Cleveland Clinic Journal of Medicine

A 54-year-old woman presented with a 7-day history of odynophagia, pharyngeal swelling, and painful skin lesions on her left ear. She had been on antiretroviral therapy for human immunodeficiency virus infection but had not been fully compliant with the treatment.

See editorial

On examination, she had painful erythematous vesicles and pustules on the left auricle and in the external auditory canal (Figure 1), as well as small vesicles and circumscribed erosions on the left anterior twothirds of her tongue (Figure 2) and left palate. Facial sensory function was normal; however, she had lagophthalmos, a flattened nasolabial fold, ptosis of the oral commissure, and a loss of the forehead wrinkles on the left side of her face—all signs of peripheral facial nerve paralysis.

Q: Which is the most likely diagnosis?

• Ramsay Hunt syndrome
• Herpes simplex
• Contact dermatitis
• Malignant external otitis
• Erysipelas

A: This patient had Ramsay Hunt syndrome, also known as herpes zoster oticus. It is a rare complication of herpes zoster in which the reactivation of latent varicella-zoster virus infection in the geniculate ganglion causes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Taste perception, hearing (eg, tinnitus, hyperacusis), and lacrimation can be affected.¹

Ramsay Hunt syndrome is generally considered a polycranial neuropathy of cranial nerves VII (facial) and VIII (acoustic). In some cases other cranial neuropathies may be present and may involve cranial nerves V (trigeminal), IX (glossopharyngeal), and X (vagus). Vestibular disturbances such as vertigo are also often reported. It is more severe in patients with immune deficiency. Because the classic symptoms are not always present at the onset, the syndrome can be misdiagnosed.

DIAGNOSIS

Once the vesicular rash caused by herpes zoster has appeared, the diagnosis is usually readily apparent. The other main disease to consider in the differential diagnosis is herpes simplex. Herpes zoster infection is characterized by a painful sensory prodrome, dermatomal distribution, and lack of a history of a similar rash. However, if the patient has had a similar vesicular rash in the same location, then recurrent zosteriform herpes simplex should be considered. A noninfectious cause to consider is contact dermatitis. However, contact dermatitis usually produces intense itch rather than pain.

If the clinical presentation is uncertain, then viral culture, direct immunofluorescence testing, and a polymerase chain reaction assay is indicated to confirm the diagnosis. Polymerase chain reaction testing is the most sensitive test.³

TREATMENT

The rapid start of antiviral therapy is particularly critical in immunocompromised patients,⁴ even if the vesicles have been present for 72 hours. Immunocompromised patients with Ramsay Hunt syndrome and other forms of complicated herpes zoster infection should be hospitalized for intravenous acyclovir therapy.

Corticosteroids and oral acyclovir (10 mg/kg three times daily for 7 days) are commonly used in Ramsay Hunt syndrome. In a recent review,⁵ combination therapy with a corticosteroid and intravenous acyclovir did not show a benefit over corticosteroids alone in promoting resolution of facial neuropathy after 6 months.⁵ However, randomized clinical trials are needed to evaluate both therapies.

Although antiviral therapy reduces pain associated with acute neuritis, pain syndromes associated with herpes zoster can still be severe. Nonsteroidal antiinflammatory drugs and acetaminophen are useful for mild pain, either alone or in combination with a weak opioid analgesic (eg, tramadol, codeine). For moderate to severe pain that disturbs sleep, a stronger opioid analgesic (eg, oxycodone, morphine) may be necessary.⁶

Vestibular suppressants may be helpful if vestibular symptoms are severe. Temporary relief of otalgia may be achieved by applying a local anesthetic to the trigger point, if in the external auditory canal. Carbamazepine may be helpful, especially in cases of idiopathic geniculate neuralgia.⁷

OTHER CONSIDERATIONS

Once drug therapy is started, the patient should be seen at 2 weeks, 6 weeks, and 3 months to monitor the evolution of nerve paralysis.⁸

A 54-year-old woman presented with a 7-day history of odynophagia, pharyngeal swelling, and painful skin lesions on her left ear. She had been on antiretroviral therapy for human immunodeficiency virus infection but had not been fully compliant with the treatment.

See editorial

On examination, she had painful erythematous vesicles and pustules on the left auricle and in the external auditory canal (Figure 1), as well as small vesicles and circumscribed erosions on the left anterior twothirds of her tongue (Figure 2) and left palate. Facial sensory function was normal; however, she had lagophthalmos, a flattened nasolabial fold, ptosis of the oral commissure, and a loss of the forehead wrinkles on the left side of her face—all signs of peripheral facial nerve paralysis.

Q: Which is the most likely diagnosis?

• Ramsay Hunt syndrome
• Herpes simplex
• Contact dermatitis
• Malignant external otitis
• Erysipelas

A: This patient had Ramsay Hunt syndrome, also known as herpes zoster oticus. It is a rare complication of herpes zoster in which the reactivation of latent varicella-zoster virus infection in the geniculate ganglion causes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Taste perception, hearing (eg, tinnitus, hyperacusis), and lacrimation can be affected.¹

Ramsay Hunt syndrome is generally considered a polycranial neuropathy of cranial nerves VII (facial) and VIII (acoustic). In some cases other cranial neuropathies may be present and may involve cranial nerves V (trigeminal), IX (glossopharyngeal), and X (vagus). Vestibular disturbances such as vertigo are also often reported. It is more severe in patients with immune deficiency. Because the classic symptoms are not always present at the onset, the syndrome can be misdiagnosed.

DIAGNOSIS

Once the vesicular rash caused by herpes zoster has appeared, the diagnosis is usually readily apparent. The other main disease to consider in the differential diagnosis is herpes simplex. Herpes zoster infection is characterized by a painful sensory prodrome, dermatomal distribution, and lack of a history of a similar rash. However, if the patient has had a similar vesicular rash in the same location, then recurrent zosteriform herpes simplex should be considered. A noninfectious cause to consider is contact dermatitis. However, contact dermatitis usually produces intense itch rather than pain.

If the clinical presentation is uncertain, then viral culture, direct immunofluorescence testing, and a polymerase chain reaction assay is indicated to confirm the diagnosis. Polymerase chain reaction testing is the most sensitive test.³

TREATMENT

The rapid start of antiviral therapy is particularly critical in immunocompromised patients,⁴ even if the vesicles have been present for 72 hours. Immunocompromised patients with Ramsay Hunt syndrome and other forms of complicated herpes zoster infection should be hospitalized for intravenous acyclovir therapy.

Corticosteroids and oral acyclovir (10 mg/kg three times daily for 7 days) are commonly used in Ramsay Hunt syndrome. In a recent review,⁵ combination therapy with a corticosteroid and intravenous acyclovir did not show a benefit over corticosteroids alone in promoting resolution of facial neuropathy after 6 months.⁵ However, randomized clinical trials are needed to evaluate both therapies.

Although antiviral therapy reduces pain associated with acute neuritis, pain syndromes associated with herpes zoster can still be severe. Nonsteroidal antiinflammatory drugs and acetaminophen are useful for mild pain, either alone or in combination with a weak opioid analgesic (eg, tramadol, codeine). For moderate to severe pain that disturbs sleep, a stronger opioid analgesic (eg, oxycodone, morphine) may be necessary.⁶

Vestibular suppressants may be helpful if vestibular symptoms are severe. Temporary relief of otalgia may be achieved by applying a local anesthetic to the trigger point, if in the external auditory canal. Carbamazepine may be helpful, especially in cases of idiopathic geniculate neuralgia.⁷

OTHER CONSIDERATIONS

Once drug therapy is started, the patient should be seen at 2 weeks, 6 weeks, and 3 months to monitor the evolution of nerve paralysis.⁸

A 54-year-old woman presented with a 7-day history of odynophagia, pharyngeal swelling, and painful skin lesions on her left ear. She had been on antiretroviral therapy for human immunodeficiency virus infection but had not been fully compliant with the treatment.

See editorial

On examination, she had painful erythematous vesicles and pustules on the left auricle and in the external auditory canal (Figure 1), as well as small vesicles and circumscribed erosions on the left anterior twothirds of her tongue (Figure 2) and left palate. Facial sensory function was normal; however, she had lagophthalmos, a flattened nasolabial fold, ptosis of the oral commissure, and a loss of the forehead wrinkles on the left side of her face—all signs of peripheral facial nerve paralysis.

Q: Which is the most likely diagnosis?

• Ramsay Hunt syndrome
• Herpes simplex
• Contact dermatitis
• Malignant external otitis
• Erysipelas

A: This patient had Ramsay Hunt syndrome, also known as herpes zoster oticus. It is a rare complication of herpes zoster in which the reactivation of latent varicella-zoster virus infection in the geniculate ganglion causes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Taste perception, hearing (eg, tinnitus, hyperacusis), and lacrimation can be affected.¹

Ramsay Hunt syndrome is generally considered a polycranial neuropathy of cranial nerves VII (facial) and VIII (acoustic). In some cases other cranial neuropathies may be present and may involve cranial nerves V (trigeminal), IX (glossopharyngeal), and X (vagus). Vestibular disturbances such as vertigo are also often reported. It is more severe in patients with immune deficiency. Because the classic symptoms are not always present at the onset, the syndrome can be misdiagnosed.

