fluid-attenuated inversion recovery (FLAIR) imaging has been utilized as a comparator to isolated diffusion-weighted MRI to help determine stroke duration. FLAIR signal positivity typically occurs 6 to 24 hours after the initial insult but is negative in stroke that occurred < 3 hours earlier.³²

MRI is limited, in terms of availability and increased study duration, especially when it comes to timely administration of thrombolysis. A benefit of this modality is less radiation and, as noted, superior sensitivity for ischemia. Diffusion-weighted MRI combined with MR perfusion analysis can help isolate areas of the ischemic penumbra. MR perfusion is performed for a similar reason as CT perfusion, although logistical execution across those modalities is significantly different. Considerations for choosing MR perfusion or CT perfusion should be made on an individual basis and based on available local resources and accepted local practice patterns.²⁶

Continue to: In the subacute setting...

Knowledge of historic details of the event, the patient (eg, known atrial fibrillation), and findings on imaging can facilitate communication between the primary care physician and inpatient teams.

In the subacute setting, MR perfusion and MR angiography of the head and the neck are often performed to identify stenosis, dissection, and more subtle mimickers of cerebrovascular accident not ascertained on initial CT evaluation. These studies are typically performed well outside the window for thrombolysis or intervention.²⁶ No guidelines specifically direct or recommend this practice pattern. The superior sensitivity and cerebral blood flow mapping of MR perfusion and MR angiography might be useful for validating a suspected diagnosis of ischemic stroke and providing phenotypic information about AIS events.

Transcranial Doppler imaging relies on bony windows to assess intracranial vascular flow, velocity, direction, and reactivity. This information can be utilized to diagnose stenosis or occlusion. This modality is principally used to evaluate for stenosis in the anterior circulation (sensitivity, 70%-90%; specificity, 90%-95%).²⁰ Evaluation of the basilar, vertebral, and internal carotid arteries is less accurate (sensitivity, 55%-80%).²⁰ Transcranial Doppler imaging is also used to assess for cerebral vasospasm after subarachnoid hemorrhage, monitor sickle cell disease patients’ overall risk for ischemic stroke, and augment thrombolysis. It is limited by the availability of an expert technician, and therefore is typically reserved for unstable patients or those who cannot receive contrast.²⁰

Carotid duplex ultrasonography. A dynamic study such as duplex ultrasonography can be strongly considered for flow imaging of the extracranial carotids to evaluate for stenosis. Indications for carotid stenting or endarterectomy include 50% to 79% occlusion of the carotid artery on the same side as a recent transient ischemic attack or AIS. Carotid stenosis > 80% warrants consideration for intervention independent of a recent cerebrovascular accident. Interventions are typically performed 2 to 14 days after stroke.³³ Although this study is of limited utility in the hyperacute setting, it is recommended within 24 hours after nondisabling stroke in the carotid territory, when (1) the patient is otherwise a candidate for a surgical or procedural intervention to address the stenosis and (2) none of the aforementioned studies that focus on neck vasculature have been performed.

Conventional (digital subtraction) ­angiography is the gold standard for mapping cerebrovascular disease because it is dynamic and highly accurate. It is, however, typically limited by the number of required personnel, its invasive nature, and the requirement for IV contrast. This study is performed during intra-arterial intervention techniques, including stent retrieval and intra-arterial thrombolysis.²⁶

Impact of imaging on treatment

Imaging helps determine the cause and some characteristics of stroke, both of which can help determine therapy. Strokes can be broadly subcategorized as hemorrhagic or ischemic; recent studies suggest that 87% are ischemic.³⁴ Knowledge of the historic details of the event, the patient (eg, known atrial fibrillation, anticoagulant use, history of falls), and findings on imaging can contribute to determine the cause of AIS, and can facilitate communication and consultation between the primary care physician and inpatient teams.³⁵

Continue to: Best practices for stroke treatment...

Best practices for stroke treatment are based on the cause of the event.³ To identify the likely cause, the aforementioned characteristics are incorporated into one of the scoring systems, which seek to clarify either the cause or the phenotypic appearance of the AIS, which helps direct further testing and treatment. (The ASCOD³⁶ and TOAST³⁷ classification schemes are commonly used phenotypic and causative classifications, respectively.) Several (not all) of the broad phenotypic imaging patterns, with myriad clinical manifestations, are reviewed below. They include:

• Embolic stroke, which, classically, involves end circulation and therefore has cortical involvement. Typically, these originate from the heart or large extracranial arteries, and higher rates of atrial fibrillation and hypercoagulable states are implicated.
• Thrombotic stroke, which, typically, is from large vessels or small vessels, and occurs as a result of atherosclerosis. These strokes are more common at the origins or bifurcations of vessels. Symptoms of thrombotic stroke classically wax and wane slightly more frequently. Lacunar strokes are typically from thrombotic causes, although there are rare episodes of an embolic source contributing to a lacunar stroke syndrome.³⁸

There is evidence for using MRI discrepancies between diffusion-weighted and FLAIR imaging to time AIS findings in so-called wake-up strokes.³⁹ The rationale is that strokes < 4.5 hours old can be identified because they would have abnormal diffusion imaging components but normal findings with FLAIR. When these criteria were utilized in considering whether to treat with thrombolysis, there was a statistically significant improvement in 90-day modified Rankin scale (odds ratio = 1.61; 95% confidence interval, 1.09-2.36), but also an increased probability of death and intracerebral hemorrhage.³⁹

This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome.

A recent multicenter, randomized, open-label trial, with blinded outcomes assessment, showcased the efficacy of thrombectomy as an adjunct when ischemic brain territory was identified without frank infarction, as ascertained by CT perfusion within the anterior circulation. This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome with favorable imaging characteristics (on the modified Rankin scale, an ordinal score of 4 with medical therapy and an ordinal score of 3 with EVT [odds ratio = 2.77; 95% confidence interval, 1.63-4.70]).²⁹ A 2018 multicenter, prospective, randomized trial with blinded assessment of endpoints extended this idea, demonstrating that, when there was mismatch of the clinical deficit (ie, high NIHSS score) and infarct volume (measured on diffusion-weighted MRI or CT perfusion), thrombectomy as late as 24 hours after the patient was last known to be well was beneficial for lesions in the anterior circulation—specifically, the intracranial internal carotid artery or the proximal middle cerebral artery.⁴⁰

^a Whether local emergency departments (EDs) should be bypassed in favor of a specialized stroke center is the subject of debate. The 2019 American Heart Association/American Stroke Association guidelines note the AHA’s Mission: Lifeline Stroke EMS algorithm, which bypasses the nearest ED in feared cases of large-vessel occlusion if travel to a comprehensive stroke center can be accomplished within 30 minutes of arrival at the scene. This is based on expert consensus.^3,12,13

CORRESPONDENCE
Brian Ford, MD, 4301 Jones Bridge Road, Bethesda, MD; brian.ford@usuhs.edu.

Stroke ranks second behind heart disease as the leading cause of mortality worldwide, accounting for 1 of every 19 deaths,¹ and remains a serious cause of morbidity. Best practices in stroke diagnosis and management can seem elusive to front-line clinicians, for 2 reasons: the rate of proliferation and nuance in stroke medicine and the fact that the typical scope of primary care practice exists apart from much of the diagnostic tools and management schema provided in stroke centers.² In this article, we describe and update the diagnosis of stroke and review imaging modalities, their nuances, and their application in practice.

Diagnosis of acute stroke

Acute stroke is diagnosed upon observation of new neurologic deficits and congruent neuroimaging. Some updated definitions favor a silent form of cerebral ischemia manifested by imaging pathology only; this form is not discussed in this article. Although there are several characteristically distinct stroke syndromes, there is no way to clinically distinguish ischemic pathology from hemorrhagic pathology.

Some common symptoms that should prompt evaluation for stroke are part of the American Stroke Association FAST mnemonic designed to promote public health awareness^3-5:

• face drooping
• arm weakness
• speech difficulty
• time to call 911.

There are several characteristically distinct stroke syndromes, but no way to differentiate ischemic and hemorrhagic pathologies clinically.

