Case Reports

Acute generalized exanthematous pustulosis (AGEP) is a potentially widespread, pustular, cutaneous eruption. In 90% of cases, AGEP results from drug administration.^1,2 It manifests as numerous subcorneal, nonfollicular, sterile pustules of rapid onset on an erythematous base,² often in conjunction with fever, peripheral leukocytosis, and neutrophilia.³ Numerous drug therapies have been implicated in the etiology of AGEP, most commonly the β-lactam antibiotics, such as the penicillin derivatives and cephalosporins.² Typically, AGEP occurs soon after drug ingestion and resolves spontaneously, shortly after the causative drug is discontinued.

Ranolazine is an antianginal, anti-ischemic medication with an undetermined mechanism of action. Its antianginal and anti-ischemic effects do not depend on reduced heart rate or blood pressure. At therapeutic levels, it inhibits the cardiac late sodium current (I_Na), reducing the sodium-induced calcium overload in ischemic cardiac myocytes. Severe adverse reactions include angioedema; paresthesia; pancytopenia; and, in animal studies, tumorigenicity.⁴ Herein we report a case of AGEP associated with the use of ranolazine.

Case Report

An 83-year-old man presented with a generalized rash of approximately 12 days’ duration. The patient reported that the small “pimple-like” bumps initially erupted on the back of the neck but gradually spread to the chest, back, and extremities. The lesions were asymptomatic at the outset and became pruritic over time. For the last several years, the patient had been taking tamsulosin for benign prostatic hypertrophy and rosuvastatin for hyperlipidemia. Twelve days prior to the exanthem, he had started taking ranolazine for symptomatic ischemia until coronary angiography could be performed. He reported having no associated fevers, chills, or malaise and had no personal history of psoriasis, though he had a maternal history of the disorder.

Examination revealed numerous nonfollicular-based pustules on diffuse erythematous patches (Figure 1). There was no mucosal involvement and the skin was negative for the Nikolsky sign. Spongiform intracorneal collections of neutrophils were visible on punch biopsy (Figures 2 and 3). Periodic acid–Schiff stains for fungi were negative.

Figure 2. A punch biopsy showed spongiform intracorneal collections of neutrophils (H&E, original magnification ×200).		Figure 3. A cornified layer of epidermis with neutrophils, as visible on punch biopsy (H&E, original magnification ×630).

The patient’s primary care physician had initiated a course of oral prednisone 5 mg daily, 3 days before he presented to our outpatient dermatology clinic, but it had little effect on the rash. Upon dermatologic evaluation, we discontinued ranolazine therapy and prescribed the following tapered course of oral prednisone: 60 mg daily for 4 days; 40 mg daily for 
3 days; 30 mg daily for 3 days; 20 mg daily for 3 days; 10 mg daily for 3 days; and 5 mg daily for 3 days). Within a week after this regimen was initiated, the rash showed improvement with eventual resolution and desquamation (Figure 4). Subsequently, the patient underwent successful angioplasty and multiple stent placement, which ultimately alleviated his angina.

Comment

Since its original description in 1968,⁵ AGEP has been misdiagnosed and underreported. Due to its rarity and clinical resemblance to more common pustular eruptions, such as exanthematous pustular psoriasis, the typical characteristics of AGEP were not clearly delineated until Beylot et al³ coined the term AGEP in 1980. Since that time, formalized criteria for the diagnosis and characterization of AGEP have been published.^1,2,6-8

Numerous drug therapies have been implicated in the etiology of AGEP, most commonly antimicrobial agents, such as β-lactam antibiotics. Many other drugs, however, also have been identified as potential causative agents,⁸ including but not limited to antifungal, anticonvulsant, and antihypertensive agents. Other less common etiologies include viral infections,^6,9-11 UV radiation, contrast media, heavy metal exposure (eg, to mercury), ingestion of urushiol (eg, in lacquered chicken), and spider bites.^2,8,12-16 Nevertheless, more than 90% 
of AGEP cases are attributed to drug exposure, with 80% of drug-induced cases believed to be caused 
by antibiotics.^1,8

The incidence of AGEP is estimated to be between 1 and 5 cases per million per year, using inclusion criteria from the EuroSCAR study, a multinational, case-controlled, pharmacoepidemiologic study of severe cutaneous adverse reactions.^8,16 The condition seems to affect males and females equally.^1,4 There are no reports of age or racial predilection.^1,6,17 It has been suggested that those with AGEP may have some form of psoriatic background.¹ Our patient had no personal history of inflammatory skin disease, although his mother had psoriasis.