DIAGNOSIS

Once the vesicular rash caused by herpes zoster has appeared, the diagnosis is usually readily apparent. The other main disease to consider in the differential diagnosis is herpes simplex. Herpes zoster infection is characterized by a painful sensory prodrome, dermatomal distribution, and lack of a history of a similar rash. However, if the patient has had a similar vesicular rash in the same location, then recurrent zosteriform herpes simplex should be considered. A noninfectious cause to consider is contact dermatitis. However, contact dermatitis usually produces intense itch rather than pain.

If the clinical presentation is uncertain, then viral culture, direct immunofluorescence testing, and a polymerase chain reaction assay is indicated to confirm the diagnosis. Polymerase chain reaction testing is the most sensitive test.³

TREATMENT

The rapid start of antiviral therapy is particularly critical in immunocompromised patients,⁴ even if the vesicles have been present for 72 hours. Immunocompromised patients with Ramsay Hunt syndrome and other forms of complicated herpes zoster infection should be hospitalized for intravenous acyclovir therapy.

Corticosteroids and oral acyclovir (10 mg/kg three times daily for 7 days) are commonly used in Ramsay Hunt syndrome. In a recent review,⁵ combination therapy with a corticosteroid and intravenous acyclovir did not show a benefit over corticosteroids alone in promoting resolution of facial neuropathy after 6 months.⁵ However, randomized clinical trials are needed to evaluate both therapies.

Although antiviral therapy reduces pain associated with acute neuritis, pain syndromes associated with herpes zoster can still be severe. Nonsteroidal antiinflammatory drugs and acetaminophen are useful for mild pain, either alone or in combination with a weak opioid analgesic (eg, tramadol, codeine). For moderate to severe pain that disturbs sleep, a stronger opioid analgesic (eg, oxycodone, morphine) may be necessary.⁶

Vestibular suppressants may be helpful if vestibular symptoms are severe. Temporary relief of otalgia may be achieved by applying a local anesthetic to the trigger point, if in the external auditory canal. Carbamazepine may be helpful, especially in cases of idiopathic geniculate neuralgia.⁷

OTHER CONSIDERATIONS

Once drug therapy is started, the patient should be seen at 2 weeks, 6 weeks, and 3 months to monitor the evolution of nerve paralysis.⁸

Varicella-zoster virus (VZV) is a highly neurotropic and ubiquitous alpha-herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. Reactivation decades later usually results in zoster (shingles), pain with a dermatomal distribution, and rash. Unlike herpes simplex virus type 1 (HSV-1), which becomes latent exclusively in cranial nerve ganglia and reactivates to produce recurrent vesicular lesions around the mouth, and unlike HSV type 2, which becomes latent exclusively in sacral ganglia and reactivates to produce genital herpes, VZV may reactivate from any ganglia to cause zoster anywhere on the body.

See related article

Reactivation of VZV from the geniculate (facial nerve) ganglion leads to the Ramsay Hunt syndrome, ie, facial paralysis accompanied by a rash around the ear (zoster oticus). The syndrome is the second most common cause of atraumatic facial paralysis after Bell palsy (idiopathic facial paralysis). Importantly, virus reactivation from the geniculate ganglion may also be accompanied by zoster rash on the hard palate or on the anterior two-thirds of the tongue (Figure 1).¹ A rash in any of these three skin or mucosal sites in a patient with facial paralysis indicates geniculate ganglionitis. To his credit, Dr. J. Ramsay Hunt recognized that although there is no somatic sensory facial branch to the oropharynx or tongue, virus can still spread from a seventh cranial nerve element to the pharynx or, via special sensory fibers, to the tongue, thus providing an anatomic explanation for zoster rash in patients with facial paralysis (geniculate zoster) not only around the ear, but also on the hard palate or on the anterior two-thirds of the tongue.²

Reprinted from Sweeney CJ, et al. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001; 71:149–154. With permission from BMJ Publishing Group Ltd.

In geniculate ganglionitis, a rash is usually seen in one but not all three of these skin and mucosal sites. Yet in this issue of the Cleveland Clinic Journal of Medicine, Grillo et al3 describe a patient with facial palsy and rash in all three sites. This remarkable finding underscores the importance of distinguishing Ramsay Hunt syndrome from Bell palsy by checking for rash on the ear, tongue, and hard palate in any patient with acute unilateral peripheral facial weakness. Ramsay Hunt syndrome results from active VZV replication in the geniculate ganglion and requires treatment with antiviral drugs, whereas Bell palsy is usually treated with steroids. Steroid treatment of Ramsay Hunt syndrome misdiagnosed as Bell palsy can potentiate the viral infection. This may partially explain why the outcome of facial paralysis in Ramsay Hunt syndrome is not as good as in idiopathic Bell palsy, in which more than 70% of patients recover full facial function.

Although only cranial nerve VII (facial) was involved in their patient, Grillo et al correctly noted the frequent involvement of other cranial nerves in Ramsay Hunt syndrome. For example, dizziness, vertigo, or hearing loss indicative of involvement of cranial nerve VIII (acoustic) is most likely due to the close proximity of the geniculate ganglion and facial nerve to the vestibulocochlear nerve in the bony facial canal. Patients with this syndrome may also develop dysarthria or dysphagia indicative of lower cranial nerve involvement, reflecting the shared derivation of the facial, glossopharyngeal, and vagus nerves from the same branchial arch. Magnetic resonance imaging, not usually performed in patients with Ramsay Hunt syndrome, may show enhancement in the geniculate ganglion as well as in the intracanalicular and tympanic segments of the facial nerve during its course through the facial canal.

The report by Grillo et al comes at an auspicious time, 100 years after an enlightening series of papers by Dr. Hunt from 1907 to 1915 in which he described herpetic inflammation of the geniculate ganglion,⁴ the sensory system of the facial nerve,⁵ and ultimately the syndrome that bears his name.^2,6 Dr. Hunt received his doctorate from the University of Pennsylvania in 1893 and later became instructor at Cornell University School of Medicine. In 1924, he became full professor at Columbia University School of Medicine. A clinician of Olympian stature, he is also credited with describing two additional syndromes (clinical features produced by carotid artery occlusion and dyssynergia cerebellaris progressiva), although the best known is zoster oticus with peripheral facial palsy.

Importantly, some patients develop peripheral facial paralysis without any rash but with a fourfold rise in antibody to VZV or in association with the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva, indicating that a proportion of patients with Bell palsy have “Ramsay Hunt syndrome zoster sine herpete” or, more accurately, “geniculate zoster sine herpete.” Treatment of such patients with acyclovir-prednisone within 7 days of onset has been shown to improve the outcome of facial palsy.

Because it is now clear that geniculate ganglionitis may present with facial palsy and zoster rash in any or all of three sites, it may be time to call peripheral facial paralysis associated with zoster rash on the ear, tongue, or palate exactly what it is: geniculate zoster. After all, zoster rash on the face is called trigeminal zoster, and zoster rash on the chest is called thoracic zoster. Most important, however, is the recognition that facial paralysis in association with rash on the ear, tongue, or hard palate reflects geniculate zoster and requires immediate antiviral treatment.

Varicella-zoster virus (VZV) is a highly neurotropic and ubiquitous alpha-herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. Reactivation decades later usually results in zoster (shingles), pain with a dermatomal distribution, and rash. Unlike herpes simplex virus type 1 (HSV-1), which becomes latent exclusively in cranial nerve ganglia and reactivates to produce recurrent vesicular lesions around the mouth, and unlike HSV type 2, which becomes latent exclusively in sacral ganglia and reactivates to produce genital herpes, VZV may reactivate from any ganglia to cause zoster anywhere on the body.

See related article

Reactivation of VZV from the geniculate (facial nerve) ganglion leads to the Ramsay Hunt syndrome, ie, facial paralysis accompanied by a rash around the ear (zoster oticus). The syndrome is the second most common cause of atraumatic facial paralysis after Bell palsy (idiopathic facial paralysis). Importantly, virus reactivation from the geniculate ganglion may also be accompanied by zoster rash on the hard palate or on the anterior two-thirds of the tongue (Figure 1).¹ A rash in any of these three skin or mucosal sites in a patient with facial paralysis indicates geniculate ganglionitis. To his credit, Dr. J. Ramsay Hunt recognized that although there is no somatic sensory facial branch to the oropharynx or tongue, virus can still spread from a seventh cranial nerve element to the pharynx or, via special sensory fibers, to the tongue, thus providing an anatomic explanation for zoster rash in patients with facial paralysis (geniculate zoster) not only around the ear, but also on the hard palate or on the anterior two-thirds of the tongue.²

Reprinted from Sweeney CJ, et al. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001; 71:149–154. With permission from BMJ Publishing Group Ltd.