Other commonly reported stroke symptoms include unilateral weakness or numbness, confusion, word-finding difficulty, visual problems, difficulty ambulating, dizziness, loss of balance or coordination, and thunderclap headache. A stroke should also be considered in the presence of any new focal neurologic deficit.^3,4

Stroke patients should be triaged by emergency medical services using a stroke screening scale, such as BE-FAST⁵ (a modification of FAST that adds balance and eye assessments); the Los Angeles Prehospital Stroke Screen (LAPSS)^6,7; the Rapid Arterial oCclusion Evaluation (RACE)⁸; and the Cincinnati Prehospital Stroke Severity Scale (CP-SSS)^9,10 (see “Stroke screening scales for early identification and triage"). Studies have not found that any single prehospital stroke scale is superior to the others for reliably predicting large-vessel occlusion; therefore, prehospital assessment is typically based on practice patterns in a given locale.¹¹ A patient (or family member or caregiver) who seeks your care for stroke symptoms should be told to call 911 and get emergency transport to a health care facility that can capably administer intravenous (IV) thrombolysis.^a

First responders should elicit “last-known-normal” time; this critical information can aid in diagnosis and drive therapeutic options, especially if patients are unaccompanied at time of transport to a higher echelon of care. A point-of-care blood glucose test should be performed by emergency medical staff, with dextrose administered for a level < 45 mg/dL. Establishing IV access for fluids, medications, and contrast can be considered if it does not delay transport. A 12-lead electrocardiogram can also be considered, again, as long as it does not delay transport to a facility capable of providing definitive therapy. Notification by emergency services staff before arrival and transport of the patient to such a facility is the essential element of prehospital care, and should be prioritized above ancillary testing beyond the stroke assessment.¹⁴

Guidelines recommend use of the National Institutes of Health Stroke Scale ­(NIHSS; www.stroke.nih.gov/resources/scale.htm) for clinical evaluation upon arrival at the ED.¹⁵ Although no scale has been identified that can reliably predict large-vessel occlusion amenable to endovascular therapy (EVT), no other score has been found to outperform the NIHSS in achieving meaningful patient outcomes.¹⁶ Furthermore, NIHSS has been validated to track clinical changes in response to therapy, is widely utilized, and is free.

Continue to: A criticism of the NIHSS...

A criticism of the NIHSS is its bias toward left-hemispheric ischemic pathology.¹⁷ NIHSS includes 11 questions on a scale of 0 to 42; typically, a score < 4 is associated with a higher chance of a positive clinical outcome.¹⁸ There is no minimum or maximum NIHSS score that precludes treatment with thrombolysis or EVT.

Other commonly used scores in acute stroke include disability assessments. The modified Rankin scale, which is used most often, features a score of 0 (symptom-free) to 6 (death). A modified Rankin scale score of 0 or 1 is considered an indication of a favorable outcome after stroke.¹⁹ Note that these functional scores are not always part of an acute assessment but can be done early in the clinical course to gauge the response to treatment, and are collected for stroke-center certification.

Imaging modalities

Imaging is recommended within 20 minutes of arrival in the ED in a stroke patient who might be a candidate for thrombolysis or thrombectomy.³ There, imaging modalities commonly performed are noncontrast-enhanced head computed tomography (NCHCT); computed tomography (CT) angiography, with or without perfusion; and diffusion-weighted magnetic resonance imaging (MRI).^20,21 In addition, more highly specialized imaging modalities are available for the evaluation of the stroke patient in specific, often limited, circumstances. All these modalities are described below and compared in the TABLE,^20,21 using the ACR Appropriateness Criteria (of the American College of Radiology),²¹ which are guidelines for appropriate imaging of stroke, based on a clinical complaint. Separate recommendations and appraisals are offered by the most recent American Heart Association/American Stroke Association (AHA/ASA) guideline.³

NCHCT. This study should be performed within 20 minutes after arrival at the ED because it provides rapid assessment of intracerebral hemorrhage, can effectively corroborate the diagnosis of some stroke mimickers, and identifies some candidates for EVT or thrombolysis^3,21,22 (typically, the decision to proceed with EVT is based on adjunct imaging studies discussed in a bit). Evaluation for intracerebral hemorrhage is required prior to administering thrombolysis. Ischemic changes can be seen with variable specificity and sensitivity on NCHCT, depending on how much time has passed since the original insult. In all historical trials, CT was the only imaging modality used in the diagnosis of acute ischemic stroke (AIS) that suggested benefit from IV thrombolysis.^23-25

Acute, subacute, and chronic changes can be seen on NCHCT, although the modality has limited sensitivity for identifying AIS (ie, approximately 75% within 6 hours after the original insult):

• Acute findings on NCHCT include intracellular edema, which causes loss of the gray matter–white matter interface and effacement of the cortical sulci. This occurs as a result of increased cellular uptake of water in response to ischemia and cell death, resulting in a decreased density of tissue (hypoattenuation) in affected areas.
• Subacute changes appear in the 2- to 5-day window, including vasogenic edema with greater mass effect, hypoattenuation, and well-defined margins.^3,20,21
• Chronic vascular findings on NCHCT include loss of brain tissue and hypoattenuation.

Continue to: NCHCT is typically performed...

NCHCT is typically performed in advance of other adjunct imaging modalities.^3,20,21 Baseline NCHCT can be performed on patients with advanced kidney disease and those who have an indwelling metallic device.

CT angiography is performed with timed contrast, providing a 3-dimensional representation of the cerebral vasculature; the entire intracranial and extracranial vasculature, including the aortic arch, can be mapped in approximately 60 seconds. CT angiography is sensitive in identifying areas of stenosis > 50% and identifies clinically significant areas of stenosis up to approximately 90% of the time.²⁶ For this reason, it is particularly helpful in identifying candidates for an interventional strategy beyond pharmacotherapeutic thrombolysis. In addition, CT angiography can visualize aneurysmal dilation and dissection, and help with the planning of interventions—specifically, the confident administration of thrombolysis or more specific planning for target lesions and EVT.

Commonly used scoring systems in acute stroke include disability assessments— not always part of the acute assessment but undertaken early in the clinical course to gauge response to treatment.

It also can help identify a host of vascular phenomena, such as arteriovenous malformations, Moyamoya disease (progressive arterial blockage within the basal ganglia and compensatory microvascularization), and some vasculopathies.^20,27 In intracranial hemorrhage, CT with angiography can help evaluate for structural malformations and identify patients at risk of hematoma expansion.²²

CT perfusion. Many stroke centers will perform a CT perfusion study,²⁸ which encompasses as many as 3 different CT sequences:

• NCHCT
• vertex-to-arch angiography with contrast bolus
• administration of contrast and capture of a dynamic sequence through 1 or 2 slabs of tissue, allowing for the generation of maps of cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) of the entire cerebral vasculature.

The interplay of these 3 sequences drives characterization of lesions (ie, CBF = CBV/MTT). An infarct is characterized by low CBF, low CBV, and elevated MTT. In penumbral tissue, MTT is elevated but CBF is slightly decreased and CBV is normal or increased. Using CT perfusion, areas throughout the ischemic penumbra can be surveyed for favorable interventional characteristics.^20,29

Continue to: A CT perfusion study adds...

A CT perfusion study adds at least 60 seconds to NCHCT. This modality can be useful in planning interventions and for stratifying appropriateness of reperfusion strategies in strokes of unknown duration.^3,30 CT perfusion can be performed on any multidetector CT scan but (1) requires specialized software and expertise to interpret and (2) subjects the patient to a significant radiation dose, which, if incorrectly administered, can be considerably higher than intended.^20,26,27

Diffusion-weighted MRI. This is the most sensitive study for demonstrating early ischemic changes; however, limitations include lack of availability, contraindication in patients with metallic indwelling implants, and duration of the study—although, at some stroke centers, diffusion-weighted MRI can be performed in ≤ 10 minutes.

MRI and NCHCT have comparable sensitivity in detecting intracranial hemorrhage. MRI is likely more sensitive in identifying areas of microhemorrhage: In diffusion-weighted MRI, the sensitivity of stroke detection increases to > 95%.³¹ The modality relies on the comparable movement of water through damaged vs normal neuronal tissue. Diffusion-weighted MRI does not require administration of concomitant contrast, which can be a benefit in patients who are allergic to gadolinium-based contrast agents or have advanced kidney disease that precludes the use of contrast. It typically does not result in adequate characterization of extracranial vasculature.

Other MRI modalities. These MRI extensions include magnetic resonance (MR) perfusion and MR angiography. Whereas diffusion-weighted MRI (discussed above) offers the most rapid and sensitive evaluation for ischemia, fluid-attenuated inversion recovery (FLAIR) imaging has been utilized as a comparator to isolated diffusion-weighted MRI to help determine stroke duration. FLAIR signal positivity typically occurs 6 to 24 hours after the initial insult but is negative in stroke that occurred < 3 hours earlier.³²

MRI is limited, in terms of availability and increased study duration, especially when it comes to timely administration of thrombolysis. A benefit of this modality is less radiation and, as noted, superior sensitivity for ischemia. Diffusion-weighted MRI combined with MR perfusion analysis can help isolate areas of the ischemic penumbra. MR perfusion is performed for a similar reason as CT perfusion, although logistical execution across those modalities is significantly different. Considerations for choosing MR perfusion or CT perfusion should be made on an individual basis and based on available local resources and accepted local practice patterns.²⁶

Continue to: In the subacute setting...

