Bell palsy is an idiopathic peripheral nerve disorder involving the facial nerve (ie, cranial nerve VII) and manifesting as acute, ipsilateral facial muscle weakness. It is named after Sir Charles Bell, who in 1821 first described the anatomy of the facial nerve.¹ Although the disorder is clinically benign, patients can be devastated by its disfigurement.

The annual incidence of Bell palsy is 20 per 100,000, with no predilection for sex or ethnicity. It can affect people at any age, but the incidence is slightly higher after age 40.^2,3 Risk factors include diabetes, pregnancy, severe preeclampsia, obesity, and hypertension.^4–7

THE FACIAL NERVE IS VULNERABLE TO TRAUMA AND COMPRESSION

A basic understanding of the neuroanatomy of the facial nerve provides clues for distinguishing a central lesion from a peripheral lesion. This differentiation is important because the causes and management differ.

The facial nerve is a mixed sensory and motor nerve, carrying fibers involved in facial expression, taste, lacrimation, salivation, and sensation of the ear. It originates in the lower pons and exits the brainstem ventrally at the pontomedullary junction. After entering the internal acoustic meatus, it travels 20 to 30 mm in the facial canal, the longest bony course of any cranial nerve, making it highly susceptible to trauma and compression by edema.⁸

In the facial canal, it makes a posterior and inferior turn, forming a bend (ie, the genu of the facial nerve). The genu is proximal to the geniculate ganglion, which contains the facial nerve’s primary sensory neurons for taste and sensation. The motor branch of the facial nerve then exits the cranium via the stylomastoid foramen and passes through the parotid gland, where it divides into temporofacial and cervicofacial trunks.⁹

The facial nerve has five terminal branches that innervate the muscles of facial expression:

• The temporal branch (muscles of the forehead and superior part of the orbicularis oculi)
• The zygomatic branch (muscles of the nasolabial fold and cheek, eg, nasalis and zygomaticus).
• The buccal branch (the buccinators and inferior part of the orbicularis oculi)
• The marginal mandibular branch (the depressors of the mouth, eg, depressor anguli and mentalis)
• The cervical branch (the platysma muscle).

INFLAMMATION IS BELIEVED TO BE RESPONSIBLE

Although the precise cause of Bell palsy is not known, one theory is that inflammation of the nerve causes focal edema, demyelination, and ischemia. Several studies have suggested that herpes virus simplex type 1 infection may be involved.¹⁰

FACIAL DROOPING, EYELID WEAKNESS, OTHER SYMPTOMS

Symptoms of Bell palsy include ipsilateral sagging of the eyebrow, drooping of the face, flattening of the nasolabial fold, and inability to fully close the eye, pucker the lips, or raise the corner of the mouth (Figure 1). Symptoms develop within hours and are maximal by 3 days.

About 70% of patients have associated ipsilateral pain around the ear. If facial pain is present with sensory and hearing loss, a tumor of the parotid gland or viral otitis must be considered.¹¹ Other complaints may include hyperacusis due to disruption of nerve fibers to the stapedius muscle, changes in taste, and dry eye from parasympathetic dysfunction. Some patients report paresthesias over the face, which most often represent motor symptoms misconstrued as sensory changes.

PHYSICAL EXAMINATION

The clinical examination should include a complete neurologic and general examination, including otoscopy and attention to the skin and parotid gland. Vesicles or scabbing around the ear should prompt testing for herpes zoster. Careful observation during the interview while the patient is talking may reveal subtle signs of weakness and provide additional clues.

A systematic approach to the assessment of a patient with suspected Bell palsy is recommended (Table 1) and outlined below:

Does the patient have peripheral facial palsy?

In Bell palsy, wrinkling of the forehead on the affected side when raising the eyebrows is either asymmetrical or absent.

If the forehead muscles are spared and the lower face is weak, this signifies a central lesion such as a stroke or other structural abnormality and not a peripheral lesion of the facial nerve (eg, Bell palsy).

Can the patient close the eyes tightly?

Normally, the patient should be able to close both eyes tightly, and the eyelashes should be buried between the eyelids. In Bell palsy, when the patient attempts to close the eyes, the affected side shows incomplete closure and the eye may remain partly open.

Assess the strength of the orbicularis oculi by trying to open the eyes. The patient who is attempting to close the eyelids tightly but cannot will demonstrate the Bell phenomenon, ie, the examiner is able to force open the eyelids, and the eyes are deviated upward and laterally.

Closely observe the blink pattern, as the involved side in Bell palsy may slightly lag behind the normal eye, and the patient may be unable to close the eye completely.

Is the smile symmetric?

Note flattening of the nasolabial fold on one side, which indicates facial weakness.

Can the patient puff out the cheeks?

Ask the patient to hold air in the mouth against resistance. This assesses the strength of the buccinator muscle.

Can the patient purse the lips?

Ask the patient to pucker or purse the lips and observe for asymmetry or weakness on the affected side.

Test the orbicularis oris muscle by trying to spread the lips apart while the patient resists, and observe for weakness on one side.

Is there a symmetric grimace?

This will test the muscles involved in depressing the angles of the mouth and platysma.

Are taste, sensation, and hearing intact?

Other testable functions of the facial nerve, including taste, sensation, and hearing, do not always need to be assessed but can be in patients with specific sensory deficits.

Facial palsy that does not improve after 3 weeks should prompt a referral to a neurologist

Abnormalities in taste can support localization of the problem either proximal or distal to the branch point of fibers mediating taste. The facial nerve supplies taste fibers to the anterior two-thirds of the tongue. Sweet and salty taste can be screened with sugar and salt. Tell the patient to close the eyes, and using a tongue blade, apply a small amount of sugar or salt on the side of the tongue. Ask the patient to identify the taste and repeat with the other sample after he or she has rinsed the mouth.

Somatic sensory fibers supplied by the facial nerve innervate the inner ear and a small area behind the ear, but these may be difficult to assess objectively. Formal audiologic testing may be needed if hearing is impaired.

Facial nerve reflexes

A number of facial reflexes can be tested, including the orbicularis oculi, palpebral-oculogyric, and corneal reflexes.¹²

The orbicularis oculi reflex is tested by gentle finger percussion of the glabella while observing for involuntary blinking with each stimulus. The afferent branch of this reflex is carried by the trigeminal nerve, while the efferent response is carried by the facial nerve. In peripheral facial nerve palsy, this reflex is weakened or absent on the affected side.

The palpebral-oculogyric reflex, or Bell phenomenon, produces upward and lateral deviation of the eyes when attempting forceful eyelid closure. In this reflex, the afferent fibers are carried by the facial nerve and the efferent fibers travel in the oculomotor nerve to the superior rectus muscle. In Bell palsy, this reflex is visible because of failure of adequate eyelid closure.

The corneal reflex is elicited by stimulating the cornea with a wisp of cotton, causing reflexive closure of the both eyes. The affected side may show slowed or absent lid closure when tested on either side. The sensory afferent fibers are carried by the trigeminal nerve, and the motor efferent fibers are carried by the facial nerve.

Grading of facial paralysis

The House-Brackmann scale is the most widely used tool for grading the degree of facial paralysis and for predicting recovery. Grades are I to VI, with grade I indicating normal function, and grade VI, complete paralysis.

Patients with some preserved motor function generally have good recovery, but those with complete paralysis may have long-term residual deficits.¹³

A DIAGNOSIS OF EXCLUSION

The diagnosis of Bell palsy is made by excluding other causes of unilateral facial paralysis, and 30% to 60% of cases of facial palsy are caused by an underlying disorder that mimics Bell palsy, including central nervous system lesion (eg, stroke, demyelinating disease), parotid gland tumor, Lyme disease, Ramsay Hunt syndrome, granulomatous disease, otitis media, cholesteatoma, diabetes, trauma, and Guillain-Barré syndrome (Table 2).^14,15 Many of these conditions have associated features that help distinguish them from Bell palsy. Facial palsy that does not improve after 3 weeks should prompt referral to a neurologist.

Brain lesions

It is uncommon to have isolated facial palsy with a cortical or subcortical brain lesion, since the corticobulbar and corticospinal tracts travel in close proximity. Cortical signs such as hemiparesis, hemisensory loss, neglect, and dysarthria suggest a lesion of the cerebral cortex. Additionally, forehead muscle sparing is expected in supranuclear lesions.

Brainstem lesions can manifest with multiple ipsilateral cranial nerve palsies and contralateral limb weakness. Sarcoidosis and leptomeningeal carcinomatosis tend to involve the skull base and present with multiple cranial neuropathies.

Tumors of the brain or parotid gland have an insidious onset and may cause systemic signs such as fevers, chills, and weight loss. Headache, seizures, and hearing loss indicate an intracranial lesion. A palpable mass near the ear, neck, or parotid gland requires imaging of the face to look for a parotid gland tumor.

Infection

A number of infections can cause acute facial paralysis. The most common is herpes simplex virus, and the next most common is varicella zoster.¹⁴ Herpes simplex virus, Ramsay Hunt syndrome, and Lyme disease may have associated pain and skin changes. Erythema of the tympanic membrane suggests otitis media, especially in the setting of ear pain and hearing loss.

Ramsay Hunt syndrome is caused by reactivation of the herpes zoster virus from the geniculate ganglion, affecting the facial nerve. Careful examination of the ear canal and the oropharynx may show vesicles.

In Lyme disease, facial palsy is the most common cranial neuropathy, seen in 50% to 63% of patients with Borrelia burgdorferi meningitis.^16,17 In people with a history of rash, arthralgia, tick bite, or travel to an endemic region, Lyme titers should be checked before starting the patient on corticosteroids.

Bilateral facial palsy is rare and occurs in fewer than 1% of patients. It has been reported in patients with Lyme disease, Guillain-Barré syndrome, sarcoidosis, diabetes mellitus, viral infection, and pontine glioma.¹⁸

DIAGNOSTIC EVALUATION

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy. However, referral to the appropriate specialist (neurologist, otolaryngologist, optometrist, ophthalmologist) is advised if the patient has sparing of the forehead muscle, multiple cranial neuropathies, signs of infection, or persistent weakness without significant improvement at 3 weeks.

Laboratory testing

A complete blood cell count with differential may point to infection or a lymphoproliferative disorder. When indicated, screening for diabetes mellitus with fasting blood glucose or hemoglobin A_1c may be helpful. In Lyme-endemic regions, patients should undergo an enzyme-linked immunosorbent assay or an indirect fluorescent antibody test to screen for the disease. If positive, the diagnosis of Lyme disease should be confirmed by Western blot. If vesicles are present on examination, check serum antibodies for herpes zoster. In the appropriate clinical setting, angiotensin-converting enzyme, human immunodeficiency virus, and inflammatory markers can be tested.

Cerebrospinal fluid analysis is generally not helpful in diagnosing Bell palsy but can differentiate it from Guillain-Barré syndrome, leptomeningeal carcinomatosis, and infection involving the central nervous system.

Imaging

Imaging is not recommended in the initial evaluation of Bell palsy unless symptoms and the examination are atypical. From 5% to 7% of cases of facial palsy are caused by a tumor (eg, facial neuroma, cholesteatoma, hemangioma, meningioma), whether benign or malignant.^14,15 Therefore, in patients with insidious onset of symptoms that do not improve in about 3 weeks, contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging of the internal auditory canal and face is warranted.

Electrodiagnostic studies

Electrodiagnostic testing is typically not part of the evaluation of acute Bell palsy, but in patients with complete paralysis, it may help assess the degree of nerve injury and the chances of recovery, especially since patients with complete paralysis have a higher risk of incomplete recovery.¹⁹ Electrodiagnostic studies should be performed at least 1 week after symptom onset to avoid false-negative results.

TREATMENT

The treatment of Bell palsy focuses on maximizing recovery and minimizing associated complications.

Protect the eyes

Patients who cannot completely close their eyes should be given instructions on ocular protective care to prevent exposure keratopathy. Frequent application of lubricant eyedrops with artificial tears during the day or ophthalmic ointment at bedtime is recommended. The physician should also recommend protective eyewear such as sunglasses during the day. Eye patching or taping at night may be useful but could be harmful if applied too loosely or too tightly. Patients with vision loss or eye irritation should be referred to an ophthalmologist.¹⁹

Corticosteroids are recommended in the first 72 hours

In two randomized clinical trials (conducted by Sullivan et al²⁰ in 511 patients and Engström et al²¹ in 829 patients), prednisolone was found to be beneficial if started within 72 hours of symptom onset.

In a double-blind, randomized, placebo-controlled study of prednisone in 58 patients, those who received the drug recovered faster, although long-term outcomes in these patients were not significantly different than those in the control group.²² The American Academy of Neurology²³ rated this study as class II, ie, not meeting all of its criteria for the highest level of evidence, class I. Nevertheless, although prednisone lacks class I evidence, its use is recommended because it is a precursor to its active metabolite, prednisolone, which has been studied extensively.

The current guidelines of the American Academy of Neurology, updated in 2012, state, “For patients with new-onset Bell palsy, steroids are highly likely to be effective and should be offered to increase the probability of recovery of facial nerve function”²³ (level A evidence, ie, established as effective). They also concluded that adverse effects of corticosteroids were generally minor and temporary.

Similarly, the guidelines of the American Academy of Otolaryngology–Head and Neck Surgery, published in 2013, recommend oral corticosteroids within 72 hours of onset of symptoms of Bell palsy for patients age 16 and older.¹⁹ The recommendation is for a 10-day course of corticosteroids with at least 5 days at a high dose (prednisolone 50 mg orally daily for 10 days, or prednisone 60 mg orally daily for 5 days, followed by a 5-day taper). The benefit of corticosteroids after 72 hours is unclear (Table 3).¹⁹

Even though the guidelines recommend corticosteroids, the decision to use them in diabetic patients and pregnant women should be individualized. Discretion is advised, as not all patients with Bell palsy need to be treated. Most recover spontaneously, especially those with mild symptoms.

Antiviral therapy may offer modest benefit

Antiviral therapy has not been shown to be beneficial in Bell palsy, and current guidelines do not recommend oral antiviral therapy alone.¹⁹ However, an antiviral combined with a corticosteroid may offer modest benefit if started within 72 hours of symptom onset (level C evidence, ie, possibly effective).²³ Patients starting antiviral therapy should understand that its benefit has not been established.

Surgical decompression remains controversial

A Cochrane systematic review in 2011 found insufficient evidence regarding the safety and efficacy of surgical intervention in Bell palsy.²⁴ Surgery should be considered only for patients with complete paralysis with a greater than 90% reduction in motor amplitude on a nerve conduction study compared with the unaffected side, and absent volitional activity on needle examination.^19,25

Acupuncture: No recommendation

Currently, there is no recommendation for acupuncture in the treatment of Bell palsy.¹⁹ A recent randomized clinical trial suggests benefit from acupuncture combined with corticosteroids,²⁶ but high-quality studies to support its use are lacking.²⁶

Physical therapy: Insufficient evidence

There is insufficient evidence to show that physical therapy has benefit—or harm—in Bell palsy. However, some low-quality studies indicated that facial exercises and mime therapy may improve function in patients with moderate paralysis.²⁷

Follow-up

Instruct patients to call at 2 weeks to report progress of symptoms

Patients should be instructed to call at 2 weeks to report progress of symptoms and to be reevaluated within or at 1 month, with close attention to facial weakness and eye irritation. Further evaluation is needed if there has been no improvement, if symptoms have worsened, or if new symptoms have appeared.

The psychosocial impact of Bell palsy cannot be discounted, as the disfigurement can have negative implications for self-esteem and social relationships. Appropriate referral to an ophthalmologist, neurologist, otolaryngologist, social worker, or a plastic surgeon may be necessary.

COMPLICATIONS AND PROGNOSIS

Most patients with Bell palsy recover completely, but up to 30% have residual symptoms at 6 months.^14,20 Furthermore, although Bell palsy usually has a monophasic course, 7% to 12% of patients have a recurrence.^3,15

Long-term complications can include residual facial weakness, facial synkinesis, facial contracture, and facial spasm.^14,28 Incomplete eye closure may benefit from surgery (tarsorrhaphy or gold-weight implantation) to prevent corneal ulceration. Facial synkinesis is due to aberrant nerve regeneration and occurs in 15% to 20% of patients after recovery from Bell palsy.²⁹ Patients may describe tearing while chewing (“crocodile tears”), involuntary movement of the corners of the mouth with blinking, or ipsilateral eye-closing when the jaw opens (“jaw-winking”). Facial contracture, facial synkinesis, and facial spasm can be treated with botulinum toxin injection.³⁰

Bell palsy is an idiopathic peripheral nerve disorder involving the facial nerve (ie, cranial nerve VII) and manifesting as acute, ipsilateral facial muscle weakness. It is named after Sir Charles Bell, who in 1821 first described the anatomy of the facial nerve.¹ Although the disorder is clinically benign, patients can be devastated by its disfigurement.

The annual incidence of Bell palsy is 20 per 100,000, with no predilection for sex or ethnicity. It can affect people at any age, but the incidence is slightly higher after age 40.^2,3 Risk factors include diabetes, pregnancy, severe preeclampsia, obesity, and hypertension.^4–7

THE FACIAL NERVE IS VULNERABLE TO TRAUMA AND COMPRESSION

A basic understanding of the neuroanatomy of the facial nerve provides clues for distinguishing a central lesion from a peripheral lesion. This differentiation is important because the causes and management differ.

The facial nerve is a mixed sensory and motor nerve, carrying fibers involved in facial expression, taste, lacrimation, salivation, and sensation of the ear. It originates in the lower pons and exits the brainstem ventrally at the pontomedullary junction. After entering the internal acoustic meatus, it travels 20 to 30 mm in the facial canal, the longest bony course of any cranial nerve, making it highly susceptible to trauma and compression by edema.⁸

In the facial canal, it makes a posterior and inferior turn, forming a bend (ie, the genu of the facial nerve). The genu is proximal to the geniculate ganglion, which contains the facial nerve’s primary sensory neurons for taste and sensation. The motor branch of the facial nerve then exits the cranium via the stylomastoid foramen and passes through the parotid gland, where it divides into temporofacial and cervicofacial trunks.⁹

The facial nerve has five terminal branches that innervate the muscles of facial expression:

• The temporal branch (muscles of the forehead and superior part of the orbicularis oculi)
• The zygomatic branch (muscles of the nasolabial fold and cheek, eg, nasalis and zygomaticus).
• The buccal branch (the buccinators and inferior part of the orbicularis oculi)
• The marginal mandibular branch (the depressors of the mouth, eg, depressor anguli and mentalis)
• The cervical branch (the platysma muscle).

INFLAMMATION IS BELIEVED TO BE RESPONSIBLE

Although the precise cause of Bell palsy is not known, one theory is that inflammation of the nerve causes focal edema, demyelination, and ischemia. Several studies have suggested that herpes virus simplex type 1 infection may be involved.¹⁰

FACIAL DROOPING, EYELID WEAKNESS, OTHER SYMPTOMS

Symptoms of Bell palsy include ipsilateral sagging of the eyebrow, drooping of the face, flattening of the nasolabial fold, and inability to fully close the eye, pucker the lips, or raise the corner of the mouth (Figure 1). Symptoms develop within hours and are maximal by 3 days.

About 70% of patients have associated ipsilateral pain around the ear. If facial pain is present with sensory and hearing loss, a tumor of the parotid gland or viral otitis must be considered.¹¹ Other complaints may include hyperacusis due to disruption of nerve fibers to the stapedius muscle, changes in taste, and dry eye from parasympathetic dysfunction. Some patients report paresthesias over the face, which most often represent motor symptoms misconstrued as sensory changes.

PHYSICAL EXAMINATION

The clinical examination should include a complete neurologic and general examination, including otoscopy and attention to the skin and parotid gland. Vesicles or scabbing around the ear should prompt testing for herpes zoster. Careful observation during the interview while the patient is talking may reveal subtle signs of weakness and provide additional clues.

A systematic approach to the assessment of a patient with suspected Bell palsy is recommended (Table 1) and outlined below:

Does the patient have peripheral facial palsy?

In Bell palsy, wrinkling of the forehead on the affected side when raising the eyebrows is either asymmetrical or absent.

If the forehead muscles are spared and the lower face is weak, this signifies a central lesion such as a stroke or other structural abnormality and not a peripheral lesion of the facial nerve (eg, Bell palsy).

Can the patient close the eyes tightly?

Normally, the patient should be able to close both eyes tightly, and the eyelashes should be buried between the eyelids. In Bell palsy, when the patient attempts to close the eyes, the affected side shows incomplete closure and the eye may remain partly open.

Assess the strength of the orbicularis oculi by trying to open the eyes. The patient who is attempting to close the eyelids tightly but cannot will demonstrate the Bell phenomenon, ie, the examiner is able to force open the eyelids, and the eyes are deviated upward and laterally.

Closely observe the blink pattern, as the involved side in Bell palsy may slightly lag behind the normal eye, and the patient may be unable to close the eye completely.

Is the smile symmetric?

Note flattening of the nasolabial fold on one side, which indicates facial weakness.

Can the patient puff out the cheeks?

Ask the patient to hold air in the mouth against resistance. This assesses the strength of the buccinator muscle.

Can the patient purse the lips?

Ask the patient to pucker or purse the lips and observe for asymmetry or weakness on the affected side.

Test the orbicularis oris muscle by trying to spread the lips apart while the patient resists, and observe for weakness on one side.

Is there a symmetric grimace?

This will test the muscles involved in depressing the angles of the mouth and platysma.

Are taste, sensation, and hearing intact?

Other testable functions of the facial nerve, including taste, sensation, and hearing, do not always need to be assessed but can be in patients with specific sensory deficits.

Facial palsy that does not improve after 3 weeks should prompt a referral to a neurologist

Abnormalities in taste can support localization of the problem either proximal or distal to the branch point of fibers mediating taste. The facial nerve supplies taste fibers to the anterior two-thirds of the tongue. Sweet and salty taste can be screened with sugar and salt. Tell the patient to close the eyes, and using a tongue blade, apply a small amount of sugar or salt on the side of the tongue. Ask the patient to identify the taste and repeat with the other sample after he or she has rinsed the mouth.

Somatic sensory fibers supplied by the facial nerve innervate the inner ear and a small area behind the ear, but these may be difficult to assess objectively. Formal audiologic testing may be needed if hearing is impaired.

Facial nerve reflexes

A number of facial reflexes can be tested, including the orbicularis oculi, palpebral-oculogyric, and corneal reflexes.¹²

The orbicularis oculi reflex is tested by gentle finger percussion of the glabella while observing for involuntary blinking with each stimulus. The afferent branch of this reflex is carried by the trigeminal nerve, while the efferent response is carried by the facial nerve. In peripheral facial nerve palsy, this reflex is weakened or absent on the affected side.

The palpebral-oculogyric reflex, or Bell phenomenon, produces upward and lateral deviation of the eyes when attempting forceful eyelid closure. In this reflex, the afferent fibers are carried by the facial nerve and the efferent fibers travel in the oculomotor nerve to the superior rectus muscle. In Bell palsy, this reflex is visible because of failure of adequate eyelid closure.

The corneal reflex is elicited by stimulating the cornea with a wisp of cotton, causing reflexive closure of the both eyes. The affected side may show slowed or absent lid closure when tested on either side. The sensory afferent fibers are carried by the trigeminal nerve, and the motor efferent fibers are carried by the facial nerve.

Grading of facial paralysis

The House-Brackmann scale is the most widely used tool for grading the degree of facial paralysis and for predicting recovery. Grades are I to VI, with grade I indicating normal function, and grade VI, complete paralysis.

