Case Reports

Phenylephrine, a sympathomimetic drug, is commonly used in eye exams to dilate the pupil of the eye and to differentiate scleritis from episcleritis. Common adverse effects (AEs) of phenylephrine include subjective burning, stinging with lacrimation, rebound hyperemia, and liberation of iris pigment into the anterior chamber. Less common, systemic AEs include tachycardia and elevation of systemic blood pressure. Although instances of allergic reactions are rare, phenylephrine has been reported to cause contact dermatitis, blepharoconjunctivitis, and as in this case, keratoconjunctivitis.

Case Report

An 83-year-old white male presented for a red eye evaluation 2 days after having undergone a comprehensive eye exam with dilation at the Malcom Randall VAMC clinic in Gainesville, Florida. The patient reported onset of blurred vision, which he described as looking through a fog. He further compared the feeling to pins sticking in his eyes. The patient noted he had experienced similar symptoms on a few other occasions following eye exams. At the most recent eye exam, proparacaine and fluorescein had been used for tonometry, and phenylephrine 2.5% and tropicamide 0.5% had been used for pupillary dilation.

The patient’s best-corrected visual acuity was counting fingers at 2 feet in the right eye (OD) and left eye (OS). The best-corrected visual acuity 2 days prior had been 20/20 OD and OS. Pupils and extraocular motilities were unremarkable. Intraocular pressures were not obtained due to concern for a possible adverse reaction to proparacaine.

Slit-lamp evaluation revealed the lids to be lax, erythematous, and edematous in both eyes (Figure 1).

The initial diagnosis was acute chemical conjunctivitis most likely due to an AE to proparacaine. The plan was to start the patient on antibiotic eye drops qid OU, prednisolone qid OU, and artificial tears every hour OU. The patient was scheduled to return to clinic 4 days later for an anterior segment follow-up.

At the follow-up visit, the patient reported significant visual improvement. His best-corrected visual acuity was 20/40-2 without improvement on pinhole OD and 20/50-2 with improvement to 20/30+ on pinhole OS. Slit-lamp evaluation revealed 1+ bulbar conjunctival injection OU, intact corneal epithelium OU, and no cells or flare in the anterior chambers OU. Due to improving punctate epitheliopathy, the frequency of the antibiotic drops, the prednisolone, and the artificial tears was reduced to bid. After 3 days, he was instructed to discontinue them. The patient was scheduled to return in 2 weeks for an anterior segment follow-up.

At the next follow-up visit, the patient reported that his vision had returned to normal, and he had no further ocular AEs. His best-corrected visual acuity was 20/20-2 OD and 20/20 OS. Slit-lamp evaluation revealed mild blepharitis OU, trace bulbar conjunctival injection OU, and complete resolution of the keratitis OU. The assessment was acute allergic conjunctivitis thought to be secondary to an AE to proparacaine OU, yet the need to rule out hypersensitivity to tropicamide and/or phenylephrine remained. The plan was to educate the patient of the possibility of allergic reaction on future visits and to recommend continued use of artificial tears as needed.

Through a careful and extensive chart review of all past visits, it was suspected that phenylephrine might be to blame rather than proparacaine. At the subsequent visit, the patient agreed to undergo testing to determine the culprit via instillation of proparacaine in one eye and tropicamide in the other. The patient had no reaction to either drop (checked 45 minutes after instillation and the following day). By process of elimination, phenylephrine was determined to be the offending agent.

Discussion

Following a thorough review of the patient’s chart, it was found that on other occasions he had presented with suspected allergic reactions following routine eye examinations. The patient reported he had experienced a reaction in 2007 but could not recall what drops were instilled in his eyes at the time. In addition, there was no documentation in his medical record of the subsequent reaction following that visit. Another reaction occurred in July 2010 with instillation of tropicamide 1%, phenylephrine 2.5%, and Fluress (fluorescein sodium and benoxinate hydrochloride ophthalmic solution USP). In October 2013, when tropicamide 0.5%, proparacaine, and fluorescein strips were instilled, there was no reaction. The next reaction occurred in October 2014, when tropicamide 0.5%, phenylephrine 2.5%, proparacaine, and fluorescein strips were instilled.

This careful review of past exam notes revealed that phenylephrine and Fluress were the only drops that had not been instilled at the October 2013 visit when no AE was reported. However, Fluress was an unlikely culprit since it was not instilled in October 2014, and the patient still experienced an AE. Therefore, the agent most likely responsible for the allergic reaction in the patient, as confirmed by a review of the past notes and by the aforementioned pharmacologic test, was deemed to be phenylephrine (Table).

Adverse reactions to topical ocular medications and specifically to diagnostic eye drops have long been recognized. Mathias, Camarasa, Barber, Ducombs, and Monsálvezhave reported on variations of conjunctivitis and periorbital erythema with positive patch testing to phenylephrine.^1-5 Geyer and colleagues reported on a study of 21 patients who had blepharoconjunctivitis after instillation of phenylephrine.⁶ In this case study patient, severe keratoconjunctivitis was the clinical manifestation observed.

Villarreal and colleagues studied 31 patients who had a previous reaction to mydriatic drops. The study found that phenylephrine was the drug that most frequently caused an AE (93.5%).⁷ One patient reacted to the preservative thimerosal, and 1 patient reacted to benoxiprocaine. Tropicamide was demonstrated to be very well tolerated as none of the patients tested positive on either the patch test or the pharmacologic test.

Tropicamide is a nonselective muscarinic antagonist commonly used for mydriasis due to its fast onset and short duration.⁸ Adverse reactions to tropicamide are rare. Three studies reported on patients who had a positive patch test to tropicamide.^9-11 However, the reaction was not provoked by direct instillation of tropicamide into the eye.

Common in-office topical anesthetics, proparacaine, tetracaine, benoxinate, and lidocaine also can cause AEs. Corneal toxicity is a well-known complication with topical anesthetic abuse, whereas allergic reactions are considered rare. The most common symptoms include stingingand discomfort upon instillation. Common signs include punctate corneal epithelial erosionsresulting indirectly from a decrease in reflex tearing, infrequent blinking, and increased tear evaporation.¹² Topical anesthetics also inhibit the migration of corneal epithelial cells and cause direct damage to the cells that are present, leading to impaired healing and epithelial defects.¹³

Manifestations of allergic reaction to topical anesthetics can include conjunctival hyperemia and edema, edematous eyelids, and lacrimation. One published case described a 60-year-old woman who developed eczematous dermatitis of the eyelids after ophthalmic anesthetic drops were instilled prior to laser surgery. Patch testing showed a positive response to benzocaine 5%, proparacaine, and tetracaine 0.5%.¹⁴

Preservatives, in general, can cause an allergic reaction. Benzalkonium chloride’s (BAK) cytotoxic sequelae include possible trabecular cell death in glaucoma patients, disruption of tear film stability (even at low concentrations), and immune-allergenic properties. One article reported BAK as one of the 30 most frequent allergens causing allergic periorbital dermatitis.¹⁵ Benzalkonium chloride is used in most brands of phenylephrine. However, preservatives in this patient’s case were ruled out as instigating agents since both phenylephrine and tropicamide contain the same preservative, BAK 0.01%, yet this patient did not develop a reaction to tropicamide when used without phenylephrine. Expired medications also were not considered to be a factor as none of the medications used on the patient were indeed expired (the Malcom Randall VAMC clinic maintains a strict policy of discarding medications 28 days after being opened).

Although uncommon, phenylephrine sometimes has been found to cause a type 4 hypersensitivity reaction, also known as cell-mediated or delayed-type hypersensitivity.¹⁶ First, helper T cells secrete cytokines. Activation of cytokines recruits and activates cytotoxic T cells, monocytes, and macrophages, leading to inflammation of the surrounding tissue. Examples of cell-mediated hypersensitivity include reactions to the tuberculin skin test and to poison ivy.

Type 1 hypersensitivity reactions, also known as immediate or anaphylactic hypersensitivity reactions, are not triggered by phenylephrine. In this type of reaction, IgE binds to the mast cell on initial exposure to an allergen. On second exposure, the allergen binds to the IgE, causing the mast cell to release mediators of inflammation, triggering physiologic responses. Examples of this type of hypersensitivity include those seen with penicillin, bee stings, hay fever, bronchial asthma, and food allergies, for example, to shellfish.

A toxic reaction’s mechanism differs from that of a type 4 hypersensitivity reaction. Toxic reactions occur due to direct cytotoxicity of a drug caused by a low or high pH and either hyper- or hypo-osmolarity. Toxicity can lead to corneal and conjunctival cell necrosis or induce apoptosis, stimulating inflammatory reactions. Clinically, toxic reactions will present with follicles, whereas allergic reactions will present with papillae.

The definitive diagnostic methods used to determine the allergic agent causing ocular or periocular AEs are patch testing and conjunctival challenge.⁷ Mathias, Camarasa, Barber, Ducombs,and Monsálvezused patch testing to confirm phenylephrine as the allergic agent in their series of cases. Patch testing entails the application of a small amount of an allergic agent that is taped onto the skin. The allergic agent is confirmed if the patient has a dermal reaction, wherein the area patched will become erythematous. When patch testing is negative or inconclusive, a conjunctival challenge is performed by instillation of the suspected allergic agent into the eye with subsequent observation to determine whether a reaction occurs. The sequelae found in Villarreal’s study included itching, lacrimation, edema, erythema, and sometimes blepharitis.⁷

A direct conjunctival challenge with the suspected culprit was not pursued in this patient’s case due to the known severity of the potential resulting reaction. The authors instead chose an indirect method of determining the implicating agent and used the process of elimination to whittle down the most likely suspect. A challenge with the medications suspected not to be likely offenders was undertaken. This spared the patient a likely repeat of the AE he had just recovered from.

Management

Allergic reactions can resolve without medical intervention. The first step is to remove the allergen. For delayed hypersensitivity reactions, treatments may include topical decongestants, cool compresses, and corticosteroids.⁸ The treatment for immediate hypersensitivity reaction differs from that of delayed hypersensitivity reaction in that antihistamines are used.^17,18

This patient reported receiving no treatment for his ocular symptoms following eye examinations in the past, yet he experienced complete resolution after each AE. In this case, both a steroid and a prophylactic antibiotic to facilitate a more rapid improvement were used.

Conclusion

Although uncommon, cases of allergic reaction to phenylephrine can occur. The incidence of phenylephrine allergy is 0.6%.6 The case study patient presented with a severe keratoconjunctivitis following routine eye examination with an accompanying history of adverse ocular signs and symptoms following multiple past exams.

It is important for all eye care clinicians to realize that AEs to diagnostic eye drops are possible and can occur following the most routine of visits. Such reactions can be caused by dilating agents, anesthetics, or preservatives, and these may be allergic or toxic. Clinicians should take special care to identify the instigating agent, and if possible, to avoid using such agents on patients during future exams. Clinicians also should understand how best to manage iatrogenic AEs when they encounter them in order to restore a patient’s visual function as quickly as possible.

Phenylephrine, a sympathomimetic drug, is commonly used in eye exams to dilate the pupil of the eye and to differentiate scleritis from episcleritis. Common adverse effects (AEs) of phenylephrine include subjective burning, stinging with lacrimation, rebound hyperemia, and liberation of iris pigment into the anterior chamber. Less common, systemic AEs include tachycardia and elevation of systemic blood pressure. Although instances of allergic reactions are rare, phenylephrine has been reported to cause contact dermatitis, blepharoconjunctivitis, and as in this case, keratoconjunctivitis.

Case Report

An 83-year-old white male presented for a red eye evaluation 2 days after having undergone a comprehensive eye exam with dilation at the Malcom Randall VAMC clinic in Gainesville, Florida. The patient reported onset of blurred vision, which he described as looking through a fog. He further compared the feeling to pins sticking in his eyes. The patient noted he had experienced similar symptoms on a few other occasions following eye exams. At the most recent eye exam, proparacaine and fluorescein had been used for tonometry, and phenylephrine 2.5% and tropicamide 0.5% had been used for pupillary dilation.

The patient’s best-corrected visual acuity was counting fingers at 2 feet in the right eye (OD) and left eye (OS). The best-corrected visual acuity 2 days prior had been 20/20 OD and OS. Pupils and extraocular motilities were unremarkable. Intraocular pressures were not obtained due to concern for a possible adverse reaction to proparacaine.

Slit-lamp evaluation revealed the lids to be lax, erythematous, and edematous in both eyes (Figure 1).

The initial diagnosis was acute chemical conjunctivitis most likely due to an AE to proparacaine. The plan was to start the patient on antibiotic eye drops qid OU, prednisolone qid OU, and artificial tears every hour OU. The patient was scheduled to return to clinic 4 days later for an anterior segment follow-up.

At the follow-up visit, the patient reported significant visual improvement. His best-corrected visual acuity was 20/40-2 without improvement on pinhole OD and 20/50-2 with improvement to 20/30+ on pinhole OS. Slit-lamp evaluation revealed 1+ bulbar conjunctival injection OU, intact corneal epithelium OU, and no cells or flare in the anterior chambers OU. Due to improving punctate epitheliopathy, the frequency of the antibiotic drops, the prednisolone, and the artificial tears was reduced to bid. After 3 days, he was instructed to discontinue them. The patient was scheduled to return in 2 weeks for an anterior segment follow-up.

At the next follow-up visit, the patient reported that his vision had returned to normal, and he had no further ocular AEs. His best-corrected visual acuity was 20/20-2 OD and 20/20 OS. Slit-lamp evaluation revealed mild blepharitis OU, trace bulbar conjunctival injection OU, and complete resolution of the keratitis OU. The assessment was acute allergic conjunctivitis thought to be secondary to an AE to proparacaine OU, yet the need to rule out hypersensitivity to tropicamide and/or phenylephrine remained. The plan was to educate the patient of the possibility of allergic reaction on future visits and to recommend continued use of artificial tears as needed.

Through a careful and extensive chart review of all past visits, it was suspected that phenylephrine might be to blame rather than proparacaine. At the subsequent visit, the patient agreed to undergo testing to determine the culprit via instillation of proparacaine in one eye and tropicamide in the other. The patient had no reaction to either drop (checked 45 minutes after instillation and the following day). By process of elimination, phenylephrine was determined to be the offending agent.

Discussion

Following a thorough review of the patient’s chart, it was found that on other occasions he had presented with suspected allergic reactions following routine eye examinations. The patient reported he had experienced a reaction in 2007 but could not recall what drops were instilled in his eyes at the time. In addition, there was no documentation in his medical record of the subsequent reaction following that visit. Another reaction occurred in July 2010 with instillation of tropicamide 1%, phenylephrine 2.5%, and Fluress (fluorescein sodium and benoxinate hydrochloride ophthalmic solution USP). In October 2013, when tropicamide 0.5%, proparacaine, and fluorescein strips were instilled, there was no reaction. The next reaction occurred in October 2014, when tropicamide 0.5%, phenylephrine 2.5%, proparacaine, and fluorescein strips were instilled.

This careful review of past exam notes revealed that phenylephrine and Fluress were the only drops that had not been instilled at the October 2013 visit when no AE was reported. However, Fluress was an unlikely culprit since it was not instilled in October 2014, and the patient still experienced an AE. Therefore, the agent most likely responsible for the allergic reaction in the patient, as confirmed by a review of the past notes and by the aforementioned pharmacologic test, was deemed to be phenylephrine (Table).

Adverse reactions to topical ocular medications and specifically to diagnostic eye drops have long been recognized. Mathias, Camarasa, Barber, Ducombs, and Monsálvezhave reported on variations of conjunctivitis and periorbital erythema with positive patch testing to phenylephrine.^1-5 Geyer and colleagues reported on a study of 21 patients who had blepharoconjunctivitis after instillation of phenylephrine.⁶ In this case study patient, severe keratoconjunctivitis was the clinical manifestation observed.

Villarreal and colleagues studied 31 patients who had a previous reaction to mydriatic drops. The study found that phenylephrine was the drug that most frequently caused an AE (93.5%).⁷ One patient reacted to the preservative thimerosal, and 1 patient reacted to benoxiprocaine. Tropicamide was demonstrated to be very well tolerated as none of the patients tested positive on either the patch test or the pharmacologic test.

Tropicamide is a nonselective muscarinic antagonist commonly used for mydriasis due to its fast onset and short duration.⁸ Adverse reactions to tropicamide are rare. Three studies reported on patients who had a positive patch test to tropicamide.^9-11 However, the reaction was not provoked by direct instillation of tropicamide into the eye.