Knowledge of historic details of the event, the patient (eg, known atrial fibrillation), and findings on imaging can facilitate communication between the primary care physician and inpatient teams.

In the subacute setting, MR perfusion and MR angiography of the head and the neck are often performed to identify stenosis, dissection, and more subtle mimickers of cerebrovascular accident not ascertained on initial CT evaluation. These studies are typically performed well outside the window for thrombolysis or intervention.²⁶ No guidelines specifically direct or recommend this practice pattern. The superior sensitivity and cerebral blood flow mapping of MR perfusion and MR angiography might be useful for validating a suspected diagnosis of ischemic stroke and providing phenotypic information about AIS events.

Transcranial Doppler imaging relies on bony windows to assess intracranial vascular flow, velocity, direction, and reactivity. This information can be utilized to diagnose stenosis or occlusion. This modality is principally used to evaluate for stenosis in the anterior circulation (sensitivity, 70%-90%; specificity, 90%-95%).²⁰ Evaluation of the basilar, vertebral, and internal carotid arteries is less accurate (sensitivity, 55%-80%).²⁰ Transcranial Doppler imaging is also used to assess for cerebral vasospasm after subarachnoid hemorrhage, monitor sickle cell disease patients’ overall risk for ischemic stroke, and augment thrombolysis. It is limited by the availability of an expert technician, and therefore is typically reserved for unstable patients or those who cannot receive contrast.²⁰

Carotid duplex ultrasonography. A dynamic study such as duplex ultrasonography can be strongly considered for flow imaging of the extracranial carotids to evaluate for stenosis. Indications for carotid stenting or endarterectomy include 50% to 79% occlusion of the carotid artery on the same side as a recent transient ischemic attack or AIS. Carotid stenosis > 80% warrants consideration for intervention independent of a recent cerebrovascular accident. Interventions are typically performed 2 to 14 days after stroke.³³ Although this study is of limited utility in the hyperacute setting, it is recommended within 24 hours after nondisabling stroke in the carotid territory, when (1) the patient is otherwise a candidate for a surgical or procedural intervention to address the stenosis and (2) none of the aforementioned studies that focus on neck vasculature have been performed.

Conventional (digital subtraction) ­angiography is the gold standard for mapping cerebrovascular disease because it is dynamic and highly accurate. It is, however, typically limited by the number of required personnel, its invasive nature, and the requirement for IV contrast. This study is performed during intra-arterial intervention techniques, including stent retrieval and intra-arterial thrombolysis.²⁶

Impact of imaging on treatment

Imaging helps determine the cause and some characteristics of stroke, both of which can help determine therapy. Strokes can be broadly subcategorized as hemorrhagic or ischemic; recent studies suggest that 87% are ischemic.³⁴ Knowledge of the historic details of the event, the patient (eg, known atrial fibrillation, anticoagulant use, history of falls), and findings on imaging can contribute to determine the cause of AIS, and can facilitate communication and consultation between the primary care physician and inpatient teams.³⁵

Continue to: Best practices for stroke treatment...

Best practices for stroke treatment are based on the cause of the event.³ To identify the likely cause, the aforementioned characteristics are incorporated into one of the scoring systems, which seek to clarify either the cause or the phenotypic appearance of the AIS, which helps direct further testing and treatment. (The ASCOD³⁶ and TOAST³⁷ classification schemes are commonly used phenotypic and causative classifications, respectively.) Several (not all) of the broad phenotypic imaging patterns, with myriad clinical manifestations, are reviewed below. They include:

• Embolic stroke, which, classically, involves end circulation and therefore has cortical involvement. Typically, these originate from the heart or large extracranial arteries, and higher rates of atrial fibrillation and hypercoagulable states are implicated.
• Thrombotic stroke, which, typically, is from large vessels or small vessels, and occurs as a result of atherosclerosis. These strokes are more common at the origins or bifurcations of vessels. Symptoms of thrombotic stroke classically wax and wane slightly more frequently. Lacunar strokes are typically from thrombotic causes, although there are rare episodes of an embolic source contributing to a lacunar stroke syndrome.³⁸

There is evidence for using MRI discrepancies between diffusion-weighted and FLAIR imaging to time AIS findings in so-called wake-up strokes.³⁹ The rationale is that strokes < 4.5 hours old can be identified because they would have abnormal diffusion imaging components but normal findings with FLAIR. When these criteria were utilized in considering whether to treat with thrombolysis, there was a statistically significant improvement in 90-day modified Rankin scale (odds ratio = 1.61; 95% confidence interval, 1.09-2.36), but also an increased probability of death and intracerebral hemorrhage.³⁹

This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome.

A recent multicenter, randomized, open-label trial, with blinded outcomes assessment, showcased the efficacy of thrombectomy as an adjunct when ischemic brain territory was identified without frank infarction, as ascertained by CT perfusion within the anterior circulation. This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome with favorable imaging characteristics (on the modified Rankin scale, an ordinal score of 4 with medical therapy and an ordinal score of 3 with EVT [odds ratio = 2.77; 95% confidence interval, 1.63-4.70]).²⁹ A 2018 multicenter, prospective, randomized trial with blinded assessment of endpoints extended this idea, demonstrating that, when there was mismatch of the clinical deficit (ie, high NIHSS score) and infarct volume (measured on diffusion-weighted MRI or CT perfusion), thrombectomy as late as 24 hours after the patient was last known to be well was beneficial for lesions in the anterior circulation—specifically, the intracranial internal carotid artery or the proximal middle cerebral artery.⁴⁰

^a Whether local emergency departments (EDs) should be bypassed in favor of a specialized stroke center is the subject of debate. The 2019 American Heart Association/American Stroke Association guidelines note the AHA’s Mission: Lifeline Stroke EMS algorithm, which bypasses the nearest ED in feared cases of large-vessel occlusion if travel to a comprehensive stroke center can be accomplished within 30 minutes of arrival at the scene. This is based on expert consensus.^3,12,13

CORRESPONDENCE
Brian Ford, MD, 4301 Jones Bridge Road, Bethesda, MD; brian.ford@usuhs.edu.

Stroke ranks second behind heart disease as the leading cause of mortality worldwide, accounting for 1 of every 19 deaths,¹ and remains a serious cause of morbidity. Best practices in stroke diagnosis and management can seem elusive to front-line clinicians, for 2 reasons: the rate of proliferation and nuance in stroke medicine and the fact that the typical scope of primary care practice exists apart from much of the diagnostic tools and management schema provided in stroke centers.² In this article, we describe and update the diagnosis of stroke and review imaging modalities, their nuances, and their application in practice.

Diagnosis of acute stroke

Acute stroke is diagnosed upon observation of new neurologic deficits and congruent neuroimaging. Some updated definitions favor a silent form of cerebral ischemia manifested by imaging pathology only; this form is not discussed in this article. Although there are several characteristically distinct stroke syndromes, there is no way to clinically distinguish ischemic pathology from hemorrhagic pathology.

Some common symptoms that should prompt evaluation for stroke are part of the American Stroke Association FAST mnemonic designed to promote public health awareness^3-5:

• face drooping
• arm weakness
• speech difficulty
• time to call 911.

There are several characteristically distinct stroke syndromes, but no way to differentiate ischemic and hemorrhagic pathologies clinically.