The dermatitis presents as the sudden onset of a diffuse exanthematous eruption, which typically produces dozens to hundreds of sterile, nonfollicular, superficial pustules on an erythematous and possibly edematous base. Atypical presentations include target lesions, purpura, and vesicles. The reaction usually begins on the face or intertriginous areas of flexural surfaces and quickly disseminates. Patients may experience burning or pruritus. Acute generalized exanthematous pustulosis may involve mucous membranes but is usually limited to 1 location, most often the oral mucosa.^1,8,16,18 Systemic signs and symptoms include fever, lymphadenopathy, pharyngitis, and hepatosplenomegaly. Unlike most drug allergies that demonstrate eosinophilia, AGEP is associated with leukocytosis and neutrophilic predominance. Only 25% of affected patients exhibit eosinophilia.¹ Approximately 30% of patients in a retrospective analysis demonstrated abnormal renal function,² and there have been reports of mildly elevated transaminases.^8,19

In the EuroSCAR study, for reasons that were not apparent, symptoms developed within 
24 hours of exposure to triggering antibiotics, whereas the median time to rash onset in response to 
non–anti-infective agents was 11 days.⁸ This finding is consistent with the delayed onset of symptoms experienced by our patient after initiating ranolazine therapy.

The differential diagnosis of AGEP primarily includes pustular psoriasis, subcorneal pustulosis, pustular folliculitis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, bullous impetigo, and occasionally erythema multiforme and toxic epidermal necrolysis, with the latter typically characterized by more mucous membrane involvement.²⁰ Biopsy does not always support a definitive diagnosis; clinical correlation is often necessary. Because of the EuroSCAR study, Sidoroff et al⁸ devised a clinical validation score based on morphology (presence of pustules and erythema, distribution, and eventual desquamation), histopathology (presence of intraepidermal pustules, spongiosis, and papillary edema), and disease course (duration of symptoms, neutrophilia, fever, acute onset, and time to resolution). A definitive score is 8 to 12 (out of 12), and our patient’s score was 10; the score may have been higher had blood work been performed, but by the time the diagnosis was made the patient’s condition had improved enough to make laboratory workup unnecessary.

Several theories have been proposed to explain the pathophysiology of AGEP. Some hold that the causative agent induces the formation of antigen-antibody complexes, thereby activating the complement system, which in turn produces neutrophil chemotaxis.^3,21 A more recent theory suggests that drug exposure causes drug-specific CD4 and CD8 cells to migrate into dermal and epidermal layers of the skin.¹⁷ Both T cells and keratinocytes express IL-8, which attracts polymorphonuclear leukocytes, causing them to accumulate in the dermis and then the epidermis. The different clinical presentations of AGEP may be attributed to other cytokines and interleukins that T cells express during this process. In the epidermis, CD8 cells kill keratinocytes, causing focal necrosis and prompting the formation of subcorneal vesicles filled primarily with CD4 cells. CD4 and CD8 cells are then localized to the dermis where neutrophils enter the vesicles, transforming them into sterile pustules.^6,16,17

Acute generalized exanthematous pustulosis has been characterized as a type IV delayed hypersensitivity reaction, with affected patients often demonstrating positive patch testing or a history of prior sensitization to the perpetrating agent.^18,19,21 Although there have been reports of positive patch testing for certain drugs, the unknown sensitivity and specificity of such testing as well as preparation-dependent variables may limit the diagnostic utility of this approach.²¹ The additional risk for inducing AGEP by patch testing the suspected drug also is a consideration. Due to our patient’s definitive clinical validation score, we did not perform this test.²¹

The AGEP eruption is typically self-limited and tends to resolve within 4 to 10 days after cessation of the triggering agent. Postpustular desquamation often occurs upon resolution of the primary lesions. Treatment usually involves discontinuation of the suspected causative agent and the use of antihistamines, antipyretics, topical corticosteroids, and emollients. Although there are reports of AGEP responsiveness to oral and intravenous steroids, such treatment rarely is required.^8,16,22 
We prescribed a tapered course of oral prednisone due to our patient’s imminent need for angioplasty.

Conclusion

This case of AGEP induced by ranolazine is notable. Given the potential widespread use of this antianginal medication and the severity of this potential adverse reaction, it is important for clinicians to recognize AGEP, discontinue ranolazine if determined to be a causative agent, and then initiate an appropriate alternative antianginal therapy.