Common in-office topical anesthetics, proparacaine, tetracaine, benoxinate, and lidocaine also can cause AEs. Corneal toxicity is a well-known complication with topical anesthetic abuse, whereas allergic reactions are considered rare. The most common symptoms include stingingand discomfort upon instillation. Common signs include punctate corneal epithelial erosionsresulting indirectly from a decrease in reflex tearing, infrequent blinking, and increased tear evaporation.¹² Topical anesthetics also inhibit the migration of corneal epithelial cells and cause direct damage to the cells that are present, leading to impaired healing and epithelial defects.¹³

Manifestations of allergic reaction to topical anesthetics can include conjunctival hyperemia and edema, edematous eyelids, and lacrimation. One published case described a 60-year-old woman who developed eczematous dermatitis of the eyelids after ophthalmic anesthetic drops were instilled prior to laser surgery. Patch testing showed a positive response to benzocaine 5%, proparacaine, and tetracaine 0.5%.¹⁴

Preservatives, in general, can cause an allergic reaction. Benzalkonium chloride’s (BAK) cytotoxic sequelae include possible trabecular cell death in glaucoma patients, disruption of tear film stability (even at low concentrations), and immune-allergenic properties. One article reported BAK as one of the 30 most frequent allergens causing allergic periorbital dermatitis.¹⁵ Benzalkonium chloride is used in most brands of phenylephrine. However, preservatives in this patient’s case were ruled out as instigating agents since both phenylephrine and tropicamide contain the same preservative, BAK 0.01%, yet this patient did not develop a reaction to tropicamide when used without phenylephrine. Expired medications also were not considered to be a factor as none of the medications used on the patient were indeed expired (the Malcom Randall VAMC clinic maintains a strict policy of discarding medications 28 days after being opened).

Although uncommon, phenylephrine sometimes has been found to cause a type 4 hypersensitivity reaction, also known as cell-mediated or delayed-type hypersensitivity.¹⁶ First, helper T cells secrete cytokines. Activation of cytokines recruits and activates cytotoxic T cells, monocytes, and macrophages, leading to inflammation of the surrounding tissue. Examples of cell-mediated hypersensitivity include reactions to the tuberculin skin test and to poison ivy.

Type 1 hypersensitivity reactions, also known as immediate or anaphylactic hypersensitivity reactions, are not triggered by phenylephrine. In this type of reaction, IgE binds to the mast cell on initial exposure to an allergen. On second exposure, the allergen binds to the IgE, causing the mast cell to release mediators of inflammation, triggering physiologic responses. Examples of this type of hypersensitivity include those seen with penicillin, bee stings, hay fever, bronchial asthma, and food allergies, for example, to shellfish.

A toxic reaction’s mechanism differs from that of a type 4 hypersensitivity reaction. Toxic reactions occur due to direct cytotoxicity of a drug caused by a low or high pH and either hyper- or hypo-osmolarity. Toxicity can lead to corneal and conjunctival cell necrosis or induce apoptosis, stimulating inflammatory reactions. Clinically, toxic reactions will present with follicles, whereas allergic reactions will present with papillae.

The definitive diagnostic methods used to determine the allergic agent causing ocular or periocular AEs are patch testing and conjunctival challenge.⁷ Mathias, Camarasa, Barber, Ducombs,and Monsálvezused patch testing to confirm phenylephrine as the allergic agent in their series of cases. Patch testing entails the application of a small amount of an allergic agent that is taped onto the skin. The allergic agent is confirmed if the patient has a dermal reaction, wherein the area patched will become erythematous. When patch testing is negative or inconclusive, a conjunctival challenge is performed by instillation of the suspected allergic agent into the eye with subsequent observation to determine whether a reaction occurs. The sequelae found in Villarreal’s study included itching, lacrimation, edema, erythema, and sometimes blepharitis.⁷

A direct conjunctival challenge with the suspected culprit was not pursued in this patient’s case due to the known severity of the potential resulting reaction. The authors instead chose an indirect method of determining the implicating agent and used the process of elimination to whittle down the most likely suspect. A challenge with the medications suspected not to be likely offenders was undertaken. This spared the patient a likely repeat of the AE he had just recovered from.

Management

Allergic reactions can resolve without medical intervention. The first step is to remove the allergen. For delayed hypersensitivity reactions, treatments may include topical decongestants, cool compresses, and corticosteroids.⁸ The treatment for immediate hypersensitivity reaction differs from that of delayed hypersensitivity reaction in that antihistamines are used.^17,18

This patient reported receiving no treatment for his ocular symptoms following eye examinations in the past, yet he experienced complete resolution after each AE. In this case, both a steroid and a prophylactic antibiotic to facilitate a more rapid improvement were used.

Conclusion

Although uncommon, cases of allergic reaction to phenylephrine can occur. The incidence of phenylephrine allergy is 0.6%.6 The case study patient presented with a severe keratoconjunctivitis following routine eye examination with an accompanying history of adverse ocular signs and symptoms following multiple past exams.

It is important for all eye care clinicians to realize that AEs to diagnostic eye drops are possible and can occur following the most routine of visits. Such reactions can be caused by dilating agents, anesthetics, or preservatives, and these may be allergic or toxic. Clinicians should take special care to identify the instigating agent, and if possible, to avoid using such agents on patients during future exams. Clinicians also should understand how best to manage iatrogenic AEs when they encounter them in order to restore a patient’s visual function as quickly as possible.

Phenylephrine, a sympathomimetic drug, is commonly used in eye exams to dilate the pupil of the eye and to differentiate scleritis from episcleritis. Common adverse effects (AEs) of phenylephrine include subjective burning, stinging with lacrimation, rebound hyperemia, and liberation of iris pigment into the anterior chamber. Less common, systemic AEs include tachycardia and elevation of systemic blood pressure. Although instances of allergic reactions are rare, phenylephrine has been reported to cause contact dermatitis, blepharoconjunctivitis, and as in this case, keratoconjunctivitis.

Case Report

An 83-year-old white male presented for a red eye evaluation 2 days after having undergone a comprehensive eye exam with dilation at the Malcom Randall VAMC clinic in Gainesville, Florida. The patient reported onset of blurred vision, which he described as looking through a fog. He further compared the feeling to pins sticking in his eyes. The patient noted he had experienced similar symptoms on a few other occasions following eye exams. At the most recent eye exam, proparacaine and fluorescein had been used for tonometry, and phenylephrine 2.5% and tropicamide 0.5% had been used for pupillary dilation.

The patient’s best-corrected visual acuity was counting fingers at 2 feet in the right eye (OD) and left eye (OS). The best-corrected visual acuity 2 days prior had been 20/20 OD and OS. Pupils and extraocular motilities were unremarkable. Intraocular pressures were not obtained due to concern for a possible adverse reaction to proparacaine.

Slit-lamp evaluation revealed the lids to be lax, erythematous, and edematous in both eyes (Figure 1).

The initial diagnosis was acute chemical conjunctivitis most likely due to an AE to proparacaine. The plan was to start the patient on antibiotic eye drops qid OU, prednisolone qid OU, and artificial tears every hour OU. The patient was scheduled to return to clinic 4 days later for an anterior segment follow-up.

At the follow-up visit, the patient reported significant visual improvement. His best-corrected visual acuity was 20/40-2 without improvement on pinhole OD and 20/50-2 with improvement to 20/30+ on pinhole OS. Slit-lamp evaluation revealed 1+ bulbar conjunctival injection OU, intact corneal epithelium OU, and no cells or flare in the anterior chambers OU. Due to improving punctate epitheliopathy, the frequency of the antibiotic drops, the prednisolone, and the artificial tears was reduced to bid. After 3 days, he was instructed to discontinue them. The patient was scheduled to return in 2 weeks for an anterior segment follow-up.

At the next follow-up visit, the patient reported that his vision had returned to normal, and he had no further ocular AEs. His best-corrected visual acuity was 20/20-2 OD and 20/20 OS. Slit-lamp evaluation revealed mild blepharitis OU, trace bulbar conjunctival injection OU, and complete resolution of the keratitis OU. The assessment was acute allergic conjunctivitis thought to be secondary to an AE to proparacaine OU, yet the need to rule out hypersensitivity to tropicamide and/or phenylephrine remained. The plan was to educate the patient of the possibility of allergic reaction on future visits and to recommend continued use of artificial tears as needed.

Through a careful and extensive chart review of all past visits, it was suspected that phenylephrine might be to blame rather than proparacaine. At the subsequent visit, the patient agreed to undergo testing to determine the culprit via instillation of proparacaine in one eye and tropicamide in the other. The patient had no reaction to either drop (checked 45 minutes after instillation and the following day). By process of elimination, phenylephrine was determined to be the offending agent.

Discussion

Following a thorough review of the patient’s chart, it was found that on other occasions he had presented with suspected allergic reactions following routine eye examinations. The patient reported he had experienced a reaction in 2007 but could not recall what drops were instilled in his eyes at the time. In addition, there was no documentation in his medical record of the subsequent reaction following that visit. Another reaction occurred in July 2010 with instillation of tropicamide 1%, phenylephrine 2.5%, and Fluress (fluorescein sodium and benoxinate hydrochloride ophthalmic solution USP). In October 2013, when tropicamide 0.5%, proparacaine, and fluorescein strips were instilled, there was no reaction. The next reaction occurred in October 2014, when tropicamide 0.5%, phenylephrine 2.5%, proparacaine, and fluorescein strips were instilled.

This careful review of past exam notes revealed that phenylephrine and Fluress were the only drops that had not been instilled at the October 2013 visit when no AE was reported. However, Fluress was an unlikely culprit since it was not instilled in October 2014, and the patient still experienced an AE. Therefore, the agent most likely responsible for the allergic reaction in the patient, as confirmed by a review of the past notes and by the aforementioned pharmacologic test, was deemed to be phenylephrine (Table).

Adverse reactions to topical ocular medications and specifically to diagnostic eye drops have long been recognized. Mathias, Camarasa, Barber, Ducombs, and Monsálvezhave reported on variations of conjunctivitis and periorbital erythema with positive patch testing to phenylephrine.^1-5 Geyer and colleagues reported on a study of 21 patients who had blepharoconjunctivitis after instillation of phenylephrine.⁶ In this case study patient, severe keratoconjunctivitis was the clinical manifestation observed.

Villarreal and colleagues studied 31 patients who had a previous reaction to mydriatic drops. The study found that phenylephrine was the drug that most frequently caused an AE (93.5%).⁷ One patient reacted to the preservative thimerosal, and 1 patient reacted to benoxiprocaine. Tropicamide was demonstrated to be very well tolerated as none of the patients tested positive on either the patch test or the pharmacologic test.

Tropicamide is a nonselective muscarinic antagonist commonly used for mydriasis due to its fast onset and short duration.⁸ Adverse reactions to tropicamide are rare. Three studies reported on patients who had a positive patch test to tropicamide.^9-11 However, the reaction was not provoked by direct instillation of tropicamide into the eye.

Common in-office topical anesthetics, proparacaine, tetracaine, benoxinate, and lidocaine also can cause AEs. Corneal toxicity is a well-known complication with topical anesthetic abuse, whereas allergic reactions are considered rare. The most common symptoms include stingingand discomfort upon instillation. Common signs include punctate corneal epithelial erosionsresulting indirectly from a decrease in reflex tearing, infrequent blinking, and increased tear evaporation.¹² Topical anesthetics also inhibit the migration of corneal epithelial cells and cause direct damage to the cells that are present, leading to impaired healing and epithelial defects.¹³

Manifestations of allergic reaction to topical anesthetics can include conjunctival hyperemia and edema, edematous eyelids, and lacrimation. One published case described a 60-year-old woman who developed eczematous dermatitis of the eyelids after ophthalmic anesthetic drops were instilled prior to laser surgery. Patch testing showed a positive response to benzocaine 5%, proparacaine, and tetracaine 0.5%.¹⁴

Preservatives, in general, can cause an allergic reaction. Benzalkonium chloride’s (BAK) cytotoxic sequelae include possible trabecular cell death in glaucoma patients, disruption of tear film stability (even at low concentrations), and immune-allergenic properties. One article reported BAK as one of the 30 most frequent allergens causing allergic periorbital dermatitis.¹⁵ Benzalkonium chloride is used in most brands of phenylephrine. However, preservatives in this patient’s case were ruled out as instigating agents since both phenylephrine and tropicamide contain the same preservative, BAK 0.01%, yet this patient did not develop a reaction to tropicamide when used without phenylephrine. Expired medications also were not considered to be a factor as none of the medications used on the patient were indeed expired (the Malcom Randall VAMC clinic maintains a strict policy of discarding medications 28 days after being opened).

Although uncommon, phenylephrine sometimes has been found to cause a type 4 hypersensitivity reaction, also known as cell-mediated or delayed-type hypersensitivity.¹⁶ First, helper T cells secrete cytokines. Activation of cytokines recruits and activates cytotoxic T cells, monocytes, and macrophages, leading to inflammation of the surrounding tissue. Examples of cell-mediated hypersensitivity include reactions to the tuberculin skin test and to poison ivy.

Type 1 hypersensitivity reactions, also known as immediate or anaphylactic hypersensitivity reactions, are not triggered by phenylephrine. In this type of reaction, IgE binds to the mast cell on initial exposure to an allergen. On second exposure, the allergen binds to the IgE, causing the mast cell to release mediators of inflammation, triggering physiologic responses. Examples of this type of hypersensitivity include those seen with penicillin, bee stings, hay fever, bronchial asthma, and food allergies, for example, to shellfish.

A toxic reaction’s mechanism differs from that of a type 4 hypersensitivity reaction. Toxic reactions occur due to direct cytotoxicity of a drug caused by a low or high pH and either hyper- or hypo-osmolarity. Toxicity can lead to corneal and conjunctival cell necrosis or induce apoptosis, stimulating inflammatory reactions. Clinically, toxic reactions will present with follicles, whereas allergic reactions will present with papillae.

The definitive diagnostic methods used to determine the allergic agent causing ocular or periocular AEs are patch testing and conjunctival challenge.⁷ Mathias, Camarasa, Barber, Ducombs,and Monsálvezused patch testing to confirm phenylephrine as the allergic agent in their series of cases. Patch testing entails the application of a small amount of an allergic agent that is taped onto the skin. The allergic agent is confirmed if the patient has a dermal reaction, wherein the area patched will become erythematous. When patch testing is negative or inconclusive, a conjunctival challenge is performed by instillation of the suspected allergic agent into the eye with subsequent observation to determine whether a reaction occurs. The sequelae found in Villarreal’s study included itching, lacrimation, edema, erythema, and sometimes blepharitis.⁷

A direct conjunctival challenge with the suspected culprit was not pursued in this patient’s case due to the known severity of the potential resulting reaction. The authors instead chose an indirect method of determining the implicating agent and used the process of elimination to whittle down the most likely suspect. A challenge with the medications suspected not to be likely offenders was undertaken. This spared the patient a likely repeat of the AE he had just recovered from.

Management

Allergic reactions can resolve without medical intervention. The first step is to remove the allergen. For delayed hypersensitivity reactions, treatments may include topical decongestants, cool compresses, and corticosteroids.⁸ The treatment for immediate hypersensitivity reaction differs from that of delayed hypersensitivity reaction in that antihistamines are used.^17,18

This patient reported receiving no treatment for his ocular symptoms following eye examinations in the past, yet he experienced complete resolution after each AE. In this case, both a steroid and a prophylactic antibiotic to facilitate a more rapid improvement were used.

Conclusion

Although uncommon, cases of allergic reaction to phenylephrine can occur. The incidence of phenylephrine allergy is 0.6%.6 The case study patient presented with a severe keratoconjunctivitis following routine eye examination with an accompanying history of adverse ocular signs and symptoms following multiple past exams.

It is important for all eye care clinicians to realize that AEs to diagnostic eye drops are possible and can occur following the most routine of visits. Such reactions can be caused by dilating agents, anesthetics, or preservatives, and these may be allergic or toxic. Clinicians should take special care to identify the instigating agent, and if possible, to avoid using such agents on patients during future exams. Clinicians also should understand how best to manage iatrogenic AEs when they encounter them in order to restore a patient’s visual function as quickly as possible.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Lupus erythematosus tumidus (LET) is a relatively rare condition but may simply be underdiagnosed in the literature. It presents as urticarialike papules and plaques in sun-exposed areas, characterized by induration and erythema. Lesions occur on the face, neck, upper extremities, and trunk and heal without scarring.^1,2 Rarely, lesions can show fine scaling and associated pruritus, but most often the lesions are asymptomatic.³

Case Report

A 45-year-old woman presented with 2 asymptomatic self-described bald spots on the top of the head of 2 months’ duration. The patient denied prior treatment of the lesions and noted one patch was resolving. She reported no involvement of the eyebrows, eyelashes, and axillary and pubic hair. A review of systems was negative. The patient denied personal or family history of lupus, thyroid disease, or vitiligo.