Other commonly reported stroke symptoms include unilateral weakness or numbness, confusion, word-finding difficulty, visual problems, difficulty ambulating, dizziness, loss of balance or coordination, and thunderclap headache. A stroke should also be considered in the presence of any new focal neurologic deficit.^3,4

Stroke patients should be triaged by emergency medical services using a stroke screening scale, such as BE-FAST⁵ (a modification of FAST that adds balance and eye assessments); the Los Angeles Prehospital Stroke Screen (LAPSS)^6,7; the Rapid Arterial oCclusion Evaluation (RACE)⁸; and the Cincinnati Prehospital Stroke Severity Scale (CP-SSS)^9,10 (see “Stroke screening scales for early identification and triage"). Studies have not found that any single prehospital stroke scale is superior to the others for reliably predicting large-vessel occlusion; therefore, prehospital assessment is typically based on practice patterns in a given locale.¹¹ A patient (or family member or caregiver) who seeks your care for stroke symptoms should be told to call 911 and get emergency transport to a health care facility that can capably administer intravenous (IV) thrombolysis.^a

First responders should elicit “last-known-normal” time; this critical information can aid in diagnosis and drive therapeutic options, especially if patients are unaccompanied at time of transport to a higher echelon of care. A point-of-care blood glucose test should be performed by emergency medical staff, with dextrose administered for a level < 45 mg/dL. Establishing IV access for fluids, medications, and contrast can be considered if it does not delay transport. A 12-lead electrocardiogram can also be considered, again, as long as it does not delay transport to a facility capable of providing definitive therapy. Notification by emergency services staff before arrival and transport of the patient to such a facility is the essential element of prehospital care, and should be prioritized above ancillary testing beyond the stroke assessment.¹⁴

Guidelines recommend use of the National Institutes of Health Stroke Scale ­(NIHSS; www.stroke.nih.gov/resources/scale.htm) for clinical evaluation upon arrival at the ED.¹⁵ Although no scale has been identified that can reliably predict large-vessel occlusion amenable to endovascular therapy (EVT), no other score has been found to outperform the NIHSS in achieving meaningful patient outcomes.¹⁶ Furthermore, NIHSS has been validated to track clinical changes in response to therapy, is widely utilized, and is free.

Continue to: A criticism of the NIHSS...

A criticism of the NIHSS is its bias toward left-hemispheric ischemic pathology.¹⁷ NIHSS includes 11 questions on a scale of 0 to 42; typically, a score < 4 is associated with a higher chance of a positive clinical outcome.¹⁸ There is no minimum or maximum NIHSS score that precludes treatment with thrombolysis or EVT.

Other commonly used scores in acute stroke include disability assessments. The modified Rankin scale, which is used most often, features a score of 0 (symptom-free) to 6 (death). A modified Rankin scale score of 0 or 1 is considered an indication of a favorable outcome after stroke.¹⁹ Note that these functional scores are not always part of an acute assessment but can be done early in the clinical course to gauge the response to treatment, and are collected for stroke-center certification.

Imaging modalities

Imaging is recommended within 20 minutes of arrival in the ED in a stroke patient who might be a candidate for thrombolysis or thrombectomy.³ There, imaging modalities commonly performed are noncontrast-enhanced head computed tomography (NCHCT); computed tomography (CT) angiography, with or without perfusion; and diffusion-weighted magnetic resonance imaging (MRI).^20,21 In addition, more highly specialized imaging modalities are available for the evaluation of the stroke patient in specific, often limited, circumstances. All these modalities are described below and compared in the TABLE,^20,21 using the ACR Appropriateness Criteria (of the American College of Radiology),²¹ which are guidelines for appropriate imaging of stroke, based on a clinical complaint. Separate recommendations and appraisals are offered by the most recent American Heart Association/American Stroke Association (AHA/ASA) guideline.³

NCHCT. This study should be performed within 20 minutes after arrival at the ED because it provides rapid assessment of intracerebral hemorrhage, can effectively corroborate the diagnosis of some stroke mimickers, and identifies some candidates for EVT or thrombolysis^3,21,22 (typically, the decision to proceed with EVT is based on adjunct imaging studies discussed in a bit). Evaluation for intracerebral hemorrhage is required prior to administering thrombolysis. Ischemic changes can be seen with variable specificity and sensitivity on NCHCT, depending on how much time has passed since the original insult. In all historical trials, CT was the only imaging modality used in the diagnosis of acute ischemic stroke (AIS) that suggested benefit from IV thrombolysis.^23-25

Acute, subacute, and chronic changes can be seen on NCHCT, although the modality has limited sensitivity for identifying AIS (ie, approximately 75% within 6 hours after the original insult):

• Acute findings on NCHCT include intracellular edema, which causes loss of the gray matter–white matter interface and effacement of the cortical sulci. This occurs as a result of increased cellular uptake of water in response to ischemia and cell death, resulting in a decreased density of tissue (hypoattenuation) in affected areas.
• Subacute changes appear in the 2- to 5-day window, including vasogenic edema with greater mass effect, hypoattenuation, and well-defined margins.^3,20,21
• Chronic vascular findings on NCHCT include loss of brain tissue and hypoattenuation.

Continue to: NCHCT is typically performed...

NCHCT is typically performed in advance of other adjunct imaging modalities.^3,20,21 Baseline NCHCT can be performed on patients with advanced kidney disease and those who have an indwelling metallic device.

CT angiography is performed with timed contrast, providing a 3-dimensional representation of the cerebral vasculature; the entire intracranial and extracranial vasculature, including the aortic arch, can be mapped in approximately 60 seconds. CT angiography is sensitive in identifying areas of stenosis > 50% and identifies clinically significant areas of stenosis up to approximately 90% of the time.²⁶ For this reason, it is particularly helpful in identifying candidates for an interventional strategy beyond pharmacotherapeutic thrombolysis. In addition, CT angiography can visualize aneurysmal dilation and dissection, and help with the planning of interventions—specifically, the confident administration of thrombolysis or more specific planning for target lesions and EVT.

Commonly used scoring systems in acute stroke include disability assessments— not always part of the acute assessment but undertaken early in the clinical course to gauge response to treatment.

It also can help identify a host of vascular phenomena, such as arteriovenous malformations, Moyamoya disease (progressive arterial blockage within the basal ganglia and compensatory microvascularization), and some vasculopathies.^20,27 In intracranial hemorrhage, CT with angiography can help evaluate for structural malformations and identify patients at risk of hematoma expansion.²²

CT perfusion. Many stroke centers will perform a CT perfusion study,²⁸ which encompasses as many as 3 different CT sequences:

• NCHCT
• vertex-to-arch angiography with contrast bolus
• administration of contrast and capture of a dynamic sequence through 1 or 2 slabs of tissue, allowing for the generation of maps of cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) of the entire cerebral vasculature.

The interplay of these 3 sequences drives characterization of lesions (ie, CBF = CBV/MTT). An infarct is characterized by low CBF, low CBV, and elevated MTT. In penumbral tissue, MTT is elevated but CBF is slightly decreased and CBV is normal or increased. Using CT perfusion, areas throughout the ischemic penumbra can be surveyed for favorable interventional characteristics.^20,29

Continue to: A CT perfusion study adds...

A CT perfusion study adds at least 60 seconds to NCHCT. This modality can be useful in planning interventions and for stratifying appropriateness of reperfusion strategies in strokes of unknown duration.^3,30 CT perfusion can be performed on any multidetector CT scan but (1) requires specialized software and expertise to interpret and (2) subjects the patient to a significant radiation dose, which, if incorrectly administered, can be considerably higher than intended.^20,26,27

Diffusion-weighted MRI. This is the most sensitive study for demonstrating early ischemic changes; however, limitations include lack of availability, contraindication in patients with metallic indwelling implants, and duration of the study—although, at some stroke centers, diffusion-weighted MRI can be performed in ≤ 10 minutes.

MRI and NCHCT have comparable sensitivity in detecting intracranial hemorrhage. MRI is likely more sensitive in identifying areas of microhemorrhage: In diffusion-weighted MRI, the sensitivity of stroke detection increases to > 95%.³¹ The modality relies on the comparable movement of water through damaged vs normal neuronal tissue. Diffusion-weighted MRI does not require administration of concomitant contrast, which can be a benefit in patients who are allergic to gadolinium-based contrast agents or have advanced kidney disease that precludes the use of contrast. It typically does not result in adequate characterization of extracranial vasculature.

Other MRI modalities. These MRI extensions include magnetic resonance (MR) perfusion and MR angiography. Whereas diffusion-weighted MRI (discussed above) offers the most rapid and sensitive evaluation for ischemia, fluid-attenuated inversion recovery (FLAIR) imaging has been utilized as a comparator to isolated diffusion-weighted MRI to help determine stroke duration. FLAIR signal positivity typically occurs 6 to 24 hours after the initial insult but is negative in stroke that occurred < 3 hours earlier.³²

MRI is limited, in terms of availability and increased study duration, especially when it comes to timely administration of thrombolysis. A benefit of this modality is less radiation and, as noted, superior sensitivity for ischemia. Diffusion-weighted MRI combined with MR perfusion analysis can help isolate areas of the ischemic penumbra. MR perfusion is performed for a similar reason as CT perfusion, although logistical execution across those modalities is significantly different. Considerations for choosing MR perfusion or CT perfusion should be made on an individual basis and based on available local resources and accepted local practice patterns.²⁶

Continue to: In the subacute setting...