Patients with some preserved motor function generally have good recovery, but those with complete paralysis may have long-term residual deficits.¹³

A DIAGNOSIS OF EXCLUSION

The diagnosis of Bell palsy is made by excluding other causes of unilateral facial paralysis, and 30% to 60% of cases of facial palsy are caused by an underlying disorder that mimics Bell palsy, including central nervous system lesion (eg, stroke, demyelinating disease), parotid gland tumor, Lyme disease, Ramsay Hunt syndrome, granulomatous disease, otitis media, cholesteatoma, diabetes, trauma, and Guillain-Barré syndrome (Table 2).^14,15 Many of these conditions have associated features that help distinguish them from Bell palsy. Facial palsy that does not improve after 3 weeks should prompt referral to a neurologist.

Brain lesions

It is uncommon to have isolated facial palsy with a cortical or subcortical brain lesion, since the corticobulbar and corticospinal tracts travel in close proximity. Cortical signs such as hemiparesis, hemisensory loss, neglect, and dysarthria suggest a lesion of the cerebral cortex. Additionally, forehead muscle sparing is expected in supranuclear lesions.

Brainstem lesions can manifest with multiple ipsilateral cranial nerve palsies and contralateral limb weakness. Sarcoidosis and leptomeningeal carcinomatosis tend to involve the skull base and present with multiple cranial neuropathies.

Tumors of the brain or parotid gland have an insidious onset and may cause systemic signs such as fevers, chills, and weight loss. Headache, seizures, and hearing loss indicate an intracranial lesion. A palpable mass near the ear, neck, or parotid gland requires imaging of the face to look for a parotid gland tumor.

Infection

A number of infections can cause acute facial paralysis. The most common is herpes simplex virus, and the next most common is varicella zoster.¹⁴ Herpes simplex virus, Ramsay Hunt syndrome, and Lyme disease may have associated pain and skin changes. Erythema of the tympanic membrane suggests otitis media, especially in the setting of ear pain and hearing loss.

Ramsay Hunt syndrome is caused by reactivation of the herpes zoster virus from the geniculate ganglion, affecting the facial nerve. Careful examination of the ear canal and the oropharynx may show vesicles.

In Lyme disease, facial palsy is the most common cranial neuropathy, seen in 50% to 63% of patients with Borrelia burgdorferi meningitis.^16,17 In people with a history of rash, arthralgia, tick bite, or travel to an endemic region, Lyme titers should be checked before starting the patient on corticosteroids.

Bilateral facial palsy is rare and occurs in fewer than 1% of patients. It has been reported in patients with Lyme disease, Guillain-Barré syndrome, sarcoidosis, diabetes mellitus, viral infection, and pontine glioma.¹⁸

DIAGNOSTIC EVALUATION

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy. However, referral to the appropriate specialist (neurologist, otolaryngologist, optometrist, ophthalmologist) is advised if the patient has sparing of the forehead muscle, multiple cranial neuropathies, signs of infection, or persistent weakness without significant improvement at 3 weeks.

Laboratory testing

A complete blood cell count with differential may point to infection or a lymphoproliferative disorder. When indicated, screening for diabetes mellitus with fasting blood glucose or hemoglobin A_1c may be helpful. In Lyme-endemic regions, patients should undergo an enzyme-linked immunosorbent assay or an indirect fluorescent antibody test to screen for the disease. If positive, the diagnosis of Lyme disease should be confirmed by Western blot. If vesicles are present on examination, check serum antibodies for herpes zoster. In the appropriate clinical setting, angiotensin-converting enzyme, human immunodeficiency virus, and inflammatory markers can be tested.

Cerebrospinal fluid analysis is generally not helpful in diagnosing Bell palsy but can differentiate it from Guillain-Barré syndrome, leptomeningeal carcinomatosis, and infection involving the central nervous system.

Imaging

Imaging is not recommended in the initial evaluation of Bell palsy unless symptoms and the examination are atypical. From 5% to 7% of cases of facial palsy are caused by a tumor (eg, facial neuroma, cholesteatoma, hemangioma, meningioma), whether benign or malignant.^14,15 Therefore, in patients with insidious onset of symptoms that do not improve in about 3 weeks, contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging of the internal auditory canal and face is warranted.

Electrodiagnostic studies

Electrodiagnostic testing is typically not part of the evaluation of acute Bell palsy, but in patients with complete paralysis, it may help assess the degree of nerve injury and the chances of recovery, especially since patients with complete paralysis have a higher risk of incomplete recovery.¹⁹ Electrodiagnostic studies should be performed at least 1 week after symptom onset to avoid false-negative results.

TREATMENT

The treatment of Bell palsy focuses on maximizing recovery and minimizing associated complications.

Protect the eyes

Patients who cannot completely close their eyes should be given instructions on ocular protective care to prevent exposure keratopathy. Frequent application of lubricant eyedrops with artificial tears during the day or ophthalmic ointment at bedtime is recommended. The physician should also recommend protective eyewear such as sunglasses during the day. Eye patching or taping at night may be useful but could be harmful if applied too loosely or too tightly. Patients with vision loss or eye irritation should be referred to an ophthalmologist.¹⁹

Corticosteroids are recommended in the first 72 hours

In two randomized clinical trials (conducted by Sullivan et al²⁰ in 511 patients and Engström et al²¹ in 829 patients), prednisolone was found to be beneficial if started within 72 hours of symptom onset.

In a double-blind, randomized, placebo-controlled study of prednisone in 58 patients, those who received the drug recovered faster, although long-term outcomes in these patients were not significantly different than those in the control group.²² The American Academy of Neurology²³ rated this study as class II, ie, not meeting all of its criteria for the highest level of evidence, class I. Nevertheless, although prednisone lacks class I evidence, its use is recommended because it is a precursor to its active metabolite, prednisolone, which has been studied extensively.

The current guidelines of the American Academy of Neurology, updated in 2012, state, “For patients with new-onset Bell palsy, steroids are highly likely to be effective and should be offered to increase the probability of recovery of facial nerve function”²³ (level A evidence, ie, established as effective). They also concluded that adverse effects of corticosteroids were generally minor and temporary.

Similarly, the guidelines of the American Academy of Otolaryngology–Head and Neck Surgery, published in 2013, recommend oral corticosteroids within 72 hours of onset of symptoms of Bell palsy for patients age 16 and older.¹⁹ The recommendation is for a 10-day course of corticosteroids with at least 5 days at a high dose (prednisolone 50 mg orally daily for 10 days, or prednisone 60 mg orally daily for 5 days, followed by a 5-day taper). The benefit of corticosteroids after 72 hours is unclear (Table 3).¹⁹

Even though the guidelines recommend corticosteroids, the decision to use them in diabetic patients and pregnant women should be individualized. Discretion is advised, as not all patients with Bell palsy need to be treated. Most recover spontaneously, especially those with mild symptoms.

Antiviral therapy may offer modest benefit

Antiviral therapy has not been shown to be beneficial in Bell palsy, and current guidelines do not recommend oral antiviral therapy alone.¹⁹ However, an antiviral combined with a corticosteroid may offer modest benefit if started within 72 hours of symptom onset (level C evidence, ie, possibly effective).²³ Patients starting antiviral therapy should understand that its benefit has not been established.

Surgical decompression remains controversial

A Cochrane systematic review in 2011 found insufficient evidence regarding the safety and efficacy of surgical intervention in Bell palsy.²⁴ Surgery should be considered only for patients with complete paralysis with a greater than 90% reduction in motor amplitude on a nerve conduction study compared with the unaffected side, and absent volitional activity on needle examination.^19,25

Acupuncture: No recommendation

Currently, there is no recommendation for acupuncture in the treatment of Bell palsy.¹⁹ A recent randomized clinical trial suggests benefit from acupuncture combined with corticosteroids,²⁶ but high-quality studies to support its use are lacking.²⁶

Physical therapy: Insufficient evidence

There is insufficient evidence to show that physical therapy has benefit—or harm—in Bell palsy. However, some low-quality studies indicated that facial exercises and mime therapy may improve function in patients with moderate paralysis.²⁷

Follow-up

Instruct patients to call at 2 weeks to report progress of symptoms

Patients should be instructed to call at 2 weeks to report progress of symptoms and to be reevaluated within or at 1 month, with close attention to facial weakness and eye irritation. Further evaluation is needed if there has been no improvement, if symptoms have worsened, or if new symptoms have appeared.

The psychosocial impact of Bell palsy cannot be discounted, as the disfigurement can have negative implications for self-esteem and social relationships. Appropriate referral to an ophthalmologist, neurologist, otolaryngologist, social worker, or a plastic surgeon may be necessary.

COMPLICATIONS AND PROGNOSIS

Most patients with Bell palsy recover completely, but up to 30% have residual symptoms at 6 months.^14,20 Furthermore, although Bell palsy usually has a monophasic course, 7% to 12% of patients have a recurrence.^3,15

Long-term complications can include residual facial weakness, facial synkinesis, facial contracture, and facial spasm.^14,28 Incomplete eye closure may benefit from surgery (tarsorrhaphy or gold-weight implantation) to prevent corneal ulceration. Facial synkinesis is due to aberrant nerve regeneration and occurs in 15% to 20% of patients after recovery from Bell palsy.²⁹ Patients may describe tearing while chewing (“crocodile tears”), involuntary movement of the corners of the mouth with blinking, or ipsilateral eye-closing when the jaw opens (“jaw-winking”). Facial contracture, facial synkinesis, and facial spasm can be treated with botulinum toxin injection.³⁰

Bell palsy is an idiopathic peripheral nerve disorder involving the facial nerve (ie, cranial nerve VII) and manifesting as acute, ipsilateral facial muscle weakness. It is named after Sir Charles Bell, who in 1821 first described the anatomy of the facial nerve.¹ Although the disorder is clinically benign, patients can be devastated by its disfigurement.

The annual incidence of Bell palsy is 20 per 100,000, with no predilection for sex or ethnicity. It can affect people at any age, but the incidence is slightly higher after age 40.^2,3 Risk factors include diabetes, pregnancy, severe preeclampsia, obesity, and hypertension.^4–7

THE FACIAL NERVE IS VULNERABLE TO TRAUMA AND COMPRESSION

A basic understanding of the neuroanatomy of the facial nerve provides clues for distinguishing a central lesion from a peripheral lesion. This differentiation is important because the causes and management differ.

The facial nerve is a mixed sensory and motor nerve, carrying fibers involved in facial expression, taste, lacrimation, salivation, and sensation of the ear. It originates in the lower pons and exits the brainstem ventrally at the pontomedullary junction. After entering the internal acoustic meatus, it travels 20 to 30 mm in the facial canal, the longest bony course of any cranial nerve, making it highly susceptible to trauma and compression by edema.⁸

In the facial canal, it makes a posterior and inferior turn, forming a bend (ie, the genu of the facial nerve). The genu is proximal to the geniculate ganglion, which contains the facial nerve’s primary sensory neurons for taste and sensation. The motor branch of the facial nerve then exits the cranium via the stylomastoid foramen and passes through the parotid gland, where it divides into temporofacial and cervicofacial trunks.⁹

The facial nerve has five terminal branches that innervate the muscles of facial expression:

• The temporal branch (muscles of the forehead and superior part of the orbicularis oculi)
• The zygomatic branch (muscles of the nasolabial fold and cheek, eg, nasalis and zygomaticus).
• The buccal branch (the buccinators and inferior part of the orbicularis oculi)
• The marginal mandibular branch (the depressors of the mouth, eg, depressor anguli and mentalis)
• The cervical branch (the platysma muscle).

INFLAMMATION IS BELIEVED TO BE RESPONSIBLE

Although the precise cause of Bell palsy is not known, one theory is that inflammation of the nerve causes focal edema, demyelination, and ischemia. Several studies have suggested that herpes virus simplex type 1 infection may be involved.¹⁰

FACIAL DROOPING, EYELID WEAKNESS, OTHER SYMPTOMS

Symptoms of Bell palsy include ipsilateral sagging of the eyebrow, drooping of the face, flattening of the nasolabial fold, and inability to fully close the eye, pucker the lips, or raise the corner of the mouth (Figure 1). Symptoms develop within hours and are maximal by 3 days.

About 70% of patients have associated ipsilateral pain around the ear. If facial pain is present with sensory and hearing loss, a tumor of the parotid gland or viral otitis must be considered.¹¹ Other complaints may include hyperacusis due to disruption of nerve fibers to the stapedius muscle, changes in taste, and dry eye from parasympathetic dysfunction. Some patients report paresthesias over the face, which most often represent motor symptoms misconstrued as sensory changes.

PHYSICAL EXAMINATION

The clinical examination should include a complete neurologic and general examination, including otoscopy and attention to the skin and parotid gland. Vesicles or scabbing around the ear should prompt testing for herpes zoster. Careful observation during the interview while the patient is talking may reveal subtle signs of weakness and provide additional clues.

A systematic approach to the assessment of a patient with suspected Bell palsy is recommended (Table 1) and outlined below:

Does the patient have peripheral facial palsy?

In Bell palsy, wrinkling of the forehead on the affected side when raising the eyebrows is either asymmetrical or absent.

If the forehead muscles are spared and the lower face is weak, this signifies a central lesion such as a stroke or other structural abnormality and not a peripheral lesion of the facial nerve (eg, Bell palsy).

Can the patient close the eyes tightly?

Normally, the patient should be able to close both eyes tightly, and the eyelashes should be buried between the eyelids. In Bell palsy, when the patient attempts to close the eyes, the affected side shows incomplete closure and the eye may remain partly open.

Assess the strength of the orbicularis oculi by trying to open the eyes. The patient who is attempting to close the eyelids tightly but cannot will demonstrate the Bell phenomenon, ie, the examiner is able to force open the eyelids, and the eyes are deviated upward and laterally.

Closely observe the blink pattern, as the involved side in Bell palsy may slightly lag behind the normal eye, and the patient may be unable to close the eye completely.

Is the smile symmetric?

Note flattening of the nasolabial fold on one side, which indicates facial weakness.

Can the patient puff out the cheeks?

Ask the patient to hold air in the mouth against resistance. This assesses the strength of the buccinator muscle.

Can the patient purse the lips?

Ask the patient to pucker or purse the lips and observe for asymmetry or weakness on the affected side.

Test the orbicularis oris muscle by trying to spread the lips apart while the patient resists, and observe for weakness on one side.

Is there a symmetric grimace?

This will test the muscles involved in depressing the angles of the mouth and platysma.

Are taste, sensation, and hearing intact?

Other testable functions of the facial nerve, including taste, sensation, and hearing, do not always need to be assessed but can be in patients with specific sensory deficits.

Facial palsy that does not improve after 3 weeks should prompt a referral to a neurologist

Abnormalities in taste can support localization of the problem either proximal or distal to the branch point of fibers mediating taste. The facial nerve supplies taste fibers to the anterior two-thirds of the tongue. Sweet and salty taste can be screened with sugar and salt. Tell the patient to close the eyes, and using a tongue blade, apply a small amount of sugar or salt on the side of the tongue. Ask the patient to identify the taste and repeat with the other sample after he or she has rinsed the mouth.

Somatic sensory fibers supplied by the facial nerve innervate the inner ear and a small area behind the ear, but these may be difficult to assess objectively. Formal audiologic testing may be needed if hearing is impaired.

Facial nerve reflexes

A number of facial reflexes can be tested, including the orbicularis oculi, palpebral-oculogyric, and corneal reflexes.¹²

The orbicularis oculi reflex is tested by gentle finger percussion of the glabella while observing for involuntary blinking with each stimulus. The afferent branch of this reflex is carried by the trigeminal nerve, while the efferent response is carried by the facial nerve. In peripheral facial nerve palsy, this reflex is weakened or absent on the affected side.

The palpebral-oculogyric reflex, or Bell phenomenon, produces upward and lateral deviation of the eyes when attempting forceful eyelid closure. In this reflex, the afferent fibers are carried by the facial nerve and the efferent fibers travel in the oculomotor nerve to the superior rectus muscle. In Bell palsy, this reflex is visible because of failure of adequate eyelid closure.

The corneal reflex is elicited by stimulating the cornea with a wisp of cotton, causing reflexive closure of the both eyes. The affected side may show slowed or absent lid closure when tested on either side. The sensory afferent fibers are carried by the trigeminal nerve, and the motor efferent fibers are carried by the facial nerve.

Grading of facial paralysis

The House-Brackmann scale is the most widely used tool for grading the degree of facial paralysis and for predicting recovery. Grades are I to VI, with grade I indicating normal function, and grade VI, complete paralysis.

Patients with some preserved motor function generally have good recovery, but those with complete paralysis may have long-term residual deficits.¹³

A DIAGNOSIS OF EXCLUSION

The diagnosis of Bell palsy is made by excluding other causes of unilateral facial paralysis, and 30% to 60% of cases of facial palsy are caused by an underlying disorder that mimics Bell palsy, including central nervous system lesion (eg, stroke, demyelinating disease), parotid gland tumor, Lyme disease, Ramsay Hunt syndrome, granulomatous disease, otitis media, cholesteatoma, diabetes, trauma, and Guillain-Barré syndrome (Table 2).^14,15 Many of these conditions have associated features that help distinguish them from Bell palsy. Facial palsy that does not improve after 3 weeks should prompt referral to a neurologist.

Brain lesions

It is uncommon to have isolated facial palsy with a cortical or subcortical brain lesion, since the corticobulbar and corticospinal tracts travel in close proximity. Cortical signs such as hemiparesis, hemisensory loss, neglect, and dysarthria suggest a lesion of the cerebral cortex. Additionally, forehead muscle sparing is expected in supranuclear lesions.

Brainstem lesions can manifest with multiple ipsilateral cranial nerve palsies and contralateral limb weakness. Sarcoidosis and leptomeningeal carcinomatosis tend to involve the skull base and present with multiple cranial neuropathies.

Tumors of the brain or parotid gland have an insidious onset and may cause systemic signs such as fevers, chills, and weight loss. Headache, seizures, and hearing loss indicate an intracranial lesion. A palpable mass near the ear, neck, or parotid gland requires imaging of the face to look for a parotid gland tumor.

Infection

A number of infections can cause acute facial paralysis. The most common is herpes simplex virus, and the next most common is varicella zoster.¹⁴ Herpes simplex virus, Ramsay Hunt syndrome, and Lyme disease may have associated pain and skin changes. Erythema of the tympanic membrane suggests otitis media, especially in the setting of ear pain and hearing loss.

Ramsay Hunt syndrome is caused by reactivation of the herpes zoster virus from the geniculate ganglion, affecting the facial nerve. Careful examination of the ear canal and the oropharynx may show vesicles.

In Lyme disease, facial palsy is the most common cranial neuropathy, seen in 50% to 63% of patients with Borrelia burgdorferi meningitis.^16,17 In people with a history of rash, arthralgia, tick bite, or travel to an endemic region, Lyme titers should be checked before starting the patient on corticosteroids.

Bilateral facial palsy is rare and occurs in fewer than 1% of patients. It has been reported in patients with Lyme disease, Guillain-Barré syndrome, sarcoidosis, diabetes mellitus, viral infection, and pontine glioma.¹⁸

DIAGNOSTIC EVALUATION

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy

Serologic testing, electrodiagnostic studies, and imaging are not routinely necessary to diagnose Bell palsy. However, referral to the appropriate specialist (neurologist, otolaryngologist, optometrist, ophthalmologist) is advised if the patient has sparing of the forehead muscle, multiple cranial neuropathies, signs of infection, or persistent weakness without significant improvement at 3 weeks.

Laboratory testing

A complete blood cell count with differential may point to infection or a lymphoproliferative disorder. When indicated, screening for diabetes mellitus with fasting blood glucose or hemoglobin A_1c may be helpful. In Lyme-endemic regions, patients should undergo an enzyme-linked immunosorbent assay or an indirect fluorescent antibody test to screen for the disease. If positive, the diagnosis of Lyme disease should be confirmed by Western blot. If vesicles are present on examination, check serum antibodies for herpes zoster. In the appropriate clinical setting, angiotensin-converting enzyme, human immunodeficiency virus, and inflammatory markers can be tested.

Cerebrospinal fluid analysis is generally not helpful in diagnosing Bell palsy but can differentiate it from Guillain-Barré syndrome, leptomeningeal carcinomatosis, and infection involving the central nervous system.

Imaging

Imaging is not recommended in the initial evaluation of Bell palsy unless symptoms and the examination are atypical. From 5% to 7% of cases of facial palsy are caused by a tumor (eg, facial neuroma, cholesteatoma, hemangioma, meningioma), whether benign or malignant.^14,15 Therefore, in patients with insidious onset of symptoms that do not improve in about 3 weeks, contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging of the internal auditory canal and face is warranted.

Electrodiagnostic studies

Electrodiagnostic testing is typically not part of the evaluation of acute Bell palsy, but in patients with complete paralysis, it may help assess the degree of nerve injury and the chances of recovery, especially since patients with complete paralysis have a higher risk of incomplete recovery.¹⁹ Electrodiagnostic studies should be performed at least 1 week after symptom onset to avoid false-negative results.

TREATMENT

The treatment of Bell palsy focuses on maximizing recovery and minimizing associated complications.

Protect the eyes

Patients who cannot completely close their eyes should be given instructions on ocular protective care to prevent exposure keratopathy. Frequent application of lubricant eyedrops with artificial tears during the day or ophthalmic ointment at bedtime is recommended. The physician should also recommend protective eyewear such as sunglasses during the day. Eye patching or taping at night may be useful but could be harmful if applied too loosely or too tightly. Patients with vision loss or eye irritation should be referred to an ophthalmologist.¹⁹

Corticosteroids are recommended in the first 72 hours

In two randomized clinical trials (conducted by Sullivan et al²⁰ in 511 patients and Engström et al²¹ in 829 patients), prednisolone was found to be beneficial if started within 72 hours of symptom onset.

In a double-blind, randomized, placebo-controlled study of prednisone in 58 patients, those who received the drug recovered faster, although long-term outcomes in these patients were not significantly different than those in the control group.²² The American Academy of Neurology²³ rated this study as class II, ie, not meeting all of its criteria for the highest level of evidence, class I. Nevertheless, although prednisone lacks class I evidence, its use is recommended because it is a precursor to its active metabolite, prednisolone, which has been studied extensively.

The current guidelines of the American Academy of Neurology, updated in 2012, state, “For patients with new-onset Bell palsy, steroids are highly likely to be effective and should be offered to increase the probability of recovery of facial nerve function”²³ (level A evidence, ie, established as effective). They also concluded that adverse effects of corticosteroids were generally minor and temporary.

Similarly, the guidelines of the American Academy of Otolaryngology–Head and Neck Surgery, published in 2013, recommend oral corticosteroids within 72 hours of onset of symptoms of Bell palsy for patients age 16 and older.¹⁹ The recommendation is for a 10-day course of corticosteroids with at least 5 days at a high dose (prednisolone 50 mg orally daily for 10 days, or prednisone 60 mg orally daily for 5 days, followed by a 5-day taper). The benefit of corticosteroids after 72 hours is unclear (Table 3).¹⁹

Even though the guidelines recommend corticosteroids, the decision to use them in diabetic patients and pregnant women should be individualized. Discretion is advised, as not all patients with Bell palsy need to be treated. Most recover spontaneously, especially those with mild symptoms.

Antiviral therapy may offer modest benefit

Antiviral therapy has not been shown to be beneficial in Bell palsy, and current guidelines do not recommend oral antiviral therapy alone.¹⁹ However, an antiviral combined with a corticosteroid may offer modest benefit if started within 72 hours of symptom onset (level C evidence, ie, possibly effective).²³ Patients starting antiviral therapy should understand that its benefit has not been established.