Clinical examination revealed a 1.1-cm round patch of nonscarring alopecia on the right vertex scalp and a 0.9-cm round patch of nonscarring alopecia with moderate hair regrowth on the left vertex scalp. There was no erythema, scaling, or induration. The rest of the scalp was normal in appearance and the eyebrows and eyelashes were uninvolved. The patient was diagnosed with alopecia areata and was treated with 10 mg/mL of intralesional triamcinolone once monthly for 4 months.

The patient initially showed improvement with moderate hair regrowth. After 4 months of treatment, she developed 3 new 1- to 1.5-cm erythematous alopecic patches on the vertex scalp and had worsening in the initial patches (Figure 1). Given the resistance to standard therapy and the onset of multiple new areas with evidence of inflammatory involvement, a punch biopsy was performed. Histopathologic examination revealed a fairly unremarkable epidermis and a dense dermal inflammatory infiltrate that was present both in the superficial and deep dermis (Figure 2). The inflammatory cells, which appeared to be predominantly comprised of lymphocytes, had a predilection for the vasculature but also were observed within the interstitial dermis. Additionally, mucin appeared to be slightly increased in the deep dermis. The lymphocytic phenotype was confirmed by immunohistochemical studies for CD20 and CD3. The most likely possibilities for this reaction pattern were LET, Jessner lymphocytic infiltrate of the skin (JLIS), gyrate erythema, and lymphoma; however, the immunohistochemical studies effectively ruled out lymphoma. Additionally, there was pronounced dermal mucin noted in the specimen. The patient was diagnosed with LET of the scalp based on the constellation of findings.

Comment

The classification of LET as a single unique entity or disease process sui generis has been in flux in the last decade. Its similarities to JLIS and other forms of chronic cutaneous lupus erythematosus (CCLE) have brought debate.^4-6 In 1930, Gougerot and Burnier⁷ documented the first case of LET in the literature, describing smooth, infiltrated, erythematous lesions with no desquamation or other superficial changes seen in 5 patients.

In 2000, interest in LET and other forms of CCLE was increasing, and reports in the literature paralleled. That year, Kuhn et al⁴ reported 40 cases of LET, characterizing the clinical and histological features of each case to demonstrate that LET should be separate from other forms of CCLE. Until then, it is likely that many lesions that should have been classified as LET were instead classified as various forms of CCLE. The investigators maintained that LET also should be distinct from JLIS because it is associated with UV exposure.⁴ Kuhn et al⁸ reviewed phototesting in 60 patients with LET in 2001 and confirmed this subset was the most photosensitive type of lupus erythematosus.

In general, the histopathologic and immunohistochemical studies in LET and JLIS can be quite similar. Relatively distinguishing histopathologic findings in JLIS include no evidence of epidermal atrophy, basal vacuolar change, or follicular plugging, as well as negative immunofluorescence studies. Both entities show a predominantly T-cell population with a smaller component of B cells and thus a distinction cannot be made based on relative proportions of T and B cells in lesions.²

In 2003, Alexiades-Armenakas et al⁶ determined immunohistochemical criteria for LET, finding a predominance of T cells and more CD4 lymphocytes than CD8 lymphocytes with a mean ratio of roughly 3 to 1. Their study results maintained LET should be classified as a form of CCLE due to the chronicity of the lesions, the serologic profile with negative anti–double-stranded DNA, anticentromere, anti-Smith, anti-Ro/Sjögren syndrome antigen A, anti-La/Sjögren syndrome antigen B, and anti-nuclear ribonucleoprotein antibodies and the rare association with systemic disease.⁶ This conclusion was further solidified by a review published that same year citing unique histopathological features when compared to subacute cutaneous LE and discoid lupus erythematosus.⁵

This case illustrates the importance of histologic evaluation in determining the correct diagnosis in a patient with alopecia areata recalcitrant to treatment. Including LET in the differential of alopecic patches on the scalp could prove beneficial for patients, as LET responds well to antimalarial drugs and photoprotection.⁹ This patient had a normal antinuclear antibody panel and no signs or symptoms of systemic lupus. It was recommended that she avoid sun exposure and begin treatment with hydroxychloroquine but she declined. At a follow-up visit 6 months later she reported the lesions had improved, but a permanent wig had been sewn over the area, so it could not be examined.

Lupus erythematosus tumidus (LET) is a relatively rare condition but may simply be underdiagnosed in the literature. It presents as urticarialike papules and plaques in sun-exposed areas, characterized by induration and erythema. Lesions occur on the face, neck, upper extremities, and trunk and heal without scarring.^1,2 Rarely, lesions can show fine scaling and associated pruritus, but most often the lesions are asymptomatic.³

Case Report

A 45-year-old woman presented with 2 asymptomatic self-described bald spots on the top of the head of 2 months’ duration. The patient denied prior treatment of the lesions and noted one patch was resolving. She reported no involvement of the eyebrows, eyelashes, and axillary and pubic hair. A review of systems was negative. The patient denied personal or family history of lupus, thyroid disease, or vitiligo.

Clinical examination revealed a 1.1-cm round patch of nonscarring alopecia on the right vertex scalp and a 0.9-cm round patch of nonscarring alopecia with moderate hair regrowth on the left vertex scalp. There was no erythema, scaling, or induration. The rest of the scalp was normal in appearance and the eyebrows and eyelashes were uninvolved. The patient was diagnosed with alopecia areata and was treated with 10 mg/mL of intralesional triamcinolone once monthly for 4 months.

The patient initially showed improvement with moderate hair regrowth. After 4 months of treatment, she developed 3 new 1- to 1.5-cm erythematous alopecic patches on the vertex scalp and had worsening in the initial patches (Figure 1). Given the resistance to standard therapy and the onset of multiple new areas with evidence of inflammatory involvement, a punch biopsy was performed. Histopathologic examination revealed a fairly unremarkable epidermis and a dense dermal inflammatory infiltrate that was present both in the superficial and deep dermis (Figure 2). The inflammatory cells, which appeared to be predominantly comprised of lymphocytes, had a predilection for the vasculature but also were observed within the interstitial dermis. Additionally, mucin appeared to be slightly increased in the deep dermis. The lymphocytic phenotype was confirmed by immunohistochemical studies for CD20 and CD3. The most likely possibilities for this reaction pattern were LET, Jessner lymphocytic infiltrate of the skin (JLIS), gyrate erythema, and lymphoma; however, the immunohistochemical studies effectively ruled out lymphoma. Additionally, there was pronounced dermal mucin noted in the specimen. The patient was diagnosed with LET of the scalp based on the constellation of findings.

Comment

The classification of LET as a single unique entity or disease process sui generis has been in flux in the last decade. Its similarities to JLIS and other forms of chronic cutaneous lupus erythematosus (CCLE) have brought debate.^4-6 In 1930, Gougerot and Burnier⁷ documented the first case of LET in the literature, describing smooth, infiltrated, erythematous lesions with no desquamation or other superficial changes seen in 5 patients.

In 2000, interest in LET and other forms of CCLE was increasing, and reports in the literature paralleled. That year, Kuhn et al⁴ reported 40 cases of LET, characterizing the clinical and histological features of each case to demonstrate that LET should be separate from other forms of CCLE. Until then, it is likely that many lesions that should have been classified as LET were instead classified as various forms of CCLE. The investigators maintained that LET also should be distinct from JLIS because it is associated with UV exposure.⁴ Kuhn et al⁸ reviewed phototesting in 60 patients with LET in 2001 and confirmed this subset was the most photosensitive type of lupus erythematosus.

In general, the histopathologic and immunohistochemical studies in LET and JLIS can be quite similar. Relatively distinguishing histopathologic findings in JLIS include no evidence of epidermal atrophy, basal vacuolar change, or follicular plugging, as well as negative immunofluorescence studies. Both entities show a predominantly T-cell population with a smaller component of B cells and thus a distinction cannot be made based on relative proportions of T and B cells in lesions.²

In 2003, Alexiades-Armenakas et al⁶ determined immunohistochemical criteria for LET, finding a predominance of T cells and more CD4 lymphocytes than CD8 lymphocytes with a mean ratio of roughly 3 to 1. Their study results maintained LET should be classified as a form of CCLE due to the chronicity of the lesions, the serologic profile with negative anti–double-stranded DNA, anticentromere, anti-Smith, anti-Ro/Sjögren syndrome antigen A, anti-La/Sjögren syndrome antigen B, and anti-nuclear ribonucleoprotein antibodies and the rare association with systemic disease.⁶ This conclusion was further solidified by a review published that same year citing unique histopathological features when compared to subacute cutaneous LE and discoid lupus erythematosus.⁵

This case illustrates the importance of histologic evaluation in determining the correct diagnosis in a patient with alopecia areata recalcitrant to treatment. Including LET in the differential of alopecic patches on the scalp could prove beneficial for patients, as LET responds well to antimalarial drugs and photoprotection.⁹ This patient had a normal antinuclear antibody panel and no signs or symptoms of systemic lupus. It was recommended that she avoid sun exposure and begin treatment with hydroxychloroquine but she declined. At a follow-up visit 6 months later she reported the lesions had improved, but a permanent wig had been sewn over the area, so it could not be examined.

Lupus erythematosus tumidus (LET) is a relatively rare condition but may simply be underdiagnosed in the literature. It presents as urticarialike papules and plaques in sun-exposed areas, characterized by induration and erythema. Lesions occur on the face, neck, upper extremities, and trunk and heal without scarring.^1,2 Rarely, lesions can show fine scaling and associated pruritus, but most often the lesions are asymptomatic.³

Case Report

A 45-year-old woman presented with 2 asymptomatic self-described bald spots on the top of the head of 2 months’ duration. The patient denied prior treatment of the lesions and noted one patch was resolving. She reported no involvement of the eyebrows, eyelashes, and axillary and pubic hair. A review of systems was negative. The patient denied personal or family history of lupus, thyroid disease, or vitiligo.

Clinical examination revealed a 1.1-cm round patch of nonscarring alopecia on the right vertex scalp and a 0.9-cm round patch of nonscarring alopecia with moderate hair regrowth on the left vertex scalp. There was no erythema, scaling, or induration. The rest of the scalp was normal in appearance and the eyebrows and eyelashes were uninvolved. The patient was diagnosed with alopecia areata and was treated with 10 mg/mL of intralesional triamcinolone once monthly for 4 months.

The patient initially showed improvement with moderate hair regrowth. After 4 months of treatment, she developed 3 new 1- to 1.5-cm erythematous alopecic patches on the vertex scalp and had worsening in the initial patches (Figure 1). Given the resistance to standard therapy and the onset of multiple new areas with evidence of inflammatory involvement, a punch biopsy was performed. Histopathologic examination revealed a fairly unremarkable epidermis and a dense dermal inflammatory infiltrate that was present both in the superficial and deep dermis (Figure 2). The inflammatory cells, which appeared to be predominantly comprised of lymphocytes, had a predilection for the vasculature but also were observed within the interstitial dermis. Additionally, mucin appeared to be slightly increased in the deep dermis. The lymphocytic phenotype was confirmed by immunohistochemical studies for CD20 and CD3. The most likely possibilities for this reaction pattern were LET, Jessner lymphocytic infiltrate of the skin (JLIS), gyrate erythema, and lymphoma; however, the immunohistochemical studies effectively ruled out lymphoma. Additionally, there was pronounced dermal mucin noted in the specimen. The patient was diagnosed with LET of the scalp based on the constellation of findings.

Comment

The classification of LET as a single unique entity or disease process sui generis has been in flux in the last decade. Its similarities to JLIS and other forms of chronic cutaneous lupus erythematosus (CCLE) have brought debate.^4-6 In 1930, Gougerot and Burnier⁷ documented the first case of LET in the literature, describing smooth, infiltrated, erythematous lesions with no desquamation or other superficial changes seen in 5 patients.

In 2000, interest in LET and other forms of CCLE was increasing, and reports in the literature paralleled. That year, Kuhn et al⁴ reported 40 cases of LET, characterizing the clinical and histological features of each case to demonstrate that LET should be separate from other forms of CCLE. Until then, it is likely that many lesions that should have been classified as LET were instead classified as various forms of CCLE. The investigators maintained that LET also should be distinct from JLIS because it is associated with UV exposure.⁴ Kuhn et al⁸ reviewed phototesting in 60 patients with LET in 2001 and confirmed this subset was the most photosensitive type of lupus erythematosus.

In general, the histopathologic and immunohistochemical studies in LET and JLIS can be quite similar. Relatively distinguishing histopathologic findings in JLIS include no evidence of epidermal atrophy, basal vacuolar change, or follicular plugging, as well as negative immunofluorescence studies. Both entities show a predominantly T-cell population with a smaller component of B cells and thus a distinction cannot be made based on relative proportions of T and B cells in lesions.²

In 2003, Alexiades-Armenakas et al⁶ determined immunohistochemical criteria for LET, finding a predominance of T cells and more CD4 lymphocytes than CD8 lymphocytes with a mean ratio of roughly 3 to 1. Their study results maintained LET should be classified as a form of CCLE due to the chronicity of the lesions, the serologic profile with negative anti–double-stranded DNA, anticentromere, anti-Smith, anti-Ro/Sjögren syndrome antigen A, anti-La/Sjögren syndrome antigen B, and anti-nuclear ribonucleoprotein antibodies and the rare association with systemic disease.⁶ This conclusion was further solidified by a review published that same year citing unique histopathological features when compared to subacute cutaneous LE and discoid lupus erythematosus.⁵

This case illustrates the importance of histologic evaluation in determining the correct diagnosis in a patient with alopecia areata recalcitrant to treatment. Including LET in the differential of alopecic patches on the scalp could prove beneficial for patients, as LET responds well to antimalarial drugs and photoprotection.⁹ This patient had a normal antinuclear antibody panel and no signs or symptoms of systemic lupus. It was recommended that she avoid sun exposure and begin treatment with hydroxychloroquine but she declined. At a follow-up visit 6 months later she reported the lesions had improved, but a permanent wig had been sewn over the area, so it could not be examined.

Psoriasis is a chronic, relapsing, inflammatory systemic disorder of the skin with an incidence of 2% to 3% and is estimated to affect 125 million individuals worldwide.¹ Environmental triggers of disease modulation may include cutaneous microbiota, smoking, alcohol use, drugs (ie, beta-blockers, lithium, antimalarials), stress, and trauma.² Comorbidities associated with cutaneous lesions include psoriatic arthritis, Crohn disease, type 2 diabetes mellitus, metabolic syndrome, stroke, and cardiovascular disease.³ In some studies, patients with psoriasis also had a 24% to 27% increased propensity for periodontal bone loss versus 10% of controls.^4,5

Oral psoriasis is rare and case reports have been preferentially published in dental journals, usually with regard to glossal lesions, leaving gingival and palatal psoriatic involvement infrequently reported in the dermatologic literature.^6,7 In fact, oral assessments involving 535 psoriatic patients from a dermatology center only yielded cases of geographic and fissured tongue.⁸ Another study at a psoriasis clinic found 3.8% (21/547) of patients with geographic tongue, 3.1% (17/547) with buccal mucosal plaques, and only 0.4% (2/547) with palatal lesions.⁹ To extend the knowledge of oral psoriasis, we provide the clinical and histopathologic findings of a patient with synchronous oral and cutaneous psoriatic lesions that responded well to the administration of adalimumab for management of recurrent cutaneous disease.

Case Report

A 51-year-old man presented to the attending periodontist for comprehensive treatment of multiple quadrants of gingival recession. His medical history was remarkable for psoriasis; Prinzmetal angina, which led to myocardial infarction; and diverticulitis. The cutaneous psoriasis began approximately 18 years prior to the current presentation and was initially managed with various topical therapeutics. At an 11-year follow-up, the patient was experiencing poor lesional control as well as severe pruritus and was prescribed etanercept by a dermatologist. His inconsistent compliance with frequency and dosing failed to achieve satisfactory disease suppression and etanercept was discontinued after approximately 2.5 years. Two years later the patient was switched to adalimumab by a dermatologist, and around this time he had developed psoriatic arthritis of the hands and knees and pitting of the nail plates. The patient elected to discontinue adalimumab usage after 3 years due to successful management of the skin lesions, cost considerations, and his perception that the psoriasis could “remain in remission.” After a 6-month lapse, the patient resumed adalimumab due to cutaneous lesional recurrence (Figure 1A).

At the current presentation, an oral examination performed 2 days after the reinstitution of adalim-umab revealed generalized severe gingivitis with an atypical inflammatory response that extended from just beyond the mucogingival junction to the marginal gingiva. The gingiva also appeared edematous with a conspicuously granular surface (Figure 1B). The hard palate displayed multiple red macules of varying sizes (Figure 1C). A maxillary gingival biopsy demonstrated hyperkeratosis, parakeratosis, spongiosis, acanthosis, elongation of the rete ridges, numerous collections of neutrophils (Munro microabscesses), and abundant lymphocytes in the subjacent connective tissue (Figure 2). Periodic acid–Schiff staining was negative for fungal hyphae. These features were consistent with oral mucosal psoriasis.