Acute generalized exanthematous pustulosis (AGEP) is a potentially widespread, pustular, cutaneous eruption. In 90% of cases, AGEP results from drug administration.^1,2 It manifests as numerous subcorneal, nonfollicular, sterile pustules of rapid onset on an erythematous base,² often in conjunction with fever, peripheral leukocytosis, and neutrophilia.³ Numerous drug therapies have been implicated in the etiology of AGEP, most commonly the β-lactam antibiotics, such as the penicillin derivatives and cephalosporins.² Typically, AGEP occurs soon after drug ingestion and resolves spontaneously, shortly after the causative drug is discontinued.

Ranolazine is an antianginal, anti-ischemic medication with an undetermined mechanism of action. Its antianginal and anti-ischemic effects do not depend on reduced heart rate or blood pressure. At therapeutic levels, it inhibits the cardiac late sodium current (I_Na), reducing the sodium-induced calcium overload in ischemic cardiac myocytes. Severe adverse reactions include angioedema; paresthesia; pancytopenia; and, in animal studies, tumorigenicity.⁴ Herein we report a case of AGEP associated with the use of ranolazine.

Case Report

An 83-year-old man presented with a generalized rash of approximately 12 days’ duration. The patient reported that the small “pimple-like” bumps initially erupted on the back of the neck but gradually spread to the chest, back, and extremities. The lesions were asymptomatic at the outset and became pruritic over time. For the last several years, the patient had been taking tamsulosin for benign prostatic hypertrophy and rosuvastatin for hyperlipidemia. Twelve days prior to the exanthem, he had started taking ranolazine for symptomatic ischemia until coronary angiography could be performed. He reported having no associated fevers, chills, or malaise and had no personal history of psoriasis, though he had a maternal history of the disorder.

Examination revealed numerous nonfollicular-based pustules on diffuse erythematous patches (Figure 1). There was no mucosal involvement and the skin was negative for the Nikolsky sign. Spongiform intracorneal collections of neutrophils were visible on punch biopsy (Figures 2 and 3). Periodic acid–Schiff stains for fungi were negative.

Figure 2. A punch biopsy showed spongiform intracorneal collections of neutrophils (H&E, original magnification ×200).		Figure 3. A cornified layer of epidermis with neutrophils, as visible on punch biopsy (H&E, original magnification ×630).

The patient’s primary care physician had initiated a course of oral prednisone 5 mg daily, 3 days before he presented to our outpatient dermatology clinic, but it had little effect on the rash. Upon dermatologic evaluation, we discontinued ranolazine therapy and prescribed the following tapered course of oral prednisone: 60 mg daily for 4 days; 40 mg daily for 
3 days; 30 mg daily for 3 days; 20 mg daily for 3 days; 10 mg daily for 3 days; and 5 mg daily for 3 days). Within a week after this regimen was initiated, the rash showed improvement with eventual resolution and desquamation (Figure 4). Subsequently, the patient underwent successful angioplasty and multiple stent placement, which ultimately alleviated his angina.

Comment

Since its original description in 1968,⁵ AGEP has been misdiagnosed and underreported. Due to its rarity and clinical resemblance to more common pustular eruptions, such as exanthematous pustular psoriasis, the typical characteristics of AGEP were not clearly delineated until Beylot et al³ coined the term AGEP in 1980. Since that time, formalized criteria for the diagnosis and characterization of AGEP have been published.^1,2,6-8

Numerous drug therapies have been implicated in the etiology of AGEP, most commonly antimicrobial agents, such as β-lactam antibiotics. Many other drugs, however, also have been identified as potential causative agents,⁸ including but not limited to antifungal, anticonvulsant, and antihypertensive agents. Other less common etiologies include viral infections,^6,9-11 UV radiation, contrast media, heavy metal exposure (eg, to mercury), ingestion of urushiol (eg, in lacquered chicken), and spider bites.^2,8,12-16 Nevertheless, more than 90% 
of AGEP cases are attributed to drug exposure, with 80% of drug-induced cases believed to be caused 
by antibiotics.^1,8

The incidence of AGEP is estimated to be between 1 and 5 cases per million per year, using inclusion criteria from the EuroSCAR study, a multinational, case-controlled, pharmacoepidemiologic study of severe cutaneous adverse reactions.^8,16 The condition seems to affect males and females equally.^1,4 There are no reports of age or racial predilection.^1,6,17 It has been suggested that those with AGEP may have some form of psoriatic background.¹ Our patient had no personal history of inflammatory skin disease, although his mother had psoriasis.