Surgical decompression remains controversial

A Cochrane systematic review in 2011 found insufficient evidence regarding the safety and efficacy of surgical intervention in Bell palsy.²⁴ Surgery should be considered only for patients with complete paralysis with a greater than 90% reduction in motor amplitude on a nerve conduction study compared with the unaffected side, and absent volitional activity on needle examination.^19,25

Acupuncture: No recommendation

Currently, there is no recommendation for acupuncture in the treatment of Bell palsy.¹⁹ A recent randomized clinical trial suggests benefit from acupuncture combined with corticosteroids,²⁶ but high-quality studies to support its use are lacking.²⁶

Physical therapy: Insufficient evidence

There is insufficient evidence to show that physical therapy has benefit—or harm—in Bell palsy. However, some low-quality studies indicated that facial exercises and mime therapy may improve function in patients with moderate paralysis.²⁷

Follow-up

Instruct patients to call at 2 weeks to report progress of symptoms

Patients should be instructed to call at 2 weeks to report progress of symptoms and to be reevaluated within or at 1 month, with close attention to facial weakness and eye irritation. Further evaluation is needed if there has been no improvement, if symptoms have worsened, or if new symptoms have appeared.

The psychosocial impact of Bell palsy cannot be discounted, as the disfigurement can have negative implications for self-esteem and social relationships. Appropriate referral to an ophthalmologist, neurologist, otolaryngologist, social worker, or a plastic surgeon may be necessary.

COMPLICATIONS AND PROGNOSIS

Most patients with Bell palsy recover completely, but up to 30% have residual symptoms at 6 months.^14,20 Furthermore, although Bell palsy usually has a monophasic course, 7% to 12% of patients have a recurrence.^3,15

Long-term complications can include residual facial weakness, facial synkinesis, facial contracture, and facial spasm.^14,28 Incomplete eye closure may benefit from surgery (tarsorrhaphy or gold-weight implantation) to prevent corneal ulceration. Facial synkinesis is due to aberrant nerve regeneration and occurs in 15% to 20% of patients after recovery from Bell palsy.²⁹ Patients may describe tearing while chewing (“crocodile tears”), involuntary movement of the corners of the mouth with blinking, or ipsilateral eye-closing when the jaw opens (“jaw-winking”). Facial contracture, facial synkinesis, and facial spasm can be treated with botulinum toxin injection.³⁰

A 45-year-old woman presents with shortness of breath that has been progressively worsening for 3 weeks. She has no history of medical conditions and is taking no medications. Her blood pressure is 132/68 mm Hg, pulse 90 beats per minute, respirations 14 per minute, and oxygen saturation 95% on room air by pulse oximetry.

Physical examination reveals clear lung fields and no jugular venous distention or peripheral edema. However, she has a grade 3 of 6 continuous murmur audible over the entire precordium that does not change in intensity with respiration.

1. Which of the following is the likely cause of this patient’s cardiac murmur?

• Ventricular septal defect
• Atrial septal defect
• Ruptured sinus of Valsalva aneurysm
• Aortic regurgitation
• Patent ductus arteriosus
• Pulmonic stenosis

Table 1 summarizes the characteristics of the murmurs caused by these various cardiac defects.

Ventricular septal defect causes murmurs that are characteristically holosystolic and heard best at the lower left sternal border with radiation to the right lower sternal border, which overlies the defect.

The murmur of restrictive ventricular septal defect is most often holosystolic because the pressure difference between the ventricles is generated almost instantly at the onset of systole with a left-to-right shunt continuing throughout ventricular contraction. In contrast, nonrestrictive ventricular septal defects generally do not generate a murmur, since pressure is equalized across the defect. This left-to-right shunting may lead to right ventricular volume overload, resulting in delayed closure of the pulmonary valve and a widely split S2. Irreversible pulmonary hypertension with shunt reversal may occur if the defect remains untreated.¹

Atrial septal defect. The most characteristic feature of atrial septal defect is a fixed split S2 resulting from right ventricular volume overload due to left-to-right atrial shunting of blood flow. As flow is shunted from the left to the right atrium and subsequently into the right ventricle, ejection of excess blood through the pulmonary valve produces a midsystolic flow murmur, heard best over the left upper sternal border, that may radiate to the back.

Ruptured sinus of Valsalva aneurysm. The pressure is higher in the aorta than in the right atrium throughout the cardiac cycle, and if a shunt is created between the two structures by a ruptured sinus of Valsalva aneurysm, the blood flow across this shunt throughout the cardiac cycle produces a continuous murmur. In contrast, if a sinus of Valsalva aneurysm ruptures into the right ventricle, the murmur is accentuated in diastole and attenuated in systole, and is often associated with pounding pulses and a thrill along either the left or right sternal border.¹

Aortic regurgitation causes a diastolic murmur as blood flows retrograde into the left ventricle through the incompetent aortic valve. This murmur is usually described as a blowing, decrescendo murmur heard best at the third left intercostal space.

Patent ductus arteriosus is a communication between the descending thoracic aorta and the pulmonary artery that fails to close at birth. The hallmark murmur associated with this defect is a continuous “machine-like” murmur located at the upper left sternal border, often radiating down the left side of the sternum into the back. Of note, increasing the systemic pressure by the Valsalva maneuver or handgrip exercise will increase the diastolic component of the continuous murmur associated with ruptured sinus of Valsalva aneurysm, helping to differentiate it from patent ductus arteriosus.²

Pulmonic stenosis causes a systolic murmur heard best at the second intercostal space along the left sternal border and having a crescendo-decrescendo intensity and harsh quality. As the right ventricle takes longer to eject its blood volume through the stenotic pulmonary valve, the delay in closure between the aortic and pulmonary valve is widened, resulting in a significant splitting of the S2. In addition, any maneuver that increases preload will also increase the intensity of the murmur.³

Our patient has a murmur that is continuous, is heard across the entire precordium, and has no respiratory variation. These features are most consistent with a sinus of Valsalva aneurysm that has ruptured into the right atrium.

The 2008 update of the joint American College of Cardiology and American Heart Association guidelines⁴ recommends further evaluation of diastolic or continuous murmurs with echocardiography, as these murmurs are most often signs of a pathologic condition. In addition, echocardiography is warranted to evaluate grade 3 or higher systolic murmurs and those that are holosystolic.⁴

SINUS OF VALSALVA ANEURYSM

Sinus of Valsalva aneurysm is rare, with an incidence of 0.09% to 0.15%. From 65% to 85% are in the right coronary cusp, 10% to 30% are in the noncoronary cusp, and fewer than 5% are in the left coronary cusp.⁵

This condition is most often congenital, accounting for up to 3.5% of congenital cardiac anomalies, though it can be acquired. Formation of the aneurysm is generally related to weakening of elastic fibers and muscular tissues that progresses over time.

Many cases of sinus of Valsalva aneurysm are associated with additional cardiac defects.¹ Ventricular septal defect is the most common coexisting congenital anomaly, occurring in up to 53% of patients and frequently associated with aneurysms involving the right coronary cusp and with sinus of Valsalva aneurysm.⁶ Other congenital anomalies often accompanying sinus of Valsalva aneurysm include pulmonary stenosis, atrial septal defect, bicuspid aortic valve, tetralogy of Fallot, patent ductus arteriosus, coarctation of the aorta, and subaortic stenosis. Another associated condition is aortic regurgitation, for which more than half of affected patients eventually require aortic valve replacement.²

Acquired sinus of Valsalva aneurysm can be the result of endocarditis, trauma, surgery, cardiac catheterization, or inflammatory or degenerative processes including, rarely, tertiary syphilis.³

Sinus of Valsalva aneurysm often remains asymptomatic, but symptoms may arise if the aneurysm ruptures, resulting in intracardiac shunting or aneurysm-associated compression of adjacent cardiac structures such as coronary arteries. Rupture may be spontaneous, secondary to chest trauma or excess exertion, or iatrogenic.

Imaging studies such as echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging are essential in diagnosing and managing sinus of Valsalva aneurysm and identifying coexisting cardiac anomalies.

Rupture occurs most commonly into the right ventricle, followed in frequency by the right atrium or left atrium. Once rupture occurs, median survival is 1 to 2 years if left untreated, with death often secondary to congestive heart failure or infective endocarditis.⁷

Surgery remains the preferred approach to the treatment of ruptured sinus of Valsalva aneurysm. Operative risk is reasonably low and long-term outcomes are good. The appropriate therapy for unruptured and asymptomatic sinus of Valsalva aneurysm remains less clear.

Successful transcatheter closure of ruptured sinus of Valsalva aneurysm has been described using Amplatzer devices, a procedure that avoids sternotomy and cardiopulmonary bypass. Despite advances in percutaneous techniques, open surgery with or without aortic valve replacement remains the current standard of care.⁸

BACK TO OUR PATIENT

In the case described above, the initial diagnostic study done to evaluate the patient’s dyspnea and murmur was transthoracic echocardiography, which demonstrated a relatively preserved ejection fraction with mild aortic regurgitation and an aneurysmal structure extending from the aortic root toward the right atrium.

Transesophageal echocardiography confirmed this finding (Figure 1). Cross-sectional imaging of the aortic valve (Figure 2) showed the aneurysm arising from the noncoronary cusp and communicating with the right atrium. Color flow Doppler (Figure 3) confirmed continuous flow between the aneurysmal sinus and right atrium throughout the cardiac cycle, consistent with the continuous murmur noted on physical examination.

The aneurysm was also noted on aortography (Figure 4) obtained before the patient underwent surgery to correct it. The surgery was successful, no complications occurred, and the murmur and associated dyspnea had completely resolved at subsequent follow-up.

This case highlights the importance of imaging studies such as echocardiography in diagnosing and managing sinus of Valsalva aneurysm, and also the importance of physical examination in guiding the diagnostic evaluation and differentiating this condition from other cardiac disorders.

A 45-year-old woman presents with shortness of breath that has been progressively worsening for 3 weeks. She has no history of medical conditions and is taking no medications. Her blood pressure is 132/68 mm Hg, pulse 90 beats per minute, respirations 14 per minute, and oxygen saturation 95% on room air by pulse oximetry.

Physical examination reveals clear lung fields and no jugular venous distention or peripheral edema. However, she has a grade 3 of 6 continuous murmur audible over the entire precordium that does not change in intensity with respiration.

1. Which of the following is the likely cause of this patient’s cardiac murmur?

• Ventricular septal defect
• Atrial septal defect
• Ruptured sinus of Valsalva aneurysm
• Aortic regurgitation
• Patent ductus arteriosus
• Pulmonic stenosis

Table 1 summarizes the characteristics of the murmurs caused by these various cardiac defects.

Ventricular septal defect causes murmurs that are characteristically holosystolic and heard best at the lower left sternal border with radiation to the right lower sternal border, which overlies the defect.

The murmur of restrictive ventricular septal defect is most often holosystolic because the pressure difference between the ventricles is generated almost instantly at the onset of systole with a left-to-right shunt continuing throughout ventricular contraction. In contrast, nonrestrictive ventricular septal defects generally do not generate a murmur, since pressure is equalized across the defect. This left-to-right shunting may lead to right ventricular volume overload, resulting in delayed closure of the pulmonary valve and a widely split S2. Irreversible pulmonary hypertension with shunt reversal may occur if the defect remains untreated.¹

Atrial septal defect. The most characteristic feature of atrial septal defect is a fixed split S2 resulting from right ventricular volume overload due to left-to-right atrial shunting of blood flow. As flow is shunted from the left to the right atrium and subsequently into the right ventricle, ejection of excess blood through the pulmonary valve produces a midsystolic flow murmur, heard best over the left upper sternal border, that may radiate to the back.

Ruptured sinus of Valsalva aneurysm. The pressure is higher in the aorta than in the right atrium throughout the cardiac cycle, and if a shunt is created between the two structures by a ruptured sinus of Valsalva aneurysm, the blood flow across this shunt throughout the cardiac cycle produces a continuous murmur. In contrast, if a sinus of Valsalva aneurysm ruptures into the right ventricle, the murmur is accentuated in diastole and attenuated in systole, and is often associated with pounding pulses and a thrill along either the left or right sternal border.¹

Aortic regurgitation causes a diastolic murmur as blood flows retrograde into the left ventricle through the incompetent aortic valve. This murmur is usually described as a blowing, decrescendo murmur heard best at the third left intercostal space.

Patent ductus arteriosus is a communication between the descending thoracic aorta and the pulmonary artery that fails to close at birth. The hallmark murmur associated with this defect is a continuous “machine-like” murmur located at the upper left sternal border, often radiating down the left side of the sternum into the back. Of note, increasing the systemic pressure by the Valsalva maneuver or handgrip exercise will increase the diastolic component of the continuous murmur associated with ruptured sinus of Valsalva aneurysm, helping to differentiate it from patent ductus arteriosus.²

Pulmonic stenosis causes a systolic murmur heard best at the second intercostal space along the left sternal border and having a crescendo-decrescendo intensity and harsh quality. As the right ventricle takes longer to eject its blood volume through the stenotic pulmonary valve, the delay in closure between the aortic and pulmonary valve is widened, resulting in a significant splitting of the S2. In addition, any maneuver that increases preload will also increase the intensity of the murmur.³

Our patient has a murmur that is continuous, is heard across the entire precordium, and has no respiratory variation. These features are most consistent with a sinus of Valsalva aneurysm that has ruptured into the right atrium.

The 2008 update of the joint American College of Cardiology and American Heart Association guidelines⁴ recommends further evaluation of diastolic or continuous murmurs with echocardiography, as these murmurs are most often signs of a pathologic condition. In addition, echocardiography is warranted to evaluate grade 3 or higher systolic murmurs and those that are holosystolic.⁴

SINUS OF VALSALVA ANEURYSM

Sinus of Valsalva aneurysm is rare, with an incidence of 0.09% to 0.15%. From 65% to 85% are in the right coronary cusp, 10% to 30% are in the noncoronary cusp, and fewer than 5% are in the left coronary cusp.⁵

This condition is most often congenital, accounting for up to 3.5% of congenital cardiac anomalies, though it can be acquired. Formation of the aneurysm is generally related to weakening of elastic fibers and muscular tissues that progresses over time.

Many cases of sinus of Valsalva aneurysm are associated with additional cardiac defects.¹ Ventricular septal defect is the most common coexisting congenital anomaly, occurring in up to 53% of patients and frequently associated with aneurysms involving the right coronary cusp and with sinus of Valsalva aneurysm.⁶ Other congenital anomalies often accompanying sinus of Valsalva aneurysm include pulmonary stenosis, atrial septal defect, bicuspid aortic valve, tetralogy of Fallot, patent ductus arteriosus, coarctation of the aorta, and subaortic stenosis. Another associated condition is aortic regurgitation, for which more than half of affected patients eventually require aortic valve replacement.²

Acquired sinus of Valsalva aneurysm can be the result of endocarditis, trauma, surgery, cardiac catheterization, or inflammatory or degenerative processes including, rarely, tertiary syphilis.³

Sinus of Valsalva aneurysm often remains asymptomatic, but symptoms may arise if the aneurysm ruptures, resulting in intracardiac shunting or aneurysm-associated compression of adjacent cardiac structures such as coronary arteries. Rupture may be spontaneous, secondary to chest trauma or excess exertion, or iatrogenic.

Imaging studies such as echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging are essential in diagnosing and managing sinus of Valsalva aneurysm and identifying coexisting cardiac anomalies.

Rupture occurs most commonly into the right ventricle, followed in frequency by the right atrium or left atrium. Once rupture occurs, median survival is 1 to 2 years if left untreated, with death often secondary to congestive heart failure or infective endocarditis.⁷

Surgery remains the preferred approach to the treatment of ruptured sinus of Valsalva aneurysm. Operative risk is reasonably low and long-term outcomes are good. The appropriate therapy for unruptured and asymptomatic sinus of Valsalva aneurysm remains less clear.

Successful transcatheter closure of ruptured sinus of Valsalva aneurysm has been described using Amplatzer devices, a procedure that avoids sternotomy and cardiopulmonary bypass. Despite advances in percutaneous techniques, open surgery with or without aortic valve replacement remains the current standard of care.⁸

BACK TO OUR PATIENT

In the case described above, the initial diagnostic study done to evaluate the patient’s dyspnea and murmur was transthoracic echocardiography, which demonstrated a relatively preserved ejection fraction with mild aortic regurgitation and an aneurysmal structure extending from the aortic root toward the right atrium.

Transesophageal echocardiography confirmed this finding (Figure 1). Cross-sectional imaging of the aortic valve (Figure 2) showed the aneurysm arising from the noncoronary cusp and communicating with the right atrium. Color flow Doppler (Figure 3) confirmed continuous flow between the aneurysmal sinus and right atrium throughout the cardiac cycle, consistent with the continuous murmur noted on physical examination.

The aneurysm was also noted on aortography (Figure 4) obtained before the patient underwent surgery to correct it. The surgery was successful, no complications occurred, and the murmur and associated dyspnea had completely resolved at subsequent follow-up.

This case highlights the importance of imaging studies such as echocardiography in diagnosing and managing sinus of Valsalva aneurysm, and also the importance of physical examination in guiding the diagnostic evaluation and differentiating this condition from other cardiac disorders.

A 45-year-old woman presents with shortness of breath that has been progressively worsening for 3 weeks. She has no history of medical conditions and is taking no medications. Her blood pressure is 132/68 mm Hg, pulse 90 beats per minute, respirations 14 per minute, and oxygen saturation 95% on room air by pulse oximetry.

Physical examination reveals clear lung fields and no jugular venous distention or peripheral edema. However, she has a grade 3 of 6 continuous murmur audible over the entire precordium that does not change in intensity with respiration.

1. Which of the following is the likely cause of this patient’s cardiac murmur?

• Ventricular septal defect
• Atrial septal defect
• Ruptured sinus of Valsalva aneurysm
• Aortic regurgitation
• Patent ductus arteriosus
• Pulmonic stenosis

Table 1 summarizes the characteristics of the murmurs caused by these various cardiac defects.

Ventricular septal defect causes murmurs that are characteristically holosystolic and heard best at the lower left sternal border with radiation to the right lower sternal border, which overlies the defect.

The murmur of restrictive ventricular septal defect is most often holosystolic because the pressure difference between the ventricles is generated almost instantly at the onset of systole with a left-to-right shunt continuing throughout ventricular contraction. In contrast, nonrestrictive ventricular septal defects generally do not generate a murmur, since pressure is equalized across the defect. This left-to-right shunting may lead to right ventricular volume overload, resulting in delayed closure of the pulmonary valve and a widely split S2. Irreversible pulmonary hypertension with shunt reversal may occur if the defect remains untreated.¹

Atrial septal defect. The most characteristic feature of atrial septal defect is a fixed split S2 resulting from right ventricular volume overload due to left-to-right atrial shunting of blood flow. As flow is shunted from the left to the right atrium and subsequently into the right ventricle, ejection of excess blood through the pulmonary valve produces a midsystolic flow murmur, heard best over the left upper sternal border, that may radiate to the back.

Ruptured sinus of Valsalva aneurysm. The pressure is higher in the aorta than in the right atrium throughout the cardiac cycle, and if a shunt is created between the two structures by a ruptured sinus of Valsalva aneurysm, the blood flow across this shunt throughout the cardiac cycle produces a continuous murmur. In contrast, if a sinus of Valsalva aneurysm ruptures into the right ventricle, the murmur is accentuated in diastole and attenuated in systole, and is often associated with pounding pulses and a thrill along either the left or right sternal border.¹

Aortic regurgitation causes a diastolic murmur as blood flows retrograde into the left ventricle through the incompetent aortic valve. This murmur is usually described as a blowing, decrescendo murmur heard best at the third left intercostal space.

Patent ductus arteriosus is a communication between the descending thoracic aorta and the pulmonary artery that fails to close at birth. The hallmark murmur associated with this defect is a continuous “machine-like” murmur located at the upper left sternal border, often radiating down the left side of the sternum into the back. Of note, increasing the systemic pressure by the Valsalva maneuver or handgrip exercise will increase the diastolic component of the continuous murmur associated with ruptured sinus of Valsalva aneurysm, helping to differentiate it from patent ductus arteriosus.²

Pulmonic stenosis causes a systolic murmur heard best at the second intercostal space along the left sternal border and having a crescendo-decrescendo intensity and harsh quality. As the right ventricle takes longer to eject its blood volume through the stenotic pulmonary valve, the delay in closure between the aortic and pulmonary valve is widened, resulting in a significant splitting of the S2. In addition, any maneuver that increases preload will also increase the intensity of the murmur.³

Our patient has a murmur that is continuous, is heard across the entire precordium, and has no respiratory variation. These features are most consistent with a sinus of Valsalva aneurysm that has ruptured into the right atrium.

The 2008 update of the joint American College of Cardiology and American Heart Association guidelines⁴ recommends further evaluation of diastolic or continuous murmurs with echocardiography, as these murmurs are most often signs of a pathologic condition. In addition, echocardiography is warranted to evaluate grade 3 or higher systolic murmurs and those that are holosystolic.⁴

SINUS OF VALSALVA ANEURYSM

Sinus of Valsalva aneurysm is rare, with an incidence of 0.09% to 0.15%. From 65% to 85% are in the right coronary cusp, 10% to 30% are in the noncoronary cusp, and fewer than 5% are in the left coronary cusp.⁵

This condition is most often congenital, accounting for up to 3.5% of congenital cardiac anomalies, though it can be acquired. Formation of the aneurysm is generally related to weakening of elastic fibers and muscular tissues that progresses over time.

Many cases of sinus of Valsalva aneurysm are associated with additional cardiac defects.¹ Ventricular septal defect is the most common coexisting congenital anomaly, occurring in up to 53% of patients and frequently associated with aneurysms involving the right coronary cusp and with sinus of Valsalva aneurysm.⁶ Other congenital anomalies often accompanying sinus of Valsalva aneurysm include pulmonary stenosis, atrial septal defect, bicuspid aortic valve, tetralogy of Fallot, patent ductus arteriosus, coarctation of the aorta, and subaortic stenosis. Another associated condition is aortic regurgitation, for which more than half of affected patients eventually require aortic valve replacement.²

Acquired sinus of Valsalva aneurysm can be the result of endocarditis, trauma, surgery, cardiac catheterization, or inflammatory or degenerative processes including, rarely, tertiary syphilis.³

Sinus of Valsalva aneurysm often remains asymptomatic, but symptoms may arise if the aneurysm ruptures, resulting in intracardiac shunting or aneurysm-associated compression of adjacent cardiac structures such as coronary arteries. Rupture may be spontaneous, secondary to chest trauma or excess exertion, or iatrogenic.

Imaging studies such as echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging are essential in diagnosing and managing sinus of Valsalva aneurysm and identifying coexisting cardiac anomalies.

Rupture occurs most commonly into the right ventricle, followed in frequency by the right atrium or left atrium. Once rupture occurs, median survival is 1 to 2 years if left untreated, with death often secondary to congestive heart failure or infective endocarditis.⁷

Surgery remains the preferred approach to the treatment of ruptured sinus of Valsalva aneurysm. Operative risk is reasonably low and long-term outcomes are good. The appropriate therapy for unruptured and asymptomatic sinus of Valsalva aneurysm remains less clear.

Successful transcatheter closure of ruptured sinus of Valsalva aneurysm has been described using Amplatzer devices, a procedure that avoids sternotomy and cardiopulmonary bypass. Despite advances in percutaneous techniques, open surgery with or without aortic valve replacement remains the current standard of care.⁸

BACK TO OUR PATIENT

In the case described above, the initial diagnostic study done to evaluate the patient’s dyspnea and murmur was transthoracic echocardiography, which demonstrated a relatively preserved ejection fraction with mild aortic regurgitation and an aneurysmal structure extending from the aortic root toward the right atrium.