Comment

Psoriasis of the oral cavity is rare and typically occurs on the tongue and less frequently on the hard palate, lip, buccal mucosa, and gingiva.^2,7 The lesions are almost always concordant with cutaneous psoriasis, and only sporadic examples exclusive to the oral mucosa have been recognized.^7,10 Gingival psoriasis usually is described as intensely erythematous and occasionally laced with white scaly streaks involving the marginal gingiva that extend toward the mucogingival junction. In general, the erythematous presentation of gingival psoriasis may not be commensurate with the degree of inflammation induced by dental plaque-based periodontal disease. Doben¹¹ documented gingival psoriasis as appearing “deeply stippled and grainy” and commented that the tissue was “friable” and incapable of maintaining a “clean incision line” during periodontal surgery. In our patient, the gingiva also had exhibited a granular surface. Patients with oral psoriasis often report soreness or a burning sensation of the gingiva, which may easily bleed on manipulation or brushing the teeth, whereas other patients are asymptomatic,¹² as in our case. Psoriasis of the hard palate usually presents as multiple painless red macules. Unlike cutaneous psoriasis, oral lesions rarely evoke pruritus.¹⁰ Histopathologically, oral psoriasis bears a striking resemblance to its cutaneous counterpart. The epithelium has a pronounced parakeratinized surface with elongated rete ridges and aggregations of Munro microabscesses. The connective tissue often is composed of dilated capillaries that closely approximate the epithelium as well as infiltrations of lymphocytes. Specimens suspected for oral psoriasis should routinely be stained with periodic acid–Schiff to rule out candidiasis coinfection. The microscopic findings of our patient were congruent with prior reports of oral psoriasis.^7,10-12 Some clinicians have questioned if psoriasis can actually occur in the oral cavity, but most authorities in the field have recognized its true existence, as evidenced by various shared HLA antigens, specifically HLA-Cw.¹³

Another group of oral lesions collectively referred to as psoriasiform mucositis, notably geographic tongue (benign migratory glossitis, erythema migrans) and its extraglossal variant geographic stomatitis,^14,15 have histopathologic features and HLAs similar to those seen in cutaneous psoriasis.¹³ Interestingly, geographic tongue has been found in 3.8% to 9.1% of cohorts with cutaneous psoriasis,^8,9 but in the extant population, the vast majority of patients with oral psoriasiform mucositis do not have cutaneous psoriasis. Other differential diagnoses for gingival psoriasis are lichen planus, human immunodeficiency virus–associated periodontitis, desquamative gingivitis, plasma cell gingivitis, erythematous candidiasis, mucous membrane pemphigoid, pemphigus vulgaris, leukemia, systemic lupus erythematosus, granulomatosis with polyangiitis, orofacial granulomatosis, localized juvenile spongiotic gingivitis hyperplasia, and primary gingivostomatitis.

Management of gingival psoriasis focuses on strategies to reduce inflammation and discomfort and measures to achieve meticulous oral plaque control. Judicious efforts should be exercised to avoid oral soft-tissue injury when performing periodontal scaling, although it has not been established whether gingival psoriasis is associated with the Köbner phenomenon, as seen with cutaneous lesions. Adjunctive measures employed for symptomatic patients have involved the use of corticosteroids (eg, lesional injection, oral rinse, systemic) and oral rinses with retinoic acid, chlorhexidine gluconate, and warm saline.^7,10,16 Prolonged utilization of corticosteroids, however, may necessitate supplemental administration of antifungal agents.

This case report represents a rare documentation of a successful outcome of gingival and palatal psoriasis subsequent to the reinstitution of adalimumab solely for treatment of recurrent cutaneous disease. There likely is a pharmacologic basis for the amelioration of oral psoriasis in our patient. Adalimumab is a bivalent IgG monoclonal antibody that binds to activated dermal dendritic cell receptors of tumor necrosis factor α, thereby attenuating a cytokine-derived inflammatory response and apoptosis.¹⁷ In fact, patients with rheumatoid arthritis showed notable reductions in both gingival inflammation and bleeding following a 3-month regimen of adalimumab.¹⁸

Conclusion

Practitioners should be aware of the phenotypic overlap of cutaneous and oral psoriasis, particularly involving the gingiva and palate. It is recommended that psoriasis patients routinely receive a dental prophylaxis and engage in oral hygiene efforts to reduce the presence of oral microbiota. Furthermore, it is emphasized that psoriatic patients who maintain an atypical erythematous presentation on the oral mucosa undergo a biopsy for identification of the lesions and correlation with disease dissemination. Prospective studies are needed to characterize the clinical courses of oral psoriasis, ascertain their correlative behavior with cutaneous flares, and determine if lesional improvement can be achieved with the use of biologic agents or other therapeutic modalities.

Psoriasis is a chronic, relapsing, inflammatory systemic disorder of the skin with an incidence of 2% to 3% and is estimated to affect 125 million individuals worldwide.¹ Environmental triggers of disease modulation may include cutaneous microbiota, smoking, alcohol use, drugs (ie, beta-blockers, lithium, antimalarials), stress, and trauma.² Comorbidities associated with cutaneous lesions include psoriatic arthritis, Crohn disease, type 2 diabetes mellitus, metabolic syndrome, stroke, and cardiovascular disease.³ In some studies, patients with psoriasis also had a 24% to 27% increased propensity for periodontal bone loss versus 10% of controls.^4,5

Oral psoriasis is rare and case reports have been preferentially published in dental journals, usually with regard to glossal lesions, leaving gingival and palatal psoriatic involvement infrequently reported in the dermatologic literature.^6,7 In fact, oral assessments involving 535 psoriatic patients from a dermatology center only yielded cases of geographic and fissured tongue.⁸ Another study at a psoriasis clinic found 3.8% (21/547) of patients with geographic tongue, 3.1% (17/547) with buccal mucosal plaques, and only 0.4% (2/547) with palatal lesions.⁹ To extend the knowledge of oral psoriasis, we provide the clinical and histopathologic findings of a patient with synchronous oral and cutaneous psoriatic lesions that responded well to the administration of adalimumab for management of recurrent cutaneous disease.

Case Report

A 51-year-old man presented to the attending periodontist for comprehensive treatment of multiple quadrants of gingival recession. His medical history was remarkable for psoriasis; Prinzmetal angina, which led to myocardial infarction; and diverticulitis. The cutaneous psoriasis began approximately 18 years prior to the current presentation and was initially managed with various topical therapeutics. At an 11-year follow-up, the patient was experiencing poor lesional control as well as severe pruritus and was prescribed etanercept by a dermatologist. His inconsistent compliance with frequency and dosing failed to achieve satisfactory disease suppression and etanercept was discontinued after approximately 2.5 years. Two years later the patient was switched to adalimumab by a dermatologist, and around this time he had developed psoriatic arthritis of the hands and knees and pitting of the nail plates. The patient elected to discontinue adalimumab usage after 3 years due to successful management of the skin lesions, cost considerations, and his perception that the psoriasis could “remain in remission.” After a 6-month lapse, the patient resumed adalimumab due to cutaneous lesional recurrence (Figure 1A).

At the current presentation, an oral examination performed 2 days after the reinstitution of adalim-umab revealed generalized severe gingivitis with an atypical inflammatory response that extended from just beyond the mucogingival junction to the marginal gingiva. The gingiva also appeared edematous with a conspicuously granular surface (Figure 1B). The hard palate displayed multiple red macules of varying sizes (Figure 1C). A maxillary gingival biopsy demonstrated hyperkeratosis, parakeratosis, spongiosis, acanthosis, elongation of the rete ridges, numerous collections of neutrophils (Munro microabscesses), and abundant lymphocytes in the subjacent connective tissue (Figure 2). Periodic acid–Schiff staining was negative for fungal hyphae. These features were consistent with oral mucosal psoriasis.

Comment

Psoriasis of the oral cavity is rare and typically occurs on the tongue and less frequently on the hard palate, lip, buccal mucosa, and gingiva.^2,7 The lesions are almost always concordant with cutaneous psoriasis, and only sporadic examples exclusive to the oral mucosa have been recognized.^7,10 Gingival psoriasis usually is described as intensely erythematous and occasionally laced with white scaly streaks involving the marginal gingiva that extend toward the mucogingival junction. In general, the erythematous presentation of gingival psoriasis may not be commensurate with the degree of inflammation induced by dental plaque-based periodontal disease. Doben¹¹ documented gingival psoriasis as appearing “deeply stippled and grainy” and commented that the tissue was “friable” and incapable of maintaining a “clean incision line” during periodontal surgery. In our patient, the gingiva also had exhibited a granular surface. Patients with oral psoriasis often report soreness or a burning sensation of the gingiva, which may easily bleed on manipulation or brushing the teeth, whereas other patients are asymptomatic,¹² as in our case. Psoriasis of the hard palate usually presents as multiple painless red macules. Unlike cutaneous psoriasis, oral lesions rarely evoke pruritus.¹⁰ Histopathologically, oral psoriasis bears a striking resemblance to its cutaneous counterpart. The epithelium has a pronounced parakeratinized surface with elongated rete ridges and aggregations of Munro microabscesses. The connective tissue often is composed of dilated capillaries that closely approximate the epithelium as well as infiltrations of lymphocytes. Specimens suspected for oral psoriasis should routinely be stained with periodic acid–Schiff to rule out candidiasis coinfection. The microscopic findings of our patient were congruent with prior reports of oral psoriasis.^7,10-12 Some clinicians have questioned if psoriasis can actually occur in the oral cavity, but most authorities in the field have recognized its true existence, as evidenced by various shared HLA antigens, specifically HLA-Cw.¹³

Another group of oral lesions collectively referred to as psoriasiform mucositis, notably geographic tongue (benign migratory glossitis, erythema migrans) and its extraglossal variant geographic stomatitis,^14,15 have histopathologic features and HLAs similar to those seen in cutaneous psoriasis.¹³ Interestingly, geographic tongue has been found in 3.8% to 9.1% of cohorts with cutaneous psoriasis,^8,9 but in the extant population, the vast majority of patients with oral psoriasiform mucositis do not have cutaneous psoriasis. Other differential diagnoses for gingival psoriasis are lichen planus, human immunodeficiency virus–associated periodontitis, desquamative gingivitis, plasma cell gingivitis, erythematous candidiasis, mucous membrane pemphigoid, pemphigus vulgaris, leukemia, systemic lupus erythematosus, granulomatosis with polyangiitis, orofacial granulomatosis, localized juvenile spongiotic gingivitis hyperplasia, and primary gingivostomatitis.

Management of gingival psoriasis focuses on strategies to reduce inflammation and discomfort and measures to achieve meticulous oral plaque control. Judicious efforts should be exercised to avoid oral soft-tissue injury when performing periodontal scaling, although it has not been established whether gingival psoriasis is associated with the Köbner phenomenon, as seen with cutaneous lesions. Adjunctive measures employed for symptomatic patients have involved the use of corticosteroids (eg, lesional injection, oral rinse, systemic) and oral rinses with retinoic acid, chlorhexidine gluconate, and warm saline.^7,10,16 Prolonged utilization of corticosteroids, however, may necessitate supplemental administration of antifungal agents.

This case report represents a rare documentation of a successful outcome of gingival and palatal psoriasis subsequent to the reinstitution of adalimumab solely for treatment of recurrent cutaneous disease. There likely is a pharmacologic basis for the amelioration of oral psoriasis in our patient. Adalimumab is a bivalent IgG monoclonal antibody that binds to activated dermal dendritic cell receptors of tumor necrosis factor α, thereby attenuating a cytokine-derived inflammatory response and apoptosis.¹⁷ In fact, patients with rheumatoid arthritis showed notable reductions in both gingival inflammation and bleeding following a 3-month regimen of adalimumab.¹⁸

Conclusion

Practitioners should be aware of the phenotypic overlap of cutaneous and oral psoriasis, particularly involving the gingiva and palate. It is recommended that psoriasis patients routinely receive a dental prophylaxis and engage in oral hygiene efforts to reduce the presence of oral microbiota. Furthermore, it is emphasized that psoriatic patients who maintain an atypical erythematous presentation on the oral mucosa undergo a biopsy for identification of the lesions and correlation with disease dissemination. Prospective studies are needed to characterize the clinical courses of oral psoriasis, ascertain their correlative behavior with cutaneous flares, and determine if lesional improvement can be achieved with the use of biologic agents or other therapeutic modalities.

Psoriasis is a chronic, relapsing, inflammatory systemic disorder of the skin with an incidence of 2% to 3% and is estimated to affect 125 million individuals worldwide.¹ Environmental triggers of disease modulation may include cutaneous microbiota, smoking, alcohol use, drugs (ie, beta-blockers, lithium, antimalarials), stress, and trauma.² Comorbidities associated with cutaneous lesions include psoriatic arthritis, Crohn disease, type 2 diabetes mellitus, metabolic syndrome, stroke, and cardiovascular disease.³ In some studies, patients with psoriasis also had a 24% to 27% increased propensity for periodontal bone loss versus 10% of controls.^4,5

Oral psoriasis is rare and case reports have been preferentially published in dental journals, usually with regard to glossal lesions, leaving gingival and palatal psoriatic involvement infrequently reported in the dermatologic literature.^6,7 In fact, oral assessments involving 535 psoriatic patients from a dermatology center only yielded cases of geographic and fissured tongue.⁸ Another study at a psoriasis clinic found 3.8% (21/547) of patients with geographic tongue, 3.1% (17/547) with buccal mucosal plaques, and only 0.4% (2/547) with palatal lesions.⁹ To extend the knowledge of oral psoriasis, we provide the clinical and histopathologic findings of a patient with synchronous oral and cutaneous psoriatic lesions that responded well to the administration of adalimumab for management of recurrent cutaneous disease.

Case Report

A 51-year-old man presented to the attending periodontist for comprehensive treatment of multiple quadrants of gingival recession. His medical history was remarkable for psoriasis; Prinzmetal angina, which led to myocardial infarction; and diverticulitis. The cutaneous psoriasis began approximately 18 years prior to the current presentation and was initially managed with various topical therapeutics. At an 11-year follow-up, the patient was experiencing poor lesional control as well as severe pruritus and was prescribed etanercept by a dermatologist. His inconsistent compliance with frequency and dosing failed to achieve satisfactory disease suppression and etanercept was discontinued after approximately 2.5 years. Two years later the patient was switched to adalimumab by a dermatologist, and around this time he had developed psoriatic arthritis of the hands and knees and pitting of the nail plates. The patient elected to discontinue adalimumab usage after 3 years due to successful management of the skin lesions, cost considerations, and his perception that the psoriasis could “remain in remission.” After a 6-month lapse, the patient resumed adalimumab due to cutaneous lesional recurrence (Figure 1A).

At the current presentation, an oral examination performed 2 days after the reinstitution of adalim-umab revealed generalized severe gingivitis with an atypical inflammatory response that extended from just beyond the mucogingival junction to the marginal gingiva. The gingiva also appeared edematous with a conspicuously granular surface (Figure 1B). The hard palate displayed multiple red macules of varying sizes (Figure 1C). A maxillary gingival biopsy demonstrated hyperkeratosis, parakeratosis, spongiosis, acanthosis, elongation of the rete ridges, numerous collections of neutrophils (Munro microabscesses), and abundant lymphocytes in the subjacent connective tissue (Figure 2). Periodic acid–Schiff staining was negative for fungal hyphae. These features were consistent with oral mucosal psoriasis.