In geniculate ganglionitis, a rash is usually seen in one but not all three of these skin and mucosal sites. Yet in this issue of the Cleveland Clinic Journal of Medicine, Grillo et al3 describe a patient with facial palsy and rash in all three sites. This remarkable finding underscores the importance of distinguishing Ramsay Hunt syndrome from Bell palsy by checking for rash on the ear, tongue, and hard palate in any patient with acute unilateral peripheral facial weakness. Ramsay Hunt syndrome results from active VZV replication in the geniculate ganglion and requires treatment with antiviral drugs, whereas Bell palsy is usually treated with steroids. Steroid treatment of Ramsay Hunt syndrome misdiagnosed as Bell palsy can potentiate the viral infection. This may partially explain why the outcome of facial paralysis in Ramsay Hunt syndrome is not as good as in idiopathic Bell palsy, in which more than 70% of patients recover full facial function.

Although only cranial nerve VII (facial) was involved in their patient, Grillo et al correctly noted the frequent involvement of other cranial nerves in Ramsay Hunt syndrome. For example, dizziness, vertigo, or hearing loss indicative of involvement of cranial nerve VIII (acoustic) is most likely due to the close proximity of the geniculate ganglion and facial nerve to the vestibulocochlear nerve in the bony facial canal. Patients with this syndrome may also develop dysarthria or dysphagia indicative of lower cranial nerve involvement, reflecting the shared derivation of the facial, glossopharyngeal, and vagus nerves from the same branchial arch. Magnetic resonance imaging, not usually performed in patients with Ramsay Hunt syndrome, may show enhancement in the geniculate ganglion as well as in the intracanalicular and tympanic segments of the facial nerve during its course through the facial canal.

The report by Grillo et al comes at an auspicious time, 100 years after an enlightening series of papers by Dr. Hunt from 1907 to 1915 in which he described herpetic inflammation of the geniculate ganglion,⁴ the sensory system of the facial nerve,⁵ and ultimately the syndrome that bears his name.^2,6 Dr. Hunt received his doctorate from the University of Pennsylvania in 1893 and later became instructor at Cornell University School of Medicine. In 1924, he became full professor at Columbia University School of Medicine. A clinician of Olympian stature, he is also credited with describing two additional syndromes (clinical features produced by carotid artery occlusion and dyssynergia cerebellaris progressiva), although the best known is zoster oticus with peripheral facial palsy.

Importantly, some patients develop peripheral facial paralysis without any rash but with a fourfold rise in antibody to VZV or in association with the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva, indicating that a proportion of patients with Bell palsy have “Ramsay Hunt syndrome zoster sine herpete” or, more accurately, “geniculate zoster sine herpete.” Treatment of such patients with acyclovir-prednisone within 7 days of onset has been shown to improve the outcome of facial palsy.

Because it is now clear that geniculate ganglionitis may present with facial palsy and zoster rash in any or all of three sites, it may be time to call peripheral facial paralysis associated with zoster rash on the ear, tongue, or palate exactly what it is: geniculate zoster. After all, zoster rash on the face is called trigeminal zoster, and zoster rash on the chest is called thoracic zoster. Most important, however, is the recognition that facial paralysis in association with rash on the ear, tongue, or hard palate reflects geniculate zoster and requires immediate antiviral treatment.

Varicella-zoster virus (VZV) is a highly neurotropic and ubiquitous alpha-herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. Reactivation decades later usually results in zoster (shingles), pain with a dermatomal distribution, and rash. Unlike herpes simplex virus type 1 (HSV-1), which becomes latent exclusively in cranial nerve ganglia and reactivates to produce recurrent vesicular lesions around the mouth, and unlike HSV type 2, which becomes latent exclusively in sacral ganglia and reactivates to produce genital herpes, VZV may reactivate from any ganglia to cause zoster anywhere on the body.

See related article

Reactivation of VZV from the geniculate (facial nerve) ganglion leads to the Ramsay Hunt syndrome, ie, facial paralysis accompanied by a rash around the ear (zoster oticus). The syndrome is the second most common cause of atraumatic facial paralysis after Bell palsy (idiopathic facial paralysis). Importantly, virus reactivation from the geniculate ganglion may also be accompanied by zoster rash on the hard palate or on the anterior two-thirds of the tongue (Figure 1).¹ A rash in any of these three skin or mucosal sites in a patient with facial paralysis indicates geniculate ganglionitis. To his credit, Dr. J. Ramsay Hunt recognized that although there is no somatic sensory facial branch to the oropharynx or tongue, virus can still spread from a seventh cranial nerve element to the pharynx or, via special sensory fibers, to the tongue, thus providing an anatomic explanation for zoster rash in patients with facial paralysis (geniculate zoster) not only around the ear, but also on the hard palate or on the anterior two-thirds of the tongue.²

Reprinted from Sweeney CJ, et al. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001; 71:149–154. With permission from BMJ Publishing Group Ltd.

In geniculate ganglionitis, a rash is usually seen in one but not all three of these skin and mucosal sites. Yet in this issue of the Cleveland Clinic Journal of Medicine, Grillo et al3 describe a patient with facial palsy and rash in all three sites. This remarkable finding underscores the importance of distinguishing Ramsay Hunt syndrome from Bell palsy by checking for rash on the ear, tongue, and hard palate in any patient with acute unilateral peripheral facial weakness. Ramsay Hunt syndrome results from active VZV replication in the geniculate ganglion and requires treatment with antiviral drugs, whereas Bell palsy is usually treated with steroids. Steroid treatment of Ramsay Hunt syndrome misdiagnosed as Bell palsy can potentiate the viral infection. This may partially explain why the outcome of facial paralysis in Ramsay Hunt syndrome is not as good as in idiopathic Bell palsy, in which more than 70% of patients recover full facial function.

Although only cranial nerve VII (facial) was involved in their patient, Grillo et al correctly noted the frequent involvement of other cranial nerves in Ramsay Hunt syndrome. For example, dizziness, vertigo, or hearing loss indicative of involvement of cranial nerve VIII (acoustic) is most likely due to the close proximity of the geniculate ganglion and facial nerve to the vestibulocochlear nerve in the bony facial canal. Patients with this syndrome may also develop dysarthria or dysphagia indicative of lower cranial nerve involvement, reflecting the shared derivation of the facial, glossopharyngeal, and vagus nerves from the same branchial arch. Magnetic resonance imaging, not usually performed in patients with Ramsay Hunt syndrome, may show enhancement in the geniculate ganglion as well as in the intracanalicular and tympanic segments of the facial nerve during its course through the facial canal.

The report by Grillo et al comes at an auspicious time, 100 years after an enlightening series of papers by Dr. Hunt from 1907 to 1915 in which he described herpetic inflammation of the geniculate ganglion,⁴ the sensory system of the facial nerve,⁵ and ultimately the syndrome that bears his name.^2,6 Dr. Hunt received his doctorate from the University of Pennsylvania in 1893 and later became instructor at Cornell University School of Medicine. In 1924, he became full professor at Columbia University School of Medicine. A clinician of Olympian stature, he is also credited with describing two additional syndromes (clinical features produced by carotid artery occlusion and dyssynergia cerebellaris progressiva), although the best known is zoster oticus with peripheral facial palsy.

Importantly, some patients develop peripheral facial paralysis without any rash but with a fourfold rise in antibody to VZV or in association with the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva, indicating that a proportion of patients with Bell palsy have “Ramsay Hunt syndrome zoster sine herpete” or, more accurately, “geniculate zoster sine herpete.” Treatment of such patients with acyclovir-prednisone within 7 days of onset has been shown to improve the outcome of facial palsy.

Because it is now clear that geniculate ganglionitis may present with facial palsy and zoster rash in any or all of three sites, it may be time to call peripheral facial paralysis associated with zoster rash on the ear, tongue, or palate exactly what it is: geniculate zoster. After all, zoster rash on the face is called trigeminal zoster, and zoster rash on the chest is called thoracic zoster. Most important, however, is the recognition that facial paralysis in association with rash on the ear, tongue, or hard palate reflects geniculate zoster and requires immediate antiviral treatment.

At first, the idea of collecting feces, putting it in a blender, and then transferring it into the gastrointestinal (GI) tract of another person might seem to be the creation of a third-grade boy writing a composition on the grossest thing he could think of. And yet, as Agito et al describe in this issue, this very procedure may hold promise for some patients suffering from recurrent and recalcitrant Clostridium difficile infection—and may help open the book on a new area of clinical biology.

The complete story on the biology of primary and recurrent C difficile infection has yet to be fully elaborated. For most patients, the plotline involves an alteration of their resident bacteria by an antibiotic that permits the overgrowth of C difficile, including spore-forming strains that can generate a significant amount of toxin. If the depletion of competitive intestinal bacteria allows for unfettered growth of this toxic bacterium, then it is predictable that replenishing the intestinal microbiome will permit balanced bacterial growth and control of C difficile multiplication.