Transesophageal echocardiography confirmed this finding (Figure 1). Cross-sectional imaging of the aortic valve (Figure 2) showed the aneurysm arising from the noncoronary cusp and communicating with the right atrium. Color flow Doppler (Figure 3) confirmed continuous flow between the aneurysmal sinus and right atrium throughout the cardiac cycle, consistent with the continuous murmur noted on physical examination.

The aneurysm was also noted on aortography (Figure 4) obtained before the patient underwent surgery to correct it. The surgery was successful, no complications occurred, and the murmur and associated dyspnea had completely resolved at subsequent follow-up.

This case highlights the importance of imaging studies such as echocardiography in diagnosing and managing sinus of Valsalva aneurysm, and also the importance of physical examination in guiding the diagnostic evaluation and differentiating this condition from other cardiac disorders.

A 76-year-old woman visiting from Ethiopia presented for further evaluation of concomitant iron and vitamin B₁₂ deficiency anemia that had developed over the previous 6 months. During that time, she had complained of ongoing fatigue and increasing paresthesias in the hands and feet.

At presentation, her hemoglobin concentration was 7.8 g/dL (reference range 11.5–15), with a mean corpuscular volume of 81.8 fL (81.5–97.0). These values were down from her baseline hemoglobin of 12 g/dL and corpuscular volume of 85.8 recorded more than 1 year ago. Serum studies showed an iron concentration of 21 µg/dL (37–170), ferritin 3 ng/mL (10–107), and percent saturation of transferrin 5% (20%–55%). Also noted was a low vitamin B₁₂ level of 108 pg/mL (180–1,241 pg/mL). She had no overt signs of gastrointestinal blood loss. She did not report altered bowel habits or use of nonsteroidal anti-inflammatory medications.

Given her country of origin, she was sent for initial stool testing for ova and parasites, which was unrevealing.

She underwent esophagogastroduodenoscopy and colonoscopy, which revealed no underlying cause of her iron deficiency or vitamin B₁₂ insufficiency. But further evaluation with capsule endoscopy showed evidence of a tapeworm in the distal duodenum (Figure 1).

She was given praziquantel in a single oral dose of 10 mg/kg. Repeat stool culture 1 month later showed no evidence of tapeworm infection, and at follow-up 3 months later, her hemoglobin had recovered to 13.2 g/dL with a corpuscular volume of 87.6 fL and no residual vitamin B₁₂ or iron deficiency. She reported complete resolution of fatigue and of paresthesias of the hands and feet.

DIPHYLLOBOTHRIUM LATUM

The appearance on capsule endoscopy indicated Diphyllobothrium latum as the likely parasite. This tapeworm is acquired by ingesting undercooked or raw fish. Infection is most common in Northern Europe but has been reported in Africa.¹

As it grows, the tapeworm develops chains of segments and can reach a length of 1 to 15 meters.¹ In humans, it typically resides in the small intestine. Most patients are asymptomatic or have moderate nonspecific symptoms such as abdominal pain and diarrhea. A key differentiating aspect of D latum infection is vitamin B₁₂ deficiency caused by consumption of the vitamin by the parasite, as well as by parasite-mediated dissociation of the vitamin B₁₂-intrinsic factor complex, thus making the vitamin unavailable to the host.

Up to 40% of people infected with D latum develop low levels of vitamin B₁₂, and 2% develop symptomatic megaloblastic anemia.² Iron deficiency anemia is uncommon but has been reported.³ In our patient, the concomitant iron deficiency was probably secondary to involvement of the duodenum, where a significant amount of dietary iron is absorbed.

The diagnosis is typically established by stool testing for ova and parasites. When stool samples do not reveal a cause of the symptoms, as in this patient, endoscopy can be used. Capsule endoscopy has not been widely used in the diagnosis of intestinal helminth infection, although reports exist describing the use of capsule endoscopy to detect intestinal parasites. Notably, as in this case, intestinal parasite infection is occasionally found during investigations of anemia and vitamin deficiencies of unknown cause.⁴

As in our patient, treatment of infection with this species of tapeworm typically involves a single oral dose of praziquantel; this off-label use has been shown to lead to resolution of symptoms in nearly all patients treated.⁵

A 76-year-old woman visiting from Ethiopia presented for further evaluation of concomitant iron and vitamin B₁₂ deficiency anemia that had developed over the previous 6 months. During that time, she had complained of ongoing fatigue and increasing paresthesias in the hands and feet.

At presentation, her hemoglobin concentration was 7.8 g/dL (reference range 11.5–15), with a mean corpuscular volume of 81.8 fL (81.5–97.0). These values were down from her baseline hemoglobin of 12 g/dL and corpuscular volume of 85.8 recorded more than 1 year ago. Serum studies showed an iron concentration of 21 µg/dL (37–170), ferritin 3 ng/mL (10–107), and percent saturation of transferrin 5% (20%–55%). Also noted was a low vitamin B₁₂ level of 108 pg/mL (180–1,241 pg/mL). She had no overt signs of gastrointestinal blood loss. She did not report altered bowel habits or use of nonsteroidal anti-inflammatory medications.

Given her country of origin, she was sent for initial stool testing for ova and parasites, which was unrevealing.

She underwent esophagogastroduodenoscopy and colonoscopy, which revealed no underlying cause of her iron deficiency or vitamin B₁₂ insufficiency. But further evaluation with capsule endoscopy showed evidence of a tapeworm in the distal duodenum (Figure 1).

She was given praziquantel in a single oral dose of 10 mg/kg. Repeat stool culture 1 month later showed no evidence of tapeworm infection, and at follow-up 3 months later, her hemoglobin had recovered to 13.2 g/dL with a corpuscular volume of 87.6 fL and no residual vitamin B₁₂ or iron deficiency. She reported complete resolution of fatigue and of paresthesias of the hands and feet.

DIPHYLLOBOTHRIUM LATUM

The appearance on capsule endoscopy indicated Diphyllobothrium latum as the likely parasite. This tapeworm is acquired by ingesting undercooked or raw fish. Infection is most common in Northern Europe but has been reported in Africa.¹

As it grows, the tapeworm develops chains of segments and can reach a length of 1 to 15 meters.¹ In humans, it typically resides in the small intestine. Most patients are asymptomatic or have moderate nonspecific symptoms such as abdominal pain and diarrhea. A key differentiating aspect of D latum infection is vitamin B₁₂ deficiency caused by consumption of the vitamin by the parasite, as well as by parasite-mediated dissociation of the vitamin B₁₂-intrinsic factor complex, thus making the vitamin unavailable to the host.

Up to 40% of people infected with D latum develop low levels of vitamin B₁₂, and 2% develop symptomatic megaloblastic anemia.² Iron deficiency anemia is uncommon but has been reported.³ In our patient, the concomitant iron deficiency was probably secondary to involvement of the duodenum, where a significant amount of dietary iron is absorbed.

The diagnosis is typically established by stool testing for ova and parasites. When stool samples do not reveal a cause of the symptoms, as in this patient, endoscopy can be used. Capsule endoscopy has not been widely used in the diagnosis of intestinal helminth infection, although reports exist describing the use of capsule endoscopy to detect intestinal parasites. Notably, as in this case, intestinal parasite infection is occasionally found during investigations of anemia and vitamin deficiencies of unknown cause.⁴

As in our patient, treatment of infection with this species of tapeworm typically involves a single oral dose of praziquantel; this off-label use has been shown to lead to resolution of symptoms in nearly all patients treated.⁵

A 76-year-old woman visiting from Ethiopia presented for further evaluation of concomitant iron and vitamin B₁₂ deficiency anemia that had developed over the previous 6 months. During that time, she had complained of ongoing fatigue and increasing paresthesias in the hands and feet.

At presentation, her hemoglobin concentration was 7.8 g/dL (reference range 11.5–15), with a mean corpuscular volume of 81.8 fL (81.5–97.0). These values were down from her baseline hemoglobin of 12 g/dL and corpuscular volume of 85.8 recorded more than 1 year ago. Serum studies showed an iron concentration of 21 µg/dL (37–170), ferritin 3 ng/mL (10–107), and percent saturation of transferrin 5% (20%–55%). Also noted was a low vitamin B₁₂ level of 108 pg/mL (180–1,241 pg/mL). She had no overt signs of gastrointestinal blood loss. She did not report altered bowel habits or use of nonsteroidal anti-inflammatory medications.

Given her country of origin, she was sent for initial stool testing for ova and parasites, which was unrevealing.

She underwent esophagogastroduodenoscopy and colonoscopy, which revealed no underlying cause of her iron deficiency or vitamin B₁₂ insufficiency. But further evaluation with capsule endoscopy showed evidence of a tapeworm in the distal duodenum (Figure 1).

She was given praziquantel in a single oral dose of 10 mg/kg. Repeat stool culture 1 month later showed no evidence of tapeworm infection, and at follow-up 3 months later, her hemoglobin had recovered to 13.2 g/dL with a corpuscular volume of 87.6 fL and no residual vitamin B₁₂ or iron deficiency. She reported complete resolution of fatigue and of paresthesias of the hands and feet.

DIPHYLLOBOTHRIUM LATUM

The appearance on capsule endoscopy indicated Diphyllobothrium latum as the likely parasite. This tapeworm is acquired by ingesting undercooked or raw fish. Infection is most common in Northern Europe but has been reported in Africa.¹

As it grows, the tapeworm develops chains of segments and can reach a length of 1 to 15 meters.¹ In humans, it typically resides in the small intestine. Most patients are asymptomatic or have moderate nonspecific symptoms such as abdominal pain and diarrhea. A key differentiating aspect of D latum infection is vitamin B₁₂ deficiency caused by consumption of the vitamin by the parasite, as well as by parasite-mediated dissociation of the vitamin B₁₂-intrinsic factor complex, thus making the vitamin unavailable to the host.

Up to 40% of people infected with D latum develop low levels of vitamin B₁₂, and 2% develop symptomatic megaloblastic anemia.² Iron deficiency anemia is uncommon but has been reported.³ In our patient, the concomitant iron deficiency was probably secondary to involvement of the duodenum, where a significant amount of dietary iron is absorbed.

The diagnosis is typically established by stool testing for ova and parasites. When stool samples do not reveal a cause of the symptoms, as in this patient, endoscopy can be used. Capsule endoscopy has not been widely used in the diagnosis of intestinal helminth infection, although reports exist describing the use of capsule endoscopy to detect intestinal parasites. Notably, as in this case, intestinal parasite infection is occasionally found during investigations of anemia and vitamin deficiencies of unknown cause.⁴

As in our patient, treatment of infection with this species of tapeworm typically involves a single oral dose of praziquantel; this off-label use has been shown to lead to resolution of symptoms in nearly all patients treated.⁵

A 62-year-old man was admitted to the intensive care unit with esophageal variceal bleeding. He had a long history of alcohol abuse with secondary cirrhosis, with a Child-Pugh score of 11 on a scale of 15 (class C—the most severe) at presentation. He also had a history of uncomplicated umbilical hernia, 6 cm in diameter without overlying trophic skin alterations.

Treatment with somatostatin, endoscopic band ligation, and prophylactic antibiotics was initiated for the variceal bleeding. The next day, he was transferred to the hepatology floor. His condition stabilized during the next week, but then he abruptly became diaphoretic and less talkative. Physical examination revealed a painful and irreducible umbilical hernia (Figure 1). He was rushed for umbilical hernia repair with resection of a necrotic segment of small bowel. His recovery after surgery was uneventful, and he was eventually discharged.

UMBILICAL HERNIA AND CIRRHOSIS

Umbilical hernia is common in cirrhotic patients suffering from ascites, with a prevalence up to 20%, which is 10 times higher than in the general population.¹ Ascites is the major predisposing factor since it causes muscle wasting and increases intra-abdominal pressure.

A unique feature of cirrhosis is low physiologic reserve, which increases the risk of death from complications of umbilical hernia and makes the patient more vulnerable to perioperative complications during repair. Because of the high operative risk, umbilical hernia repair has traditionally been reserved for the most complicated cases, such as strangulation of the bowel or rupture of the skin with leakage of ascitic fluid.^2,3 Many patients are thus managed conservatively, with watchful waiting.

However, the natural course of umbilical hernia tends toward complications (eg, bowel incarceration, rupture of the overlying skin), which necessitate urgent repair.⁴ The risk of death with hernia repair in this urgent setting is seven times higher than for elective hernia repair in cirrhotic patients.⁵ More recent data indicate that elective repair in patients with well-compensated cirrhosis carries complication and mortality rates similar to those in noncirrhotic patients.^5–8 Therefore, patients who should undergo umbilical hernia repair are not only those with complicated umbilical hernia (strangulation or ascites leak), but also those with well-compensated cirrhosis at risk of complications.

Factors that pose a particularly high risk of complications of repair are large hernia (> 5 cm), hernia associated with pain, intermittent incarceration, and trophic alterations of the overlying skin.¹ In these patients, elective repair should be considered if hepatic function is preserved, if ascites is well managed (sodium restriction, diuretics, and sometimes even preoperative transjugular intrahepatic portosystemic shunt placement), and if the patient is not expected to undergo liver transplantation in the near future. If liver transplantation is anticipated in the short term, umbilical hernia can be managed concomitantly. Management of ascites after umbilical hernia repair is essential for prevention of recurrence.

A 62-year-old man was admitted to the intensive care unit with esophageal variceal bleeding. He had a long history of alcohol abuse with secondary cirrhosis, with a Child-Pugh score of 11 on a scale of 15 (class C—the most severe) at presentation. He also had a history of uncomplicated umbilical hernia, 6 cm in diameter without overlying trophic skin alterations.

Treatment with somatostatin, endoscopic band ligation, and prophylactic antibiotics was initiated for the variceal bleeding. The next day, he was transferred to the hepatology floor. His condition stabilized during the next week, but then he abruptly became diaphoretic and less talkative. Physical examination revealed a painful and irreducible umbilical hernia (Figure 1). He was rushed for umbilical hernia repair with resection of a necrotic segment of small bowel. His recovery after surgery was uneventful, and he was eventually discharged.

UMBILICAL HERNIA AND CIRRHOSIS

Umbilical hernia is common in cirrhotic patients suffering from ascites, with a prevalence up to 20%, which is 10 times higher than in the general population.¹ Ascites is the major predisposing factor since it causes muscle wasting and increases intra-abdominal pressure.

A unique feature of cirrhosis is low physiologic reserve, which increases the risk of death from complications of umbilical hernia and makes the patient more vulnerable to perioperative complications during repair. Because of the high operative risk, umbilical hernia repair has traditionally been reserved for the most complicated cases, such as strangulation of the bowel or rupture of the skin with leakage of ascitic fluid.^2,3 Many patients are thus managed conservatively, with watchful waiting.

However, the natural course of umbilical hernia tends toward complications (eg, bowel incarceration, rupture of the overlying skin), which necessitate urgent repair.⁴ The risk of death with hernia repair in this urgent setting is seven times higher than for elective hernia repair in cirrhotic patients.⁵ More recent data indicate that elective repair in patients with well-compensated cirrhosis carries complication and mortality rates similar to those in noncirrhotic patients.^5–8 Therefore, patients who should undergo umbilical hernia repair are not only those with complicated umbilical hernia (strangulation or ascites leak), but also those with well-compensated cirrhosis at risk of complications.

Factors that pose a particularly high risk of complications of repair are large hernia (> 5 cm), hernia associated with pain, intermittent incarceration, and trophic alterations of the overlying skin.¹ In these patients, elective repair should be considered if hepatic function is preserved, if ascites is well managed (sodium restriction, diuretics, and sometimes even preoperative transjugular intrahepatic portosystemic shunt placement), and if the patient is not expected to undergo liver transplantation in the near future. If liver transplantation is anticipated in the short term, umbilical hernia can be managed concomitantly. Management of ascites after umbilical hernia repair is essential for prevention of recurrence.

A 62-year-old man was admitted to the intensive care unit with esophageal variceal bleeding. He had a long history of alcohol abuse with secondary cirrhosis, with a Child-Pugh score of 11 on a scale of 15 (class C—the most severe) at presentation. He also had a history of uncomplicated umbilical hernia, 6 cm in diameter without overlying trophic skin alterations.

Treatment with somatostatin, endoscopic band ligation, and prophylactic antibiotics was initiated for the variceal bleeding. The next day, he was transferred to the hepatology floor. His condition stabilized during the next week, but then he abruptly became diaphoretic and less talkative. Physical examination revealed a painful and irreducible umbilical hernia (Figure 1). He was rushed for umbilical hernia repair with resection of a necrotic segment of small bowel. His recovery after surgery was uneventful, and he was eventually discharged.

UMBILICAL HERNIA AND CIRRHOSIS

Umbilical hernia is common in cirrhotic patients suffering from ascites, with a prevalence up to 20%, which is 10 times higher than in the general population.¹ Ascites is the major predisposing factor since it causes muscle wasting and increases intra-abdominal pressure.

A unique feature of cirrhosis is low physiologic reserve, which increases the risk of death from complications of umbilical hernia and makes the patient more vulnerable to perioperative complications during repair. Because of the high operative risk, umbilical hernia repair has traditionally been reserved for the most complicated cases, such as strangulation of the bowel or rupture of the skin with leakage of ascitic fluid.^2,3 Many patients are thus managed conservatively, with watchful waiting.

However, the natural course of umbilical hernia tends toward complications (eg, bowel incarceration, rupture of the overlying skin), which necessitate urgent repair.⁴ The risk of death with hernia repair in this urgent setting is seven times higher than for elective hernia repair in cirrhotic patients.⁵ More recent data indicate that elective repair in patients with well-compensated cirrhosis carries complication and mortality rates similar to those in noncirrhotic patients.^5–8 Therefore, patients who should undergo umbilical hernia repair are not only those with complicated umbilical hernia (strangulation or ascites leak), but also those with well-compensated cirrhosis at risk of complications.

Factors that pose a particularly high risk of complications of repair are large hernia (> 5 cm), hernia associated with pain, intermittent incarceration, and trophic alterations of the overlying skin.¹ In these patients, elective repair should be considered if hepatic function is preserved, if ascites is well managed (sodium restriction, diuretics, and sometimes even preoperative transjugular intrahepatic portosystemic shunt placement), and if the patient is not expected to undergo liver transplantation in the near future. If liver transplantation is anticipated in the short term, umbilical hernia can be managed concomitantly. Management of ascites after umbilical hernia repair is essential for prevention of recurrence.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

The art of medicine includes picking the right drug for the right patient, especially when we can choose between different classes of efficacious therapies. But, in view of our growing understanding of the human genome, can science replace art?

That question is part of the promise of pharmacogenetics, the study of how inter-individual genetic differences influence a patient’s response to a specific drug. A patient’s genome dictates the expression of specific enzymes that metabolize a drug with various efficiencies: variant alleles may result in slightly different proteins that express different enzymatic activity, ie, different substrate affinities for a drug resulting in more or less efficient metabolism. Genomic differences may also dictate whether a specific biochemical pathway is dominant in generating a specific pathophysiologic response, in which case drugs that affect that pathway may be strikingly effective. This may partly explain the various responses to different antihypertensive drugs.

Another less well-understood example of pharmacogenetics is the link between specific HLA haplotypes and a dramatic increase in allergic reactions to specific medications, such as the link between HLA-B*57:01 and abacavir hypersensitivity.

In this issue of the Journal, DiPiero et al discuss thiopurine methyltransferase (TPMT), an enzyme responsible for the degradation of azathioprine, and how knowing the genetically determined relative activity of this enzyme should influence our initial dosing of this and related drugs. Patients with certain variant alleles of TPMT degrade azathioprine more slowly, and these patients are at higher risk of myelosuppressive toxicity from the drug when it is given at the full weight-based dose. The TPMT test is expensive but not prohibitively so, and it would seem that genomic testing is a reasonable clinical and cost-effective option.

As in the abacavir scenario noted above, genomic-based dosing of azathioprine makes scientific sense and offers proof of principle for the validity of pharmacogenomics. But is it truly a clinical game-changer?

The answer depends in part on how the prescribing physician doses the drug, which depends in part on what disease is being treated, how fast the drug needs to be at full dose, and whether there are equally effective alternatives. Recommendations have been offered that state if TPMT activity is normal, we can start at the usual maintenance dose of 1.5 to 2 mg/kg/day (or occasionally more). But if the patient is heterozygous for the wild-type gene and thus is a slower drug metabolizer, then initial dosing “should” be reduced to 25 to 50 mg/day, with close observation of the white blood cell count as the dose is slowly increased to the target. The very rare patient who is homozygous for a non–wild-type allele should not be given the drug.

My usual practice has been to start patients on 50 mg or less daily and slowly titrate up, asking them how they are tolerating the drug and watching the white count—notably, the same approach to be taken if I had done genotyping before starting the drug and had found the patient to be heterozygous for the TPMT gene.

Interestingly, one pragmatic clinical trial tested whether genotyping patients before starting azathioprine—with subsequent suggested dosing of the drug based on the genotype as above—was safer and cheaper than letting physicians dose as they chose.¹ It turned out that physicians participating in this study still dosed their patients conservatively. Even knowing that they might be able to give full doses from the start in patients with normal TPMT activity, many chose not to. I assume that many of those physicians felt as I do that there was no urgency in reaching the presumed-to-be-effective full weight-based therapeutic dose. (We don’t have a good clinical marker of azathioprine’s efficacy). At 4 months, the maintenance dose was about the same in all groups.

We have robust evidence to support the role of pharmacogenetics in informing the dosing of several medications, more than just the ones I have mentioned here. And in the right settings, we should use pharmacogenetic testing to limit toxicity and perhaps enhance efficacy in our drug selection. As the field moves rapidly forward, we will have many opportunities to improve clinical care by using our patients’ genomic information.

But like it or bemoan it, even when we have science in the house, the art of medicine still plays a role in our clinical decisions.

The art of medicine includes picking the right drug for the right patient, especially when we can choose between different classes of efficacious therapies. But, in view of our growing understanding of the human genome, can science replace art?

That question is part of the promise of pharmacogenetics, the study of how inter-individual genetic differences influence a patient’s response to a specific drug. A patient’s genome dictates the expression of specific enzymes that metabolize a drug with various efficiencies: variant alleles may result in slightly different proteins that express different enzymatic activity, ie, different substrate affinities for a drug resulting in more or less efficient metabolism. Genomic differences may also dictate whether a specific biochemical pathway is dominant in generating a specific pathophysiologic response, in which case drugs that affect that pathway may be strikingly effective. This may partly explain the various responses to different antihypertensive drugs.

Another less well-understood example of pharmacogenetics is the link between specific HLA haplotypes and a dramatic increase in allergic reactions to specific medications, such as the link between HLA-B*57:01 and abacavir hypersensitivity.

In this issue of the Journal, DiPiero et al discuss thiopurine methyltransferase (TPMT), an enzyme responsible for the degradation of azathioprine, and how knowing the genetically determined relative activity of this enzyme should influence our initial dosing of this and related drugs. Patients with certain variant alleles of TPMT degrade azathioprine more slowly, and these patients are at higher risk of myelosuppressive toxicity from the drug when it is given at the full weight-based dose. The TPMT test is expensive but not prohibitively so, and it would seem that genomic testing is a reasonable clinical and cost-effective option.

As in the abacavir scenario noted above, genomic-based dosing of azathioprine makes scientific sense and offers proof of principle for the validity of pharmacogenomics. But is it truly a clinical game-changer?