Comment

Psoriasis of the oral cavity is rare and typically occurs on the tongue and less frequently on the hard palate, lip, buccal mucosa, and gingiva.^2,7 The lesions are almost always concordant with cutaneous psoriasis, and only sporadic examples exclusive to the oral mucosa have been recognized.^7,10 Gingival psoriasis usually is described as intensely erythematous and occasionally laced with white scaly streaks involving the marginal gingiva that extend toward the mucogingival junction. In general, the erythematous presentation of gingival psoriasis may not be commensurate with the degree of inflammation induced by dental plaque-based periodontal disease. Doben¹¹ documented gingival psoriasis as appearing “deeply stippled and grainy” and commented that the tissue was “friable” and incapable of maintaining a “clean incision line” during periodontal surgery. In our patient, the gingiva also had exhibited a granular surface. Patients with oral psoriasis often report soreness or a burning sensation of the gingiva, which may easily bleed on manipulation or brushing the teeth, whereas other patients are asymptomatic,¹² as in our case. Psoriasis of the hard palate usually presents as multiple painless red macules. Unlike cutaneous psoriasis, oral lesions rarely evoke pruritus.¹⁰ Histopathologically, oral psoriasis bears a striking resemblance to its cutaneous counterpart. The epithelium has a pronounced parakeratinized surface with elongated rete ridges and aggregations of Munro microabscesses. The connective tissue often is composed of dilated capillaries that closely approximate the epithelium as well as infiltrations of lymphocytes. Specimens suspected for oral psoriasis should routinely be stained with periodic acid–Schiff to rule out candidiasis coinfection. The microscopic findings of our patient were congruent with prior reports of oral psoriasis.^7,10-12 Some clinicians have questioned if psoriasis can actually occur in the oral cavity, but most authorities in the field have recognized its true existence, as evidenced by various shared HLA antigens, specifically HLA-Cw.¹³

Another group of oral lesions collectively referred to as psoriasiform mucositis, notably geographic tongue (benign migratory glossitis, erythema migrans) and its extraglossal variant geographic stomatitis,^14,15 have histopathologic features and HLAs similar to those seen in cutaneous psoriasis.¹³ Interestingly, geographic tongue has been found in 3.8% to 9.1% of cohorts with cutaneous psoriasis,^8,9 but in the extant population, the vast majority of patients with oral psoriasiform mucositis do not have cutaneous psoriasis. Other differential diagnoses for gingival psoriasis are lichen planus, human immunodeficiency virus–associated periodontitis, desquamative gingivitis, plasma cell gingivitis, erythematous candidiasis, mucous membrane pemphigoid, pemphigus vulgaris, leukemia, systemic lupus erythematosus, granulomatosis with polyangiitis, orofacial granulomatosis, localized juvenile spongiotic gingivitis hyperplasia, and primary gingivostomatitis.

Management of gingival psoriasis focuses on strategies to reduce inflammation and discomfort and measures to achieve meticulous oral plaque control. Judicious efforts should be exercised to avoid oral soft-tissue injury when performing periodontal scaling, although it has not been established whether gingival psoriasis is associated with the Köbner phenomenon, as seen with cutaneous lesions. Adjunctive measures employed for symptomatic patients have involved the use of corticosteroids (eg, lesional injection, oral rinse, systemic) and oral rinses with retinoic acid, chlorhexidine gluconate, and warm saline.^7,10,16 Prolonged utilization of corticosteroids, however, may necessitate supplemental administration of antifungal agents.

This case report represents a rare documentation of a successful outcome of gingival and palatal psoriasis subsequent to the reinstitution of adalimumab solely for treatment of recurrent cutaneous disease. There likely is a pharmacologic basis for the amelioration of oral psoriasis in our patient. Adalimumab is a bivalent IgG monoclonal antibody that binds to activated dermal dendritic cell receptors of tumor necrosis factor α, thereby attenuating a cytokine-derived inflammatory response and apoptosis.¹⁷ In fact, patients with rheumatoid arthritis showed notable reductions in both gingival inflammation and bleeding following a 3-month regimen of adalimumab.¹⁸

Conclusion

Practitioners should be aware of the phenotypic overlap of cutaneous and oral psoriasis, particularly involving the gingiva and palate. It is recommended that psoriasis patients routinely receive a dental prophylaxis and engage in oral hygiene efforts to reduce the presence of oral microbiota. Furthermore, it is emphasized that psoriatic patients who maintain an atypical erythematous presentation on the oral mucosa undergo a biopsy for identification of the lesions and correlation with disease dissemination. Prospective studies are needed to characterize the clinical courses of oral psoriasis, ascertain their correlative behavior with cutaneous flares, and determine if lesional improvement can be achieved with the use of biologic agents or other therapeutic modalities.

Case

A 31-year-old white man presented to the ED with abdominal and rectal pain accompanied by multiple episodes of bloody diarrhea. He stated he had mild rectal pain the previous night but was pain-free and in his usual state of health the morning of his presentation. Approximately 2 hours before presenting to the ED, however, he began experiencing mild stomach pain, then bloody diarrhea which he described as bright red and “filling the toilet bowl with blood.” He had no history of inflammatory bowel disease or other gastrointestinal (GI) disorder, no recent travel, no complaints of nausea or vomiting, and no infectious symptoms. He described a remote history of external hemorrhoids, and review of his family history was significant for multiple paternal relatives with aortic aneurysms. He was not taking any medications and was a nonsmoker with a normal body mass index (24.3 kg/m²).

Upon arrival at the ED, the patient’s vital signs were: heart rate, 112 beats/min; and blood pressure, 139/102 mm Hg; respiratory rate and temperature were normal, as was the patient’s oxygen saturation on room air. Physical examination was notable for no subjective or objective findings of orthostatic hypotension; increased bowel sounds and diffuse mild abdominal tenderness; and no external hemorrhoids, fissures, or rectal tenderness. Laboratory evaluation was significant for hemoglobin (Hgb), 15.0 g/dL; blood urea nitrogen (BUN)-to-creatinine (Cr) ratio, 11.6; and anion gap, 17 mEq/L.

Upon initial presentation, there was some concern for an infection. However, as the patient continued to have bowel movements consisting almost entirely of frank blood and did not have any infectious signs, a vascular etiology was more strongly considered. Given the patient’s relatively stable vital signs, BUN-to-Cr ratio of less than 20, and lack of orthostatic hypotension, there was low concern for an upper GI etiology, and endoscopy was not obtained emergently. The patient instead underwent abdominal computed tomography angiography (CTA), which identified active extravasation and contrast pooling within the cecum and appendix (Figure 1).

Discussion

Acute lower GI bleeding has an estimated annual hospitalization rate of 36 patients per 100,000, or about half the rate for upper GI bleeding.^1,2 The majority of patients (>80%) will have spontaneous resolution and can be worked up nonemergently.³ Of the remaining 20%, some patients will have severe hematochezia (defined as continuous bleeding during the first 24 hours of hospitalization that results in a decreased Hgb level of 2 g/dL or more, or a decreased Hgb level that necessitates transfusion of 2 U or more of PRBCs). In patients with significant bleeding, the first priority in the ED is hemodynamic stabilization, including close monitoring, establishing two large-bore intravenous (IV) lines, and volume resuscitation, with transfusion as needed.

Etiology and Work-Up

Assessment of the etiology of hematochezia begins with ruling out an upper GI source of the bleed; 10% to 15% of patients presenting with hematochezia without hematemesis are ultimately diagnosed with an upper GI etiology. ^4,5

BUN-to-Cr Ratio. In a study of patients presenting with hematochezia but no hematemesis or renal failure, Srygley et al⁶ found a BUN-to-Cr ratio greater than 93% to be sensitive for an upper GI source, with a likelihood ratio of 7.5. The proposed etiology is some combination of absorption of digested blood products and prerenal azotemia due to hypovolemia.

Tachycardia and Orthostatic Hypotension. There have been discussions in the literature about other findings to rule in/out upper GI bleeding. While some studies have found statistically significant results between upper and lower GI bleeding for tachycardia and orthostatic hypotension (increased percentage of both in upper GI bleeding), there is disagreement about whether these findings are clinically significant.^7-9

Nasogastric Lavage. Although nasogastric (NG) lavage is no longer the standard of care in the ED due to poor sensitivity and marked discomfort to the patient, most current gastroenterology guidelines still recommend its use; therefore, NG may be requested by the GI consultant.^10-12

Diagnosis

Once an upper GI source has been ruled out, identification of the lesion is the next step. The differential diagnosis includes common sources such as diverticular disease, angiodysplasia, colitis, anorectal sources, and neoplasm.⁵ Less common, but associated with a high risk of mortality, is aortoenteric fistula (100% mortality without surgical intervention).⁵

Colonoscopy. Emergent colonoscopy can be used for both diagnosis and (potential) therapeutic intervention and is therefore the first option of choice.^1,3,4,9 However, as seen in our case, some patients experience such profound hemorrhage that visualization of the colon may be difficult or impossible; patients may also be too unstable to await bowel preparation or undergo a procedure.

Computed Tomography Angiography. For patients in whom colonoscopy is contraindicated, CTA is the imaging modality of choice, and has a 91% to 92% sensitivity in identifying active bleeding (>0.35 mL/min).^13-16

Computed tomography of the abdomen and pelvis with contrast alone, as opposed to CTA, is insufficient for detecting GI bleeding, as it is timed so that imaging is obtained when the contrast is in the portal venous capillary beds, rather than in the arteries or arterioles. By protocol, though, many institutions require abdominal and pelvic CTA to include both arterial phase and venous phase images, allowing for assessment of both active arterial bleeding and alternative lower GI sources of hematochezia (eg, mesenteric ischemia).

When ordering a CT study, an awareness of local practice is important in understanding the information that will be obtained from the study. Protocols for lower GI bleed that include CTA have reported accuracy and efficiency without worsening of renal function, despite the increased contrast load.¹⁷

Triphasic CT Enterography. Another CT modality to consider is triphasic CT enterography, which uses IV and oral contrast. In a preliminary trial, this modality achieved a specificity of 100% (sensitivity 42%) in detecting GI bleeding.¹⁸

Red Blood Cell Scintigraphy. An additional imaging modality that has been the subject of much debate in the GI literature is tagged RBC scintigraphy with Technetium-99m. Various studies have found bleeding-site confirmation in 24% to 97% of patients, and correct localization in 41% to 100% of patients. Given the extensive variability within the literature on selection criteria, localization, site confirmation, and other variables, as well as evidence from one prospective trial by Zink et al¹⁹ that found a significant disagreement between CTA and scintigraphy, RBC scintigraphy is not recommended as an alternative imaging modality for the rapid diagnosis of an acute lower GI bleed.

Conclusion

Severe hematochezia is a potential surgical emergency with a broad differential diagnosis. While emergent colonoscopy is an excellent first option, in patients with severe hematochezia, there may be too much blood in the colon to obtain adequate visual images; additionally, depending on practice setting, emergency colonoscopy may not be immediately available. In either case, CTA—a readily available, noninvasive, rapid, and repeatable diagnostic tool—should be considered as an alternate to colonoscopy, particularly in patients with brisk hematochezia.

If a patient with severe hematochezia presents to the ED, the emergency physician (EP) must recognize that the degree of hemorrhage may not correlate with the patient’s vital signs or initial laboratory values. For this reason, the EP must have a high index of suspicion, and consider CTA to allow for a rapid definitive diagnosis and prompt discussion between surgical, interventional radiology, and/or gastroenterology teams to improve clinical outcomes and decrease morbidity and mortality.²⁰

Case

A 31-year-old white man presented to the ED with abdominal and rectal pain accompanied by multiple episodes of bloody diarrhea. He stated he had mild rectal pain the previous night but was pain-free and in his usual state of health the morning of his presentation. Approximately 2 hours before presenting to the ED, however, he began experiencing mild stomach pain, then bloody diarrhea which he described as bright red and “filling the toilet bowl with blood.” He had no history of inflammatory bowel disease or other gastrointestinal (GI) disorder, no recent travel, no complaints of nausea or vomiting, and no infectious symptoms. He described a remote history of external hemorrhoids, and review of his family history was significant for multiple paternal relatives with aortic aneurysms. He was not taking any medications and was a nonsmoker with a normal body mass index (24.3 kg/m²).

Upon arrival at the ED, the patient’s vital signs were: heart rate, 112 beats/min; and blood pressure, 139/102 mm Hg; respiratory rate and temperature were normal, as was the patient’s oxygen saturation on room air. Physical examination was notable for no subjective or objective findings of orthostatic hypotension; increased bowel sounds and diffuse mild abdominal tenderness; and no external hemorrhoids, fissures, or rectal tenderness. Laboratory evaluation was significant for hemoglobin (Hgb), 15.0 g/dL; blood urea nitrogen (BUN)-to-creatinine (Cr) ratio, 11.6; and anion gap, 17 mEq/L.

Upon initial presentation, there was some concern for an infection. However, as the patient continued to have bowel movements consisting almost entirely of frank blood and did not have any infectious signs, a vascular etiology was more strongly considered. Given the patient’s relatively stable vital signs, BUN-to-Cr ratio of less than 20, and lack of orthostatic hypotension, there was low concern for an upper GI etiology, and endoscopy was not obtained emergently. The patient instead underwent abdominal computed tomography angiography (CTA), which identified active extravasation and contrast pooling within the cecum and appendix (Figure 1).

Discussion

Acute lower GI bleeding has an estimated annual hospitalization rate of 36 patients per 100,000, or about half the rate for upper GI bleeding.^1,2 The majority of patients (>80%) will have spontaneous resolution and can be worked up nonemergently.³ Of the remaining 20%, some patients will have severe hematochezia (defined as continuous bleeding during the first 24 hours of hospitalization that results in a decreased Hgb level of 2 g/dL or more, or a decreased Hgb level that necessitates transfusion of 2 U or more of PRBCs). In patients with significant bleeding, the first priority in the ED is hemodynamic stabilization, including close monitoring, establishing two large-bore intravenous (IV) lines, and volume resuscitation, with transfusion as needed.

Etiology and Work-Up

Assessment of the etiology of hematochezia begins with ruling out an upper GI source of the bleed; 10% to 15% of patients presenting with hematochezia without hematemesis are ultimately diagnosed with an upper GI etiology. ^4,5

BUN-to-Cr Ratio. In a study of patients presenting with hematochezia but no hematemesis or renal failure, Srygley et al⁶ found a BUN-to-Cr ratio greater than 93% to be sensitive for an upper GI source, with a likelihood ratio of 7.5. The proposed etiology is some combination of absorption of digested blood products and prerenal azotemia due to hypovolemia.

Tachycardia and Orthostatic Hypotension. There have been discussions in the literature about other findings to rule in/out upper GI bleeding. While some studies have found statistically significant results between upper and lower GI bleeding for tachycardia and orthostatic hypotension (increased percentage of both in upper GI bleeding), there is disagreement about whether these findings are clinically significant.^7-9

Nasogastric Lavage. Although nasogastric (NG) lavage is no longer the standard of care in the ED due to poor sensitivity and marked discomfort to the patient, most current gastroenterology guidelines still recommend its use; therefore, NG may be requested by the GI consultant.^10-12

Diagnosis

Once an upper GI source has been ruled out, identification of the lesion is the next step. The differential diagnosis includes common sources such as diverticular disease, angiodysplasia, colitis, anorectal sources, and neoplasm.⁵ Less common, but associated with a high risk of mortality, is aortoenteric fistula (100% mortality without surgical intervention).⁵

Colonoscopy. Emergent colonoscopy can be used for both diagnosis and (potential) therapeutic intervention and is therefore the first option of choice.^1,3,4,9 However, as seen in our case, some patients experience such profound hemorrhage that visualization of the colon may be difficult or impossible; patients may also be too unstable to await bowel preparation or undergo a procedure.

Computed Tomography Angiography. For patients in whom colonoscopy is contraindicated, CTA is the imaging modality of choice, and has a 91% to 92% sensitivity in identifying active bleeding (>0.35 mL/min).^13-16

Computed tomography of the abdomen and pelvis with contrast alone, as opposed to CTA, is insufficient for detecting GI bleeding, as it is timed so that imaging is obtained when the contrast is in the portal venous capillary beds, rather than in the arteries or arterioles. By protocol, though, many institutions require abdominal and pelvic CTA to include both arterial phase and venous phase images, allowing for assessment of both active arterial bleeding and alternative lower GI sources of hematochezia (eg, mesenteric ischemia).

When ordering a CT study, an awareness of local practice is important in understanding the information that will be obtained from the study. Protocols for lower GI bleed that include CTA have reported accuracy and efficiency without worsening of renal function, despite the increased contrast load.¹⁷

Triphasic CT Enterography. Another CT modality to consider is triphasic CT enterography, which uses IV and oral contrast. In a preliminary trial, this modality achieved a specificity of 100% (sensitivity 42%) in detecting GI bleeding.¹⁸

Red Blood Cell Scintigraphy. An additional imaging modality that has been the subject of much debate in the GI literature is tagged RBC scintigraphy with Technetium-99m. Various studies have found bleeding-site confirmation in 24% to 97% of patients, and correct localization in 41% to 100% of patients. Given the extensive variability within the literature on selection criteria, localization, site confirmation, and other variables, as well as evidence from one prospective trial by Zink et al¹⁹ that found a significant disagreement between CTA and scintigraphy, RBC scintigraphy is not recommended as an alternative imaging modality for the rapid diagnosis of an acute lower GI bleed.

Conclusion

Severe hematochezia is a potential surgical emergency with a broad differential diagnosis. While emergent colonoscopy is an excellent first option, in patients with severe hematochezia, there may be too much blood in the colon to obtain adequate visual images; additionally, depending on practice setting, emergency colonoscopy may not be immediately available. In either case, CTA—a readily available, noninvasive, rapid, and repeatable diagnostic tool—should be considered as an alternate to colonoscopy, particularly in patients with brisk hematochezia.