Knowledge of historic details of the event, the patient (eg, known atrial fibrillation), and findings on imaging can facilitate communication between the primary care physician and inpatient teams.

In the subacute setting, MR perfusion and MR angiography of the head and the neck are often performed to identify stenosis, dissection, and more subtle mimickers of cerebrovascular accident not ascertained on initial CT evaluation. These studies are typically performed well outside the window for thrombolysis or intervention.²⁶ No guidelines specifically direct or recommend this practice pattern. The superior sensitivity and cerebral blood flow mapping of MR perfusion and MR angiography might be useful for validating a suspected diagnosis of ischemic stroke and providing phenotypic information about AIS events.

Transcranial Doppler imaging relies on bony windows to assess intracranial vascular flow, velocity, direction, and reactivity. This information can be utilized to diagnose stenosis or occlusion. This modality is principally used to evaluate for stenosis in the anterior circulation (sensitivity, 70%-90%; specificity, 90%-95%).²⁰ Evaluation of the basilar, vertebral, and internal carotid arteries is less accurate (sensitivity, 55%-80%).²⁰ Transcranial Doppler imaging is also used to assess for cerebral vasospasm after subarachnoid hemorrhage, monitor sickle cell disease patients’ overall risk for ischemic stroke, and augment thrombolysis. It is limited by the availability of an expert technician, and therefore is typically reserved for unstable patients or those who cannot receive contrast.²⁰

Carotid duplex ultrasonography. A dynamic study such as duplex ultrasonography can be strongly considered for flow imaging of the extracranial carotids to evaluate for stenosis. Indications for carotid stenting or endarterectomy include 50% to 79% occlusion of the carotid artery on the same side as a recent transient ischemic attack or AIS. Carotid stenosis > 80% warrants consideration for intervention independent of a recent cerebrovascular accident. Interventions are typically performed 2 to 14 days after stroke.³³ Although this study is of limited utility in the hyperacute setting, it is recommended within 24 hours after nondisabling stroke in the carotid territory, when (1) the patient is otherwise a candidate for a surgical or procedural intervention to address the stenosis and (2) none of the aforementioned studies that focus on neck vasculature have been performed.

Conventional (digital subtraction) ­angiography is the gold standard for mapping cerebrovascular disease because it is dynamic and highly accurate. It is, however, typically limited by the number of required personnel, its invasive nature, and the requirement for IV contrast. This study is performed during intra-arterial intervention techniques, including stent retrieval and intra-arterial thrombolysis.²⁶

Impact of imaging on treatment

Imaging helps determine the cause and some characteristics of stroke, both of which can help determine therapy. Strokes can be broadly subcategorized as hemorrhagic or ischemic; recent studies suggest that 87% are ischemic.³⁴ Knowledge of the historic details of the event, the patient (eg, known atrial fibrillation, anticoagulant use, history of falls), and findings on imaging can contribute to determine the cause of AIS, and can facilitate communication and consultation between the primary care physician and inpatient teams.³⁵

Continue to: Best practices for stroke treatment...

Best practices for stroke treatment are based on the cause of the event.³ To identify the likely cause, the aforementioned characteristics are incorporated into one of the scoring systems, which seek to clarify either the cause or the phenotypic appearance of the AIS, which helps direct further testing and treatment. (The ASCOD³⁶ and TOAST³⁷ classification schemes are commonly used phenotypic and causative classifications, respectively.) Several (not all) of the broad phenotypic imaging patterns, with myriad clinical manifestations, are reviewed below. They include:

• Embolic stroke, which, classically, involves end circulation and therefore has cortical involvement. Typically, these originate from the heart or large extracranial arteries, and higher rates of atrial fibrillation and hypercoagulable states are implicated.
• Thrombotic stroke, which, typically, is from large vessels or small vessels, and occurs as a result of atherosclerosis. These strokes are more common at the origins or bifurcations of vessels. Symptoms of thrombotic stroke classically wax and wane slightly more frequently. Lacunar strokes are typically from thrombotic causes, although there are rare episodes of an embolic source contributing to a lacunar stroke syndrome.³⁸

There is evidence for using MRI discrepancies between diffusion-weighted and FLAIR imaging to time AIS findings in so-called wake-up strokes.³⁹ The rationale is that strokes < 4.5 hours old can be identified because they would have abnormal diffusion imaging components but normal findings with FLAIR. When these criteria were utilized in considering whether to treat with thrombolysis, there was a statistically significant improvement in 90-day modified Rankin scale (odds ratio = 1.61; 95% confidence interval, 1.09-2.36), but also an increased probability of death and intracerebral hemorrhage.³⁹

This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome.

A recent multicenter, randomized, open-label trial, with blinded outcomes assessment, showcased the efficacy of thrombectomy as an adjunct when ischemic brain territory was identified without frank infarction, as ascertained by CT perfusion within the anterior circulation. This trial showed that thrombectomy could be performed as long as 16 hours after the patient was last well-appearing and still result in an improved outcome with favorable imaging characteristics (on the modified Rankin scale, an ordinal score of 4 with medical therapy and an ordinal score of 3 with EVT [odds ratio = 2.77; 95% confidence interval, 1.63-4.70]).²⁹ A 2018 multicenter, prospective, randomized trial with blinded assessment of endpoints extended this idea, demonstrating that, when there was mismatch of the clinical deficit (ie, high NIHSS score) and infarct volume (measured on diffusion-weighted MRI or CT perfusion), thrombectomy as late as 24 hours after the patient was last known to be well was beneficial for lesions in the anterior circulation—specifically, the intracranial internal carotid artery or the proximal middle cerebral artery.⁴⁰

^a Whether local emergency departments (EDs) should be bypassed in favor of a specialized stroke center is the subject of debate. The 2019 American Heart Association/American Stroke Association guidelines note the AHA’s Mission: Lifeline Stroke EMS algorithm, which bypasses the nearest ED in feared cases of large-vessel occlusion if travel to a comprehensive stroke center can be accomplished within 30 minutes of arrival at the scene. This is based on expert consensus.^3,12,13

CORRESPONDENCE
Brian Ford, MD, 4301 Jones Bridge Road, Bethesda, MD; brian.ford@usuhs.edu.

THE CASE

A 67-year-old man with a history of gout, tobacco use, hypertension, hyperlipidemia, prediabetes, and newly diagnosed heart failure with reduced ejection fraction presented with a new concern for sudden-onset, atraumatic right upper extremity pain and swelling. The patient had awakened with these symptoms and on the following day went to the emergency department (ED) for evaluation. Review of the ED documentation highlighted that the patient was afebrile and was found to have a slight leukocytosis (11.7 x 10³/µL) and an elevated C-reactive protein level (4 mg/dL; normal range, 0.3 to 1 mg/dL). A right upper extremity x-ray was unremarkable. The patient was treated with cephalexin and colchicine for cellulitis and possible acute gout.

Three days after the ED visit, the patient presented to his primary care clinic, reporting adherence to the prescribed therapies (cephalexin and colchicine) but no improvement in symptoms. He was again afebrile, and his blood pressure was controlled to goal (118/80 mm Hg). On exam, he had significant nonpitting, unilateral edema extending from the elbow through the fingers without erythema, warmth, or rash (FIGURE). A right upper extremity ultrasound was obtained; results were negative for deep vein thrombosis.

Medication reconciliation completed during the clinic visit revealed that the patient had started and continued to take newly prescribed medications for the treatment of heart failure, including metoprolol succinate, lisinopril, and furosemide. The patient confirmed that these were started 7 days prior to symptom onset.

THE DIAGNOSIS

Given the clinical resemblance to angioedema and the recent initiation of lisinopril, the patient was asked to hold this medication. He was also advised to discontinue the cephalexin and colchicine, given low suspicion for cellulitis and gout. Six days later, he returned to clinic and reported significantly improved pain and swelling.

DISCUSSION

Angioedema is a common condition in the United States, affecting approximately 15% of the general population.¹ When associated with hypotension, respiratory compromise, and other end-organ dysfunction, it is treated as anaphylaxis. Angioedema without anaphylaxis can be categorized as either histaminergic or nonhistaminergic; the former is more common.²

Certain patient and disease characteristics are more prevalent in select subsets of angioedema, although there are no features that automatically identify an etiology. Here are some factors to consider:

Recent exposures. Within the histaminergic category, allergic angioedema has the longest list of potential causes, including medications (notably, antibiotics, nonsteroidal anti-inflammatory drugs, opiates, and perioperative medications), foods, latex, and insect stings and/or bites.² Nonhistaminergic subtypes, which include hereditary and acquired angioedema, are caused by deficiencies or mutations in complement or coagulation pathways, which can be more challenging to diagnose.