The answer depends in part on how the prescribing physician doses the drug, which depends in part on what disease is being treated, how fast the drug needs to be at full dose, and whether there are equally effective alternatives. Recommendations have been offered that state if TPMT activity is normal, we can start at the usual maintenance dose of 1.5 to 2 mg/kg/day (or occasionally more). But if the patient is heterozygous for the wild-type gene and thus is a slower drug metabolizer, then initial dosing “should” be reduced to 25 to 50 mg/day, with close observation of the white blood cell count as the dose is slowly increased to the target. The very rare patient who is homozygous for a non–wild-type allele should not be given the drug.

My usual practice has been to start patients on 50 mg or less daily and slowly titrate up, asking them how they are tolerating the drug and watching the white count—notably, the same approach to be taken if I had done genotyping before starting the drug and had found the patient to be heterozygous for the TPMT gene.

Interestingly, one pragmatic clinical trial tested whether genotyping patients before starting azathioprine—with subsequent suggested dosing of the drug based on the genotype as above—was safer and cheaper than letting physicians dose as they chose.¹ It turned out that physicians participating in this study still dosed their patients conservatively. Even knowing that they might be able to give full doses from the start in patients with normal TPMT activity, many chose not to. I assume that many of those physicians felt as I do that there was no urgency in reaching the presumed-to-be-effective full weight-based therapeutic dose. (We don’t have a good clinical marker of azathioprine’s efficacy). At 4 months, the maintenance dose was about the same in all groups.

We have robust evidence to support the role of pharmacogenetics in informing the dosing of several medications, more than just the ones I have mentioned here. And in the right settings, we should use pharmacogenetic testing to limit toxicity and perhaps enhance efficacy in our drug selection. As the field moves rapidly forward, we will have many opportunities to improve clinical care by using our patients’ genomic information.

But like it or bemoan it, even when we have science in the house, the art of medicine still plays a role in our clinical decisions.

The art of medicine includes picking the right drug for the right patient, especially when we can choose between different classes of efficacious therapies. But, in view of our growing understanding of the human genome, can science replace art?

That question is part of the promise of pharmacogenetics, the study of how inter-individual genetic differences influence a patient’s response to a specific drug. A patient’s genome dictates the expression of specific enzymes that metabolize a drug with various efficiencies: variant alleles may result in slightly different proteins that express different enzymatic activity, ie, different substrate affinities for a drug resulting in more or less efficient metabolism. Genomic differences may also dictate whether a specific biochemical pathway is dominant in generating a specific pathophysiologic response, in which case drugs that affect that pathway may be strikingly effective. This may partly explain the various responses to different antihypertensive drugs.

Another less well-understood example of pharmacogenetics is the link between specific HLA haplotypes and a dramatic increase in allergic reactions to specific medications, such as the link between HLA-B*57:01 and abacavir hypersensitivity.

In this issue of the Journal, DiPiero et al discuss thiopurine methyltransferase (TPMT), an enzyme responsible for the degradation of azathioprine, and how knowing the genetically determined relative activity of this enzyme should influence our initial dosing of this and related drugs. Patients with certain variant alleles of TPMT degrade azathioprine more slowly, and these patients are at higher risk of myelosuppressive toxicity from the drug when it is given at the full weight-based dose. The TPMT test is expensive but not prohibitively so, and it would seem that genomic testing is a reasonable clinical and cost-effective option.

As in the abacavir scenario noted above, genomic-based dosing of azathioprine makes scientific sense and offers proof of principle for the validity of pharmacogenomics. But is it truly a clinical game-changer?

The answer depends in part on how the prescribing physician doses the drug, which depends in part on what disease is being treated, how fast the drug needs to be at full dose, and whether there are equally effective alternatives. Recommendations have been offered that state if TPMT activity is normal, we can start at the usual maintenance dose of 1.5 to 2 mg/kg/day (or occasionally more). But if the patient is heterozygous for the wild-type gene and thus is a slower drug metabolizer, then initial dosing “should” be reduced to 25 to 50 mg/day, with close observation of the white blood cell count as the dose is slowly increased to the target. The very rare patient who is homozygous for a non–wild-type allele should not be given the drug.

My usual practice has been to start patients on 50 mg or less daily and slowly titrate up, asking them how they are tolerating the drug and watching the white count—notably, the same approach to be taken if I had done genotyping before starting the drug and had found the patient to be heterozygous for the TPMT gene.

Interestingly, one pragmatic clinical trial tested whether genotyping patients before starting azathioprine—with subsequent suggested dosing of the drug based on the genotype as above—was safer and cheaper than letting physicians dose as they chose.¹ It turned out that physicians participating in this study still dosed their patients conservatively. Even knowing that they might be able to give full doses from the start in patients with normal TPMT activity, many chose not to. I assume that many of those physicians felt as I do that there was no urgency in reaching the presumed-to-be-effective full weight-based therapeutic dose. (We don’t have a good clinical marker of azathioprine’s efficacy). At 4 months, the maintenance dose was about the same in all groups.

We have robust evidence to support the role of pharmacogenetics in informing the dosing of several medications, more than just the ones I have mentioned here. And in the right settings, we should use pharmacogenetic testing to limit toxicity and perhaps enhance efficacy in our drug selection. As the field moves rapidly forward, we will have many opportunities to improve clinical care by using our patients’ genomic information.

But like it or bemoan it, even when we have science in the house, the art of medicine still plays a role in our clinical decisions.

The thiopurines azathioprine, mercaptopurine, and thioguanine are prodrugs that are converted to active thioguanine nucleotide metabolites or methylated by thiopurine methyltransferase (TPMT) to compounds with less pharmacologic activity. In the absence of TPMT activity, patients are likely to have higher concentrations of thioguanine nucleotides, which can pose an increased risk of severe life-threatening myelosuppression. Determining TPMT activity, either directly by phenotyping or indirectly by determining the specific genetic allele (different alleles have different enzymatic activity), can help identify patients at greater risk of severe myelosuppression. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

THIOPURINES AND TPMT

Azathioprine, mercaptopurine, and thioguanine are used for treating autoimmune and inflammatory diseases^1–3 and certain types of cancer such as leukemias and lymphomas.^1,4–6 Typically, azathioprine is used to treat nonmalignant conditions, thioguanine is used to treat malignancies, and mercaptopurine can be used to treat both malignant and nonmalignant conditions.

Although the exact mechanism of action of these drugs has not been completely elucidated, the active thioguanine nucleotide metabolites are thought to be incorporated into the DNA of leukocytes, resulting in DNA damage that subsequently leads to cell death and myelosuppression.^7–9

Variants of the TPMT gene may alter the activity of the TPMT enzyme, resulting in individual variability in thiopurine metabolism. Compared with people with normal (high) TPMT activity, those with intermediate or low TPMT activity metabolize the drugs more slowly, and are likely to have higher thioguanine nucleotide concentrations and therefore an increased risk of myelosuppression.

One of the earliest correlations between TPMT activity and thiopurine-induced myelosuppression was described in a pediatric patient with acute lymphocytic leukemia.¹⁰ After being prescribed a conventional mercaptopurine dosage (75 mg/m² daily), the patient developed severe myelosuppression and was observed to have a thioguanine nucleotide metabolite concentration seven times the observed population median. TPMT phenotyping demonstrated that the patient had low TPMT activity. Reducing the mercaptopurine dose by approximately 90% resulted in normalization of thioguanine nucleotide metabolite concentrations, and the myelosuppression subsequently resolved.

Approximately 10% of the population has intermediate TPMT activity and 0.3% has low or absent TPMT activity, though these percentages vary depending on ancestry.¹ Research has demonstrated that approximately 30% to 60% of those with intermediate TPMT activity cannot tolerate a full thiopurine dose (eg, azathioprine 2–3 mg/kg/day or mercaptopurine 1.5 mg/kg/day).¹ Almost all patients with low TPMT activity will develop life-threating myelosuppression if prescribed a full thiopurine dose.¹

SHOULD TPMT ACTIVITY BE DETERMINED FOR EVERY PATIENT PRESCRIBED A THIOPURINE?

Although determining TPMT activity in thiopurine-naïve patients will assist clinicians in selecting a thiopurine starting dose or in deciding if an alternative agent is warranted, there are instances when a clinician may elect to not perform a TPMT genotype or phenotype test. For example, determining TPMT activity is not recommended for patients who previously tolerated thiopurine therapy at full steady-state doses.

The required starting dose of a thiopurine can influence the decision on whether or not to test for TPMT activity. TPMT genotyping or phenotyping may be of most benefit for patients requiring immediate full doses of a thiopurine.¹¹ Ideally, TPMT activity should be determined before prescribing immediate full doses of a thiopurine. This could be achieved by preemptively ordering a TPMT test in patients likely to require immunosuppression—for example, in patients diagnosed with inflammatory or autoimmune diseases. If therapy cannot be delayed and TPMT activity is unknown, ordering a TPMT test at the time of prescribing a full thiopurine dose is still of benefit. Depending on the clinical laboratory utilized for testing, TPMT phenotype results are usually reported in 3 to 5 days, and TPMT genotype results are usually reported in 5 to 7 days. Because most patients will not reach steady-state concentrations for 2 to 6 weeks, clinicians could initiate immediate full doses of a thiopurine and modify therapy based on TPMT test results before accumulation of thioguanine nucleotide metabolites occurs. Caution should be used with this approach, particularly in situations where the clinical laboratory may not return results in a timely manner.

For patients who are candidates for an initial low dose of a thiopurine, clinicians may choose to slowly titrate doses based on response and tolerability instead of determining TPMT activity.¹¹ Depending on the starting dose and how slowly titration occurs, initiating a thiopurine at a low dose and titrating based on response can be a feasible approach for patients with intermediate TPMT activity. Because drastic thiopurine dose reductions of approximately 10-fold are required for patients with low TPMT activity, which is a much smaller dosage than most clinicians will initially prescribe, the starting dosage will likely not be low enough to prevent myelosuppression in patients with low TPMT activity.^1,10

Determining TPMT activity can help clinicians establish an appropriate titration schedule. Patients with normal TPMT activity will usually reach thiopurine steady-state concentrations in 2 weeks, and the dosage can be titrated based on response.¹ Alterations in TPMT activity influence the pharmacokinetic parameters of thiopurines, and the time to reach steady-state is extended to 4 or 6 weeks for those with intermediate or low TPMT activity.¹ Increasing the thiopurine dosage before reaching steady state can lead to the prescribing of doses that will not be tolerated, resulting in myelosuppression.

Factors to consider when deciding if TPMT activity should be assessed include the disease state being treated and corresponding starting dose, the need for immediate full doses, and previous documented tolerance of thiopurines at steady-state doses. As with many aspects of medicine that have multiple options, coupled with an increase in patient access to healthcare information, the decision to test for TPMT activity may include shared decision-making between patients and providers. Although TPMT genotyping or phenotyping can help identify those at greatest risk of severe myelosuppression, such assays do not replace routine monitoring for myelosuppression, hepatotoxicity, or pancreatitis that may be caused by thiopurines.

WHAT TESTS ARE AVAILABLE TO DETERMINE TPMT ACTIVITY?

Patients with intermediate or low TPMT activity can be identified by either genotyping or phenotyping. There are considerations, though, that clinicians should be aware of before selecting a particular test.

TPMT genotyping

Four TPMT alleles, TPMT*2, *3A, *3B, and *3C, account for over 90% of inactivating polymorphisms.¹² Therefore, most reference laboratories only analyze for those genetic variants. Based on the reported test result, a predicted phenotype (eg, normal, intermediate, or low TPMT activity) can be assigned. Table 1 lists the predicted phenotypes for select genotyping results.

TPMT phenotyping

Phenotyping quantitates TPMT enzyme activity in erythrocytes, and based on the result, patients are classified as having normal, intermediate, or low TPMT activity. Because internal standards and other testing conditions may differ between reference laboratories, test results must be interpreted in the context of the laboratory that performed the assay.

Which test is right for my patient?

In most cases, either the genotype or the phenotype test provides sufficient information to guide thiopurine therapy. There are certain circumstances, though, in which the genotype or phenotype test is less informative.

TPMT genotyping, when performed using a blood specimen, is not recommended in those with a history of allogeneic bone marrow transplantation, as the result would reflect the donor’s genotype, not the patient’s. In such instances, monitoring of white blood cell counts and thiopurine metabolites may be more beneficial.

TPMT phenotyping may be inaccurate if performed within 30 to 90 days of an erythrocyte transfusion, as the test result may be influenced by donor erythrocytes. If a patient is receiving erythrocyte transfusions, TPMT genotyping is preferable to phenotyping.

Test cost may also be a consideration when determining if the genotype or phenotype test is best for your patient. Costs vary by laboratory, but phenotyping is generally less expensive than genotyping. The cost of genotyping, though, continues to decrease.¹³ The approximate commercial cost is $200 for phenotyping and $450 for genotyping, but laboratory fees may be substantially higher. Several insurance plans, including Medicare, cover TPMT testing, but reimbursement and copayments vary, depending on the patient’s specific plan.

There are conflicting data as to whether determining TPMT status is^11,14–18 or is not¹⁹ cost-effective. Multiple studies suggest that the cost of genotyping a sufficient number of patients to identify a single individual at high risk of myelosuppression is cheaper than the costs associated with treating an adverse event. Additional cost-benefit studies are needed, particularly studies that consider how bundled payments and outcomes-based reimbursement influence cost-effectiveness.

MODIFYING THIOPURINE THERAPY BASED ON TPMT ACTIVITY

There is a strong correlation between TPMT activity and tolerated thiopurine doses, with those having intermediate or low TPMT activity requiring lower doses.^10,20–23 Adjusting mercaptopurine doses based on TPMT activity to prevent hematopoietic toxicity has been successfully demonstrated in pediatric patients with acute lymphoblastic leukemia.²⁴ Furthermore, reducing initial thiopurine doses to avoid myelosuppression and titrating based on response has been shown to not compromise outcomes.^1,25,26 The Clinical Pharmacogenetic Implementation Consortium (CPIC) has developed an evidence-based guideline on how to adjust thiopurine doses based on TPMT activity,¹ summarized in Table 2. These dosing recommendations are classified as “strong.”

Patients with normal TPMT activity should be prescribed the usual thiopurine starting dose as indicated by disease-specific guidelines.

For those with intermediate TPMT activity, the CPIC guideline recommends reducing the initial targeted full dose of azathioprine and mercaptopurine by 30% to 70% and reducing the targeted full dose of thioguanine by 30% to 50%. The percentage of dose reduction depends on the targeted full dose. Siegel and Sands²⁷ suggested that for those who are diagnosed with inflammatory bowel disease and have intermediate TPMT activity, azathioprine should be initiated at a low dose and titrated to 1.25 mg/kg and mercaptopurine should be initiated at a low dose and titrated to 0.75 mg/kg. Based on these titration goals, if the targeted full dose for mercaptopurine is 1 mg/kg, then a dose reduction of approximately 30% would be more appropriate. If the targeted full dose is 1.5 mg/kg, a dose reduction of approximately 50% would be more appropriate. Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 2 to 4 weeks to reach steady state before dose titration.

For those with low TPMT activity, alternative therapy should be considered for nonmalignant conditions because of the risk of severe myelosuppression. For malignancy, or if a thiopurine is warranted for a nonmalignant condition, consider a 90% dose reduction and give the drug three times per week instead of daily. For example, acute lymphoblastic leukemia patients with low TPMT activity can be started on mercaptopurine 10 mg/m² three times per week instead of the usual starting dose.¹⁰ Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 4 to 6 weeks to reach steady state before dose titration.

RECOMMENDATIONS

Individuals with intermediate or low TPMT activity have an increased risk of myelosuppression. Because of the elevated risk for morbidity and death, especially for patients with low TPMT activity, multiple guidelines and regulatory agencies recommend TPMT genotyping or phenotyping if a thiopurine is prescribed.^25,28–32 Although additional cost-benefit analysis studies are needed, evidence suggests testing for TPMT activity may be cheaper than the costs associated with treating myelosuppression.

In view of treatment guidelines, the recommendations of regulatory agencies, cost-benefit analyses, and the availability of gene-based dosing recommendations, we consider the benefits of testing for TPMT activity to greatly outweigh any associated risks. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

The thiopurines azathioprine, mercaptopurine, and thioguanine are prodrugs that are converted to active thioguanine nucleotide metabolites or methylated by thiopurine methyltransferase (TPMT) to compounds with less pharmacologic activity. In the absence of TPMT activity, patients are likely to have higher concentrations of thioguanine nucleotides, which can pose an increased risk of severe life-threatening myelosuppression. Determining TPMT activity, either directly by phenotyping or indirectly by determining the specific genetic allele (different alleles have different enzymatic activity), can help identify patients at greater risk of severe myelosuppression. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

THIOPURINES AND TPMT

Azathioprine, mercaptopurine, and thioguanine are used for treating autoimmune and inflammatory diseases^1–3 and certain types of cancer such as leukemias and lymphomas.^1,4–6 Typically, azathioprine is used to treat nonmalignant conditions, thioguanine is used to treat malignancies, and mercaptopurine can be used to treat both malignant and nonmalignant conditions.

Although the exact mechanism of action of these drugs has not been completely elucidated, the active thioguanine nucleotide metabolites are thought to be incorporated into the DNA of leukocytes, resulting in DNA damage that subsequently leads to cell death and myelosuppression.^7–9

Variants of the TPMT gene may alter the activity of the TPMT enzyme, resulting in individual variability in thiopurine metabolism. Compared with people with normal (high) TPMT activity, those with intermediate or low TPMT activity metabolize the drugs more slowly, and are likely to have higher thioguanine nucleotide concentrations and therefore an increased risk of myelosuppression.

One of the earliest correlations between TPMT activity and thiopurine-induced myelosuppression was described in a pediatric patient with acute lymphocytic leukemia.¹⁰ After being prescribed a conventional mercaptopurine dosage (75 mg/m² daily), the patient developed severe myelosuppression and was observed to have a thioguanine nucleotide metabolite concentration seven times the observed population median. TPMT phenotyping demonstrated that the patient had low TPMT activity. Reducing the mercaptopurine dose by approximately 90% resulted in normalization of thioguanine nucleotide metabolite concentrations, and the myelosuppression subsequently resolved.

Approximately 10% of the population has intermediate TPMT activity and 0.3% has low or absent TPMT activity, though these percentages vary depending on ancestry.¹ Research has demonstrated that approximately 30% to 60% of those with intermediate TPMT activity cannot tolerate a full thiopurine dose (eg, azathioprine 2–3 mg/kg/day or mercaptopurine 1.5 mg/kg/day).¹ Almost all patients with low TPMT activity will develop life-threating myelosuppression if prescribed a full thiopurine dose.¹

SHOULD TPMT ACTIVITY BE DETERMINED FOR EVERY PATIENT PRESCRIBED A THIOPURINE?

Although determining TPMT activity in thiopurine-naïve patients will assist clinicians in selecting a thiopurine starting dose or in deciding if an alternative agent is warranted, there are instances when a clinician may elect to not perform a TPMT genotype or phenotype test. For example, determining TPMT activity is not recommended for patients who previously tolerated thiopurine therapy at full steady-state doses.

The required starting dose of a thiopurine can influence the decision on whether or not to test for TPMT activity. TPMT genotyping or phenotyping may be of most benefit for patients requiring immediate full doses of a thiopurine.¹¹ Ideally, TPMT activity should be determined before prescribing immediate full doses of a thiopurine. This could be achieved by preemptively ordering a TPMT test in patients likely to require immunosuppression—for example, in patients diagnosed with inflammatory or autoimmune diseases. If therapy cannot be delayed and TPMT activity is unknown, ordering a TPMT test at the time of prescribing a full thiopurine dose is still of benefit. Depending on the clinical laboratory utilized for testing, TPMT phenotype results are usually reported in 3 to 5 days, and TPMT genotype results are usually reported in 5 to 7 days. Because most patients will not reach steady-state concentrations for 2 to 6 weeks, clinicians could initiate immediate full doses of a thiopurine and modify therapy based on TPMT test results before accumulation of thioguanine nucleotide metabolites occurs. Caution should be used with this approach, particularly in situations where the clinical laboratory may not return results in a timely manner.

For patients who are candidates for an initial low dose of a thiopurine, clinicians may choose to slowly titrate doses based on response and tolerability instead of determining TPMT activity.¹¹ Depending on the starting dose and how slowly titration occurs, initiating a thiopurine at a low dose and titrating based on response can be a feasible approach for patients with intermediate TPMT activity. Because drastic thiopurine dose reductions of approximately 10-fold are required for patients with low TPMT activity, which is a much smaller dosage than most clinicians will initially prescribe, the starting dosage will likely not be low enough to prevent myelosuppression in patients with low TPMT activity.^1,10

Determining TPMT activity can help clinicians establish an appropriate titration schedule. Patients with normal TPMT activity will usually reach thiopurine steady-state concentrations in 2 weeks, and the dosage can be titrated based on response.¹ Alterations in TPMT activity influence the pharmacokinetic parameters of thiopurines, and the time to reach steady-state is extended to 4 or 6 weeks for those with intermediate or low TPMT activity.¹ Increasing the thiopurine dosage before reaching steady state can lead to the prescribing of doses that will not be tolerated, resulting in myelosuppression.

Factors to consider when deciding if TPMT activity should be assessed include the disease state being treated and corresponding starting dose, the need for immediate full doses, and previous documented tolerance of thiopurines at steady-state doses. As with many aspects of medicine that have multiple options, coupled with an increase in patient access to healthcare information, the decision to test for TPMT activity may include shared decision-making between patients and providers. Although TPMT genotyping or phenotyping can help identify those at greatest risk of severe myelosuppression, such assays do not replace routine monitoring for myelosuppression, hepatotoxicity, or pancreatitis that may be caused by thiopurines.

WHAT TESTS ARE AVAILABLE TO DETERMINE TPMT ACTIVITY?

Patients with intermediate or low TPMT activity can be identified by either genotyping or phenotyping. There are considerations, though, that clinicians should be aware of before selecting a particular test.

TPMT genotyping

Four TPMT alleles, TPMT*2, *3A, *3B, and *3C, account for over 90% of inactivating polymorphisms.¹² Therefore, most reference laboratories only analyze for those genetic variants. Based on the reported test result, a predicted phenotype (eg, normal, intermediate, or low TPMT activity) can be assigned. Table 1 lists the predicted phenotypes for select genotyping results.

TPMT phenotyping

Phenotyping quantitates TPMT enzyme activity in erythrocytes, and based on the result, patients are classified as having normal, intermediate, or low TPMT activity. Because internal standards and other testing conditions may differ between reference laboratories, test results must be interpreted in the context of the laboratory that performed the assay.

Which test is right for my patient?

In most cases, either the genotype or the phenotype test provides sufficient information to guide thiopurine therapy. There are certain circumstances, though, in which the genotype or phenotype test is less informative.

TPMT genotyping, when performed using a blood specimen, is not recommended in those with a history of allogeneic bone marrow transplantation, as the result would reflect the donor’s genotype, not the patient’s. In such instances, monitoring of white blood cell counts and thiopurine metabolites may be more beneficial.

TPMT phenotyping may be inaccurate if performed within 30 to 90 days of an erythrocyte transfusion, as the test result may be influenced by donor erythrocytes. If a patient is receiving erythrocyte transfusions, TPMT genotyping is preferable to phenotyping.

Test cost may also be a consideration when determining if the genotype or phenotype test is best for your patient. Costs vary by laboratory, but phenotyping is generally less expensive than genotyping. The cost of genotyping, though, continues to decrease.¹³ The approximate commercial cost is $200 for phenotyping and $450 for genotyping, but laboratory fees may be substantially higher. Several insurance plans, including Medicare, cover TPMT testing, but reimbursement and copayments vary, depending on the patient’s specific plan.