If a patient with severe hematochezia presents to the ED, the emergency physician (EP) must recognize that the degree of hemorrhage may not correlate with the patient’s vital signs or initial laboratory values. For this reason, the EP must have a high index of suspicion, and consider CTA to allow for a rapid definitive diagnosis and prompt discussion between surgical, interventional radiology, and/or gastroenterology teams to improve clinical outcomes and decrease morbidity and mortality.²⁰

Case

A 31-year-old white man presented to the ED with abdominal and rectal pain accompanied by multiple episodes of bloody diarrhea. He stated he had mild rectal pain the previous night but was pain-free and in his usual state of health the morning of his presentation. Approximately 2 hours before presenting to the ED, however, he began experiencing mild stomach pain, then bloody diarrhea which he described as bright red and “filling the toilet bowl with blood.” He had no history of inflammatory bowel disease or other gastrointestinal (GI) disorder, no recent travel, no complaints of nausea or vomiting, and no infectious symptoms. He described a remote history of external hemorrhoids, and review of his family history was significant for multiple paternal relatives with aortic aneurysms. He was not taking any medications and was a nonsmoker with a normal body mass index (24.3 kg/m²).

Upon arrival at the ED, the patient’s vital signs were: heart rate, 112 beats/min; and blood pressure, 139/102 mm Hg; respiratory rate and temperature were normal, as was the patient’s oxygen saturation on room air. Physical examination was notable for no subjective or objective findings of orthostatic hypotension; increased bowel sounds and diffuse mild abdominal tenderness; and no external hemorrhoids, fissures, or rectal tenderness. Laboratory evaluation was significant for hemoglobin (Hgb), 15.0 g/dL; blood urea nitrogen (BUN)-to-creatinine (Cr) ratio, 11.6; and anion gap, 17 mEq/L.

Upon initial presentation, there was some concern for an infection. However, as the patient continued to have bowel movements consisting almost entirely of frank blood and did not have any infectious signs, a vascular etiology was more strongly considered. Given the patient’s relatively stable vital signs, BUN-to-Cr ratio of less than 20, and lack of orthostatic hypotension, there was low concern for an upper GI etiology, and endoscopy was not obtained emergently. The patient instead underwent abdominal computed tomography angiography (CTA), which identified active extravasation and contrast pooling within the cecum and appendix (Figure 1).

Discussion

Acute lower GI bleeding has an estimated annual hospitalization rate of 36 patients per 100,000, or about half the rate for upper GI bleeding.^1,2 The majority of patients (>80%) will have spontaneous resolution and can be worked up nonemergently.³ Of the remaining 20%, some patients will have severe hematochezia (defined as continuous bleeding during the first 24 hours of hospitalization that results in a decreased Hgb level of 2 g/dL or more, or a decreased Hgb level that necessitates transfusion of 2 U or more of PRBCs). In patients with significant bleeding, the first priority in the ED is hemodynamic stabilization, including close monitoring, establishing two large-bore intravenous (IV) lines, and volume resuscitation, with transfusion as needed.

Etiology and Work-Up

Assessment of the etiology of hematochezia begins with ruling out an upper GI source of the bleed; 10% to 15% of patients presenting with hematochezia without hematemesis are ultimately diagnosed with an upper GI etiology. ^4,5

BUN-to-Cr Ratio. In a study of patients presenting with hematochezia but no hematemesis or renal failure, Srygley et al⁶ found a BUN-to-Cr ratio greater than 93% to be sensitive for an upper GI source, with a likelihood ratio of 7.5. The proposed etiology is some combination of absorption of digested blood products and prerenal azotemia due to hypovolemia.

Tachycardia and Orthostatic Hypotension. There have been discussions in the literature about other findings to rule in/out upper GI bleeding. While some studies have found statistically significant results between upper and lower GI bleeding for tachycardia and orthostatic hypotension (increased percentage of both in upper GI bleeding), there is disagreement about whether these findings are clinically significant.^7-9

Nasogastric Lavage. Although nasogastric (NG) lavage is no longer the standard of care in the ED due to poor sensitivity and marked discomfort to the patient, most current gastroenterology guidelines still recommend its use; therefore, NG may be requested by the GI consultant.^10-12

Diagnosis

Once an upper GI source has been ruled out, identification of the lesion is the next step. The differential diagnosis includes common sources such as diverticular disease, angiodysplasia, colitis, anorectal sources, and neoplasm.⁵ Less common, but associated with a high risk of mortality, is aortoenteric fistula (100% mortality without surgical intervention).⁵

Colonoscopy. Emergent colonoscopy can be used for both diagnosis and (potential) therapeutic intervention and is therefore the first option of choice.^1,3,4,9 However, as seen in our case, some patients experience such profound hemorrhage that visualization of the colon may be difficult or impossible; patients may also be too unstable to await bowel preparation or undergo a procedure.

Computed Tomography Angiography. For patients in whom colonoscopy is contraindicated, CTA is the imaging modality of choice, and has a 91% to 92% sensitivity in identifying active bleeding (>0.35 mL/min).^13-16

Computed tomography of the abdomen and pelvis with contrast alone, as opposed to CTA, is insufficient for detecting GI bleeding, as it is timed so that imaging is obtained when the contrast is in the portal venous capillary beds, rather than in the arteries or arterioles. By protocol, though, many institutions require abdominal and pelvic CTA to include both arterial phase and venous phase images, allowing for assessment of both active arterial bleeding and alternative lower GI sources of hematochezia (eg, mesenteric ischemia).

When ordering a CT study, an awareness of local practice is important in understanding the information that will be obtained from the study. Protocols for lower GI bleed that include CTA have reported accuracy and efficiency without worsening of renal function, despite the increased contrast load.¹⁷

Triphasic CT Enterography. Another CT modality to consider is triphasic CT enterography, which uses IV and oral contrast. In a preliminary trial, this modality achieved a specificity of 100% (sensitivity 42%) in detecting GI bleeding.¹⁸

Red Blood Cell Scintigraphy. An additional imaging modality that has been the subject of much debate in the GI literature is tagged RBC scintigraphy with Technetium-99m. Various studies have found bleeding-site confirmation in 24% to 97% of patients, and correct localization in 41% to 100% of patients. Given the extensive variability within the literature on selection criteria, localization, site confirmation, and other variables, as well as evidence from one prospective trial by Zink et al¹⁹ that found a significant disagreement between CTA and scintigraphy, RBC scintigraphy is not recommended as an alternative imaging modality for the rapid diagnosis of an acute lower GI bleed.

Conclusion

Severe hematochezia is a potential surgical emergency with a broad differential diagnosis. While emergent colonoscopy is an excellent first option, in patients with severe hematochezia, there may be too much blood in the colon to obtain adequate visual images; additionally, depending on practice setting, emergency colonoscopy may not be immediately available. In either case, CTA—a readily available, noninvasive, rapid, and repeatable diagnostic tool—should be considered as an alternate to colonoscopy, particularly in patients with brisk hematochezia.

If a patient with severe hematochezia presents to the ED, the emergency physician (EP) must recognize that the degree of hemorrhage may not correlate with the patient’s vital signs or initial laboratory values. For this reason, the EP must have a high index of suspicion, and consider CTA to allow for a rapid definitive diagnosis and prompt discussion between surgical, interventional radiology, and/or gastroenterology teams to improve clinical outcomes and decrease morbidity and mortality.²⁰

Case

A 24-year-old woman presented to the ED for evaluation of a 3-week history of worsening headache and a 5-day history of increasingly blurry vision. The patient stated that she had initially contacted her primary care physician, but instead presented to the ED because he had no open appointments until the following week and recommended that she go to the ED.

The patient described her headache as a pulsating and throbbing pain over her entire head, which only mildly improved after taking over-the-counter (OTC) ibuprofen. She further noted that her headache was somewhat worse when lying down, and reported the sensation of hearing her own pulsating heartbeat in her ears.

The patient had no personal or family history of migraines, tension headaches, aneurysms, clotting disorders, bleeding disorders, or renal disease, and stated that she had never experienced this type of headache before. She denied photophobia, phonophobia, neck stiffness, fever, vomiting, cough, numbness or weakness in her extremities, or pain anywhere else in her body.

Over the past 5 days, the patient noticed her vision had become increasingly blurry. She was not on any prescription medications, stating the only medication she used was occasional OTC ibuprofen. She had no known allergy to medications and denied smoking or recreational drug use; she admitted to occasional alcohol consumption.

The patient resided with her husband, who had no similar symptoms. Physical examination showed an obese woman (height, 5 ft 6 in; weight, 195 lb; body mass index, 32 kg/m²), lying supine in apparent discomfort. Vital signs at presentation were all normal, and oxygen saturation was normal on room air.

A bedside ocular examination showed 20/100 in both eyes while using glasses; no visual field cuts or obvious central scotoma was present. The patient was alert and oriented to time and place. The neurological examination showed intact cranial nerves, 5/5 strength in all extremities, intact sensation in all extremities, no pronator drift, negative Romberg test, and a normal gait. Fundoscopic examination revealed mildly blurred medial optic discs bilaterally. The rest of the physical examination was normal.

Discussion

Pseudotumor cerebri, more commonly referred to as idiopathic intracranial hypertension (IIH), is characterized by increased intracranial pressure (ICP) with no explanatory findings on imaging studies or in cerebrospinal fluid (CSF) analysis, and may be accompanied by symptoms of chronic headache, tinnitus, papilledema and progressive vision loss caused by optic nerve damage.¹ Though historically IIH was referred to by several other names, including “benign intracranial hypertension,” the condition is not benign—when untreated, IIH can cause chronic disabling headaches and permanent vision loss.¹

Clinical Course

The clinical course of IIH is unpredictable: In some patients, vision loss occurs gradually over the course of several weeks, while in others, loss occurs over a several month period. There are also patients with IIH who do not experience any alteration or loss of vision. Furthermore, some patients will experience permanent resolution of symptoms after a single lumbar puncture (LP); others have symptom recurrence after less than 24 hours; and some patients spontaneously remit on their own with no treatment whatsoever.^1-4

Etiology

In the United States, IIH is a rare cause of headache, occurring in just 1 person per 100,000 annually.¹ Though 90% of IIH cases occur in obese women of childbearing age, the etiology of IIH is unknown. Lumbar puncture usually alleviates the patient’s headache, but the CSF pressure typically returns to its pre-tap levels after a few hours.^4,5 Neither CSF overproduction nor insufficient CSF resorption is responsible for causing IIH. One theory on the etiology of IIH proposes its cause to be due to a congenital malformation of the venous sinuses. This theory would explain why the symptoms so closely mimic those of venous sinus thrombosis, and why some IIH patients experience relief of symptoms after placement of a venous sinus stent.²

Symptoms

As noted previously, the most common symptom of IIH is headache, which patients usually describe as pressure-like and throbbing, and often involving retro-ocular pain. One feature in over half of patients is pulse-synchronous tinnitus (ie, hearing their own heartbeat in their ears). Eye pain, photophobia, blurry vision, and nausea/vomiting are all common symptoms in IIH, but these symptoms are also present in other causes of headache. The IIH headache might be relapsing and remitting, and can last from a few hours to weeks.^2-4,6

Diagnosis

Imaging Studies. Noncontrast computed tomography (CT) imaging studies do not typically demonstrate any abnormal findings.¹ Magnetic resonance imaging (MRI) studies show some inconsistent and subtle findings, such as flattening of the backs of the eyeballs, empty sella, or tortuous optic nerves.¹

Lumbar Puncture. On LP, a very high opening pressure is a hallmark of IIH. An opening pressure <20 cm H₂O is generally considered normal, 20 cm to 25 cm H₂O is “equivocal,” and >25 cm H₂O is abnormal.⁷ Patients presenting with IIH commonly have an opening pressure that exceeds 200 cm H₂O.^1-3 Extremely high pressures, however, are not required for the diagnosis, but some elevations in opening pressure will always be present.^2,5 With the exception of a high opening pressure, the patient’s CSF analysis is normal.

Differential Diagnosis

Idiopathic intracranial hypertension is essentially a diagnosis of exclusion, one that is made after exclusion of all other potential causes of increased ICP (Table). Since contrast CT and MRI can identify subtle anatomical deformities and small lesions, their absence on these studies can help establish a diagnosis of IIH.

Venous Sinus Thrombosis. Venous sinus thrombosis is a rare but devastating condition that also cannot be diagnosed from a noncontrast CT but must always be considered in the differential diagnosis of IIH.^8-10 Venous sinus thrombosis is characterized by a clot in one of the large venous sinuses that drain blood from the brain; the clot causes pressure to back up into the smaller cerebral vasculature, eventually inducing either a hemorrhagic stroke from a stressed vessel rupturing, or an ischemic stroke from lack of blood flow to the affected area of the brain. This condition is even more rare than IIH (0.5 cases per 100,000 population), but it can be devastating if missed, carrying a mortality rate as high as 15% in some studies.¹¹

Risk Factors

Risk factors known to cause cerebral venous clots include genetic thrombophilias, pregnancy or recent pregnancy, oral contraceptive use, inflammatory bowel disease, severe dehydration, local infection/trauma, and substance abuse. Regardless of risk factors, the most recent guidelines of the American Heart Association/American Stroke Association recommend imaging studies of the cerebral venous sinuses for any patient presenting with new-onset symptoms suggestive of IIH (Class 1, Level of Evidence C).¹¹ The two imaging options for evaluation of the cerebral venous sinuses are CT venography or MR venography. Since the 2013 American College of Radiology Appropriateness Criteria do not indicate a preference of one modality over the other, the choice of can be left to your radiologist.¹²

Patient Disposition

Patients with IIH typically do not require inpatient admission. Only about 3% of IIH patients will have a fulminant course of rapid-onset of vision loss, but even the most severe and acute cases will deteriorate over weeks, not hours or days.¹³ Never­theless, close neurology follow-up is essential. If rapid and thorough outpatient neurological care is unavailable, admission is required.

Management

Not every patient with IIH experiences amelioration or resolution of symptoms following an LP; moreover, there is no clear way to differentiate patients who will experience therapeutic effects from LP from those who will not. Serial LPs as treatment for IIH have been discussed in the literature, but a ventriculoperitoneal shunt is a more practical approach in patients who do not respond to an initial LP.^2,14

CSF Volume. The volume of CSF that can be removed safely may be 15 to 25 mL or more. A 1974 paper by Johnston and Paterson¹⁵ described five pseudotumor patients whose CSF was drained until their pressure had normalized; the amount removed varied from 15 to 25 mL, without adverse effects. A 1975 case series by Weisberg⁶ described safe removal of up to 30 mL of CSF in pseudotumor patients—the precise amount removed was determined by that which was necessary to lower the CSF pressure into the normal range. In 2007, a case report by Aly and Lawther¹⁶ of a pregnant woman with IIH describes twice weekly LP drainage of 30 mL.

There is nothing in the current literature to suggest that removing 10 to 30 mL of CSF instead of the 4 to 8 mL typically drawn in a diagnostic LP is going to pose any risk to the patient. The main complication associated with therapeutic LP is post-LP headache.^5,17,18 There are currently no studies documenting outcomes after specific amounts of CSF removal.

Lifestyle Modifications: Weight Loss. No prospective, randomized controlled trials have proven weight loss to be effective in ameliorating the symptoms of IIH; however, several studies have found that rapid weight loss—whether through aggressive dieting or gastric bypass surgery—can improve symptoms dramatically within several months.^19,20 One small study by Johnson et al has suggested that a 6% weight reduction is associated with marked improvement in papilledema.²¹Pharmacotherapy. The accepted first-line medication to alleviate symptoms of IIH is acetazolamide, and its use is supported by a recent randomized controlled trial conducted by the Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC).²² Most neurologists will administer a starting dose of acetazolamide 500 mg twice a day, and then increase the dose until symptoms are controlled or adverse effects appear (eg, fatigue, nausea/vomiting/diarrhea, electrolyte abnormalities, kidney stones) that contraindicate further dosage increases. In the NORDIC trial, patients were given up to 4 g of acetazolamide daily.²²

Other medications, including loop diuretics and corticosteroids, should not be used except under the direct supervision of a neurologist.^2,14

Refractory Cases

A patient who fails conservative treatment should be referred to a neurosurgeon for placement of a CSF shunt, optic nerve sheath fenestration, or placement of a venous sinus stent.²³

Case Conclusion

After a noncontrast CT of the head was interpreted as completely normal, an LP was performed with the patient in the left lateral recumbent position. The opening CSF pressure exceeded 55 cm H₂O (the upper limit of the manometer). The CSF was clear, and opening pressure was rechecked after each 5 mL draw. After 15 mL had been removed, the patient reported a sudden, dramatic disappearance of her headache and clearing of her vision. After 19 mL of CSF had been removed, the CSF pressure had dropped into the normal range (<20 cm H₂O), and the procedure was ended.