But the C difficile story is only part of a biologic anthology that is still being written. The microbial biome accounts for probably 90% of the DNA that each of us carries. This microbial DNA, although diverse since it represents nuclear material from many species of bacteria, is not distributed randomly among individuals. There are at least several enterotypes (patterns of gut bacterial ecosystems) that can be identified by molecular techniques. The GI microbiome patterns of couples and household contacts are more similar than would be expected by chance alone, and patterns are seemingly influenced by dietary intake (carnivores differ from vegans) and perhaps by the host’s unique immune responsiveness. Our intestinal microbiome may exert a greater influence on our overall health than we previously thought.

The gut microbiome not only participates in digestion of what we eat and synthesizes some necessary nutritional factors, it also generates small molecules capable of regulating aspects of our systemic immune response. Altering the microbiome, by fecal transplantation or other means, may well contribute to the development or suppression of inflammatory disorders as diverse as spondylitis, atherosclerosis, immune thrombocytopenia, and allergies.

Soon, peptic ulcer disease may not be the only condition treated by therapies directed at bacteria within our GI tract. This is an evolving story that may seem weird but is worth following.

At first, the idea of collecting feces, putting it in a blender, and then transferring it into the gastrointestinal (GI) tract of another person might seem to be the creation of a third-grade boy writing a composition on the grossest thing he could think of. And yet, as Agito et al describe in this issue, this very procedure may hold promise for some patients suffering from recurrent and recalcitrant Clostridium difficile infection—and may help open the book on a new area of clinical biology.

The complete story on the biology of primary and recurrent C difficile infection has yet to be fully elaborated. For most patients, the plotline involves an alteration of their resident bacteria by an antibiotic that permits the overgrowth of C difficile, including spore-forming strains that can generate a significant amount of toxin. If the depletion of competitive intestinal bacteria allows for unfettered growth of this toxic bacterium, then it is predictable that replenishing the intestinal microbiome will permit balanced bacterial growth and control of C difficile multiplication.

But the C difficile story is only part of a biologic anthology that is still being written. The microbial biome accounts for probably 90% of the DNA that each of us carries. This microbial DNA, although diverse since it represents nuclear material from many species of bacteria, is not distributed randomly among individuals. There are at least several enterotypes (patterns of gut bacterial ecosystems) that can be identified by molecular techniques. The GI microbiome patterns of couples and household contacts are more similar than would be expected by chance alone, and patterns are seemingly influenced by dietary intake (carnivores differ from vegans) and perhaps by the host’s unique immune responsiveness. Our intestinal microbiome may exert a greater influence on our overall health than we previously thought.

The gut microbiome not only participates in digestion of what we eat and synthesizes some necessary nutritional factors, it also generates small molecules capable of regulating aspects of our systemic immune response. Altering the microbiome, by fecal transplantation or other means, may well contribute to the development or suppression of inflammatory disorders as diverse as spondylitis, atherosclerosis, immune thrombocytopenia, and allergies.

Soon, peptic ulcer disease may not be the only condition treated by therapies directed at bacteria within our GI tract. This is an evolving story that may seem weird but is worth following.

At first, the idea of collecting feces, putting it in a blender, and then transferring it into the gastrointestinal (GI) tract of another person might seem to be the creation of a third-grade boy writing a composition on the grossest thing he could think of. And yet, as Agito et al describe in this issue, this very procedure may hold promise for some patients suffering from recurrent and recalcitrant Clostridium difficile infection—and may help open the book on a new area of clinical biology.

The complete story on the biology of primary and recurrent C difficile infection has yet to be fully elaborated. For most patients, the plotline involves an alteration of their resident bacteria by an antibiotic that permits the overgrowth of C difficile, including spore-forming strains that can generate a significant amount of toxin. If the depletion of competitive intestinal bacteria allows for unfettered growth of this toxic bacterium, then it is predictable that replenishing the intestinal microbiome will permit balanced bacterial growth and control of C difficile multiplication.

But the C difficile story is only part of a biologic anthology that is still being written. The microbial biome accounts for probably 90% of the DNA that each of us carries. This microbial DNA, although diverse since it represents nuclear material from many species of bacteria, is not distributed randomly among individuals. There are at least several enterotypes (patterns of gut bacterial ecosystems) that can be identified by molecular techniques. The GI microbiome patterns of couples and household contacts are more similar than would be expected by chance alone, and patterns are seemingly influenced by dietary intake (carnivores differ from vegans) and perhaps by the host’s unique immune responsiveness. Our intestinal microbiome may exert a greater influence on our overall health than we previously thought.

The gut microbiome not only participates in digestion of what we eat and synthesizes some necessary nutritional factors, it also generates small molecules capable of regulating aspects of our systemic immune response. Altering the microbiome, by fecal transplantation or other means, may well contribute to the development or suppression of inflammatory disorders as diverse as spondylitis, atherosclerosis, immune thrombocytopenia, and allergies.

Soon, peptic ulcer disease may not be the only condition treated by therapies directed at bacteria within our GI tract. This is an evolving story that may seem weird but is worth following.

If you had a serious disease, would you agree to an alternative treatment that was cheap, safe, and effective—but seemed disgusting? Would you recommend it to patients?

Such a disease is recurrent Clostridium difficile infection, and such a treatment is fecal microbiota transplantation—instillation of blenderized feces from a healthy donor (ideally, the patient’s spouse or “significant other”) into the patient’s colon to restore a healthy population of bacteria.^1,2 The rationale behind this procedure is simple: antibiotics and other factors disrupt the normal balance of the colonic flora, allowing C difficile to proliferate, but the imbalance can be corrected by reintroducing the normal flora.¹

In this article, we will review how recurrent C difficile infection occurs and the importance of the gut microbiota in resisting colonization with this pathogen. We will also describe the protocol used for fecal microbiota transplantation.

C DIFFICILE INFECTION OFTEN RECURS

C difficile is the most common cause of hospital-acquired diarrhea and an important cause of morbidity and death in hospitalized patients.^3,4 The cost of this infection is estimated to be more than $1.1 billion per year and its incidence is rising, partly because of the emergence of more-virulent strains that make treatment of recurrent infection more difficult.^5,6

C difficile infection is characterized by diarrhea associated with findings suggestive of pseudomembranous colitis or, in fulminant cases, ileus or megacolon.⁷ Recurrent C difficile infection is defined as the return of symptoms within 8 weeks after successful treatment.⁷

C difficile produces two types of toxins. Toxin A is an enterotoxin, causing increased intestinal permeability and fluid secretion, while toxin B is a cytotoxin, causing intense colonic inflammation. People who have a poor host immune response to these toxins tend to develop more diarrhea and colonic inflammation.⁸

A more virulent strain of C difficile has emerged. Known as BI/NAP1/027, this strain is resistant to quinolones, and it also produces a binary toxin that has a partial gene deletion that allows for increased production of toxins A and B in vitro.^9,10 More cases of severe and recurrent C difficile infection have been associated with the increasing number of people infected with this hypervirulent strain.^9,10

C difficile infection recurs in about 20% to 30% of cases after antibiotic treatment for it, usually within 30 days, and the risk of a subsequent episode doubles after two or more occurrences.^10,11 Metronidazole (Flagyl) and vancomycin are the primary treatments; alternative treatments include fidaxomicin (Dificid), ¹⁰ rifaximin (Xifaxan),¹² nitazoxanide,¹³ and tolevamer (a novel polymer that binds C difficile toxins).¹⁴

Table 1 summarizes the treatment regimen for C difficile infection in adults, based on clinical practice guidelines from the US Centers for Disease Control and Prevention (CDC).⁷

THE NORMAL GUT MICROBIOTA KEEPS PATHOGENS OUT

Immediately after birth, the sterile human gut becomes colonized by a diverse community of microorganisms.¹⁵ This gut microbiota performs various functions, such as synthesizing vitamin K and vitamin B complex, helping digest food, maintaining the mucosal integrity of the gut, and priming the mucosal immune response to maintain homeostasis of commensal microbiota.¹⁶

However, the most important role of the gut microbiota is “colonization resistance” or preventing exogenous or potentially pathogenic organisms from establishing a colony within the gut.¹⁷ It involves competition for nutrients and occupation of binding sites on the gut epithelium by indigenous flora.¹⁶ Other factors such as the mucosal barrier, salivation, swallowing, gastric acidity, desquamation of mucosal membrane cells, intestinal motility, and secretion of antibodies also play major roles in colonization resistance.¹⁷

ANTIBIOTICS DISRUPT THE GUT FLORA

Physical or chemical injuries (the latter by antimicrobial or antineoplastic agents, eg) may disrupt the gut microbiota. In this situation, opportunistic pathogens such as C difficile colonize the gut mucosa, stimulate an immune reaction, and release toxins that cause diarrhea and inflammation.¹⁸C difficile will try to compete for nutrients and adhesion sites until it dominates the intestinal tract.

When C difficile spores are ingested, they replicate in the gut and eventually release toxins. Antibiotic therapy may eliminate C difficile bacteria but not the spores; hence, C difficile infection can recur after the antibiotic is discontinued unless the indigenous bacteria can restrain C difficile from spreading.¹⁹

HOW DOES FECAL MICROBIOTA TRANSPLANTATION WORK?