There are conflicting data as to whether determining TPMT status is^11,14–18 or is not¹⁹ cost-effective. Multiple studies suggest that the cost of genotyping a sufficient number of patients to identify a single individual at high risk of myelosuppression is cheaper than the costs associated with treating an adverse event. Additional cost-benefit studies are needed, particularly studies that consider how bundled payments and outcomes-based reimbursement influence cost-effectiveness.

MODIFYING THIOPURINE THERAPY BASED ON TPMT ACTIVITY

There is a strong correlation between TPMT activity and tolerated thiopurine doses, with those having intermediate or low TPMT activity requiring lower doses.^10,20–23 Adjusting mercaptopurine doses based on TPMT activity to prevent hematopoietic toxicity has been successfully demonstrated in pediatric patients with acute lymphoblastic leukemia.²⁴ Furthermore, reducing initial thiopurine doses to avoid myelosuppression and titrating based on response has been shown to not compromise outcomes.^1,25,26 The Clinical Pharmacogenetic Implementation Consortium (CPIC) has developed an evidence-based guideline on how to adjust thiopurine doses based on TPMT activity,¹ summarized in Table 2. These dosing recommendations are classified as “strong.”

Patients with normal TPMT activity should be prescribed the usual thiopurine starting dose as indicated by disease-specific guidelines.

For those with intermediate TPMT activity, the CPIC guideline recommends reducing the initial targeted full dose of azathioprine and mercaptopurine by 30% to 70% and reducing the targeted full dose of thioguanine by 30% to 50%. The percentage of dose reduction depends on the targeted full dose. Siegel and Sands²⁷ suggested that for those who are diagnosed with inflammatory bowel disease and have intermediate TPMT activity, azathioprine should be initiated at a low dose and titrated to 1.25 mg/kg and mercaptopurine should be initiated at a low dose and titrated to 0.75 mg/kg. Based on these titration goals, if the targeted full dose for mercaptopurine is 1 mg/kg, then a dose reduction of approximately 30% would be more appropriate. If the targeted full dose is 1.5 mg/kg, a dose reduction of approximately 50% would be more appropriate. Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 2 to 4 weeks to reach steady state before dose titration.

For those with low TPMT activity, alternative therapy should be considered for nonmalignant conditions because of the risk of severe myelosuppression. For malignancy, or if a thiopurine is warranted for a nonmalignant condition, consider a 90% dose reduction and give the drug three times per week instead of daily. For example, acute lymphoblastic leukemia patients with low TPMT activity can be started on mercaptopurine 10 mg/m² three times per week instead of the usual starting dose.¹⁰ Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 4 to 6 weeks to reach steady state before dose titration.

RECOMMENDATIONS

Individuals with intermediate or low TPMT activity have an increased risk of myelosuppression. Because of the elevated risk for morbidity and death, especially for patients with low TPMT activity, multiple guidelines and regulatory agencies recommend TPMT genotyping or phenotyping if a thiopurine is prescribed.^25,28–32 Although additional cost-benefit analysis studies are needed, evidence suggests testing for TPMT activity may be cheaper than the costs associated with treating myelosuppression.

In view of treatment guidelines, the recommendations of regulatory agencies, cost-benefit analyses, and the availability of gene-based dosing recommendations, we consider the benefits of testing for TPMT activity to greatly outweigh any associated risks. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

The thiopurines azathioprine, mercaptopurine, and thioguanine are prodrugs that are converted to active thioguanine nucleotide metabolites or methylated by thiopurine methyltransferase (TPMT) to compounds with less pharmacologic activity. In the absence of TPMT activity, patients are likely to have higher concentrations of thioguanine nucleotides, which can pose an increased risk of severe life-threatening myelosuppression. Determining TPMT activity, either directly by phenotyping or indirectly by determining the specific genetic allele (different alleles have different enzymatic activity), can help identify patients at greater risk of severe myelosuppression. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

THIOPURINES AND TPMT

Azathioprine, mercaptopurine, and thioguanine are used for treating autoimmune and inflammatory diseases^1–3 and certain types of cancer such as leukemias and lymphomas.^1,4–6 Typically, azathioprine is used to treat nonmalignant conditions, thioguanine is used to treat malignancies, and mercaptopurine can be used to treat both malignant and nonmalignant conditions.

Although the exact mechanism of action of these drugs has not been completely elucidated, the active thioguanine nucleotide metabolites are thought to be incorporated into the DNA of leukocytes, resulting in DNA damage that subsequently leads to cell death and myelosuppression.^7–9

Variants of the TPMT gene may alter the activity of the TPMT enzyme, resulting in individual variability in thiopurine metabolism. Compared with people with normal (high) TPMT activity, those with intermediate or low TPMT activity metabolize the drugs more slowly, and are likely to have higher thioguanine nucleotide concentrations and therefore an increased risk of myelosuppression.

One of the earliest correlations between TPMT activity and thiopurine-induced myelosuppression was described in a pediatric patient with acute lymphocytic leukemia.¹⁰ After being prescribed a conventional mercaptopurine dosage (75 mg/m² daily), the patient developed severe myelosuppression and was observed to have a thioguanine nucleotide metabolite concentration seven times the observed population median. TPMT phenotyping demonstrated that the patient had low TPMT activity. Reducing the mercaptopurine dose by approximately 90% resulted in normalization of thioguanine nucleotide metabolite concentrations, and the myelosuppression subsequently resolved.

Approximately 10% of the population has intermediate TPMT activity and 0.3% has low or absent TPMT activity, though these percentages vary depending on ancestry.¹ Research has demonstrated that approximately 30% to 60% of those with intermediate TPMT activity cannot tolerate a full thiopurine dose (eg, azathioprine 2–3 mg/kg/day or mercaptopurine 1.5 mg/kg/day).¹ Almost all patients with low TPMT activity will develop life-threating myelosuppression if prescribed a full thiopurine dose.¹

SHOULD TPMT ACTIVITY BE DETERMINED FOR EVERY PATIENT PRESCRIBED A THIOPURINE?

Although determining TPMT activity in thiopurine-naïve patients will assist clinicians in selecting a thiopurine starting dose or in deciding if an alternative agent is warranted, there are instances when a clinician may elect to not perform a TPMT genotype or phenotype test. For example, determining TPMT activity is not recommended for patients who previously tolerated thiopurine therapy at full steady-state doses.

The required starting dose of a thiopurine can influence the decision on whether or not to test for TPMT activity. TPMT genotyping or phenotyping may be of most benefit for patients requiring immediate full doses of a thiopurine.¹¹ Ideally, TPMT activity should be determined before prescribing immediate full doses of a thiopurine. This could be achieved by preemptively ordering a TPMT test in patients likely to require immunosuppression—for example, in patients diagnosed with inflammatory or autoimmune diseases. If therapy cannot be delayed and TPMT activity is unknown, ordering a TPMT test at the time of prescribing a full thiopurine dose is still of benefit. Depending on the clinical laboratory utilized for testing, TPMT phenotype results are usually reported in 3 to 5 days, and TPMT genotype results are usually reported in 5 to 7 days. Because most patients will not reach steady-state concentrations for 2 to 6 weeks, clinicians could initiate immediate full doses of a thiopurine and modify therapy based on TPMT test results before accumulation of thioguanine nucleotide metabolites occurs. Caution should be used with this approach, particularly in situations where the clinical laboratory may not return results in a timely manner.

For patients who are candidates for an initial low dose of a thiopurine, clinicians may choose to slowly titrate doses based on response and tolerability instead of determining TPMT activity.¹¹ Depending on the starting dose and how slowly titration occurs, initiating a thiopurine at a low dose and titrating based on response can be a feasible approach for patients with intermediate TPMT activity. Because drastic thiopurine dose reductions of approximately 10-fold are required for patients with low TPMT activity, which is a much smaller dosage than most clinicians will initially prescribe, the starting dosage will likely not be low enough to prevent myelosuppression in patients with low TPMT activity.^1,10

Determining TPMT activity can help clinicians establish an appropriate titration schedule. Patients with normal TPMT activity will usually reach thiopurine steady-state concentrations in 2 weeks, and the dosage can be titrated based on response.¹ Alterations in TPMT activity influence the pharmacokinetic parameters of thiopurines, and the time to reach steady-state is extended to 4 or 6 weeks for those with intermediate or low TPMT activity.¹ Increasing the thiopurine dosage before reaching steady state can lead to the prescribing of doses that will not be tolerated, resulting in myelosuppression.

Factors to consider when deciding if TPMT activity should be assessed include the disease state being treated and corresponding starting dose, the need for immediate full doses, and previous documented tolerance of thiopurines at steady-state doses. As with many aspects of medicine that have multiple options, coupled with an increase in patient access to healthcare information, the decision to test for TPMT activity may include shared decision-making between patients and providers. Although TPMT genotyping or phenotyping can help identify those at greatest risk of severe myelosuppression, such assays do not replace routine monitoring for myelosuppression, hepatotoxicity, or pancreatitis that may be caused by thiopurines.

WHAT TESTS ARE AVAILABLE TO DETERMINE TPMT ACTIVITY?

Patients with intermediate or low TPMT activity can be identified by either genotyping or phenotyping. There are considerations, though, that clinicians should be aware of before selecting a particular test.

TPMT genotyping

Four TPMT alleles, TPMT*2, *3A, *3B, and *3C, account for over 90% of inactivating polymorphisms.¹² Therefore, most reference laboratories only analyze for those genetic variants. Based on the reported test result, a predicted phenotype (eg, normal, intermediate, or low TPMT activity) can be assigned. Table 1 lists the predicted phenotypes for select genotyping results.

TPMT phenotyping

Phenotyping quantitates TPMT enzyme activity in erythrocytes, and based on the result, patients are classified as having normal, intermediate, or low TPMT activity. Because internal standards and other testing conditions may differ between reference laboratories, test results must be interpreted in the context of the laboratory that performed the assay.

Which test is right for my patient?

In most cases, either the genotype or the phenotype test provides sufficient information to guide thiopurine therapy. There are certain circumstances, though, in which the genotype or phenotype test is less informative.

TPMT genotyping, when performed using a blood specimen, is not recommended in those with a history of allogeneic bone marrow transplantation, as the result would reflect the donor’s genotype, not the patient’s. In such instances, monitoring of white blood cell counts and thiopurine metabolites may be more beneficial.

TPMT phenotyping may be inaccurate if performed within 30 to 90 days of an erythrocyte transfusion, as the test result may be influenced by donor erythrocytes. If a patient is receiving erythrocyte transfusions, TPMT genotyping is preferable to phenotyping.

Test cost may also be a consideration when determining if the genotype or phenotype test is best for your patient. Costs vary by laboratory, but phenotyping is generally less expensive than genotyping. The cost of genotyping, though, continues to decrease.¹³ The approximate commercial cost is $200 for phenotyping and $450 for genotyping, but laboratory fees may be substantially higher. Several insurance plans, including Medicare, cover TPMT testing, but reimbursement and copayments vary, depending on the patient’s specific plan.

There are conflicting data as to whether determining TPMT status is^11,14–18 or is not¹⁹ cost-effective. Multiple studies suggest that the cost of genotyping a sufficient number of patients to identify a single individual at high risk of myelosuppression is cheaper than the costs associated with treating an adverse event. Additional cost-benefit studies are needed, particularly studies that consider how bundled payments and outcomes-based reimbursement influence cost-effectiveness.

MODIFYING THIOPURINE THERAPY BASED ON TPMT ACTIVITY

There is a strong correlation between TPMT activity and tolerated thiopurine doses, with those having intermediate or low TPMT activity requiring lower doses.^10,20–23 Adjusting mercaptopurine doses based on TPMT activity to prevent hematopoietic toxicity has been successfully demonstrated in pediatric patients with acute lymphoblastic leukemia.²⁴ Furthermore, reducing initial thiopurine doses to avoid myelosuppression and titrating based on response has been shown to not compromise outcomes.^1,25,26 The Clinical Pharmacogenetic Implementation Consortium (CPIC) has developed an evidence-based guideline on how to adjust thiopurine doses based on TPMT activity,¹ summarized in Table 2. These dosing recommendations are classified as “strong.”

Patients with normal TPMT activity should be prescribed the usual thiopurine starting dose as indicated by disease-specific guidelines.

For those with intermediate TPMT activity, the CPIC guideline recommends reducing the initial targeted full dose of azathioprine and mercaptopurine by 30% to 70% and reducing the targeted full dose of thioguanine by 30% to 50%. The percentage of dose reduction depends on the targeted full dose. Siegel and Sands²⁷ suggested that for those who are diagnosed with inflammatory bowel disease and have intermediate TPMT activity, azathioprine should be initiated at a low dose and titrated to 1.25 mg/kg and mercaptopurine should be initiated at a low dose and titrated to 0.75 mg/kg. Based on these titration goals, if the targeted full dose for mercaptopurine is 1 mg/kg, then a dose reduction of approximately 30% would be more appropriate. If the targeted full dose is 1.5 mg/kg, a dose reduction of approximately 50% would be more appropriate. Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 2 to 4 weeks to reach steady state before dose titration.

For those with low TPMT activity, alternative therapy should be considered for nonmalignant conditions because of the risk of severe myelosuppression. For malignancy, or if a thiopurine is warranted for a nonmalignant condition, consider a 90% dose reduction and give the drug three times per week instead of daily. For example, acute lymphoblastic leukemia patients with low TPMT activity can be started on mercaptopurine 10 mg/m² three times per week instead of the usual starting dose.¹⁰ Thiopurine doses should be titrated based on response and disease-specific guidelines, allowing 4 to 6 weeks to reach steady state before dose titration.

RECOMMENDATIONS

Individuals with intermediate or low TPMT activity have an increased risk of myelosuppression. Because of the elevated risk for morbidity and death, especially for patients with low TPMT activity, multiple guidelines and regulatory agencies recommend TPMT genotyping or phenotyping if a thiopurine is prescribed.^25,28–32 Although additional cost-benefit analysis studies are needed, evidence suggests testing for TPMT activity may be cheaper than the costs associated with treating myelosuppression.

In view of treatment guidelines, the recommendations of regulatory agencies, cost-benefit analyses, and the availability of gene-based dosing recommendations, we consider the benefits of testing for TPMT activity to greatly outweigh any associated risks. Therefore, we recommend that TPMT testing be strongly considered before initiating therapy with a thiopurine.

A 28-day-old uncircumcised male infant presents to the emergency department with fever of 38.9° C, decreased feeding, and irritability. The physical examination is normal with the exception of the irritability and your assessment of mild dehydration. The infant undergoes a sepsis work-up. The CBC is remarkable for a WBC of 16,500/mm³ with 44% neutrophils, 52% lymphocytes, and 4% monocytes. Platelet count is normal. Cerebrospinal fluid (CSF) shows no white or red blood cells with normal glucose and protein. The urinalysis (UA) has a positive 1+ leukocyte esterase (LE) with 10 WBC per high-power field (HPF), but negative nitrite and 1+ bacteria microscopically. The child is admitted to the hospital for empiric antibiotics pending blood, urine, and CSF cultures. What are the chances that a urinary tract infection (UTI) is the origin of the febrile presentation?

UTIs are currently the most common serious bacterial infection (SBI) in < 2-year-old febrile children without an apparent source of fever (Pediatrics 2011;128:595-610). Since 2000, the prevalence of UTIs in all febrile infants and young children without an apparent source is unchanged, being approximately 5%. The rate of UTIs in fever-without-apparent-source presentations at < 90 days of age is higher, ranging from 6%-15% in different studies.

Meanwhile bacteremia, sepsis, meningitis, and other previously common SBIs, mostly caused by Haemophilus influenzae type b (Hib) or pneumococcus, have decreased. We recognize these reductions as effects of universal implementation of Hib (mid-1990s) and pneumococcal (2000 and 2010) conjugate vaccines.

Given the case above, other pertinent facts are that uncircumcised males have more UTIs in the first months of life (J. Pediatr. 1996;128:23-7) and approximately 5% of young infants with UTIs also are concurrently bacteremic (Pediatrics 1999;104:79-86;J. Pediatr. 1994;124:513-9)

The elephant in the room is the fact that we also need to be cognizant of asymptomatic bacteriuria (AB). AB is colonization of the lower urinary tract without infection. Patients with AB may meet culture criteria for UTI (whether we consider > 50,000 or > 100,000 colony-forming units/mL), but there is no evidence of true infection, that is no inflammation or mucosal injury. So children with AB are not at risk for renal injury or later renal damage and do not require antibiotic treatment.

But when AB patients develop fever, for example with an enterovirus infection, their urine cultures (together with the fever) can do a good imitation of a UTI, unless we focus on the UA results. It not only remains critical to detect true UTIs in infants < 90 days old, such as the one in our case above, but also to distinguish UTI from AB.

The 1999 American Academy of Pediatrics’ UTI guidelines (Pediatrics 1999;103:843-52) included UA results as suggestive of UTI. They stated that a positive LE or nitrite test or > 5 WBC/HPF in a spun urine, or bacteria visualized in unspun gram-stained specimen suggest, but cannot be diagnostic of a UTI. Recommendation five in the guidelines states that UTI diagnosis required 100,000 CFU/mL in culture of sterilely obtained catheterized urine as the threshold criterion (strength of evidence: strong). However, AB was not fully considered because, in part, data defining AB was incomplete in 1999.

The 1999 guidelines also stated, “The urinalysis … can be valuable in selecting individuals for prompt initiation of treatment while waiting for the results of the urine culture.” So, UA was considered adjunctive. UA’s main function was to allow empiric therapy of sufficiently ill children, given positive results for LE, nitrites, or microscopic visualization of > 5 WBC/HPF or bacteria in the spun urine.

In the 2011 AAP guidelines for UTI, things have changed (Pediatrics 2011;128:595-610). The third action statement tells us that both the UA and culture taken together are necessary for UTI diagnosis. To paraphrase: The diagnosis of UTI requires urinalysis results suggesting infection (pyuria or microscopic bacteriuria) plus > 50,000 CFU/mL of a uropathogen in urine from catheterization or suprapubic aspiration. But remember that these guidelines do not apply specifically to the youngest of infants, that is < 2 months old.

Both of these criteria were changes from the 1999 UTI guidelines. Previously pyuria or microscopic bacteriuria were not considered necessary to diagnose UTI, and >100,000 CFU/mL rather than > 50,000 CFU/mL of a single pathogen species was the critical diagnostic result for catheterized urine. For suprapubic aspiration urine samples, > 10,000 CFU/HPF were considered adequate for UTI diagnoses in 1999.

Now, a recent study of children < 90 days of age (including those < 2 months of age) reports that pyuria (> 3 WBC/HPF) plus > 50,000 CFU/mL are the keys to diagnosing UTI (Pediatrics 2015;135:965-71). One caveat is that the study population was febrile infants < 90 days old with concurrent bacteremia (bacteremic UTI). Bacteremic UTI was studied to reduce as much as possible the chance that AB patients might be inadvertently included in the study. One other conclusion of this new study is that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

These data in an overall younger population than that covered by the 2011 guidelines adds evidence that pyuria (but not microscopic bacteriuria) is critical to diagnosing UTI. Pyuria plus positive culture has been a combination for the pediatric infectious diseases practitioner’s toolkit for decades. Likewise, it seems to me that primary care pediatric clinicians also often decide whether to undertake the expense of culture based on UA results. For example, a completely normal UA may obviate need for culture except in selected unusual cases.

Requiring UA evidence of inflammation to diagnose UTI (per the 2011 guidelines and the recommendations of the authors of the recent 2015 study) makes sense because most UTIs in otherwise healthy children are caused by gram-negative organisms (> 90% from Escherichia coli) (J. Pediatr. 1994;124:513-9). Why are UA results so important?

A positive nitrite test strongly suggests UTI because nitrites in the urine indicate viable gram-negative organisms also are present in the urine. Nitrates in the urine are converted to nitrites by metabolic activity of gram-negative pathogens. For WBCs or LE in the urine, their presence indicates inflammation in the urinary tract, Consider that lipopolysaccharide (LPS), also known as gram-negative endotoxin, is a major component of the cell membrane of > 90% of uropathogens like E. coli. Moreover, LPS elicits about the strongest innate immune response via toll-like receptor 4 (TLR4) from monocytes/macrophages, inducing a large pro-inflammatory and chemotactic response – interleukin-6, interleukin-8, tetrahydrofuran-alpha. Remember that LPS is also a major cause of fever and of shock during gram-negative sepsis.

So a UTI diagnosis based on a “positive” culture without evidence of metabolic products of gram negatives (nitrites) or without inflammation (no pyuria or negative LE) should be questioned. The combination of > 50,000 CFU/mL with no detectable LE or < 3-5 WBC/HPF in a febrile child is most likely evidence for AB in a child with the fever caused by some non-UTI process.

In contrast, selected SBIs may occur when the culture is “positive” without inflammation or nitrites. The first of three examples is a renal parenchymal abscess, where bacteria enter the urine sporadically in only small numbers, and do not actually infect the urinary tract mucosa. The scenario of no inflammation but “positive” culture also may occur when a large bacteremic load causes results in organisms filtering through the kidney into the urine, again without urinary mucosal infection, such as Staphylococcus aureus, group A streptococcus, or group B streptococcus bacteremia/sepsis. The third scenario with a “positive” culture and no pyuria can be with organisms that have blunted abilities to induce inflammation, such as enterococcus. Enterococcal cell components have weak inflammatory and chemotactic capability. So a urinary mucosal infection in the collecting system or bladder may occur without much if any pyuria. In fact, the patients from the recent study with insufficient evidence of pyuria/inflammation were those who had either gram-positive organisms or considerably less than 50,000 CFU/mL of gram-negative organisms.

The sensitivity and specificity of the LE or pyuria was higher in the recent study (Pediatrics 2015;135:965-71) than any prior study. The authors comment that they had not expected such a high sensitivity of 97.6% (94.5-99.2) for LE in confirmed bacteremic UTI, nor did they expect the high specificity of 93.9% (87.9-97.5). The presence of microscopic pyuria defined as > 3 WBC/HPF was nearly as sensitive, 96%, and specific, 91.3%. Disappointingly, positive nitrite testing was only 39.5% sensitive, but it was 100% specific. This likely reflects the short time that urine resides in the bladder of infants < 90 days of age, so there is insufficient time for the pathogens to metabolically convert the nitrates to nitrites.

So how would the UA help with our example case? There is microscopic bacteriuria, pyuria, and positive LE, but negative nitrites. Using the suggestions of the authors of the recent report (Pediatrics 2015;135:965-71) and those of another report on the utility of UA results (Acta Paediatr. 2010;99:581-4), the UA in our case indicates that we should be highly suspicious of a UTI in this child < 2 months old for whom the 2011 guidelines do not directly apply. But remember that these impressive sensitivity and specificity values relate to bacteremic UTI. Whether they apply to nonbacteremic UTI is not known. Likewise, the authors caution that their study design did not allow calculation of positive or negative predictive values – aspects that would clarify things even further.

So we still cannot be more than highly suspicious. Without a positive predictive value, we do not know the odds of this case having a UTI with mathematical precision. The authors do point out that only one of their subjects had a completely normal UA and actually had a bacteremic UTI. If you guessed that it was a gram-positive pathogen, you win the prize. So it seems reasonable to predict that a normal UA has a high specificity for not being a UTI (87.8%), but a positive UA remains only highly suggestive. It is still not clear if a negative UA statistically justifies not submitting the culture of the sterilely obtained urine because we still don’t have a negative predictive value.

Bottom line: The 2011 UTI guidelines provide good advice on diagnosing UTIs.