To definitively rule out venous sinus thrombosis, a CT venogram was performed in the ED, and interpreted as normal. All other CSF results (cell count, protein, glucose, and gram stain) were normal. After complete resolution of the patient’s symptoms, she was discharged home with a prescription for acetazolamide 500 mg twice daily and instructions to follow-up with a neurologist within 48 hours. At discharge, the patient also received weight-loss counseling and was instructed to return immediately to the ED if her headache recurred or if she experienced any new neurological symptoms.

Summary

Idiopathic intracranial hypertension, also referred to as pseudotumor cerebri, is a rare but potentially vision-threatening cause of headache. Patients with signs and symptoms of IIH often initially present to the ED for evaluation and management. While the etiology of IIH is poorly understood, its clinical picture is unique: elevated ICP (sometimes markedly so) with no other significant findings on noncontrast head CT or CSF analysis. Venous sinus thrombosis, a life-threatening mimic of IIH, must always be included in the differential diagnosis.

Idiopathic intracranial hypertension is initially treated with rapid weight loss and acetazolamide. Many patients experience instant, though sometimes only transient, symptom relief from LP. No definitive studies to support any specific approach, including “therapeutic lumbar punctures.” The condition is rarely fulminant, and hospital admission is not typically required as long as urgent outpatient neurology follow-up is available.

Case

A 24-year-old woman presented to the ED for evaluation of a 3-week history of worsening headache and a 5-day history of increasingly blurry vision. The patient stated that she had initially contacted her primary care physician, but instead presented to the ED because he had no open appointments until the following week and recommended that she go to the ED.

The patient described her headache as a pulsating and throbbing pain over her entire head, which only mildly improved after taking over-the-counter (OTC) ibuprofen. She further noted that her headache was somewhat worse when lying down, and reported the sensation of hearing her own pulsating heartbeat in her ears.

The patient had no personal or family history of migraines, tension headaches, aneurysms, clotting disorders, bleeding disorders, or renal disease, and stated that she had never experienced this type of headache before. She denied photophobia, phonophobia, neck stiffness, fever, vomiting, cough, numbness or weakness in her extremities, or pain anywhere else in her body.

Over the past 5 days, the patient noticed her vision had become increasingly blurry. She was not on any prescription medications, stating the only medication she used was occasional OTC ibuprofen. She had no known allergy to medications and denied smoking or recreational drug use; she admitted to occasional alcohol consumption.

The patient resided with her husband, who had no similar symptoms. Physical examination showed an obese woman (height, 5 ft 6 in; weight, 195 lb; body mass index, 32 kg/m²), lying supine in apparent discomfort. Vital signs at presentation were all normal, and oxygen saturation was normal on room air.

A bedside ocular examination showed 20/100 in both eyes while using glasses; no visual field cuts or obvious central scotoma was present. The patient was alert and oriented to time and place. The neurological examination showed intact cranial nerves, 5/5 strength in all extremities, intact sensation in all extremities, no pronator drift, negative Romberg test, and a normal gait. Fundoscopic examination revealed mildly blurred medial optic discs bilaterally. The rest of the physical examination was normal.

Discussion

Pseudotumor cerebri, more commonly referred to as idiopathic intracranial hypertension (IIH), is characterized by increased intracranial pressure (ICP) with no explanatory findings on imaging studies or in cerebrospinal fluid (CSF) analysis, and may be accompanied by symptoms of chronic headache, tinnitus, papilledema and progressive vision loss caused by optic nerve damage.¹ Though historically IIH was referred to by several other names, including “benign intracranial hypertension,” the condition is not benign—when untreated, IIH can cause chronic disabling headaches and permanent vision loss.¹

Clinical Course

The clinical course of IIH is unpredictable: In some patients, vision loss occurs gradually over the course of several weeks, while in others, loss occurs over a several month period. There are also patients with IIH who do not experience any alteration or loss of vision. Furthermore, some patients will experience permanent resolution of symptoms after a single lumbar puncture (LP); others have symptom recurrence after less than 24 hours; and some patients spontaneously remit on their own with no treatment whatsoever.^1-4

Etiology

In the United States, IIH is a rare cause of headache, occurring in just 1 person per 100,000 annually.¹ Though 90% of IIH cases occur in obese women of childbearing age, the etiology of IIH is unknown. Lumbar puncture usually alleviates the patient’s headache, but the CSF pressure typically returns to its pre-tap levels after a few hours.^4,5 Neither CSF overproduction nor insufficient CSF resorption is responsible for causing IIH. One theory on the etiology of IIH proposes its cause to be due to a congenital malformation of the venous sinuses. This theory would explain why the symptoms so closely mimic those of venous sinus thrombosis, and why some IIH patients experience relief of symptoms after placement of a venous sinus stent.²

Symptoms

As noted previously, the most common symptom of IIH is headache, which patients usually describe as pressure-like and throbbing, and often involving retro-ocular pain. One feature in over half of patients is pulse-synchronous tinnitus (ie, hearing their own heartbeat in their ears). Eye pain, photophobia, blurry vision, and nausea/vomiting are all common symptoms in IIH, but these symptoms are also present in other causes of headache. The IIH headache might be relapsing and remitting, and can last from a few hours to weeks.^2-4,6

Diagnosis

Imaging Studies. Noncontrast computed tomography (CT) imaging studies do not typically demonstrate any abnormal findings.¹ Magnetic resonance imaging (MRI) studies show some inconsistent and subtle findings, such as flattening of the backs of the eyeballs, empty sella, or tortuous optic nerves.¹

Lumbar Puncture. On LP, a very high opening pressure is a hallmark of IIH. An opening pressure <20 cm H₂O is generally considered normal, 20 cm to 25 cm H₂O is “equivocal,” and >25 cm H₂O is abnormal.⁷ Patients presenting with IIH commonly have an opening pressure that exceeds 200 cm H₂O.^1-3 Extremely high pressures, however, are not required for the diagnosis, but some elevations in opening pressure will always be present.^2,5 With the exception of a high opening pressure, the patient’s CSF analysis is normal.

Differential Diagnosis

Idiopathic intracranial hypertension is essentially a diagnosis of exclusion, one that is made after exclusion of all other potential causes of increased ICP (Table). Since contrast CT and MRI can identify subtle anatomical deformities and small lesions, their absence on these studies can help establish a diagnosis of IIH.

Venous Sinus Thrombosis. Venous sinus thrombosis is a rare but devastating condition that also cannot be diagnosed from a noncontrast CT but must always be considered in the differential diagnosis of IIH.^8-10 Venous sinus thrombosis is characterized by a clot in one of the large venous sinuses that drain blood from the brain; the clot causes pressure to back up into the smaller cerebral vasculature, eventually inducing either a hemorrhagic stroke from a stressed vessel rupturing, or an ischemic stroke from lack of blood flow to the affected area of the brain. This condition is even more rare than IIH (0.5 cases per 100,000 population), but it can be devastating if missed, carrying a mortality rate as high as 15% in some studies.¹¹

Risk Factors

Risk factors known to cause cerebral venous clots include genetic thrombophilias, pregnancy or recent pregnancy, oral contraceptive use, inflammatory bowel disease, severe dehydration, local infection/trauma, and substance abuse. Regardless of risk factors, the most recent guidelines of the American Heart Association/American Stroke Association recommend imaging studies of the cerebral venous sinuses for any patient presenting with new-onset symptoms suggestive of IIH (Class 1, Level of Evidence C).¹¹ The two imaging options for evaluation of the cerebral venous sinuses are CT venography or MR venography. Since the 2013 American College of Radiology Appropriateness Criteria do not indicate a preference of one modality over the other, the choice of can be left to your radiologist.¹²

Patient Disposition

Patients with IIH typically do not require inpatient admission. Only about 3% of IIH patients will have a fulminant course of rapid-onset of vision loss, but even the most severe and acute cases will deteriorate over weeks, not hours or days.¹³ Never­theless, close neurology follow-up is essential. If rapid and thorough outpatient neurological care is unavailable, admission is required.

Management

Not every patient with IIH experiences amelioration or resolution of symptoms following an LP; moreover, there is no clear way to differentiate patients who will experience therapeutic effects from LP from those who will not. Serial LPs as treatment for IIH have been discussed in the literature, but a ventriculoperitoneal shunt is a more practical approach in patients who do not respond to an initial LP.^2,14

CSF Volume. The volume of CSF that can be removed safely may be 15 to 25 mL or more. A 1974 paper by Johnston and Paterson¹⁵ described five pseudotumor patients whose CSF was drained until their pressure had normalized; the amount removed varied from 15 to 25 mL, without adverse effects. A 1975 case series by Weisberg⁶ described safe removal of up to 30 mL of CSF in pseudotumor patients—the precise amount removed was determined by that which was necessary to lower the CSF pressure into the normal range. In 2007, a case report by Aly and Lawther¹⁶ of a pregnant woman with IIH describes twice weekly LP drainage of 30 mL.

There is nothing in the current literature to suggest that removing 10 to 30 mL of CSF instead of the 4 to 8 mL typically drawn in a diagnostic LP is going to pose any risk to the patient. The main complication associated with therapeutic LP is post-LP headache.^5,17,18 There are currently no studies documenting outcomes after specific amounts of CSF removal.

Lifestyle Modifications: Weight Loss. No prospective, randomized controlled trials have proven weight loss to be effective in ameliorating the symptoms of IIH; however, several studies have found that rapid weight loss—whether through aggressive dieting or gastric bypass surgery—can improve symptoms dramatically within several months.^19,20 One small study by Johnson et al has suggested that a 6% weight reduction is associated with marked improvement in papilledema.²¹Pharmacotherapy. The accepted first-line medication to alleviate symptoms of IIH is acetazolamide, and its use is supported by a recent randomized controlled trial conducted by the Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC).²² Most neurologists will administer a starting dose of acetazolamide 500 mg twice a day, and then increase the dose until symptoms are controlled or adverse effects appear (eg, fatigue, nausea/vomiting/diarrhea, electrolyte abnormalities, kidney stones) that contraindicate further dosage increases. In the NORDIC trial, patients were given up to 4 g of acetazolamide daily.²²

Other medications, including loop diuretics and corticosteroids, should not be used except under the direct supervision of a neurologist.^2,14

Refractory Cases

A patient who fails conservative treatment should be referred to a neurosurgeon for placement of a CSF shunt, optic nerve sheath fenestration, or placement of a venous sinus stent.²³

Case Conclusion

After a noncontrast CT of the head was interpreted as completely normal, an LP was performed with the patient in the left lateral recumbent position. The opening CSF pressure exceeded 55 cm H₂O (the upper limit of the manometer). The CSF was clear, and opening pressure was rechecked after each 5 mL draw. After 15 mL had been removed, the patient reported a sudden, dramatic disappearance of her headache and clearing of her vision. After 19 mL of CSF had been removed, the CSF pressure had dropped into the normal range (<20 cm H₂O), and the procedure was ended.

To definitively rule out venous sinus thrombosis, a CT venogram was performed in the ED, and interpreted as normal. All other CSF results (cell count, protein, glucose, and gram stain) were normal. After complete resolution of the patient’s symptoms, she was discharged home with a prescription for acetazolamide 500 mg twice daily and instructions to follow-up with a neurologist within 48 hours. At discharge, the patient also received weight-loss counseling and was instructed to return immediately to the ED if her headache recurred or if she experienced any new neurological symptoms.

Summary

Idiopathic intracranial hypertension, also referred to as pseudotumor cerebri, is a rare but potentially vision-threatening cause of headache. Patients with signs and symptoms of IIH often initially present to the ED for evaluation and management. While the etiology of IIH is poorly understood, its clinical picture is unique: elevated ICP (sometimes markedly so) with no other significant findings on noncontrast head CT or CSF analysis. Venous sinus thrombosis, a life-threatening mimic of IIH, must always be included in the differential diagnosis.

Idiopathic intracranial hypertension is initially treated with rapid weight loss and acetazolamide. Many patients experience instant, though sometimes only transient, symptom relief from LP. No definitive studies to support any specific approach, including “therapeutic lumbar punctures.” The condition is rarely fulminant, and hospital admission is not typically required as long as urgent outpatient neurology follow-up is available.

Case

A 24-year-old woman presented to the ED for evaluation of a 3-week history of worsening headache and a 5-day history of increasingly blurry vision. The patient stated that she had initially contacted her primary care physician, but instead presented to the ED because he had no open appointments until the following week and recommended that she go to the ED.

The patient described her headache as a pulsating and throbbing pain over her entire head, which only mildly improved after taking over-the-counter (OTC) ibuprofen. She further noted that her headache was somewhat worse when lying down, and reported the sensation of hearing her own pulsating heartbeat in her ears.

The patient had no personal or family history of migraines, tension headaches, aneurysms, clotting disorders, bleeding disorders, or renal disease, and stated that she had never experienced this type of headache before. She denied photophobia, phonophobia, neck stiffness, fever, vomiting, cough, numbness or weakness in her extremities, or pain anywhere else in her body.

Over the past 5 days, the patient noticed her vision had become increasingly blurry. She was not on any prescription medications, stating the only medication she used was occasional OTC ibuprofen. She had no known allergy to medications and denied smoking or recreational drug use; she admitted to occasional alcohol consumption.

The patient resided with her husband, who had no similar symptoms. Physical examination showed an obese woman (height, 5 ft 6 in; weight, 195 lb; body mass index, 32 kg/m²), lying supine in apparent discomfort. Vital signs at presentation were all normal, and oxygen saturation was normal on room air.

A bedside ocular examination showed 20/100 in both eyes while using glasses; no visual field cuts or obvious central scotoma was present. The patient was alert and oriented to time and place. The neurological examination showed intact cranial nerves, 5/5 strength in all extremities, intact sensation in all extremities, no pronator drift, negative Romberg test, and a normal gait. Fundoscopic examination revealed mildly blurred medial optic discs bilaterally. The rest of the physical examination was normal.

Discussion

Pseudotumor cerebri, more commonly referred to as idiopathic intracranial hypertension (IIH), is characterized by increased intracranial pressure (ICP) with no explanatory findings on imaging studies or in cerebrospinal fluid (CSF) analysis, and may be accompanied by symptoms of chronic headache, tinnitus, papilledema and progressive vision loss caused by optic nerve damage.¹ Though historically IIH was referred to by several other names, including “benign intracranial hypertension,” the condition is not benign—when untreated, IIH can cause chronic disabling headaches and permanent vision loss.¹

Clinical Course

The clinical course of IIH is unpredictable: In some patients, vision loss occurs gradually over the course of several weeks, while in others, loss occurs over a several month period. There are also patients with IIH who do not experience any alteration or loss of vision. Furthermore, some patients will experience permanent resolution of symptoms after a single lumbar puncture (LP); others have symptom recurrence after less than 24 hours; and some patients spontaneously remit on their own with no treatment whatsoever.^1-4

Etiology

In the United States, IIH is a rare cause of headache, occurring in just 1 person per 100,000 annually.¹ Though 90% of IIH cases occur in obese women of childbearing age, the etiology of IIH is unknown. Lumbar puncture usually alleviates the patient’s headache, but the CSF pressure typically returns to its pre-tap levels after a few hours.^4,5 Neither CSF overproduction nor insufficient CSF resorption is responsible for causing IIH. One theory on the etiology of IIH proposes its cause to be due to a congenital malformation of the venous sinuses. This theory would explain why the symptoms so closely mimic those of venous sinus thrombosis, and why some IIH patients experience relief of symptoms after placement of a venous sinus stent.²

Symptoms

As noted previously, the most common symptom of IIH is headache, which patients usually describe as pressure-like and throbbing, and often involving retro-ocular pain. One feature in over half of patients is pulse-synchronous tinnitus (ie, hearing their own heartbeat in their ears). Eye pain, photophobia, blurry vision, and nausea/vomiting are all common symptoms in IIH, but these symptoms are also present in other causes of headache. The IIH headache might be relapsing and remitting, and can last from a few hours to weeks.^2-4,6

Diagnosis

Imaging Studies. Noncontrast computed tomography (CT) imaging studies do not typically demonstrate any abnormal findings.¹ Magnetic resonance imaging (MRI) studies show some inconsistent and subtle findings, such as flattening of the backs of the eyeballs, empty sella, or tortuous optic nerves.¹

Lumbar Puncture. On LP, a very high opening pressure is a hallmark of IIH. An opening pressure <20 cm H₂O is generally considered normal, 20 cm to 25 cm H₂O is “equivocal,” and >25 cm H₂O is abnormal.⁷ Patients presenting with IIH commonly have an opening pressure that exceeds 200 cm H₂O.^1-3 Extremely high pressures, however, are not required for the diagnosis, but some elevations in opening pressure will always be present.^2,5 With the exception of a high opening pressure, the patient’s CSF analysis is normal.