The dermatitis presents as the sudden onset of a diffuse exanthematous eruption, which typically produces dozens to hundreds of sterile, nonfollicular, superficial pustules on an erythematous and possibly edematous base. Atypical presentations include target lesions, purpura, and vesicles. The reaction usually begins on the face or intertriginous areas of flexural surfaces and quickly disseminates. Patients may experience burning or pruritus. Acute generalized exanthematous pustulosis may involve mucous membranes but is usually limited to 1 location, most often the oral mucosa.^1,8,16,18 Systemic signs and symptoms include fever, lymphadenopathy, pharyngitis, and hepatosplenomegaly. Unlike most drug allergies that demonstrate eosinophilia, AGEP is associated with leukocytosis and neutrophilic predominance. Only 25% of affected patients exhibit eosinophilia.¹ Approximately 30% of patients in a retrospective analysis demonstrated abnormal renal function,² and there have been reports of mildly elevated transaminases.^8,19

In the EuroSCAR study, for reasons that were not apparent, symptoms developed within 
24 hours of exposure to triggering antibiotics, whereas the median time to rash onset in response to 
non–anti-infective agents was 11 days.⁸ This finding is consistent with the delayed onset of symptoms experienced by our patient after initiating ranolazine therapy.

The differential diagnosis of AGEP primarily includes pustular psoriasis, subcorneal pustulosis, pustular folliculitis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, bullous impetigo, and occasionally erythema multiforme and toxic epidermal necrolysis, with the latter typically characterized by more mucous membrane involvement.²⁰ Biopsy does not always support a definitive diagnosis; clinical correlation is often necessary. Because of the EuroSCAR study, Sidoroff et al⁸ devised a clinical validation score based on morphology (presence of pustules and erythema, distribution, and eventual desquamation), histopathology (presence of intraepidermal pustules, spongiosis, and papillary edema), and disease course (duration of symptoms, neutrophilia, fever, acute onset, and time to resolution). A definitive score is 8 to 12 (out of 12), and our patient’s score was 10; the score may have been higher had blood work been performed, but by the time the diagnosis was made the patient’s condition had improved enough to make laboratory workup unnecessary.

Several theories have been proposed to explain the pathophysiology of AGEP. Some hold that the causative agent induces the formation of antigen-antibody complexes, thereby activating the complement system, which in turn produces neutrophil chemotaxis.^3,21 A more recent theory suggests that drug exposure causes drug-specific CD4 and CD8 cells to migrate into dermal and epidermal layers of the skin.¹⁷ Both T cells and keratinocytes express IL-8, which attracts polymorphonuclear leukocytes, causing them to accumulate in the dermis and then the epidermis. The different clinical presentations of AGEP may be attributed to other cytokines and interleukins that T cells express during this process. In the epidermis, CD8 cells kill keratinocytes, causing focal necrosis and prompting the formation of subcorneal vesicles filled primarily with CD4 cells. CD4 and CD8 cells are then localized to the dermis where neutrophils enter the vesicles, transforming them into sterile pustules.^6,16,17

Acute generalized exanthematous pustulosis has been characterized as a type IV delayed hypersensitivity reaction, with affected patients often demonstrating positive patch testing or a history of prior sensitization to the perpetrating agent.^18,19,21 Although there have been reports of positive patch testing for certain drugs, the unknown sensitivity and specificity of such testing as well as preparation-dependent variables may limit the diagnostic utility of this approach.²¹ The additional risk for inducing AGEP by patch testing the suspected drug also is a consideration. Due to our patient’s definitive clinical validation score, we did not perform this test.²¹

The AGEP eruption is typically self-limited and tends to resolve within 4 to 10 days after cessation of the triggering agent. Postpustular desquamation often occurs upon resolution of the primary lesions. Treatment usually involves discontinuation of the suspected causative agent and the use of antihistamines, antipyretics, topical corticosteroids, and emollients. Although there are reports of AGEP responsiveness to oral and intravenous steroids, such treatment rarely is required.^8,16,22 
We prescribed a tapered course of oral prednisone due to our patient’s imminent need for angioplasty.