Fecal microbiota transplantation involves instilling processed stool that contains essential intestinal bacteria (eg, Bacteroides species) from a healthy screened donor into the diseased gastrointestinal tract of a suitable recipient (Figure 1).¹

The aim of this procedure is to reestablish the normal composition of the gut flora, restore balance in metabolism, and stimulate both the acquired and the humoral immune responses in the intestinal mucosa after disruption of the normal flora.20–23 One study showed that patients who have recurrent C difficile infections have fewer protective microorganisms (ie, Firmicutes and Bacteriodetes) in their gut, but after fecal microbiota transplantation their microbiota was found to be similar to that of the donor, and their symptoms promptly resolved.18

STUDIES UP TO NOW

The principle of transplanting donor stool to treat various gastrointestinal diseases has been practiced in veterinary medicine for decades in a process known as transfaunation.²⁴ Fecal microbiota transplantation was first performed in humans in the late 1950s in patients with fulminant pseudomembranous colitis that did not respond to standard antibiotic therapy for C difficile infection.²⁵ Since then, a number of case reports and case series have described instillation of donor stool via nasogastric tube,²⁶ via colonoscope,^27–31 and via enema.³² Regardless of the protocols used, disease resolution has been shown in 92% of cases and few adverse effects have been reported, even though transmission of infectious pathogens is theoretically possible.³³

A recent multicenter long-term follow-up study³⁴ showed that diarrhea resolved within 90 days after fecal microbiota transplantation in 70 (91%) of 77 patients, while resolution of C difficile infection after a further course of antibiotics with or without repeating fecal microbiota transplantation was seen in 76 (98%) of 77 patients.³⁴ Some patients were reported to have improvement of preexisting allergies, and a few patients developed peripheral neuropathy and autoimmune diseases such as Sjögren syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.³³

As the important role of the gut microbiota in resisting colonization by C difficile is becoming more recognized, scientists are beginning to understand and explore the additional potential benefits of fecal microbiota transplantation on other microbiotarelated dysfunctions.² The Human Microbiome Project is focusing on characterizing and understanding the role of the microbial components of the human genetic and metabolic landscape in relation to human health and disease.³⁵ Earlier observational studies showed fecal microbiota transplantation to be beneficial in inflammatory bowel disease, ^36,37 irritable bowel syndrome,^38,39 multiple sclerosis,⁴⁰ rheumatologic⁴⁰ and autoimmune diseases,⁴¹ and metabolic syndrome,⁴² likely owing to the role of the microbiota in immunity and energy metabolism. Although these reports may provide insight into the unexplored possibilities of fecal microbiota transplantation, further clinical investigations with randomized controlled trials are still necessary.

THE CURRENT PROTOCOL FOR FECAL MICROBIOTA TRANSPLANTATION

As yet, there is no standardized protocol for fecal microbiota transplantation, since no completed randomized trial supporting its efficacy and safety has been published. However, a group of experts in infectious disease and gastroenterology have published a formal standard practice guideline,¹⁹ as summarized below.

Primary indications for fecal microbiota transplantation

• Recurrent C difficile infection—at least three episodes of mild to moderate C difficile infection and failure of a 6- to 8-week taper with vancomycin with or without an alternative antibiotic such as rifaximin or nitazoxanide, or at least two episodes of severe C difficile infection resulting in hospitalization and associated with significant morbidity
• Mild to moderate C difficile infection not responding to standard therapy for at least 1 week
• Severe or fulminant C difficile colitis that has not responded to standard therapy after 48 hours.

Who is a likely donor?

The gut microbiota is continuously replenished with bacteria from the environment in which we live, and we constantly acquire organisms from people who live in that same environment. Hence, the preferred donor is someone who has intimate physical contact with the recipient.^33,43,44 The preferred stool donor (in order of preference) is a spouse or significant partner, a family household member, or any other healthy donor.^26,36

Who should not be a donor?

It is the responsibility of the physician performing the fecal microbiota transplantation to make sure that the possibility of transmitting disease to the recipient is minimized. Extensive history-taking and physical examination must never be omitted, since not all diseases or conditions can be detected by laboratory screening alone, especially if testing was done during the early stage or window period of a given disease.¹⁹ Nevertheless, the donor’s blood and stool should be screened for transmissible diseases such as human immunodeficiency virus (HIV), hepatitis, syphilis, enteric bacteria, parasites, and C difficile.

The recipient has the option to be tested for transmissible diseases such as HIV and hepatitis in order to avoid future questions about transmission after fecal microbiota transplantation. A positive screening test must always be verified with confirmatory testing.¹⁹

Table 2 summarizes the exclusion criteria and screening tests performed for donors according to the practice guidelines for fecal microbiota transplantation formulated by Bakken et al.¹⁹

Preprocedure instructions and stool preparation

The physician should orient both the donor and recipient regarding “do’s and don’ts” before fecal microbiota transplantation. Table 3 summarizes the preprocedure instructions and steps for stool preparation.

Route of administration

The route of administration may vary depending on the clinical situation. Upper-gastrointestinal administration is performed via nasogastric or nasojejunal tube or gastroscopy. Lower-gastrointestinal administration is performed via colonoscopy (the route of choice) or retention enema.

The upper-gastrointestinal route (nasogastric tube, jejunal catheter, or gastroscope). The nasogastric or nasojejunal tube or gastroscope is inserted into the upper-gastrointestinal tract, and positioning is confirmed by radiography. From 25 to 50 mL of stool suspension is drawn up in a syringe and instilled into the tubing followed by flushing with 25 mL of normal saline.²⁶ Immediately after instillation, the tube is removed and the patient is allowed to go home and continue with his or her usual diet.

This approach is easier to perform, costs less, and poses lower risk of intestinal perforation than the colonoscopic approach. Disadvantages include the possibility that stool suspension may not reach distal areas of the colon, especially in patients with ileus and small-bowel obstruction. There is also a higher risk of bacterial overgrowth in elderly patients who have lower gastric acid levels.³³

The lower-gastrointestinal route (colonoscopy, retention enema). Colonoscopy is currently considered the first-line approach for fecal microbiota transplantation.⁴⁵ After giving informed consent, the patient undergoes standard colonoscopy under sedation. An initial colonoscopic examination is performed, and biopsy specimans are obtained if necessary. Approximately 20 mL of stool suspension is drawn up in a syringe and injected via the biopsy channel of the colonoscope every 5 to 10 cm as the scope is withdrawn, for a total volume of 250 to 500 mL.^19,27 The patient should be advised to refrain from defecating for 30 to 45 minutes after fecal microbiota transplantation.⁴⁶

This approach allows direct visualization of the entire colon, allowing instillation of stool suspension in certain areas where C difficile may predominate or hide (eg, in diverticuli).^27,47 One disadvantage to this route of administration is the risk of colon perforation, especially if the patient has toxic colitis.

Instillation via retention enema may be done at home with a standard enema kit.³² Disadvantages include the need for multiple instillations over 3 to 5 days,³⁶ back-leakage of stool suspension causing discomfort to patients, and stool suspension reaching only to the splenic flexure.⁴⁸

MEASUREMENT OF OUTCOME

Fecal microbiota transplantation is considered successful if symptoms resolve and there is no relapse within 8 weeks. Testing for C difficile in asymptomatic patients is not recommended since patients can be colonized with C difficile without necessarily developing disease.¹⁹ There is currently no consensus on treatment recommendations for patients who do not respond to fecal microbiota transplantation, although some reports showed resolution of diarrhea after a repeat 2-week standard course of oral vancomycin²⁶ or repeated instillation of feces collected from new donors.⁴⁹

IS IT READY FOR PRIME TIME?

Fecal microbiota transplantation has been used primarily as an alternative treatment for recurrent C difficile infection, although other indications for its use are currently being identified and studied. This procedure is now being done in several specialized centers in the United States and abroad, and although the protocol may vary by institution, the clinical outcomes have been consistently promising.

The Fecal Therapy to Eliminate Associated Long-standing Diarrhea (FECAL) trial, currently underway, is the first randomized trial to assess the efficacy of fecal microbiota transplantation for treatment of recurrent C difficile infection.⁵⁰ Clinical trials such as this one should satisfy our doubts about the efficacy of fecal microbiota transplantation and hopefully pave the way for its application in the near future.

An increasing number of patients are learning to overcome the “yuck factor” associated with fecal microbiota transplantation once they understand its safety and benefits.⁵¹ Moreover, the Human Microbiome Project is attempting to identify specific organisms in stool that may specifically treat C difficile infection, hence eliminating the need for whole-stool transplantation in the near future. Although fecal microbiota transplantation is still in its infancy, its low cost, safety, and effectiveness in treating recurrent C difficile infection will likely lead to the procedure becoming widely adopted in mainstream clinical practice.

Editor’s note: On January 16, 2013, after this article was completed, a randomized controlled trial of fecal microbiota transplantation was published in the New England Journal of Medicine. That trial, “Duodenal infusion of donor feces for recurrent Clostridium difficile,” found: “The infusion of donor feces was significantly more effective for the treatment of recurrent C difficile infection than the use of vancomycin.” The study is available online at http://www.nejm.org/doi/full/10.1056/NEJMoa1205037 (subscription required).