1. We have more data that evidence of inflammation is essential for diagnosing gram-negative UTIs.

2. We also have more evidence that 50,000 CFU/mL is a good threshold for diagnosing UTIs.

3. It appears that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

4. And we now have more evidence that these criteria also apply to infants < 2 months of age.

To close the loop on our case, the child’s CSF and blood cultures were negative, but the urine culture revealed > 100,000 CFU/mL of E. coli susceptible to second- and third-generation cephalosporins, ciprofloxacin, and nitrofurantoin, but resistant to trimethoprim-sulfamethoxazole.

Have a great summer and watch for UTIs in your young patients < 90 days old and fever without apparent focus.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. E-mail Dr. Harrison at pdnews@frontlinemedcom.com. 

A 28-day-old uncircumcised male infant presents to the emergency department with fever of 38.9° C, decreased feeding, and irritability. The physical examination is normal with the exception of the irritability and your assessment of mild dehydration. The infant undergoes a sepsis work-up. The CBC is remarkable for a WBC of 16,500/mm³ with 44% neutrophils, 52% lymphocytes, and 4% monocytes. Platelet count is normal. Cerebrospinal fluid (CSF) shows no white or red blood cells with normal glucose and protein. The urinalysis (UA) has a positive 1+ leukocyte esterase (LE) with 10 WBC per high-power field (HPF), but negative nitrite and 1+ bacteria microscopically. The child is admitted to the hospital for empiric antibiotics pending blood, urine, and CSF cultures. What are the chances that a urinary tract infection (UTI) is the origin of the febrile presentation?

UTIs are currently the most common serious bacterial infection (SBI) in < 2-year-old febrile children without an apparent source of fever (Pediatrics 2011;128:595-610). Since 2000, the prevalence of UTIs in all febrile infants and young children without an apparent source is unchanged, being approximately 5%. The rate of UTIs in fever-without-apparent-source presentations at < 90 days of age is higher, ranging from 6%-15% in different studies.

Meanwhile bacteremia, sepsis, meningitis, and other previously common SBIs, mostly caused by Haemophilus influenzae type b (Hib) or pneumococcus, have decreased. We recognize these reductions as effects of universal implementation of Hib (mid-1990s) and pneumococcal (2000 and 2010) conjugate vaccines.

Given the case above, other pertinent facts are that uncircumcised males have more UTIs in the first months of life (J. Pediatr. 1996;128:23-7) and approximately 5% of young infants with UTIs also are concurrently bacteremic (Pediatrics 1999;104:79-86;J. Pediatr. 1994;124:513-9)

The elephant in the room is the fact that we also need to be cognizant of asymptomatic bacteriuria (AB). AB is colonization of the lower urinary tract without infection. Patients with AB may meet culture criteria for UTI (whether we consider > 50,000 or > 100,000 colony-forming units/mL), but there is no evidence of true infection, that is no inflammation or mucosal injury. So children with AB are not at risk for renal injury or later renal damage and do not require antibiotic treatment.

But when AB patients develop fever, for example with an enterovirus infection, their urine cultures (together with the fever) can do a good imitation of a UTI, unless we focus on the UA results. It not only remains critical to detect true UTIs in infants < 90 days old, such as the one in our case above, but also to distinguish UTI from AB.

The 1999 American Academy of Pediatrics’ UTI guidelines (Pediatrics 1999;103:843-52) included UA results as suggestive of UTI. They stated that a positive LE or nitrite test or > 5 WBC/HPF in a spun urine, or bacteria visualized in unspun gram-stained specimen suggest, but cannot be diagnostic of a UTI. Recommendation five in the guidelines states that UTI diagnosis required 100,000 CFU/mL in culture of sterilely obtained catheterized urine as the threshold criterion (strength of evidence: strong). However, AB was not fully considered because, in part, data defining AB was incomplete in 1999.

The 1999 guidelines also stated, “The urinalysis … can be valuable in selecting individuals for prompt initiation of treatment while waiting for the results of the urine culture.” So, UA was considered adjunctive. UA’s main function was to allow empiric therapy of sufficiently ill children, given positive results for LE, nitrites, or microscopic visualization of > 5 WBC/HPF or bacteria in the spun urine.

In the 2011 AAP guidelines for UTI, things have changed (Pediatrics 2011;128:595-610). The third action statement tells us that both the UA and culture taken together are necessary for UTI diagnosis. To paraphrase: The diagnosis of UTI requires urinalysis results suggesting infection (pyuria or microscopic bacteriuria) plus > 50,000 CFU/mL of a uropathogen in urine from catheterization or suprapubic aspiration. But remember that these guidelines do not apply specifically to the youngest of infants, that is < 2 months old.

Both of these criteria were changes from the 1999 UTI guidelines. Previously pyuria or microscopic bacteriuria were not considered necessary to diagnose UTI, and >100,000 CFU/mL rather than > 50,000 CFU/mL of a single pathogen species was the critical diagnostic result for catheterized urine. For suprapubic aspiration urine samples, > 10,000 CFU/HPF were considered adequate for UTI diagnoses in 1999.

Now, a recent study of children < 90 days of age (including those < 2 months of age) reports that pyuria (> 3 WBC/HPF) plus > 50,000 CFU/mL are the keys to diagnosing UTI (Pediatrics 2015;135:965-71). One caveat is that the study population was febrile infants < 90 days old with concurrent bacteremia (bacteremic UTI). Bacteremic UTI was studied to reduce as much as possible the chance that AB patients might be inadvertently included in the study. One other conclusion of this new study is that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

These data in an overall younger population than that covered by the 2011 guidelines adds evidence that pyuria (but not microscopic bacteriuria) is critical to diagnosing UTI. Pyuria plus positive culture has been a combination for the pediatric infectious diseases practitioner’s toolkit for decades. Likewise, it seems to me that primary care pediatric clinicians also often decide whether to undertake the expense of culture based on UA results. For example, a completely normal UA may obviate need for culture except in selected unusual cases.

Requiring UA evidence of inflammation to diagnose UTI (per the 2011 guidelines and the recommendations of the authors of the recent 2015 study) makes sense because most UTIs in otherwise healthy children are caused by gram-negative organisms (> 90% from Escherichia coli) (J. Pediatr. 1994;124:513-9). Why are UA results so important?

A positive nitrite test strongly suggests UTI because nitrites in the urine indicate viable gram-negative organisms also are present in the urine. Nitrates in the urine are converted to nitrites by metabolic activity of gram-negative pathogens. For WBCs or LE in the urine, their presence indicates inflammation in the urinary tract, Consider that lipopolysaccharide (LPS), also known as gram-negative endotoxin, is a major component of the cell membrane of > 90% of uropathogens like E. coli. Moreover, LPS elicits about the strongest innate immune response via toll-like receptor 4 (TLR4) from monocytes/macrophages, inducing a large pro-inflammatory and chemotactic response – interleukin-6, interleukin-8, tetrahydrofuran-alpha. Remember that LPS is also a major cause of fever and of shock during gram-negative sepsis.

So a UTI diagnosis based on a “positive” culture without evidence of metabolic products of gram negatives (nitrites) or without inflammation (no pyuria or negative LE) should be questioned. The combination of > 50,000 CFU/mL with no detectable LE or < 3-5 WBC/HPF in a febrile child is most likely evidence for AB in a child with the fever caused by some non-UTI process.

In contrast, selected SBIs may occur when the culture is “positive” without inflammation or nitrites. The first of three examples is a renal parenchymal abscess, where bacteria enter the urine sporadically in only small numbers, and do not actually infect the urinary tract mucosa. The scenario of no inflammation but “positive” culture also may occur when a large bacteremic load causes results in organisms filtering through the kidney into the urine, again without urinary mucosal infection, such as Staphylococcus aureus, group A streptococcus, or group B streptococcus bacteremia/sepsis. The third scenario with a “positive” culture and no pyuria can be with organisms that have blunted abilities to induce inflammation, such as enterococcus. Enterococcal cell components have weak inflammatory and chemotactic capability. So a urinary mucosal infection in the collecting system or bladder may occur without much if any pyuria. In fact, the patients from the recent study with insufficient evidence of pyuria/inflammation were those who had either gram-positive organisms or considerably less than 50,000 CFU/mL of gram-negative organisms.

The sensitivity and specificity of the LE or pyuria was higher in the recent study (Pediatrics 2015;135:965-71) than any prior study. The authors comment that they had not expected such a high sensitivity of 97.6% (94.5-99.2) for LE in confirmed bacteremic UTI, nor did they expect the high specificity of 93.9% (87.9-97.5). The presence of microscopic pyuria defined as > 3 WBC/HPF was nearly as sensitive, 96%, and specific, 91.3%. Disappointingly, positive nitrite testing was only 39.5% sensitive, but it was 100% specific. This likely reflects the short time that urine resides in the bladder of infants < 90 days of age, so there is insufficient time for the pathogens to metabolically convert the nitrates to nitrites.

So how would the UA help with our example case? There is microscopic bacteriuria, pyuria, and positive LE, but negative nitrites. Using the suggestions of the authors of the recent report (Pediatrics 2015;135:965-71) and those of another report on the utility of UA results (Acta Paediatr. 2010;99:581-4), the UA in our case indicates that we should be highly suspicious of a UTI in this child < 2 months old for whom the 2011 guidelines do not directly apply. But remember that these impressive sensitivity and specificity values relate to bacteremic UTI. Whether they apply to nonbacteremic UTI is not known. Likewise, the authors caution that their study design did not allow calculation of positive or negative predictive values – aspects that would clarify things even further.

So we still cannot be more than highly suspicious. Without a positive predictive value, we do not know the odds of this case having a UTI with mathematical precision. The authors do point out that only one of their subjects had a completely normal UA and actually had a bacteremic UTI. If you guessed that it was a gram-positive pathogen, you win the prize. So it seems reasonable to predict that a normal UA has a high specificity for not being a UTI (87.8%), but a positive UA remains only highly suggestive. It is still not clear if a negative UA statistically justifies not submitting the culture of the sterilely obtained urine because we still don’t have a negative predictive value.

Bottom line: The 2011 UTI guidelines provide good advice on diagnosing UTIs.

1. We have more data that evidence of inflammation is essential for diagnosing gram-negative UTIs.

2. We also have more evidence that 50,000 CFU/mL is a good threshold for diagnosing UTIs.

3. It appears that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

4. And we now have more evidence that these criteria also apply to infants < 2 months of age.

To close the loop on our case, the child’s CSF and blood cultures were negative, but the urine culture revealed > 100,000 CFU/mL of E. coli susceptible to second- and third-generation cephalosporins, ciprofloxacin, and nitrofurantoin, but resistant to trimethoprim-sulfamethoxazole.

Have a great summer and watch for UTIs in your young patients < 90 days old and fever without apparent focus.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. E-mail Dr. Harrison at pdnews@frontlinemedcom.com. 

A 28-day-old uncircumcised male infant presents to the emergency department with fever of 38.9° C, decreased feeding, and irritability. The physical examination is normal with the exception of the irritability and your assessment of mild dehydration. The infant undergoes a sepsis work-up. The CBC is remarkable for a WBC of 16,500/mm³ with 44% neutrophils, 52% lymphocytes, and 4% monocytes. Platelet count is normal. Cerebrospinal fluid (CSF) shows no white or red blood cells with normal glucose and protein. The urinalysis (UA) has a positive 1+ leukocyte esterase (LE) with 10 WBC per high-power field (HPF), but negative nitrite and 1+ bacteria microscopically. The child is admitted to the hospital for empiric antibiotics pending blood, urine, and CSF cultures. What are the chances that a urinary tract infection (UTI) is the origin of the febrile presentation?

UTIs are currently the most common serious bacterial infection (SBI) in < 2-year-old febrile children without an apparent source of fever (Pediatrics 2011;128:595-610). Since 2000, the prevalence of UTIs in all febrile infants and young children without an apparent source is unchanged, being approximately 5%. The rate of UTIs in fever-without-apparent-source presentations at < 90 days of age is higher, ranging from 6%-15% in different studies.

Meanwhile bacteremia, sepsis, meningitis, and other previously common SBIs, mostly caused by Haemophilus influenzae type b (Hib) or pneumococcus, have decreased. We recognize these reductions as effects of universal implementation of Hib (mid-1990s) and pneumococcal (2000 and 2010) conjugate vaccines.

Given the case above, other pertinent facts are that uncircumcised males have more UTIs in the first months of life (J. Pediatr. 1996;128:23-7) and approximately 5% of young infants with UTIs also are concurrently bacteremic (Pediatrics 1999;104:79-86;J. Pediatr. 1994;124:513-9)

The elephant in the room is the fact that we also need to be cognizant of asymptomatic bacteriuria (AB). AB is colonization of the lower urinary tract without infection. Patients with AB may meet culture criteria for UTI (whether we consider > 50,000 or > 100,000 colony-forming units/mL), but there is no evidence of true infection, that is no inflammation or mucosal injury. So children with AB are not at risk for renal injury or later renal damage and do not require antibiotic treatment.

But when AB patients develop fever, for example with an enterovirus infection, their urine cultures (together with the fever) can do a good imitation of a UTI, unless we focus on the UA results. It not only remains critical to detect true UTIs in infants < 90 days old, such as the one in our case above, but also to distinguish UTI from AB.

The 1999 American Academy of Pediatrics’ UTI guidelines (Pediatrics 1999;103:843-52) included UA results as suggestive of UTI. They stated that a positive LE or nitrite test or > 5 WBC/HPF in a spun urine, or bacteria visualized in unspun gram-stained specimen suggest, but cannot be diagnostic of a UTI. Recommendation five in the guidelines states that UTI diagnosis required 100,000 CFU/mL in culture of sterilely obtained catheterized urine as the threshold criterion (strength of evidence: strong). However, AB was not fully considered because, in part, data defining AB was incomplete in 1999.

The 1999 guidelines also stated, “The urinalysis … can be valuable in selecting individuals for prompt initiation of treatment while waiting for the results of the urine culture.” So, UA was considered adjunctive. UA’s main function was to allow empiric therapy of sufficiently ill children, given positive results for LE, nitrites, or microscopic visualization of > 5 WBC/HPF or bacteria in the spun urine.

In the 2011 AAP guidelines for UTI, things have changed (Pediatrics 2011;128:595-610). The third action statement tells us that both the UA and culture taken together are necessary for UTI diagnosis. To paraphrase: The diagnosis of UTI requires urinalysis results suggesting infection (pyuria or microscopic bacteriuria) plus > 50,000 CFU/mL of a uropathogen in urine from catheterization or suprapubic aspiration. But remember that these guidelines do not apply specifically to the youngest of infants, that is < 2 months old.

Both of these criteria were changes from the 1999 UTI guidelines. Previously pyuria or microscopic bacteriuria were not considered necessary to diagnose UTI, and >100,000 CFU/mL rather than > 50,000 CFU/mL of a single pathogen species was the critical diagnostic result for catheterized urine. For suprapubic aspiration urine samples, > 10,000 CFU/HPF were considered adequate for UTI diagnoses in 1999.

Now, a recent study of children < 90 days of age (including those < 2 months of age) reports that pyuria (> 3 WBC/HPF) plus > 50,000 CFU/mL are the keys to diagnosing UTI (Pediatrics 2015;135:965-71). One caveat is that the study population was febrile infants < 90 days old with concurrent bacteremia (bacteremic UTI). Bacteremic UTI was studied to reduce as much as possible the chance that AB patients might be inadvertently included in the study. One other conclusion of this new study is that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

These data in an overall younger population than that covered by the 2011 guidelines adds evidence that pyuria (but not microscopic bacteriuria) is critical to diagnosing UTI. Pyuria plus positive culture has been a combination for the pediatric infectious diseases practitioner’s toolkit for decades. Likewise, it seems to me that primary care pediatric clinicians also often decide whether to undertake the expense of culture based on UA results. For example, a completely normal UA may obviate need for culture except in selected unusual cases.

Requiring UA evidence of inflammation to diagnose UTI (per the 2011 guidelines and the recommendations of the authors of the recent 2015 study) makes sense because most UTIs in otherwise healthy children are caused by gram-negative organisms (> 90% from Escherichia coli) (J. Pediatr. 1994;124:513-9). Why are UA results so important?

A positive nitrite test strongly suggests UTI because nitrites in the urine indicate viable gram-negative organisms also are present in the urine. Nitrates in the urine are converted to nitrites by metabolic activity of gram-negative pathogens. For WBCs or LE in the urine, their presence indicates inflammation in the urinary tract, Consider that lipopolysaccharide (LPS), also known as gram-negative endotoxin, is a major component of the cell membrane of > 90% of uropathogens like E. coli. Moreover, LPS elicits about the strongest innate immune response via toll-like receptor 4 (TLR4) from monocytes/macrophages, inducing a large pro-inflammatory and chemotactic response – interleukin-6, interleukin-8, tetrahydrofuran-alpha. Remember that LPS is also a major cause of fever and of shock during gram-negative sepsis.

So a UTI diagnosis based on a “positive” culture without evidence of metabolic products of gram negatives (nitrites) or without inflammation (no pyuria or negative LE) should be questioned. The combination of > 50,000 CFU/mL with no detectable LE or < 3-5 WBC/HPF in a febrile child is most likely evidence for AB in a child with the fever caused by some non-UTI process.

In contrast, selected SBIs may occur when the culture is “positive” without inflammation or nitrites. The first of three examples is a renal parenchymal abscess, where bacteria enter the urine sporadically in only small numbers, and do not actually infect the urinary tract mucosa. The scenario of no inflammation but “positive” culture also may occur when a large bacteremic load causes results in organisms filtering through the kidney into the urine, again without urinary mucosal infection, such as Staphylococcus aureus, group A streptococcus, or group B streptococcus bacteremia/sepsis. The third scenario with a “positive” culture and no pyuria can be with organisms that have blunted abilities to induce inflammation, such as enterococcus. Enterococcal cell components have weak inflammatory and chemotactic capability. So a urinary mucosal infection in the collecting system or bladder may occur without much if any pyuria. In fact, the patients from the recent study with insufficient evidence of pyuria/inflammation were those who had either gram-positive organisms or considerably less than 50,000 CFU/mL of gram-negative organisms.

The sensitivity and specificity of the LE or pyuria was higher in the recent study (Pediatrics 2015;135:965-71) than any prior study. The authors comment that they had not expected such a high sensitivity of 97.6% (94.5-99.2) for LE in confirmed bacteremic UTI, nor did they expect the high specificity of 93.9% (87.9-97.5). The presence of microscopic pyuria defined as > 3 WBC/HPF was nearly as sensitive, 96%, and specific, 91.3%. Disappointingly, positive nitrite testing was only 39.5% sensitive, but it was 100% specific. This likely reflects the short time that urine resides in the bladder of infants < 90 days of age, so there is insufficient time for the pathogens to metabolically convert the nitrates to nitrites.

So how would the UA help with our example case? There is microscopic bacteriuria, pyuria, and positive LE, but negative nitrites. Using the suggestions of the authors of the recent report (Pediatrics 2015;135:965-71) and those of another report on the utility of UA results (Acta Paediatr. 2010;99:581-4), the UA in our case indicates that we should be highly suspicious of a UTI in this child < 2 months old for whom the 2011 guidelines do not directly apply. But remember that these impressive sensitivity and specificity values relate to bacteremic UTI. Whether they apply to nonbacteremic UTI is not known. Likewise, the authors caution that their study design did not allow calculation of positive or negative predictive values – aspects that would clarify things even further.

So we still cannot be more than highly suspicious. Without a positive predictive value, we do not know the odds of this case having a UTI with mathematical precision. The authors do point out that only one of their subjects had a completely normal UA and actually had a bacteremic UTI. If you guessed that it was a gram-positive pathogen, you win the prize. So it seems reasonable to predict that a normal UA has a high specificity for not being a UTI (87.8%), but a positive UA remains only highly suggestive. It is still not clear if a negative UA statistically justifies not submitting the culture of the sterilely obtained urine because we still don’t have a negative predictive value.

Bottom line: The 2011 UTI guidelines provide good advice on diagnosing UTIs.

1. We have more data that evidence of inflammation is essential for diagnosing gram-negative UTIs.

2. We also have more evidence that 50,000 CFU/mL is a good threshold for diagnosing UTIs.

3. It appears that microscopic bacteriuria did not add significantly to the either sensitivity or specificity.

4. And we now have more evidence that these criteria also apply to infants < 2 months of age.

To close the loop on our case, the child’s CSF and blood cultures were negative, but the urine culture revealed > 100,000 CFU/mL of E. coli susceptible to second- and third-generation cephalosporins, ciprofloxacin, and nitrofurantoin, but resistant to trimethoprim-sulfamethoxazole.

Have a great summer and watch for UTIs in your young patients < 90 days old and fever without apparent focus.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. E-mail Dr. Harrison at pdnews@frontlinemedcom.com. 

Clinical informatics has been growing significantly in this age of precision medicine, healthcare reform, and population health. Over the last decade, there have been great efforts focused on implementation and integration of electronic health records (EHRs). With the explosive use of mobile technologies, doctors can engage, educate, and empower their patients in ways that have never before been possible. An interconnected digital healthcare data network is slowly but steadily taking shape. We will eventually reach a new era in which clinicians can harness the power of information technology (IT) to receive, report, and analyze healthcare data in order to predict and prevent adverse health outcomes for individuals and populations.

However, there is still much left to be done—the current state of EHRs is not delivering its full potential. In fact, many providers would argue that EHRs have taken us steps backward in our quest to achieve higher efficiency, safety, and quality. As members of the Society of Hospital Medicine (SHM) IT Committee, we have heard the frustration of hospitalists at each of our IT interest group meetings and other forums. This frustration does not come from resistance to adopt or accept technology, but arises from the gap between where we currently are with health IT and where each of us knows we could and should be. For us to attain the full potential of health IT, providers with a clinical perspective must engage and lead in this area. We believe hospitalists are uniquely qualified and positioned to provide such leadership.

Understanding the great demand for specialized physician informatics experts, the American Board of Medical Specialties (ABMS) approved clinical informatics as a board-eligible subspecialty in 2011, and the first board exam was offered in October 2013. The board certification recognizes both the vital role of practicing informatics in healthcare and the sophisticated knowledge and skills it requires. Appropriately, the exam assesses not only knowledge of informatics, but also quality, safety, leadership, and change management. There is a narrow window of opportunity for hospitalists who are currently involved in health IT to become certified in clinical informatics during a grandfather period. Physicians can grandfather into board eligibility via the “practice pathway” through 2017 if they have been working in informatics professionally for at least 25% of their time during any three of the previous five years. Starting in 2018, only graduates of two-year Accreditation Council for Graduate Medical Education (ACGME)-accredited fellowships will be board eligible.

Hospitalists, given their broad understanding of hospital operations, their firsthand end-user experience of EHRs, the high percentage that come from the tech-savvy generation, and their flexible working schedule, are well-positioned to become physician leaders in this field. Recognizing the high value of these skills in hospitalists, the SHM IT Committee has made encouraging SHM members to become board certified in clinical informatics one of its priorities. In fact, we believe that hospital medicine could have more clinical informatics board-certified physicians than any other specialty. If you have been contributing to health IT projects over the last few years, you may already be qualified to sit for the board exam of clinical informatics.

Currently, there are fewer than 800 physicians board certified in clinical informatics, and there has been a high pass rate of about 90% for the board certification exam. We encourage every board-eligible hospitalist who has been practicing informatics to apply for the board exam. For more information, you may refer to the webpage created by the SHM IT committee and seek advice from SHM IT committee members from the HMX IT community forum.^1,2 The future potential of health IT is simply beyond imagination, and hospitalists can, and should, be the major driving force.