Continue to: Acquired angioedema may also...

Acquired angioedema may also be associated with the use of angiotensin-converting enzyme (ACE) inhibitors. Risk factors for ACE inhibitor–induced angioedema include history of smoking, increasing age, and female gender.³ African-American race has been correlated with increased incidence of angioedema, with rates 4 to 5 times that of Whites,¹ but race is now identified as a social and not a biological construct and should not be relied on to make medical decisions about prescribing.

The rate of occurrence for ACE inhibitor–induced angioedema is highest within the first 30 days of medication use²; however, it can occur anytime. The absolute risk has been estimated as 0.3% per year.⁴

Patient age. Histaminergic angioedema can occur at any age. The hereditary subtype of nonhistaminergic angioedema is more common in younger individuals, typically occurring in infancy to the second decade of life, and tends to run in families, while the acquired subtype often manifests in adults older than 40.²

Physical exam findings. The typical manifestation of nonhistaminergic angioedema is firm, nonpitting, nonpruritic swelling resulting from fluid shifts to the reticular dermis and subcutaneous or submucosal tissue. In comparison, histaminergic reactions commonly involve deeper dermal tissue.

The patient’s age, tobacco history, and recent initiation of an ACE inhibitor made acquired angioedema a more likely etiology.

Commonly affected anatomic sites also vary by angioedema type but do not directly distinguish a cause. Allergic and ACE inhibitor–induced subtypes more commonly involve the lips, tongue, larynx, and face, whereas hereditary and other acquired etiologies are more likely to affect the periphery, abdomen, face, larynx, and genitourinary systems.² So the way that this patient presented was a bit unusual.

Continue to: Symptom history

Symptom history. Allergic angioedema often has a rapid onset and resolution, whereas hereditary and acquired subtypes appear more gradually.² While the presence of urticaria distinguishes a histaminergic reaction, both histaminergic and nonhistaminergic angioedema may manifest without this symptom.

In our patient, the timeline of gradual symptom manifestation and the physical exam findings, as well as the patient’s age, tobacco history, and recent initiation of an ACE inhibitor, made acquired angioedema a more likely etiology.

Treatment for ACE inhibitor–induced angioedema, in addition to airway support, entails drug discontinuation. This typically leads to symptom resolution within 24 to 48 hours.² Treatment with corticosteroids, antihistamines, and epinephrine is usually ineffective. Switching to an alternative ACE inhibitor is not recommended, as other members of the class carry the same risk. Instead, angiotensin receptor blockers (ARBs) are an appropriate substitute, as the incidence of cross-reactivity in ACE inhibitor–intolerant patients is estimated to be 10% or less,⁵ and the risk for recurrence has been shown to be no different than with placebo.^3,4

Our patient was transitioned to losartan 25 mg/d without recurrence of his symptoms and with continued blood pressure control (125/60 mm Hg).

THE TAKEAWAY

Angioedema is a common condition. While many medications are associated with histaminergic angioedema, ACE inhibitors are a common cause of the acquired subtype of nonhistaminergic angioedema. Commonly affected sites include the lips, tongue, and face; however, this diagnosis is not dependent on location and may manifest at other sites, as seen in this case. Treatment involves medication discontinuation. When switching the patient’s medication, other members of the ACE inhibitor class should be avoided. ARBs are an appropriate alternative without increased risk for recurrence.

CORRESPONDENCE
Katherine Montag Schafer, University of Minnesota— Department of Family Medicine and Community Health, 1414 Maryland Avenue E, St Paul, MN 55106; monta080@umn.edu

THE CASE

A 67-year-old man with a history of gout, tobacco use, hypertension, hyperlipidemia, prediabetes, and newly diagnosed heart failure with reduced ejection fraction presented with a new concern for sudden-onset, atraumatic right upper extremity pain and swelling. The patient had awakened with these symptoms and on the following day went to the emergency department (ED) for evaluation. Review of the ED documentation highlighted that the patient was afebrile and was found to have a slight leukocytosis (11.7 x 10³/µL) and an elevated C-reactive protein level (4 mg/dL; normal range, 0.3 to 1 mg/dL). A right upper extremity x-ray was unremarkable. The patient was treated with cephalexin and colchicine for cellulitis and possible acute gout.

Three days after the ED visit, the patient presented to his primary care clinic, reporting adherence to the prescribed therapies (cephalexin and colchicine) but no improvement in symptoms. He was again afebrile, and his blood pressure was controlled to goal (118/80 mm Hg). On exam, he had significant nonpitting, unilateral edema extending from the elbow through the fingers without erythema, warmth, or rash (FIGURE). A right upper extremity ultrasound was obtained; results were negative for deep vein thrombosis.

Medication reconciliation completed during the clinic visit revealed that the patient had started and continued to take newly prescribed medications for the treatment of heart failure, including metoprolol succinate, lisinopril, and furosemide. The patient confirmed that these were started 7 days prior to symptom onset.

THE DIAGNOSIS

Given the clinical resemblance to angioedema and the recent initiation of lisinopril, the patient was asked to hold this medication. He was also advised to discontinue the cephalexin and colchicine, given low suspicion for cellulitis and gout. Six days later, he returned to clinic and reported significantly improved pain and swelling.

DISCUSSION

Angioedema is a common condition in the United States, affecting approximately 15% of the general population.¹ When associated with hypotension, respiratory compromise, and other end-organ dysfunction, it is treated as anaphylaxis. Angioedema without anaphylaxis can be categorized as either histaminergic or nonhistaminergic; the former is more common.²

Certain patient and disease characteristics are more prevalent in select subsets of angioedema, although there are no features that automatically identify an etiology. Here are some factors to consider:

Recent exposures. Within the histaminergic category, allergic angioedema has the longest list of potential causes, including medications (notably, antibiotics, nonsteroidal anti-inflammatory drugs, opiates, and perioperative medications), foods, latex, and insect stings and/or bites.² Nonhistaminergic subtypes, which include hereditary and acquired angioedema, are caused by deficiencies or mutations in complement or coagulation pathways, which can be more challenging to diagnose.

Continue to: Acquired angioedema may also...

Acquired angioedema may also be associated with the use of angiotensin-converting enzyme (ACE) inhibitors. Risk factors for ACE inhibitor–induced angioedema include history of smoking, increasing age, and female gender.³ African-American race has been correlated with increased incidence of angioedema, with rates 4 to 5 times that of Whites,¹ but race is now identified as a social and not a biological construct and should not be relied on to make medical decisions about prescribing.

The rate of occurrence for ACE inhibitor–induced angioedema is highest within the first 30 days of medication use²; however, it can occur anytime. The absolute risk has been estimated as 0.3% per year.⁴

Patient age. Histaminergic angioedema can occur at any age. The hereditary subtype of nonhistaminergic angioedema is more common in younger individuals, typically occurring in infancy to the second decade of life, and tends to run in families, while the acquired subtype often manifests in adults older than 40.²

Physical exam findings. The typical manifestation of nonhistaminergic angioedema is firm, nonpitting, nonpruritic swelling resulting from fluid shifts to the reticular dermis and subcutaneous or submucosal tissue. In comparison, histaminergic reactions commonly involve deeper dermal tissue.

The patient’s age, tobacco history, and recent initiation of an ACE inhibitor made acquired angioedema a more likely etiology.

Commonly affected anatomic sites also vary by angioedema type but do not directly distinguish a cause. Allergic and ACE inhibitor–induced subtypes more commonly involve the lips, tongue, larynx, and face, whereas hereditary and other acquired etiologies are more likely to affect the periphery, abdomen, face, larynx, and genitourinary systems.² So the way that this patient presented was a bit unusual.

Continue to: Symptom history

Symptom history. Allergic angioedema often has a rapid onset and resolution, whereas hereditary and acquired subtypes appear more gradually.² While the presence of urticaria distinguishes a histaminergic reaction, both histaminergic and nonhistaminergic angioedema may manifest without this symptom.

In our patient, the timeline of gradual symptom manifestation and the physical exam findings, as well as the patient’s age, tobacco history, and recent initiation of an ACE inhibitor, made acquired angioedema a more likely etiology.