Conclusion

This case of AGEP induced by ranolazine is notable. Given the potential widespread use of this antianginal medication and the severity of this potential adverse reaction, it is important for clinicians to recognize AGEP, discontinue ranolazine if determined to be a causative agent, and then initiate an appropriate alternative antianginal therapy.

Acute generalized exanthematous pustulosis (AGEP) is a potentially widespread, pustular, cutaneous eruption. In 90% of cases, AGEP results from drug administration.^1,2 It manifests as numerous subcorneal, nonfollicular, sterile pustules of rapid onset on an erythematous base,² often in conjunction with fever, peripheral leukocytosis, and neutrophilia.³ Numerous drug therapies have been implicated in the etiology of AGEP, most commonly the β-lactam antibiotics, such as the penicillin derivatives and cephalosporins.² Typically, AGEP occurs soon after drug ingestion and resolves spontaneously, shortly after the causative drug is discontinued.

Ranolazine is an antianginal, anti-ischemic medication with an undetermined mechanism of action. Its antianginal and anti-ischemic effects do not depend on reduced heart rate or blood pressure. At therapeutic levels, it inhibits the cardiac late sodium current (I_Na), reducing the sodium-induced calcium overload in ischemic cardiac myocytes. Severe adverse reactions include angioedema; paresthesia; pancytopenia; and, in animal studies, tumorigenicity.⁴ Herein we report a case of AGEP associated with the use of ranolazine.

Case Report

An 83-year-old man presented with a generalized rash of approximately 12 days’ duration. The patient reported that the small “pimple-like” bumps initially erupted on the back of the neck but gradually spread to the chest, back, and extremities. The lesions were asymptomatic at the outset and became pruritic over time. For the last several years, the patient had been taking tamsulosin for benign prostatic hypertrophy and rosuvastatin for hyperlipidemia. Twelve days prior to the exanthem, he had started taking ranolazine for symptomatic ischemia until coronary angiography could be performed. He reported having no associated fevers, chills, or malaise and had no personal history of psoriasis, though he had a maternal history of the disorder.

Examination revealed numerous nonfollicular-based pustules on diffuse erythematous patches (Figure 1). There was no mucosal involvement and the skin was negative for the Nikolsky sign. Spongiform intracorneal collections of neutrophils were visible on punch biopsy (Figures 2 and 3). Periodic acid–Schiff stains for fungi were negative.

Figure 2. A punch biopsy showed spongiform intracorneal collections of neutrophils (H&E, original magnification ×200).		Figure 3. A cornified layer of epidermis with neutrophils, as visible on punch biopsy (H&E, original magnification ×630).

The patient’s primary care physician had initiated a course of oral prednisone 5 mg daily, 3 days before he presented to our outpatient dermatology clinic, but it had little effect on the rash. Upon dermatologic evaluation, we discontinued ranolazine therapy and prescribed the following tapered course of oral prednisone: 60 mg daily for 4 days; 40 mg daily for 
3 days; 30 mg daily for 3 days; 20 mg daily for 3 days; 10 mg daily for 3 days; and 5 mg daily for 3 days). Within a week after this regimen was initiated, the rash showed improvement with eventual resolution and desquamation (Figure 4). Subsequently, the patient underwent successful angioplasty and multiple stent placement, which ultimately alleviated his angina.

Comment

Since its original description in 1968,⁵ AGEP has been misdiagnosed and underreported. Due to its rarity and clinical resemblance to more common pustular eruptions, such as exanthematous pustular psoriasis, the typical characteristics of AGEP were not clearly delineated until Beylot et al³ coined the term AGEP in 1980. Since that time, formalized criteria for the diagnosis and characterization of AGEP have been published.^1,2,6-8

Numerous drug therapies have been implicated in the etiology of AGEP, most commonly antimicrobial agents, such as β-lactam antibiotics. Many other drugs, however, also have been identified as potential causative agents,⁸ including but not limited to antifungal, anticonvulsant, and antihypertensive agents. Other less common etiologies include viral infections,^6,9-11 UV radiation, contrast media, heavy metal exposure (eg, to mercury), ingestion of urushiol (eg, in lacquered chicken), and spider bites.^2,8,12-16 Nevertheless, more than 90% 
of AGEP cases are attributed to drug exposure, with 80% of drug-induced cases believed to be caused 
by antibiotics.^1,8

The incidence of AGEP is estimated to be between 1 and 5 cases per million per year, using inclusion criteria from the EuroSCAR study, a multinational, case-controlled, pharmacoepidemiologic study of severe cutaneous adverse reactions.^8,16 The condition seems to affect males and females equally.^1,4 There are no reports of age or racial predilection.^1,6,17 It has been suggested that those with AGEP may have some form of psoriatic background.¹ Our patient had no personal history of inflammatory skin disease, although his mother had psoriasis.