If you had a serious disease, would you agree to an alternative treatment that was cheap, safe, and effective—but seemed disgusting? Would you recommend it to patients?

Such a disease is recurrent Clostridium difficile infection, and such a treatment is fecal microbiota transplantation—instillation of blenderized feces from a healthy donor (ideally, the patient’s spouse or “significant other”) into the patient’s colon to restore a healthy population of bacteria.^1,2 The rationale behind this procedure is simple: antibiotics and other factors disrupt the normal balance of the colonic flora, allowing C difficile to proliferate, but the imbalance can be corrected by reintroducing the normal flora.¹

In this article, we will review how recurrent C difficile infection occurs and the importance of the gut microbiota in resisting colonization with this pathogen. We will also describe the protocol used for fecal microbiota transplantation.

C DIFFICILE INFECTION OFTEN RECURS

C difficile is the most common cause of hospital-acquired diarrhea and an important cause of morbidity and death in hospitalized patients.^3,4 The cost of this infection is estimated to be more than $1.1 billion per year and its incidence is rising, partly because of the emergence of more-virulent strains that make treatment of recurrent infection more difficult.^5,6

C difficile infection is characterized by diarrhea associated with findings suggestive of pseudomembranous colitis or, in fulminant cases, ileus or megacolon.⁷ Recurrent C difficile infection is defined as the return of symptoms within 8 weeks after successful treatment.⁷

C difficile produces two types of toxins. Toxin A is an enterotoxin, causing increased intestinal permeability and fluid secretion, while toxin B is a cytotoxin, causing intense colonic inflammation. People who have a poor host immune response to these toxins tend to develop more diarrhea and colonic inflammation.⁸

A more virulent strain of C difficile has emerged. Known as BI/NAP1/027, this strain is resistant to quinolones, and it also produces a binary toxin that has a partial gene deletion that allows for increased production of toxins A and B in vitro.^9,10 More cases of severe and recurrent C difficile infection have been associated with the increasing number of people infected with this hypervirulent strain.^9,10

C difficile infection recurs in about 20% to 30% of cases after antibiotic treatment for it, usually within 30 days, and the risk of a subsequent episode doubles after two or more occurrences.^10,11 Metronidazole (Flagyl) and vancomycin are the primary treatments; alternative treatments include fidaxomicin (Dificid), ¹⁰ rifaximin (Xifaxan),¹² nitazoxanide,¹³ and tolevamer (a novel polymer that binds C difficile toxins).¹⁴

Table 1 summarizes the treatment regimen for C difficile infection in adults, based on clinical practice guidelines from the US Centers for Disease Control and Prevention (CDC).⁷

THE NORMAL GUT MICROBIOTA KEEPS PATHOGENS OUT

Immediately after birth, the sterile human gut becomes colonized by a diverse community of microorganisms.¹⁵ This gut microbiota performs various functions, such as synthesizing vitamin K and vitamin B complex, helping digest food, maintaining the mucosal integrity of the gut, and priming the mucosal immune response to maintain homeostasis of commensal microbiota.¹⁶

However, the most important role of the gut microbiota is “colonization resistance” or preventing exogenous or potentially pathogenic organisms from establishing a colony within the gut.¹⁷ It involves competition for nutrients and occupation of binding sites on the gut epithelium by indigenous flora.¹⁶ Other factors such as the mucosal barrier, salivation, swallowing, gastric acidity, desquamation of mucosal membrane cells, intestinal motility, and secretion of antibodies also play major roles in colonization resistance.¹⁷

ANTIBIOTICS DISRUPT THE GUT FLORA

Physical or chemical injuries (the latter by antimicrobial or antineoplastic agents, eg) may disrupt the gut microbiota. In this situation, opportunistic pathogens such as C difficile colonize the gut mucosa, stimulate an immune reaction, and release toxins that cause diarrhea and inflammation.¹⁸C difficile will try to compete for nutrients and adhesion sites until it dominates the intestinal tract.

When C difficile spores are ingested, they replicate in the gut and eventually release toxins. Antibiotic therapy may eliminate C difficile bacteria but not the spores; hence, C difficile infection can recur after the antibiotic is discontinued unless the indigenous bacteria can restrain C difficile from spreading.¹⁹

HOW DOES FECAL MICROBIOTA TRANSPLANTATION WORK?

Fecal microbiota transplantation involves instilling processed stool that contains essential intestinal bacteria (eg, Bacteroides species) from a healthy screened donor into the diseased gastrointestinal tract of a suitable recipient (Figure 1).¹

The aim of this procedure is to reestablish the normal composition of the gut flora, restore balance in metabolism, and stimulate both the acquired and the humoral immune responses in the intestinal mucosa after disruption of the normal flora.20–23 One study showed that patients who have recurrent C difficile infections have fewer protective microorganisms (ie, Firmicutes and Bacteriodetes) in their gut, but after fecal microbiota transplantation their microbiota was found to be similar to that of the donor, and their symptoms promptly resolved.18

STUDIES UP TO NOW

The principle of transplanting donor stool to treat various gastrointestinal diseases has been practiced in veterinary medicine for decades in a process known as transfaunation.²⁴ Fecal microbiota transplantation was first performed in humans in the late 1950s in patients with fulminant pseudomembranous colitis that did not respond to standard antibiotic therapy for C difficile infection.²⁵ Since then, a number of case reports and case series have described instillation of donor stool via nasogastric tube,²⁶ via colonoscope,^27–31 and via enema.³² Regardless of the protocols used, disease resolution has been shown in 92% of cases and few adverse effects have been reported, even though transmission of infectious pathogens is theoretically possible.³³

A recent multicenter long-term follow-up study³⁴ showed that diarrhea resolved within 90 days after fecal microbiota transplantation in 70 (91%) of 77 patients, while resolution of C difficile infection after a further course of antibiotics with or without repeating fecal microbiota transplantation was seen in 76 (98%) of 77 patients.³⁴ Some patients were reported to have improvement of preexisting allergies, and a few patients developed peripheral neuropathy and autoimmune diseases such as Sjögren syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.³³

As the important role of the gut microbiota in resisting colonization by C difficile is becoming more recognized, scientists are beginning to understand and explore the additional potential benefits of fecal microbiota transplantation on other microbiotarelated dysfunctions.² The Human Microbiome Project is focusing on characterizing and understanding the role of the microbial components of the human genetic and metabolic landscape in relation to human health and disease.³⁵ Earlier observational studies showed fecal microbiota transplantation to be beneficial in inflammatory bowel disease, ^36,37 irritable bowel syndrome,^38,39 multiple sclerosis,⁴⁰ rheumatologic⁴⁰ and autoimmune diseases,⁴¹ and metabolic syndrome,⁴² likely owing to the role of the microbiota in immunity and energy metabolism. Although these reports may provide insight into the unexplored possibilities of fecal microbiota transplantation, further clinical investigations with randomized controlled trials are still necessary.

THE CURRENT PROTOCOL FOR FECAL MICROBIOTA TRANSPLANTATION

As yet, there is no standardized protocol for fecal microbiota transplantation, since no completed randomized trial supporting its efficacy and safety has been published. However, a group of experts in infectious disease and gastroenterology have published a formal standard practice guideline,¹⁹ as summarized below.

Primary indications for fecal microbiota transplantation

• Recurrent C difficile infection—at least three episodes of mild to moderate C difficile infection and failure of a 6- to 8-week taper with vancomycin with or without an alternative antibiotic such as rifaximin or nitazoxanide, or at least two episodes of severe C difficile infection resulting in hospitalization and associated with significant morbidity
• Mild to moderate C difficile infection not responding to standard therapy for at least 1 week
• Severe or fulminant C difficile colitis that has not responded to standard therapy after 48 hours.

Who is a likely donor?

The gut microbiota is continuously replenished with bacteria from the environment in which we live, and we constantly acquire organisms from people who live in that same environment. Hence, the preferred donor is someone who has intimate physical contact with the recipient.^33,43,44 The preferred stool donor (in order of preference) is a spouse or significant partner, a family household member, or any other healthy donor.^26,36

Who should not be a donor?

It is the responsibility of the physician performing the fecal microbiota transplantation to make sure that the possibility of transmitting disease to the recipient is minimized. Extensive history-taking and physical examination must never be omitted, since not all diseases or conditions can be detected by laboratory screening alone, especially if testing was done during the early stage or window period of a given disease.¹⁹ Nevertheless, the donor’s blood and stool should be screened for transmissible diseases such as human immunodeficiency virus (HIV), hepatitis, syphilis, enteric bacteria, parasites, and C difficile.