Cheng-Kai Kao, MD, assistant professor of medicine, medical director of informatics, University of Chicago

Kendall Rogers, MD, SFHM, associate professor of medicine, chief, division of hospital medicine, University of New Mexico

References

1. Society of Hospital Medicine. Are you a hospitalist frustrated with health IT? Become part of the solution. Accessed June 7, 2015.
2. Society of Hospital Medicine. HMX Healthcare Information Technology community forum. Accessed June 7, 2015.

Clinical informatics has been growing significantly in this age of precision medicine, healthcare reform, and population health. Over the last decade, there have been great efforts focused on implementation and integration of electronic health records (EHRs). With the explosive use of mobile technologies, doctors can engage, educate, and empower their patients in ways that have never before been possible. An interconnected digital healthcare data network is slowly but steadily taking shape. We will eventually reach a new era in which clinicians can harness the power of information technology (IT) to receive, report, and analyze healthcare data in order to predict and prevent adverse health outcomes for individuals and populations.

However, there is still much left to be done—the current state of EHRs is not delivering its full potential. In fact, many providers would argue that EHRs have taken us steps backward in our quest to achieve higher efficiency, safety, and quality. As members of the Society of Hospital Medicine (SHM) IT Committee, we have heard the frustration of hospitalists at each of our IT interest group meetings and other forums. This frustration does not come from resistance to adopt or accept technology, but arises from the gap between where we currently are with health IT and where each of us knows we could and should be. For us to attain the full potential of health IT, providers with a clinical perspective must engage and lead in this area. We believe hospitalists are uniquely qualified and positioned to provide such leadership.

Understanding the great demand for specialized physician informatics experts, the American Board of Medical Specialties (ABMS) approved clinical informatics as a board-eligible subspecialty in 2011, and the first board exam was offered in October 2013. The board certification recognizes both the vital role of practicing informatics in healthcare and the sophisticated knowledge and skills it requires. Appropriately, the exam assesses not only knowledge of informatics, but also quality, safety, leadership, and change management. There is a narrow window of opportunity for hospitalists who are currently involved in health IT to become certified in clinical informatics during a grandfather period. Physicians can grandfather into board eligibility via the “practice pathway” through 2017 if they have been working in informatics professionally for at least 25% of their time during any three of the previous five years. Starting in 2018, only graduates of two-year Accreditation Council for Graduate Medical Education (ACGME)-accredited fellowships will be board eligible.

Hospitalists, given their broad understanding of hospital operations, their firsthand end-user experience of EHRs, the high percentage that come from the tech-savvy generation, and their flexible working schedule, are well-positioned to become physician leaders in this field. Recognizing the high value of these skills in hospitalists, the SHM IT Committee has made encouraging SHM members to become board certified in clinical informatics one of its priorities. In fact, we believe that hospital medicine could have more clinical informatics board-certified physicians than any other specialty. If you have been contributing to health IT projects over the last few years, you may already be qualified to sit for the board exam of clinical informatics.

Currently, there are fewer than 800 physicians board certified in clinical informatics, and there has been a high pass rate of about 90% for the board certification exam. We encourage every board-eligible hospitalist who has been practicing informatics to apply for the board exam. For more information, you may refer to the webpage created by the SHM IT committee and seek advice from SHM IT committee members from the HMX IT community forum.^1,2 The future potential of health IT is simply beyond imagination, and hospitalists can, and should, be the major driving force.

Cheng-Kai Kao, MD, assistant professor of medicine, medical director of informatics, University of Chicago

Kendall Rogers, MD, SFHM, associate professor of medicine, chief, division of hospital medicine, University of New Mexico

References

1. Society of Hospital Medicine. Are you a hospitalist frustrated with health IT? Become part of the solution. Accessed June 7, 2015.
2. Society of Hospital Medicine. HMX Healthcare Information Technology community forum. Accessed June 7, 2015.

Clinical informatics has been growing significantly in this age of precision medicine, healthcare reform, and population health. Over the last decade, there have been great efforts focused on implementation and integration of electronic health records (EHRs). With the explosive use of mobile technologies, doctors can engage, educate, and empower their patients in ways that have never before been possible. An interconnected digital healthcare data network is slowly but steadily taking shape. We will eventually reach a new era in which clinicians can harness the power of information technology (IT) to receive, report, and analyze healthcare data in order to predict and prevent adverse health outcomes for individuals and populations.

However, there is still much left to be done—the current state of EHRs is not delivering its full potential. In fact, many providers would argue that EHRs have taken us steps backward in our quest to achieve higher efficiency, safety, and quality. As members of the Society of Hospital Medicine (SHM) IT Committee, we have heard the frustration of hospitalists at each of our IT interest group meetings and other forums. This frustration does not come from resistance to adopt or accept technology, but arises from the gap between where we currently are with health IT and where each of us knows we could and should be. For us to attain the full potential of health IT, providers with a clinical perspective must engage and lead in this area. We believe hospitalists are uniquely qualified and positioned to provide such leadership.

Understanding the great demand for specialized physician informatics experts, the American Board of Medical Specialties (ABMS) approved clinical informatics as a board-eligible subspecialty in 2011, and the first board exam was offered in October 2013. The board certification recognizes both the vital role of practicing informatics in healthcare and the sophisticated knowledge and skills it requires. Appropriately, the exam assesses not only knowledge of informatics, but also quality, safety, leadership, and change management. There is a narrow window of opportunity for hospitalists who are currently involved in health IT to become certified in clinical informatics during a grandfather period. Physicians can grandfather into board eligibility via the “practice pathway” through 2017 if they have been working in informatics professionally for at least 25% of their time during any three of the previous five years. Starting in 2018, only graduates of two-year Accreditation Council for Graduate Medical Education (ACGME)-accredited fellowships will be board eligible.

Hospitalists, given their broad understanding of hospital operations, their firsthand end-user experience of EHRs, the high percentage that come from the tech-savvy generation, and their flexible working schedule, are well-positioned to become physician leaders in this field. Recognizing the high value of these skills in hospitalists, the SHM IT Committee has made encouraging SHM members to become board certified in clinical informatics one of its priorities. In fact, we believe that hospital medicine could have more clinical informatics board-certified physicians than any other specialty. If you have been contributing to health IT projects over the last few years, you may already be qualified to sit for the board exam of clinical informatics.

Currently, there are fewer than 800 physicians board certified in clinical informatics, and there has been a high pass rate of about 90% for the board certification exam. We encourage every board-eligible hospitalist who has been practicing informatics to apply for the board exam. For more information, you may refer to the webpage created by the SHM IT committee and seek advice from SHM IT committee members from the HMX IT community forum.^1,2 The future potential of health IT is simply beyond imagination, and hospitalists can, and should, be the major driving force.

Cheng-Kai Kao, MD, assistant professor of medicine, medical director of informatics, University of Chicago

Kendall Rogers, MD, SFHM, associate professor of medicine, chief, division of hospital medicine, University of New Mexico

References

1. Society of Hospital Medicine. Are you a hospitalist frustrated with health IT? Become part of the solution. Accessed June 7, 2015.
2. Society of Hospital Medicine. HMX Healthcare Information Technology community forum. Accessed June 7, 2015.

Editor’s note: First in a two-part series on hospitalists as expert witnesses.

Recently, you have found yourself pondering whether you want to be an expert witness for the prosecution on behalf of one of your patients or for the defense on behalf of one of your fellow colleagues. You enjoy tackling confrontational questions head on, are intellectually curious, and are articulate both orally and in writing. You like to look at complex fact patterns and simplify them, and “Law and Order” is your favorite television show. But, seriously, are you ready to be an expert witness?

The expert witness plays an essential role in determining medical negligence under the United States system of jurisprudence. Generally, expert witnesses are asked to testify regarding the standards of care relevant to the given case, identify any deviations from those standards, and render an opinion as to whether those breaches are the most likely cause of the injury. Without the expert’s explanation of the range of acceptable treatments within the standard of care and interpretation of medical facts, juries would not have the technical expertise needed to determine whether or not malpractice occurred.

This article, the first in a two-part series on hospitalists as expert witnesses, addresses the nuts and bolts of serving as an expert witness, including the role of the expert witness, time commitments, compensation, privacy or lack thereof, and the ever-present internal struggle about whether or not to choose to participate actively in our legal system.

Hospitalists who have developed a niche in a small area of expertise in which they can dominate a certain market, or those who have developed a national reputation, can charge a significant amount of money depending on their area of expertise.

The Role of the Expert Witness

First, let’s take a small step back, as the hospitalist’s role as an expert witness is largely dependent on how the expert witness is going to be used by the attorney. An expert witness is someone who has been qualified as an authority to assist others—namely, the attorneys, judge, and jury—in understanding complicated technical subjects that are beyond the understanding of the average lay person.

Thus, attorneys retain expert witnesses for a whole host of reasons, including:

• Evaluating their client’s claim initially to determine if the patient has a valid claim;
• Writing an expert report to be used for settlement, mediation, arbitration, or as an exhibit to a motion for summary judgment;
• Consulting with the attorney in order to form an opinion in the case, which will be used to shape the prosecution or defense, including in a response to the complaint, in discovery, or at trial (“Confidential, Non-testifying Consultant Only Expert”); or
• Testifying at a deposition and/or in court at trial (“Disclosed, Nothing the Expert Touches is Confidential, Testifying Expert”).

The first thing you need to do, therefore, is make sure your role and the scope of your area of expertise are clearly defined and that you are comfortable performing the tasks that are described in more detail below in a timely manner. As you will soon learn, testifying under oath can be a grueling experience.

Time Commitment

Is it worth the time commitment? Here, again, a lot depends on not only the expert witness’s role but also where in the course of the litigation the expert is brought on board the trial team. Is it ninety days before trial, before the lawsuit has even been filed, or somewhere in between? Have court deadlines already been issued that require the rescheduling of patient obligations?

Assuming you have been brought onboard as an expert before the complaint has been filed, you should expect to encounter the following noninclusive time constraints:

• Preparing litigation budgets and bills;
• Preparing a current curriculum vitae;
• Reviewing the entire file of paper;
• Assisting in drafting or responding to the complaint;
• Assisting in drafting and/or responding to discovery;
• Preparing an expert report;
• Preparing a rebuttal expert report;
• Preparing for your deposition;
• Attending your deposition;
• Assisting in the deposition of the other side’s expert witness;
• Assisting in preparing for trial;
• Preparing to take the stand at trial;
• Attending trial; and/or
• Assisting in identifying or responding to any post-trial appealable issues.

Although you should be compensated for each of these tasks, these tasks take away time you could be engaging in patient care.

Compensation

It should be a no brainer, but make sure you get paid. The expert witness business is built upon reputation, integrity, credibility, and expertise. Consequently, hospitalists who have developed a niche in a small area of expertise in which they can dominate a certain market, or those who have developed a national reputation, can charge a significant amount of money depending on their area of expertise. In the absence of substantial experience, expert witness rates are dependent on the location of the case, the dollar amount at stake, and the novelty of the legal disputes at issue.

You should immediately request a written agreement that states exactly who is responsible for paying your bills, when those bills will be paid, and, in addition to your hourly rate and what services that rate covers, the specific out-of-pocket expenses that will be paid, including those that are needed to cover postage, copies, travel, lodging, and any other incidentals.

Privacy, or Lack Thereof

Thanks to the Internet, unless a protective order is in place, and even that is likely to be narrowly tailored, opposing counsels can easily pull copies of all of your past deposition and trial transcripts, divorce records, past curriculum vitae, and articles you may have written in medical school or in practice. They can also use the Internet to identify who you usually testify for, whether your testimony has ever been refused by the judge, where you live, and even whether you own any property.

In essence, any and all public dirt on your private life can be extracted and used as fodder at the next trial. Are you prepared to become an overnight public figure?

The Internal Struggle

Finally, there is no question that the decision of whether to serve as an expert witness in a malpractice case is one of the most difficult, yet most important, nonpatient care decisions a physician can make. Expert testimony is essential to medical malpractice litigation, however. Many hospitalists may find themselves balancing their duty to patients who should have access to the courts and fair compensation from injuries caused by physicians who are impaired or who deviated from the standard of care against the professional and social pressure not to testify against colleagues and not to participate in a legal system that many hospitalists feel victimizes members of their profession.

The legal system, nonetheless, relies on competent medical expertise that is just and fair and relies on medical professionals to provide that expertise. Are you ready for the challenge? If you are, the second article in this two-part series will serve as a primer for your expert report, deposition, and testimony at trial.

Steven Harris is a nationally recognized healthcare attorney and a member of the law firm McDonald Hopkins LLC in Chicago. Write to him at sharris@mcdonaldhopkins.com.

Editor’s note: First in a two-part series on hospitalists as expert witnesses.

Recently, you have found yourself pondering whether you want to be an expert witness for the prosecution on behalf of one of your patients or for the defense on behalf of one of your fellow colleagues. You enjoy tackling confrontational questions head on, are intellectually curious, and are articulate both orally and in writing. You like to look at complex fact patterns and simplify them, and “Law and Order” is your favorite television show. But, seriously, are you ready to be an expert witness?

The expert witness plays an essential role in determining medical negligence under the United States system of jurisprudence. Generally, expert witnesses are asked to testify regarding the standards of care relevant to the given case, identify any deviations from those standards, and render an opinion as to whether those breaches are the most likely cause of the injury. Without the expert’s explanation of the range of acceptable treatments within the standard of care and interpretation of medical facts, juries would not have the technical expertise needed to determine whether or not malpractice occurred.

This article, the first in a two-part series on hospitalists as expert witnesses, addresses the nuts and bolts of serving as an expert witness, including the role of the expert witness, time commitments, compensation, privacy or lack thereof, and the ever-present internal struggle about whether or not to choose to participate actively in our legal system.

Hospitalists who have developed a niche in a small area of expertise in which they can dominate a certain market, or those who have developed a national reputation, can charge a significant amount of money depending on their area of expertise.

The Role of the Expert Witness

First, let’s take a small step back, as the hospitalist’s role as an expert witness is largely dependent on how the expert witness is going to be used by the attorney. An expert witness is someone who has been qualified as an authority to assist others—namely, the attorneys, judge, and jury—in understanding complicated technical subjects that are beyond the understanding of the average lay person.

Thus, attorneys retain expert witnesses for a whole host of reasons, including:

• Evaluating their client’s claim initially to determine if the patient has a valid claim;
• Writing an expert report to be used for settlement, mediation, arbitration, or as an exhibit to a motion for summary judgment;
• Consulting with the attorney in order to form an opinion in the case, which will be used to shape the prosecution or defense, including in a response to the complaint, in discovery, or at trial (“Confidential, Non-testifying Consultant Only Expert”); or
• Testifying at a deposition and/or in court at trial (“Disclosed, Nothing the Expert Touches is Confidential, Testifying Expert”).

The first thing you need to do, therefore, is make sure your role and the scope of your area of expertise are clearly defined and that you are comfortable performing the tasks that are described in more detail below in a timely manner. As you will soon learn, testifying under oath can be a grueling experience.

Time Commitment

Is it worth the time commitment? Here, again, a lot depends on not only the expert witness’s role but also where in the course of the litigation the expert is brought on board the trial team. Is it ninety days before trial, before the lawsuit has even been filed, or somewhere in between? Have court deadlines already been issued that require the rescheduling of patient obligations?

Assuming you have been brought onboard as an expert before the complaint has been filed, you should expect to encounter the following noninclusive time constraints:

• Preparing litigation budgets and bills;
• Preparing a current curriculum vitae;
• Reviewing the entire file of paper;
• Assisting in drafting or responding to the complaint;
• Assisting in drafting and/or responding to discovery;
• Preparing an expert report;
• Preparing a rebuttal expert report;
• Preparing for your deposition;
• Attending your deposition;
• Assisting in the deposition of the other side’s expert witness;
• Assisting in preparing for trial;
• Preparing to take the stand at trial;
• Attending trial; and/or
• Assisting in identifying or responding to any post-trial appealable issues.

Although you should be compensated for each of these tasks, these tasks take away time you could be engaging in patient care.

Compensation

It should be a no brainer, but make sure you get paid. The expert witness business is built upon reputation, integrity, credibility, and expertise. Consequently, hospitalists who have developed a niche in a small area of expertise in which they can dominate a certain market, or those who have developed a national reputation, can charge a significant amount of money depending on their area of expertise. In the absence of substantial experience, expert witness rates are dependent on the location of the case, the dollar amount at stake, and the novelty of the legal disputes at issue.

You should immediately request a written agreement that states exactly who is responsible for paying your bills, when those bills will be paid, and, in addition to your hourly rate and what services that rate covers, the specific out-of-pocket expenses that will be paid, including those that are needed to cover postage, copies, travel, lodging, and any other incidentals.

Privacy, or Lack Thereof

Thanks to the Internet, unless a protective order is in place, and even that is likely to be narrowly tailored, opposing counsels can easily pull copies of all of your past deposition and trial transcripts, divorce records, past curriculum vitae, and articles you may have written in medical school or in practice. They can also use the Internet to identify who you usually testify for, whether your testimony has ever been refused by the judge, where you live, and even whether you own any property.

In essence, any and all public dirt on your private life can be extracted and used as fodder at the next trial. Are you prepared to become an overnight public figure?

The Internal Struggle

Finally, there is no question that the decision of whether to serve as an expert witness in a malpractice case is one of the most difficult, yet most important, nonpatient care decisions a physician can make. Expert testimony is essential to medical malpractice litigation, however. Many hospitalists may find themselves balancing their duty to patients who should have access to the courts and fair compensation from injuries caused by physicians who are impaired or who deviated from the standard of care against the professional and social pressure not to testify against colleagues and not to participate in a legal system that many hospitalists feel victimizes members of their profession.

The legal system, nonetheless, relies on competent medical expertise that is just and fair and relies on medical professionals to provide that expertise. Are you ready for the challenge? If you are, the second article in this two-part series will serve as a primer for your expert report, deposition, and testimony at trial.

Steven Harris is a nationally recognized healthcare attorney and a member of the law firm McDonald Hopkins LLC in Chicago. Write to him at sharris@mcdonaldhopkins.com.

Editor’s note: First in a two-part series on hospitalists as expert witnesses.

Recently, you have found yourself pondering whether you want to be an expert witness for the prosecution on behalf of one of your patients or for the defense on behalf of one of your fellow colleagues. You enjoy tackling confrontational questions head on, are intellectually curious, and are articulate both orally and in writing. You like to look at complex fact patterns and simplify them, and “Law and Order” is your favorite television show. But, seriously, are you ready to be an expert witness?

The expert witness plays an essential role in determining medical negligence under the United States system of jurisprudence. Generally, expert witnesses are asked to testify regarding the standards of care relevant to the given case, identify any deviations from those standards, and render an opinion as to whether those breaches are the most likely cause of the injury. Without the expert’s explanation of the range of acceptable treatments within the standard of care and interpretation of medical facts, juries would not have the technical expertise needed to determine whether or not malpractice occurred.

This article, the first in a two-part series on hospitalists as expert witnesses, addresses the nuts and bolts of serving as an expert witness, including the role of the expert witness, time commitments, compensation, privacy or lack thereof, and the ever-present internal struggle about whether or not to choose to participate actively in our legal system.

Hospitalists who have developed a niche in a small area of expertise in which they can dominate a certain market, or those who have developed a national reputation, can charge a significant amount of money depending on their area of expertise.

The Role of the Expert Witness

First, let’s take a small step back, as the hospitalist’s role as an expert witness is largely dependent on how the expert witness is going to be used by the attorney. An expert witness is someone who has been qualified as an authority to assist others—namely, the attorneys, judge, and jury—in understanding complicated technical subjects that are beyond the understanding of the average lay person.

Thus, attorneys retain expert witnesses for a whole host of reasons, including:

• Evaluating their client’s claim initially to determine if the patient has a valid claim;
• Writing an expert report to be used for settlement, mediation, arbitration, or as an exhibit to a motion for summary judgment;
• Consulting with the attorney in order to form an opinion in the case, which will be used to shape the prosecution or defense, including in a response to the complaint, in discovery, or at trial (“Confidential, Non-testifying Consultant Only Expert”); or
• Testifying at a deposition and/or in court at trial (“Disclosed, Nothing the Expert Touches is Confidential, Testifying Expert”).

The first thing you need to do, therefore, is make sure your role and the scope of your area of expertise are clearly defined and that you are comfortable performing the tasks that are described in more detail below in a timely manner. As you will soon learn, testifying under oath can be a grueling experience.

Time Commitment

Is it worth the time commitment? Here, again, a lot depends on not only the expert witness’s role but also where in the course of the litigation the expert is brought on board the trial team. Is it ninety days before trial, before the lawsuit has even been filed, or somewhere in between? Have court deadlines already been issued that require the rescheduling of patient obligations?

Assuming you have been brought onboard as an expert before the complaint has been filed, you should expect to encounter the following noninclusive time constraints:

• Preparing litigation budgets and bills;
• Preparing a current curriculum vitae;
• Reviewing the entire file of paper;
• Assisting in drafting or responding to the complaint;
• Assisting in drafting and/or responding to discovery;
• Preparing an expert report;
• Preparing a rebuttal expert report;
• Preparing for your deposition;
• Attending your deposition;
• Assisting in the deposition of the other side’s expert witness;
• Assisting in preparing for trial;
• Preparing to take the stand at trial;
• Attending trial; and/or
• Assisting in identifying or responding to any post-trial appealable issues.

Although you should be compensated for each of these tasks, these tasks take away time you could be engaging in patient care.

Compensation

It should be a no brainer, but make sure you get paid. The expert witness business is built upon reputation, integrity, credibility, and expertise. Consequently, hospitalists who have developed a niche in a small area of expertise in which they can dominate a certain market, or those who have developed a national reputation, can charge a significant amount of money depending on their area of expertise. In the absence of substantial experience, expert witness rates are dependent on the location of the case, the dollar amount at stake, and the novelty of the legal disputes at issue.

You should immediately request a written agreement that states exactly who is responsible for paying your bills, when those bills will be paid, and, in addition to your hourly rate and what services that rate covers, the specific out-of-pocket expenses that will be paid, including those that are needed to cover postage, copies, travel, lodging, and any other incidentals.

Privacy, or Lack Thereof

Thanks to the Internet, unless a protective order is in place, and even that is likely to be narrowly tailored, opposing counsels can easily pull copies of all of your past deposition and trial transcripts, divorce records, past curriculum vitae, and articles you may have written in medical school or in practice. They can also use the Internet to identify who you usually testify for, whether your testimony has ever been refused by the judge, where you live, and even whether you own any property.

In essence, any and all public dirt on your private life can be extracted and used as fodder at the next trial. Are you prepared to become an overnight public figure?

The Internal Struggle

Finally, there is no question that the decision of whether to serve as an expert witness in a malpractice case is one of the most difficult, yet most important, nonpatient care decisions a physician can make. Expert testimony is essential to medical malpractice litigation, however. Many hospitalists may find themselves balancing their duty to patients who should have access to the courts and fair compensation from injuries caused by physicians who are impaired or who deviated from the standard of care against the professional and social pressure not to testify against colleagues and not to participate in a legal system that many hospitalists feel victimizes members of their profession.

The legal system, nonetheless, relies on competent medical expertise that is just and fair and relies on medical professionals to provide that expertise. Are you ready for the challenge? If you are, the second article in this two-part series will serve as a primer for your expert report, deposition, and testimony at trial.

Steven Harris is a nationally recognized healthcare attorney and a member of the law firm McDonald Hopkins LLC in Chicago. Write to him at sharris@mcdonaldhopkins.com.