Treatment for ACE inhibitor–induced angioedema, in addition to airway support, entails drug discontinuation. This typically leads to symptom resolution within 24 to 48 hours.² Treatment with corticosteroids, antihistamines, and epinephrine is usually ineffective. Switching to an alternative ACE inhibitor is not recommended, as other members of the class carry the same risk. Instead, angiotensin receptor blockers (ARBs) are an appropriate substitute, as the incidence of cross-reactivity in ACE inhibitor–intolerant patients is estimated to be 10% or less,⁵ and the risk for recurrence has been shown to be no different than with placebo.^3,4

Our patient was transitioned to losartan 25 mg/d without recurrence of his symptoms and with continued blood pressure control (125/60 mm Hg).

THE TAKEAWAY

Angioedema is a common condition. While many medications are associated with histaminergic angioedema, ACE inhibitors are a common cause of the acquired subtype of nonhistaminergic angioedema. Commonly affected sites include the lips, tongue, and face; however, this diagnosis is not dependent on location and may manifest at other sites, as seen in this case. Treatment involves medication discontinuation. When switching the patient’s medication, other members of the ACE inhibitor class should be avoided. ARBs are an appropriate alternative without increased risk for recurrence.

CORRESPONDENCE
Katherine Montag Schafer, University of Minnesota— Department of Family Medicine and Community Health, 1414 Maryland Avenue E, St Paul, MN 55106; monta080@umn.edu

THE CASE

A 67-year-old man with a history of gout, tobacco use, hypertension, hyperlipidemia, prediabetes, and newly diagnosed heart failure with reduced ejection fraction presented with a new concern for sudden-onset, atraumatic right upper extremity pain and swelling. The patient had awakened with these symptoms and on the following day went to the emergency department (ED) for evaluation. Review of the ED documentation highlighted that the patient was afebrile and was found to have a slight leukocytosis (11.7 x 10³/µL) and an elevated C-reactive protein level (4 mg/dL; normal range, 0.3 to 1 mg/dL). A right upper extremity x-ray was unremarkable. The patient was treated with cephalexin and colchicine for cellulitis and possible acute gout.

Three days after the ED visit, the patient presented to his primary care clinic, reporting adherence to the prescribed therapies (cephalexin and colchicine) but no improvement in symptoms. He was again afebrile, and his blood pressure was controlled to goal (118/80 mm Hg). On exam, he had significant nonpitting, unilateral edema extending from the elbow through the fingers without erythema, warmth, or rash (FIGURE). A right upper extremity ultrasound was obtained; results were negative for deep vein thrombosis.

Medication reconciliation completed during the clinic visit revealed that the patient had started and continued to take newly prescribed medications for the treatment of heart failure, including metoprolol succinate, lisinopril, and furosemide. The patient confirmed that these were started 7 days prior to symptom onset.

THE DIAGNOSIS

Given the clinical resemblance to angioedema and the recent initiation of lisinopril, the patient was asked to hold this medication. He was also advised to discontinue the cephalexin and colchicine, given low suspicion for cellulitis and gout. Six days later, he returned to clinic and reported significantly improved pain and swelling.

DISCUSSION

Angioedema is a common condition in the United States, affecting approximately 15% of the general population.¹ When associated with hypotension, respiratory compromise, and other end-organ dysfunction, it is treated as anaphylaxis. Angioedema without anaphylaxis can be categorized as either histaminergic or nonhistaminergic; the former is more common.²

Certain patient and disease characteristics are more prevalent in select subsets of angioedema, although there are no features that automatically identify an etiology. Here are some factors to consider:

Recent exposures. Within the histaminergic category, allergic angioedema has the longest list of potential causes, including medications (notably, antibiotics, nonsteroidal anti-inflammatory drugs, opiates, and perioperative medications), foods, latex, and insect stings and/or bites.² Nonhistaminergic subtypes, which include hereditary and acquired angioedema, are caused by deficiencies or mutations in complement or coagulation pathways, which can be more challenging to diagnose.

Continue to: Acquired angioedema may also...

Acquired angioedema may also be associated with the use of angiotensin-converting enzyme (ACE) inhibitors. Risk factors for ACE inhibitor–induced angioedema include history of smoking, increasing age, and female gender.³ African-American race has been correlated with increased incidence of angioedema, with rates 4 to 5 times that of Whites,¹ but race is now identified as a social and not a biological construct and should not be relied on to make medical decisions about prescribing.

The rate of occurrence for ACE inhibitor–induced angioedema is highest within the first 30 days of medication use²; however, it can occur anytime. The absolute risk has been estimated as 0.3% per year.⁴

Patient age. Histaminergic angioedema can occur at any age. The hereditary subtype of nonhistaminergic angioedema is more common in younger individuals, typically occurring in infancy to the second decade of life, and tends to run in families, while the acquired subtype often manifests in adults older than 40.²

Physical exam findings. The typical manifestation of nonhistaminergic angioedema is firm, nonpitting, nonpruritic swelling resulting from fluid shifts to the reticular dermis and subcutaneous or submucosal tissue. In comparison, histaminergic reactions commonly involve deeper dermal tissue.

The patient’s age, tobacco history, and recent initiation of an ACE inhibitor made acquired angioedema a more likely etiology.

Commonly affected anatomic sites also vary by angioedema type but do not directly distinguish a cause. Allergic and ACE inhibitor–induced subtypes more commonly involve the lips, tongue, larynx, and face, whereas hereditary and other acquired etiologies are more likely to affect the periphery, abdomen, face, larynx, and genitourinary systems.² So the way that this patient presented was a bit unusual.

Continue to: Symptom history

Symptom history. Allergic angioedema often has a rapid onset and resolution, whereas hereditary and acquired subtypes appear more gradually.² While the presence of urticaria distinguishes a histaminergic reaction, both histaminergic and nonhistaminergic angioedema may manifest without this symptom.

In our patient, the timeline of gradual symptom manifestation and the physical exam findings, as well as the patient’s age, tobacco history, and recent initiation of an ACE inhibitor, made acquired angioedema a more likely etiology.

Treatment for ACE inhibitor–induced angioedema, in addition to airway support, entails drug discontinuation. This typically leads to symptom resolution within 24 to 48 hours.² Treatment with corticosteroids, antihistamines, and epinephrine is usually ineffective. Switching to an alternative ACE inhibitor is not recommended, as other members of the class carry the same risk. Instead, angiotensin receptor blockers (ARBs) are an appropriate substitute, as the incidence of cross-reactivity in ACE inhibitor–intolerant patients is estimated to be 10% or less,⁵ and the risk for recurrence has been shown to be no different than with placebo.^3,4

Our patient was transitioned to losartan 25 mg/d without recurrence of his symptoms and with continued blood pressure control (125/60 mm Hg).

THE TAKEAWAY

Angioedema is a common condition. While many medications are associated with histaminergic angioedema, ACE inhibitors are a common cause of the acquired subtype of nonhistaminergic angioedema. Commonly affected sites include the lips, tongue, and face; however, this diagnosis is not dependent on location and may manifest at other sites, as seen in this case. Treatment involves medication discontinuation. When switching the patient’s medication, other members of the ACE inhibitor class should be avoided. ARBs are an appropriate alternative without increased risk for recurrence.

CORRESPONDENCE
Katherine Montag Schafer, University of Minnesota— Department of Family Medicine and Community Health, 1414 Maryland Avenue E, St Paul, MN 55106; monta080@umn.edu

Pruritus, defined as a sensation that induces a desire to scratch¹ and classified as acute or chronic (lasting > 6 weeks),² is one of the most common complaints among primary care patients: Approximately 1% of ambulatory visits in the United States are linked to pruritus.³

Chronic pruritus impairs quality of life; its impact has been compared to that of chronic pain.⁴ Treatment should therefore be instituted promptly. Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition, as we describe here. When persistent pruritus is refractory to treatment, systemic causes should be fully explored.

In this article, we discuss the pathogenesis and management of pruritus without skin eruption in the adult nonpregnant patient. We also present practice recommendations to help you determine whether your patient’s pruritus is indicative of a serious systemic condition.

An incomplete understanding of the pathophysiology of pruritus

The pathophysiology of pruritus is not fully understood. It is generally recognized, however, that pruritus starts in the peripheral nerves located in the dermal–epidermal junction of the skin.⁵ The sensation is then transmitted along unmyelinated slow-conducting C fibers to the dorsal horn of the spinal cord.^5,6 There are 2 types of C fibers that transmit the itch impulse⁶: A histamine-dependent type and a non-­histamine-dependent type, which might explain why pruritus can be refractory to antihistamine treatment.⁶

Once the itch impulse has moved from the spinal cord, it travels along the spinothalamic tract up to the contralateral thalamus.¹ From there, the impulse ascends to the cerebral cortex.¹ In the cortex, the impulse triggers multiple areas of the brain, such as those responsible for sensation, motor function, reward, memory, and emotion.⁷

Although this condition might appear benign, chronic pruritus can be a symptom of a serious condition.