Differential Diagnosis

Idiopathic intracranial hypertension is essentially a diagnosis of exclusion, one that is made after exclusion of all other potential causes of increased ICP (Table). Since contrast CT and MRI can identify subtle anatomical deformities and small lesions, their absence on these studies can help establish a diagnosis of IIH.

Venous Sinus Thrombosis. Venous sinus thrombosis is a rare but devastating condition that also cannot be diagnosed from a noncontrast CT but must always be considered in the differential diagnosis of IIH.^8-10 Venous sinus thrombosis is characterized by a clot in one of the large venous sinuses that drain blood from the brain; the clot causes pressure to back up into the smaller cerebral vasculature, eventually inducing either a hemorrhagic stroke from a stressed vessel rupturing, or an ischemic stroke from lack of blood flow to the affected area of the brain. This condition is even more rare than IIH (0.5 cases per 100,000 population), but it can be devastating if missed, carrying a mortality rate as high as 15% in some studies.¹¹

Risk Factors

Risk factors known to cause cerebral venous clots include genetic thrombophilias, pregnancy or recent pregnancy, oral contraceptive use, inflammatory bowel disease, severe dehydration, local infection/trauma, and substance abuse. Regardless of risk factors, the most recent guidelines of the American Heart Association/American Stroke Association recommend imaging studies of the cerebral venous sinuses for any patient presenting with new-onset symptoms suggestive of IIH (Class 1, Level of Evidence C).¹¹ The two imaging options for evaluation of the cerebral venous sinuses are CT venography or MR venography. Since the 2013 American College of Radiology Appropriateness Criteria do not indicate a preference of one modality over the other, the choice of can be left to your radiologist.¹²

Patient Disposition

Patients with IIH typically do not require inpatient admission. Only about 3% of IIH patients will have a fulminant course of rapid-onset of vision loss, but even the most severe and acute cases will deteriorate over weeks, not hours or days.¹³ Never­theless, close neurology follow-up is essential. If rapid and thorough outpatient neurological care is unavailable, admission is required.

Management

Not every patient with IIH experiences amelioration or resolution of symptoms following an LP; moreover, there is no clear way to differentiate patients who will experience therapeutic effects from LP from those who will not. Serial LPs as treatment for IIH have been discussed in the literature, but a ventriculoperitoneal shunt is a more practical approach in patients who do not respond to an initial LP.^2,14

CSF Volume. The volume of CSF that can be removed safely may be 15 to 25 mL or more. A 1974 paper by Johnston and Paterson¹⁵ described five pseudotumor patients whose CSF was drained until their pressure had normalized; the amount removed varied from 15 to 25 mL, without adverse effects. A 1975 case series by Weisberg⁶ described safe removal of up to 30 mL of CSF in pseudotumor patients—the precise amount removed was determined by that which was necessary to lower the CSF pressure into the normal range. In 2007, a case report by Aly and Lawther¹⁶ of a pregnant woman with IIH describes twice weekly LP drainage of 30 mL.

There is nothing in the current literature to suggest that removing 10 to 30 mL of CSF instead of the 4 to 8 mL typically drawn in a diagnostic LP is going to pose any risk to the patient. The main complication associated with therapeutic LP is post-LP headache.^5,17,18 There are currently no studies documenting outcomes after specific amounts of CSF removal.

Lifestyle Modifications: Weight Loss. No prospective, randomized controlled trials have proven weight loss to be effective in ameliorating the symptoms of IIH; however, several studies have found that rapid weight loss—whether through aggressive dieting or gastric bypass surgery—can improve symptoms dramatically within several months.^19,20 One small study by Johnson et al has suggested that a 6% weight reduction is associated with marked improvement in papilledema.²¹Pharmacotherapy. The accepted first-line medication to alleviate symptoms of IIH is acetazolamide, and its use is supported by a recent randomized controlled trial conducted by the Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC).²² Most neurologists will administer a starting dose of acetazolamide 500 mg twice a day, and then increase the dose until symptoms are controlled or adverse effects appear (eg, fatigue, nausea/vomiting/diarrhea, electrolyte abnormalities, kidney stones) that contraindicate further dosage increases. In the NORDIC trial, patients were given up to 4 g of acetazolamide daily.²²

Other medications, including loop diuretics and corticosteroids, should not be used except under the direct supervision of a neurologist.^2,14

Refractory Cases

A patient who fails conservative treatment should be referred to a neurosurgeon for placement of a CSF shunt, optic nerve sheath fenestration, or placement of a venous sinus stent.²³

Case Conclusion

After a noncontrast CT of the head was interpreted as completely normal, an LP was performed with the patient in the left lateral recumbent position. The opening CSF pressure exceeded 55 cm H₂O (the upper limit of the manometer). The CSF was clear, and opening pressure was rechecked after each 5 mL draw. After 15 mL had been removed, the patient reported a sudden, dramatic disappearance of her headache and clearing of her vision. After 19 mL of CSF had been removed, the CSF pressure had dropped into the normal range (<20 cm H₂O), and the procedure was ended.

To definitively rule out venous sinus thrombosis, a CT venogram was performed in the ED, and interpreted as normal. All other CSF results (cell count, protein, glucose, and gram stain) were normal. After complete resolution of the patient’s symptoms, she was discharged home with a prescription for acetazolamide 500 mg twice daily and instructions to follow-up with a neurologist within 48 hours. At discharge, the patient also received weight-loss counseling and was instructed to return immediately to the ED if her headache recurred or if she experienced any new neurological symptoms.

Summary

Idiopathic intracranial hypertension, also referred to as pseudotumor cerebri, is a rare but potentially vision-threatening cause of headache. Patients with signs and symptoms of IIH often initially present to the ED for evaluation and management. While the etiology of IIH is poorly understood, its clinical picture is unique: elevated ICP (sometimes markedly so) with no other significant findings on noncontrast head CT or CSF analysis. Venous sinus thrombosis, a life-threatening mimic of IIH, must always be included in the differential diagnosis.

Idiopathic intracranial hypertension is initially treated with rapid weight loss and acetazolamide. Many patients experience instant, though sometimes only transient, symptom relief from LP. No definitive studies to support any specific approach, including “therapeutic lumbar punctures.” The condition is rarely fulminant, and hospital admission is not typically required as long as urgent outpatient neurology follow-up is available.

A 45-year-old woman with a history of polycystic ovary syndrome presented to the ED for evaluation of acute abdominal pain. The patient’s surgical history was significant for a cesarean delivery 6 months prior to presentation. Abdominal examination revealed a well-healed suprapubic cesarean incision scar, which was tender upon palpation. A computed tomography (CT) scan of the abdomen and pelvis with contrast were ordered; representative images are shown above (Figure 1a-1d).

What is the diagnosis? What are the associated complications and preferred management for this entity?

Answer

The scout image from the CT scan shows multiple dilated loops of small bowel (white arrows, Figure 2a) and only a small amount of air within a decompressed colon (red arrow, Figure 2a). The multiplanar CT image confirmed multiple dilated small bowel loops (white arrows, Figure 2b) and the decompressed large bowel (red arrows, Figure 2b), indicating the presence of a small bowel obstruction. A distal small bowel loop (white arrows, Figure 2c and 2d) was identified in a hernia sac within the walls of the rectus abdominis muscle (red arrows, Figure 2c and 2d). Mesenteric stranding within the hernia sac was suggestive of incarceration (black arrow, Figure 2d). No signs of intestinal ischemia, such as pneumatosis or wall thickening, were present.

An exploratory laparotomy was emergently performed, which confirmed the presence of incarcerated small bowel within the posterior rectus sheath defect without evidence of strangulation. Reduction of small bowel and primary closure of the hernia defect was subsequently performed without complication.

Abdominal Wall Hernias

Abdominal wall hernias are common in the United States, with more than 1 million abdominal wall hernia repairs performed annually.¹ A posterior rectus sheath hernia is a rare type of abdominal wall hernia; the majority are postsurgical (as seen in this patient) or posttraumatic, with only a few reported congenital cases.²

Anatomy

The rectus sheath encloses the rectus abdominis muscle and is composed of the aponeuroses of the transversus abdominis, external oblique, and internal oblique muscles. The aponeuroses form an anterior and posterior sheath, which together serve as a strong barrier against the herniation of abdominal contents, accounting for the rarity of a spontaneous rectus sheath hernia. However, inferior to the umbilicus (below the arcuate line), the posterior rectus sheath is composed primarily of transversalis fascia, which may make this region more susceptible to herniation.³ Additional predisposing factors to herniation include increased muscle weakness and elevated intra-abdominal pressure, such as that which occurs during pregnancy or from ascites.⁴

Clinical Presentation

Like other abdominal wall hernias, the clinical presentation of posterior rectus sheath hernias is nonspecific. Patients may be asymptomatic or may develop abdominal pain, distension, and vomiting as a result of acute complications that necessitate emergent surgery. During history-taking, inquiry into a patient’s surgical history is crucial because it may raise clinical suspicion for an abdominal wall hernia, as was the case in our patient, who recently had a cesarean delivery.

Diagnosis

Because prompt and accurate diagnosis of acute complications of abdominal wall hernias is essential, imaging studies are typically required for diagnosis. Computed tomography is the modality of choice based on its ability to provide superior anatomic detail of the abdominal wall, permitting identification of hernias and differentiating them from other abdominal masses, such as hematomas, abscesses, or tumors. Additionally, CT is able to detect early signs of hernia sac complications, including bowel obstruction, incarceration, and strangulation.⁵

Treatment

Treatment for a posterior rectus sheath hernia is surgical with primary closure being the preferred method. Prosthetic repair may also be performed, particularly when the hernia defect is large, but it has been shown to be associated with an increased risk of intestinal strangulation.³

A 45-year-old woman with a history of polycystic ovary syndrome presented to the ED for evaluation of acute abdominal pain. The patient’s surgical history was significant for a cesarean delivery 6 months prior to presentation. Abdominal examination revealed a well-healed suprapubic cesarean incision scar, which was tender upon palpation. A computed tomography (CT) scan of the abdomen and pelvis with contrast were ordered; representative images are shown above (Figure 1a-1d).

What is the diagnosis? What are the associated complications and preferred management for this entity?

Answer

The scout image from the CT scan shows multiple dilated loops of small bowel (white arrows, Figure 2a) and only a small amount of air within a decompressed colon (red arrow, Figure 2a). The multiplanar CT image confirmed multiple dilated small bowel loops (white arrows, Figure 2b) and the decompressed large bowel (red arrows, Figure 2b), indicating the presence of a small bowel obstruction. A distal small bowel loop (white arrows, Figure 2c and 2d) was identified in a hernia sac within the walls of the rectus abdominis muscle (red arrows, Figure 2c and 2d). Mesenteric stranding within the hernia sac was suggestive of incarceration (black arrow, Figure 2d). No signs of intestinal ischemia, such as pneumatosis or wall thickening, were present.

An exploratory laparotomy was emergently performed, which confirmed the presence of incarcerated small bowel within the posterior rectus sheath defect without evidence of strangulation. Reduction of small bowel and primary closure of the hernia defect was subsequently performed without complication.

Abdominal Wall Hernias

Abdominal wall hernias are common in the United States, with more than 1 million abdominal wall hernia repairs performed annually.¹ A posterior rectus sheath hernia is a rare type of abdominal wall hernia; the majority are postsurgical (as seen in this patient) or posttraumatic, with only a few reported congenital cases.²

Anatomy

The rectus sheath encloses the rectus abdominis muscle and is composed of the aponeuroses of the transversus abdominis, external oblique, and internal oblique muscles. The aponeuroses form an anterior and posterior sheath, which together serve as a strong barrier against the herniation of abdominal contents, accounting for the rarity of a spontaneous rectus sheath hernia. However, inferior to the umbilicus (below the arcuate line), the posterior rectus sheath is composed primarily of transversalis fascia, which may make this region more susceptible to herniation.³ Additional predisposing factors to herniation include increased muscle weakness and elevated intra-abdominal pressure, such as that which occurs during pregnancy or from ascites.⁴

Clinical Presentation

Like other abdominal wall hernias, the clinical presentation of posterior rectus sheath hernias is nonspecific. Patients may be asymptomatic or may develop abdominal pain, distension, and vomiting as a result of acute complications that necessitate emergent surgery. During history-taking, inquiry into a patient’s surgical history is crucial because it may raise clinical suspicion for an abdominal wall hernia, as was the case in our patient, who recently had a cesarean delivery.

Diagnosis

Because prompt and accurate diagnosis of acute complications of abdominal wall hernias is essential, imaging studies are typically required for diagnosis. Computed tomography is the modality of choice based on its ability to provide superior anatomic detail of the abdominal wall, permitting identification of hernias and differentiating them from other abdominal masses, such as hematomas, abscesses, or tumors. Additionally, CT is able to detect early signs of hernia sac complications, including bowel obstruction, incarceration, and strangulation.⁵

Treatment

Treatment for a posterior rectus sheath hernia is surgical with primary closure being the preferred method. Prosthetic repair may also be performed, particularly when the hernia defect is large, but it has been shown to be associated with an increased risk of intestinal strangulation.³

A 45-year-old woman with a history of polycystic ovary syndrome presented to the ED for evaluation of acute abdominal pain. The patient’s surgical history was significant for a cesarean delivery 6 months prior to presentation. Abdominal examination revealed a well-healed suprapubic cesarean incision scar, which was tender upon palpation. A computed tomography (CT) scan of the abdomen and pelvis with contrast were ordered; representative images are shown above (Figure 1a-1d).

What is the diagnosis? What are the associated complications and preferred management for this entity?

Answer

The scout image from the CT scan shows multiple dilated loops of small bowel (white arrows, Figure 2a) and only a small amount of air within a decompressed colon (red arrow, Figure 2a). The multiplanar CT image confirmed multiple dilated small bowel loops (white arrows, Figure 2b) and the decompressed large bowel (red arrows, Figure 2b), indicating the presence of a small bowel obstruction. A distal small bowel loop (white arrows, Figure 2c and 2d) was identified in a hernia sac within the walls of the rectus abdominis muscle (red arrows, Figure 2c and 2d). Mesenteric stranding within the hernia sac was suggestive of incarceration (black arrow, Figure 2d). No signs of intestinal ischemia, such as pneumatosis or wall thickening, were present.

An exploratory laparotomy was emergently performed, which confirmed the presence of incarcerated small bowel within the posterior rectus sheath defect without evidence of strangulation. Reduction of small bowel and primary closure of the hernia defect was subsequently performed without complication.

Abdominal Wall Hernias

Abdominal wall hernias are common in the United States, with more than 1 million abdominal wall hernia repairs performed annually.¹ A posterior rectus sheath hernia is a rare type of abdominal wall hernia; the majority are postsurgical (as seen in this patient) or posttraumatic, with only a few reported congenital cases.²

Anatomy

The rectus sheath encloses the rectus abdominis muscle and is composed of the aponeuroses of the transversus abdominis, external oblique, and internal oblique muscles. The aponeuroses form an anterior and posterior sheath, which together serve as a strong barrier against the herniation of abdominal contents, accounting for the rarity of a spontaneous rectus sheath hernia. However, inferior to the umbilicus (below the arcuate line), the posterior rectus sheath is composed primarily of transversalis fascia, which may make this region more susceptible to herniation.³ Additional predisposing factors to herniation include increased muscle weakness and elevated intra-abdominal pressure, such as that which occurs during pregnancy or from ascites.⁴

Clinical Presentation

Like other abdominal wall hernias, the clinical presentation of posterior rectus sheath hernias is nonspecific. Patients may be asymptomatic or may develop abdominal pain, distension, and vomiting as a result of acute complications that necessitate emergent surgery. During history-taking, inquiry into a patient’s surgical history is crucial because it may raise clinical suspicion for an abdominal wall hernia, as was the case in our patient, who recently had a cesarean delivery.

Diagnosis

Because prompt and accurate diagnosis of acute complications of abdominal wall hernias is essential, imaging studies are typically required for diagnosis. Computed tomography is the modality of choice based on its ability to provide superior anatomic detail of the abdominal wall, permitting identification of hernias and differentiating them from other abdominal masses, such as hematomas, abscesses, or tumors. Additionally, CT is able to detect early signs of hernia sac complications, including bowel obstruction, incarceration, and strangulation.⁵

Treatment

Treatment for a posterior rectus sheath hernia is surgical with primary closure being the preferred method. Prosthetic repair may also be performed, particularly when the hernia defect is large, but it has been shown to be associated with an increased risk of intestinal strangulation.³

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