The recipient has the option to be tested for transmissible diseases such as HIV and hepatitis in order to avoid future questions about transmission after fecal microbiota transplantation. A positive screening test must always be verified with confirmatory testing.¹⁹

Table 2 summarizes the exclusion criteria and screening tests performed for donors according to the practice guidelines for fecal microbiota transplantation formulated by Bakken et al.¹⁹

Preprocedure instructions and stool preparation

The physician should orient both the donor and recipient regarding “do’s and don’ts” before fecal microbiota transplantation. Table 3 summarizes the preprocedure instructions and steps for stool preparation.

Route of administration

The route of administration may vary depending on the clinical situation. Upper-gastrointestinal administration is performed via nasogastric or nasojejunal tube or gastroscopy. Lower-gastrointestinal administration is performed via colonoscopy (the route of choice) or retention enema.

The upper-gastrointestinal route (nasogastric tube, jejunal catheter, or gastroscope). The nasogastric or nasojejunal tube or gastroscope is inserted into the upper-gastrointestinal tract, and positioning is confirmed by radiography. From 25 to 50 mL of stool suspension is drawn up in a syringe and instilled into the tubing followed by flushing with 25 mL of normal saline.²⁶ Immediately after instillation, the tube is removed and the patient is allowed to go home and continue with his or her usual diet.

This approach is easier to perform, costs less, and poses lower risk of intestinal perforation than the colonoscopic approach. Disadvantages include the possibility that stool suspension may not reach distal areas of the colon, especially in patients with ileus and small-bowel obstruction. There is also a higher risk of bacterial overgrowth in elderly patients who have lower gastric acid levels.³³

The lower-gastrointestinal route (colonoscopy, retention enema). Colonoscopy is currently considered the first-line approach for fecal microbiota transplantation.⁴⁵ After giving informed consent, the patient undergoes standard colonoscopy under sedation. An initial colonoscopic examination is performed, and biopsy specimans are obtained if necessary. Approximately 20 mL of stool suspension is drawn up in a syringe and injected via the biopsy channel of the colonoscope every 5 to 10 cm as the scope is withdrawn, for a total volume of 250 to 500 mL.^19,27 The patient should be advised to refrain from defecating for 30 to 45 minutes after fecal microbiota transplantation.⁴⁶

This approach allows direct visualization of the entire colon, allowing instillation of stool suspension in certain areas where C difficile may predominate or hide (eg, in diverticuli).^27,47 One disadvantage to this route of administration is the risk of colon perforation, especially if the patient has toxic colitis.

Instillation via retention enema may be done at home with a standard enema kit.³² Disadvantages include the need for multiple instillations over 3 to 5 days,³⁶ back-leakage of stool suspension causing discomfort to patients, and stool suspension reaching only to the splenic flexure.⁴⁸

MEASUREMENT OF OUTCOME

Fecal microbiota transplantation is considered successful if symptoms resolve and there is no relapse within 8 weeks. Testing for C difficile in asymptomatic patients is not recommended since patients can be colonized with C difficile without necessarily developing disease.¹⁹ There is currently no consensus on treatment recommendations for patients who do not respond to fecal microbiota transplantation, although some reports showed resolution of diarrhea after a repeat 2-week standard course of oral vancomycin²⁶ or repeated instillation of feces collected from new donors.⁴⁹

IS IT READY FOR PRIME TIME?

Fecal microbiota transplantation has been used primarily as an alternative treatment for recurrent C difficile infection, although other indications for its use are currently being identified and studied. This procedure is now being done in several specialized centers in the United States and abroad, and although the protocol may vary by institution, the clinical outcomes have been consistently promising.

The Fecal Therapy to Eliminate Associated Long-standing Diarrhea (FECAL) trial, currently underway, is the first randomized trial to assess the efficacy of fecal microbiota transplantation for treatment of recurrent C difficile infection.⁵⁰ Clinical trials such as this one should satisfy our doubts about the efficacy of fecal microbiota transplantation and hopefully pave the way for its application in the near future.

An increasing number of patients are learning to overcome the “yuck factor” associated with fecal microbiota transplantation once they understand its safety and benefits.⁵¹ Moreover, the Human Microbiome Project is attempting to identify specific organisms in stool that may specifically treat C difficile infection, hence eliminating the need for whole-stool transplantation in the near future. Although fecal microbiota transplantation is still in its infancy, its low cost, safety, and effectiveness in treating recurrent C difficile infection will likely lead to the procedure becoming widely adopted in mainstream clinical practice.

Editor’s note: On January 16, 2013, after this article was completed, a randomized controlled trial of fecal microbiota transplantation was published in the New England Journal of Medicine. That trial, “Duodenal infusion of donor feces for recurrent Clostridium difficile,” found: “The infusion of donor feces was significantly more effective for the treatment of recurrent C difficile infection than the use of vancomycin.” The study is available online at http://www.nejm.org/doi/full/10.1056/NEJMoa1205037 (subscription required).

If you had a serious disease, would you agree to an alternative treatment that was cheap, safe, and effective—but seemed disgusting? Would you recommend it to patients?

Such a disease is recurrent Clostridium difficile infection, and such a treatment is fecal microbiota transplantation—instillation of blenderized feces from a healthy donor (ideally, the patient’s spouse or “significant other”) into the patient’s colon to restore a healthy population of bacteria.^1,2 The rationale behind this procedure is simple: antibiotics and other factors disrupt the normal balance of the colonic flora, allowing C difficile to proliferate, but the imbalance can be corrected by reintroducing the normal flora.¹

In this article, we will review how recurrent C difficile infection occurs and the importance of the gut microbiota in resisting colonization with this pathogen. We will also describe the protocol used for fecal microbiota transplantation.

C DIFFICILE INFECTION OFTEN RECURS

C difficile is the most common cause of hospital-acquired diarrhea and an important cause of morbidity and death in hospitalized patients.^3,4 The cost of this infection is estimated to be more than $1.1 billion per year and its incidence is rising, partly because of the emergence of more-virulent strains that make treatment of recurrent infection more difficult.^5,6

C difficile infection is characterized by diarrhea associated with findings suggestive of pseudomembranous colitis or, in fulminant cases, ileus or megacolon.⁷ Recurrent C difficile infection is defined as the return of symptoms within 8 weeks after successful treatment.⁷

C difficile produces two types of toxins. Toxin A is an enterotoxin, causing increased intestinal permeability and fluid secretion, while toxin B is a cytotoxin, causing intense colonic inflammation. People who have a poor host immune response to these toxins tend to develop more diarrhea and colonic inflammation.⁸

A more virulent strain of C difficile has emerged. Known as BI/NAP1/027, this strain is resistant to quinolones, and it also produces a binary toxin that has a partial gene deletion that allows for increased production of toxins A and B in vitro.^9,10 More cases of severe and recurrent C difficile infection have been associated with the increasing number of people infected with this hypervirulent strain.^9,10

C difficile infection recurs in about 20% to 30% of cases after antibiotic treatment for it, usually within 30 days, and the risk of a subsequent episode doubles after two or more occurrences.^10,11 Metronidazole (Flagyl) and vancomycin are the primary treatments; alternative treatments include fidaxomicin (Dificid), ¹⁰ rifaximin (Xifaxan),¹² nitazoxanide,¹³ and tolevamer (a novel polymer that binds C difficile toxins).¹⁴

Table 1 summarizes the treatment regimen for C difficile infection in adults, based on clinical practice guidelines from the US Centers for Disease Control and Prevention (CDC).⁷

THE NORMAL GUT MICROBIOTA KEEPS PATHOGENS OUT

Immediately after birth, the sterile human gut becomes colonized by a diverse community of microorganisms.¹⁵ This gut microbiota performs various functions, such as synthesizing vitamin K and vitamin B complex, helping digest food, maintaining the mucosal integrity of the gut, and priming the mucosal immune response to maintain homeostasis of commensal microbiota.¹⁶

However, the most important role of the gut microbiota is “colonization resistance” or preventing exogenous or potentially pathogenic organisms from establishing a colony within the gut.¹⁷ It involves competition for nutrients and occupation of binding sites on the gut epithelium by indigenous flora.¹⁶ Other factors such as the mucosal barrier, salivation, swallowing, gastric acidity, desquamation of mucosal membrane cells, intestinal motility, and secretion of antibodies also play major roles in colonization resistance.¹⁷

ANTIBIOTICS DISRUPT THE GUT FLORA

Physical or chemical injuries (the latter by antimicrobial or antineoplastic agents, eg) may disrupt the gut microbiota. In this situation, opportunistic pathogens such as C difficile colonize the gut mucosa, stimulate an immune reaction, and release toxins that cause diarrhea and inflammation.¹⁸C difficile will try to compete for nutrients and adhesion sites until it dominates the intestinal tract.

When C difficile spores are ingested, they replicate in the gut and eventually release toxins. Antibiotic therapy may eliminate C difficile bacteria but not the spores; hence, C difficile infection can recur after the antibiotic is discontinued unless the indigenous bacteria can restrain C difficile from spreading.¹⁹

HOW DOES FECAL MICROBIOTA TRANSPLANTATION WORK?