Several chemical mediators have been found to be peripheral and central inducers of pruritus: histamine, endogenous opioids, substance P, and serotonin.² There are indications that certain receptors, such as mu-opioid receptors and kappa-opioid receptors, are key contributors to itch as well.²

A diverse etiology

The International Forum for the Study of Itch (IFSI) has established 6 main categories of causes of pruritus(TABLE 1)²:

• dermatologic
• systemic
• neurologic
• psychogenic
• mixed
• other.

Continue to: In this review...

In this review, we focus on the work-up and management of 3 of those categories: systemic, neurologic, and psychogenic causes of pruritus.

Systemic causes

Research has shown that 14% to 24% of patients who seek the care of a dermatologist for chronic itch without skin lesions have a systemic illness.⁸

Renal disease. Approximately 40% of patients with end-stage renal disease who are on hemodialysis or peritoneal dialysis have uremic pruritus.2 The itch is mostly generalized but can be pronounced on the back. For most patients, the itch is worse at night, causing a major impact on quality of life.⁶

Liver disease. In hepatic disease, there is often impairment in the secretion of bile, which can lead to cholestatic pruritus.² This condition commonly affects the hands and feet first; later, it becomes generalized.² Cholestatic pruritus can be elicited by tight-fitting clothing. Relief is not achieved by scratching.⁹ This type of itch effects 70% of patients with primary biliary cirrhosis and 15% of patients with hepatitis C infection.⁹

Hematologic disorders. Pruritus is a hallmark symptom of polycythemia rubra vera. Almost 50% of patients with this disorder report pruritus that occurs after exposure to water⁹; aquagenic pruritus can precede the formal diagnosis of polycythemia rubra vera by years.² It has been speculated that platelet aggregation in this disorder leads to release of serotonin and histamine, which, in turn, causes itch.⁹

Continue to: Endocrine disorders

Endocrine disorders. Approximately 4% to 11% of patients with thyrotoxicosis have pruritus.¹ It has been suggested that vasodilation, increased skin temperature, and a decreased itch threshold from untreated Graves disease might be inciting factors.

Malignancy. In generalized chronic pruritus without a known cause, strongly consider the likelihood of underlying malignancy^8,10; for 10% of these patients, their chronic pruritus is a paraneoplastic sign. Paraneoplastic pruritus is characterized as an itch that predates clinical onset, or occurs early in the course, of a malignancy.⁹ The condition is most strongly linked to cancers of the liver, gallbladder, biliary tract, hematologic system, and skin.¹¹

Palpate the liver, spleen, lymph nodes, and thyroid for organomegaly, which could indicate a serious systemic condition as the cause of pruritus.

Chronic pruritus affects 30% of patients with Hodgkin lymphoma.⁹ General pruritus can precede this diagnosis by months, even years.¹ In Hodgkin lymphoma patients who are in remission, a return of pruritic symptoms can be a harbinger of recurrence.⁹

Neurologic causes

A recent study found that 8% to 15% of patients referred to a dermatology clinic for chronic pruritus without skin eruption had underlying neurologic pathology.¹² Although the specific mechanisms of neuropathic itch are still poorly understood, it has been theorized that the itch emanates from neuronal damage, which can come from peripheral or central nervous system lesions.⁹

Brachioradial pruritus. There are divergent theories about the etiology of brachioradial pruritus. One hypothesis is that the condition is caused by cervical nerve-root impingement at the level of C5-C8 that leads to nerve damage²; another is that chronic exposure to sunlight causes injury to peripheral cutaneous nerves.² Brachioradial pruritus is localized to the dorsolateral forearm; it can also involve the neck, back, shoulder, upper arm, and chest, unilaterally and bilaterally. This pruritus can be intermittent and become worse upon exposure to sunlight.²

Continue to: Notalgia paresthetica

Notalgia paresthetica. This condition might also cause neuropathic pruritus as a consequence of nerve impingement. The itch of notalgia paresthesia is located on the skin, medial to the scapular border on the upper or mid-back.² It has been postulated that the itch is caused by nerve entrapment of the posterior rami of spinal nerves arising from T2-T6.⁹ However, another theory suggests that the itch is caused by damage to peripheral nerves.⁹ The itch of notalgia paresthetica can wax and wane.²

Poststroke pruritus. Brain lesions, most often caused by stroke, can cause neuropathic itch. One of the best-known syndromes related to poststroke itch is Wallenberg syndrome (ischemia from a lateral medullary infarction), which typically presents with itch, thermalgic hypoesthesia of the face, cerebellar dysfunction, nausea, and vomiting.⁷

Shingles. More than one-half of patients who develop postherpetic neuralgia as a consequence of a herpes zoster infection also develop neuropathic pruritus.⁹ It is thought that postherpetic pruritus shares a comparable pathophysiology with postherpetic neuralgia, in which neurons involved in itch stimuli become damaged.⁷

Diabetes mellitus. Pruritus from diabetes can be classified as systemic or neuropathic. Diabetes is one of the most common causes of small-fiber polyneuropathy, which can cause neuropathic pruritus.¹³

Multiple sclerosis. Central nervous system lesions that affect sensory pathways can lead to neuropathic itch in multiple sclerosis. Patients can have severe episodes of generalized pruritus. It has been hypothesized that the neuropathic itch in multiple sclerosis is induced by activation of artificial synapses in demyelinated areas.²

Continue to: Psychogenic pruritus

Chronic pruritus can be a comorbidity of psychiatric illness. A retrospective study found that pruritus occurs in 32% to 42% of psychiatric inpatients.¹⁴ Depression, anxiety, bipolar disorders, obsessive–compulsive disorders, somatoform disorders, psychosis, and substance abuse all have a strong link to psychogenic excoriation.¹⁵ Psychogenic excoriation, which can cause secondary skin lesions, occurs in psychiatric patients who excessively pick and scratch normal skin because they perceive an itch sensation or have a delusion of infestation.² Affected skin can be marked by scattered crusted lesions (FIGURE) anywhere on the body that the patient can reach—most commonly, the extremities.²

Delusion of infestation. Patients with a delusion of infestation have a strong belief that their body is infected by some kind of insect or microorganism.¹⁶ Before a diagnosis of delusion of infestation can be made, other organic causes must be excluded, including withdrawal from such substances as cocaine, amphetamines, and alcohol.¹⁶ Patients with a delusion of infestation can have, and maintain, a symptomatic response with continuing use of an atypical antipsychotic agent, including risperidone and olanzapine.¹⁷

Evaluation and diagnostic work-up

A thorough medical history, review of systems, medication review, social history, and family history are important when evaluating a patient with chronic pruritus.¹⁸ These items can be valuable in formulating a differential diagnosis, even before a physical examination.

Physical examination. The physical exam should include detailed inspection of the entire skin and hair¹⁸; such a comprehensive physical exam can determine whether the source of the itch is cutaneous.⁷ This, in turn, can help further narrow the differential diagnosis. It is crucial that the physical exam include palpation of the liver, spleen, lymph nodes, and thyroid for organomegaly,⁸ which could indicate a serious systemic condition, such as lymphoma.

The ice-pack sign—in which an ice pack applied to the pruritic area provides immediate relief—is considered pathognomonic for brachioradial pruritus.

The ice-pack sign—in which an ice pack is applied to the pruritic area, the patient experiences immediate relief of pruritus, and the itch returns soon after the ice pack is removed—is considered pathognomonic for brachioradial pruritus.¹⁹

Continue to: Chronic pruritus with abnormal findings...

Chronic pruritus with abnormal findings on the physical exam should prompt an initial work-up.¹⁸ Also consider an initial work-up for a patient with chronic pruritus whose symptom has not been relieved with conservative treatment.¹⁸

Laboratory testing. The initial laboratory work-up could include any of the following evaluations: complete blood count, measurement of thyroid-stimulating hormone, comprehensive metabolic panel (liver function, renal function, and the serum glucose level) and the erythrocyte sedimentation rate (TABLE 2).¹⁸ If warranted by the evaluation and physical exam, blood work can also include serologic studies for human immunodeficiency virus infection and ­hepatitis.¹⁷