Fecal microbiota transplantation involves instilling processed stool that contains essential intestinal bacteria (eg, Bacteroides species) from a healthy screened donor into the diseased gastrointestinal tract of a suitable recipient (Figure 1).¹

The aim of this procedure is to reestablish the normal composition of the gut flora, restore balance in metabolism, and stimulate both the acquired and the humoral immune responses in the intestinal mucosa after disruption of the normal flora.20–23 One study showed that patients who have recurrent C difficile infections have fewer protective microorganisms (ie, Firmicutes and Bacteriodetes) in their gut, but after fecal microbiota transplantation their microbiota was found to be similar to that of the donor, and their symptoms promptly resolved.18

STUDIES UP TO NOW

The principle of transplanting donor stool to treat various gastrointestinal diseases has been practiced in veterinary medicine for decades in a process known as transfaunation.²⁴ Fecal microbiota transplantation was first performed in humans in the late 1950s in patients with fulminant pseudomembranous colitis that did not respond to standard antibiotic therapy for C difficile infection.²⁵ Since then, a number of case reports and case series have described instillation of donor stool via nasogastric tube,²⁶ via colonoscope,^27–31 and via enema.³² Regardless of the protocols used, disease resolution has been shown in 92% of cases and few adverse effects have been reported, even though transmission of infectious pathogens is theoretically possible.³³

A recent multicenter long-term follow-up study³⁴ showed that diarrhea resolved within 90 days after fecal microbiota transplantation in 70 (91%) of 77 patients, while resolution of C difficile infection after a further course of antibiotics with or without repeating fecal microbiota transplantation was seen in 76 (98%) of 77 patients.³⁴ Some patients were reported to have improvement of preexisting allergies, and a few patients developed peripheral neuropathy and autoimmune diseases such as Sjögren syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.³³

As the important role of the gut microbiota in resisting colonization by C difficile is becoming more recognized, scientists are beginning to understand and explore the additional potential benefits of fecal microbiota transplantation on other microbiotarelated dysfunctions.² The Human Microbiome Project is focusing on characterizing and understanding the role of the microbial components of the human genetic and metabolic landscape in relation to human health and disease.³⁵ Earlier observational studies showed fecal microbiota transplantation to be beneficial in inflammatory bowel disease, ^36,37 irritable bowel syndrome,^38,39 multiple sclerosis,⁴⁰ rheumatologic⁴⁰ and autoimmune diseases,⁴¹ and metabolic syndrome,⁴² likely owing to the role of the microbiota in immunity and energy metabolism. Although these reports may provide insight into the unexplored possibilities of fecal microbiota transplantation, further clinical investigations with randomized controlled trials are still necessary.

THE CURRENT PROTOCOL FOR FECAL MICROBIOTA TRANSPLANTATION

As yet, there is no standardized protocol for fecal microbiota transplantation, since no completed randomized trial supporting its efficacy and safety has been published. However, a group of experts in infectious disease and gastroenterology have published a formal standard practice guideline,¹⁹ as summarized below.

Primary indications for fecal microbiota transplantation

• Recurrent C difficile infection—at least three episodes of mild to moderate C difficile infection and failure of a 6- to 8-week taper with vancomycin with or without an alternative antibiotic such as rifaximin or nitazoxanide, or at least two episodes of severe C difficile infection resulting in hospitalization and associated with significant morbidity
• Mild to moderate C difficile infection not responding to standard therapy for at least 1 week
• Severe or fulminant C difficile colitis that has not responded to standard therapy after 48 hours.

Who is a likely donor?

The gut microbiota is continuously replenished with bacteria from the environment in which we live, and we constantly acquire organisms from people who live in that same environment. Hence, the preferred donor is someone who has intimate physical contact with the recipient.^33,43,44 The preferred stool donor (in order of preference) is a spouse or significant partner, a family household member, or any other healthy donor.^26,36

Who should not be a donor?

It is the responsibility of the physician performing the fecal microbiota transplantation to make sure that the possibility of transmitting disease to the recipient is minimized. Extensive history-taking and physical examination must never be omitted, since not all diseases or conditions can be detected by laboratory screening alone, especially if testing was done during the early stage or window period of a given disease.¹⁹ Nevertheless, the donor’s blood and stool should be screened for transmissible diseases such as human immunodeficiency virus (HIV), hepatitis, syphilis, enteric bacteria, parasites, and C difficile.

The recipient has the option to be tested for transmissible diseases such as HIV and hepatitis in order to avoid future questions about transmission after fecal microbiota transplantation. A positive screening test must always be verified with confirmatory testing.¹⁹

Table 2 summarizes the exclusion criteria and screening tests performed for donors according to the practice guidelines for fecal microbiota transplantation formulated by Bakken et al.¹⁹

Preprocedure instructions and stool preparation

The physician should orient both the donor and recipient regarding “do’s and don’ts” before fecal microbiota transplantation. Table 3 summarizes the preprocedure instructions and steps for stool preparation.

Route of administration

The route of administration may vary depending on the clinical situation. Upper-gastrointestinal administration is performed via nasogastric or nasojejunal tube or gastroscopy. Lower-gastrointestinal administration is performed via colonoscopy (the route of choice) or retention enema.

The upper-gastrointestinal route (nasogastric tube, jejunal catheter, or gastroscope). The nasogastric or nasojejunal tube or gastroscope is inserted into the upper-gastrointestinal tract, and positioning is confirmed by radiography. From 25 to 50 mL of stool suspension is drawn up in a syringe and instilled into the tubing followed by flushing with 25 mL of normal saline.²⁶ Immediately after instillation, the tube is removed and the patient is allowed to go home and continue with his or her usual diet.

This approach is easier to perform, costs less, and poses lower risk of intestinal perforation than the colonoscopic approach. Disadvantages include the possibility that stool suspension may not reach distal areas of the colon, especially in patients with ileus and small-bowel obstruction. There is also a higher risk of bacterial overgrowth in elderly patients who have lower gastric acid levels.³³

The lower-gastrointestinal route (colonoscopy, retention enema). Colonoscopy is currently considered the first-line approach for fecal microbiota transplantation.⁴⁵ After giving informed consent, the patient undergoes standard colonoscopy under sedation. An initial colonoscopic examination is performed, and biopsy specimans are obtained if necessary. Approximately 20 mL of stool suspension is drawn up in a syringe and injected via the biopsy channel of the colonoscope every 5 to 10 cm as the scope is withdrawn, for a total volume of 250 to 500 mL.^19,27 The patient should be advised to refrain from defecating for 30 to 45 minutes after fecal microbiota transplantation.⁴⁶

This approach allows direct visualization of the entire colon, allowing instillation of stool suspension in certain areas where C difficile may predominate or hide (eg, in diverticuli).^27,47 One disadvantage to this route of administration is the risk of colon perforation, especially if the patient has toxic colitis.

Instillation via retention enema may be done at home with a standard enema kit.³² Disadvantages include the need for multiple instillations over 3 to 5 days,³⁶ back-leakage of stool suspension causing discomfort to patients, and stool suspension reaching only to the splenic flexure.⁴⁸

MEASUREMENT OF OUTCOME

Fecal microbiota transplantation is considered successful if symptoms resolve and there is no relapse within 8 weeks. Testing for C difficile in asymptomatic patients is not recommended since patients can be colonized with C difficile without necessarily developing disease.¹⁹ There is currently no consensus on treatment recommendations for patients who do not respond to fecal microbiota transplantation, although some reports showed resolution of diarrhea after a repeat 2-week standard course of oral vancomycin²⁶ or repeated instillation of feces collected from new donors.⁴⁹

IS IT READY FOR PRIME TIME?

Fecal microbiota transplantation has been used primarily as an alternative treatment for recurrent C difficile infection, although other indications for its use are currently being identified and studied. This procedure is now being done in several specialized centers in the United States and abroad, and although the protocol may vary by institution, the clinical outcomes have been consistently promising.

The Fecal Therapy to Eliminate Associated Long-standing Diarrhea (FECAL) trial, currently underway, is the first randomized trial to assess the efficacy of fecal microbiota transplantation for treatment of recurrent C difficile infection.⁵⁰ Clinical trials such as this one should satisfy our doubts about the efficacy of fecal microbiota transplantation and hopefully pave the way for its application in the near future.

An increasing number of patients are learning to overcome the “yuck factor” associated with fecal microbiota transplantation once they understand its safety and benefits.⁵¹ Moreover, the Human Microbiome Project is attempting to identify specific organisms in stool that may specifically treat C difficile infection, hence eliminating the need for whole-stool transplantation in the near future. Although fecal microbiota transplantation is still in its infancy, its low cost, safety, and effectiveness in treating recurrent C difficile infection will likely lead to the procedure becoming widely adopted in mainstream clinical practice.

Editor’s note: On January 16, 2013, after this article was completed, a randomized controlled trial of fecal microbiota transplantation was published in the New England Journal of Medicine. That trial, “Duodenal infusion of donor feces for recurrent Clostridium difficile,” found: “The infusion of donor feces was significantly more effective for the treatment of recurrent C difficile infection than the use of vancomycin.” The study is available online at http://www.nejm.org/doi/full/10.1056/NEJMoa1205037 (subscription required).