The dermatitis presents as the sudden onset of a diffuse exanthematous eruption, which typically produces dozens to hundreds of sterile, nonfollicular, superficial pustules on an erythematous and possibly edematous base. Atypical presentations include target lesions, purpura, and vesicles. The reaction usually begins on the face or intertriginous areas of flexural surfaces and quickly disseminates. Patients may experience burning or pruritus. Acute generalized exanthematous pustulosis may involve mucous membranes but is usually limited to 1 location, most often the oral mucosa.^1,8,16,18 Systemic signs and symptoms include fever, lymphadenopathy, pharyngitis, and hepatosplenomegaly. Unlike most drug allergies that demonstrate eosinophilia, AGEP is associated with leukocytosis and neutrophilic predominance. Only 25% of affected patients exhibit eosinophilia.¹ Approximately 30% of patients in a retrospective analysis demonstrated abnormal renal function,² and there have been reports of mildly elevated transaminases.^8,19

In the EuroSCAR study, for reasons that were not apparent, symptoms developed within 
24 hours of exposure to triggering antibiotics, whereas the median time to rash onset in response to 
non–anti-infective agents was 11 days.⁸ This finding is consistent with the delayed onset of symptoms experienced by our patient after initiating ranolazine therapy.

The differential diagnosis of AGEP primarily includes pustular psoriasis, subcorneal pustulosis, pustular folliculitis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, bullous impetigo, and occasionally erythema multiforme and toxic epidermal necrolysis, with the latter typically characterized by more mucous membrane involvement.²⁰ Biopsy does not always support a definitive diagnosis; clinical correlation is often necessary. Because of the EuroSCAR study, Sidoroff et al⁸ devised a clinical validation score based on morphology (presence of pustules and erythema, distribution, and eventual desquamation), histopathology (presence of intraepidermal pustules, spongiosis, and papillary edema), and disease course (duration of symptoms, neutrophilia, fever, acute onset, and time to resolution). A definitive score is 8 to 12 (out of 12), and our patient’s score was 10; the score may have been higher had blood work been performed, but by the time the diagnosis was made the patient’s condition had improved enough to make laboratory workup unnecessary.

Several theories have been proposed to explain the pathophysiology of AGEP. Some hold that the causative agent induces the formation of antigen-antibody complexes, thereby activating the complement system, which in turn produces neutrophil chemotaxis.^3,21 A more recent theory suggests that drug exposure causes drug-specific CD4 and CD8 cells to migrate into dermal and epidermal layers of the skin.¹⁷ Both T cells and keratinocytes express IL-8, which attracts polymorphonuclear leukocytes, causing them to accumulate in the dermis and then the epidermis. The different clinical presentations of AGEP may be attributed to other cytokines and interleukins that T cells express during this process. In the epidermis, CD8 cells kill keratinocytes, causing focal necrosis and prompting the formation of subcorneal vesicles filled primarily with CD4 cells. CD4 and CD8 cells are then localized to the dermis where neutrophils enter the vesicles, transforming them into sterile pustules.^6,16,17

Acute generalized exanthematous pustulosis has been characterized as a type IV delayed hypersensitivity reaction, with affected patients often demonstrating positive patch testing or a history of prior sensitization to the perpetrating agent.^18,19,21 Although there have been reports of positive patch testing for certain drugs, the unknown sensitivity and specificity of such testing as well as preparation-dependent variables may limit the diagnostic utility of this approach.²¹ The additional risk for inducing AGEP by patch testing the suspected drug also is a consideration. Due to our patient’s definitive clinical validation score, we did not perform this test.²¹

The AGEP eruption is typically self-limited and tends to resolve within 4 to 10 days after cessation of the triggering agent. Postpustular desquamation often occurs upon resolution of the primary lesions. Treatment usually involves discontinuation of the suspected causative agent and the use of antihistamines, antipyretics, topical corticosteroids, and emollients. Although there are reports of AGEP responsiveness to oral and intravenous steroids, such treatment rarely is required.^8,16,22 
We prescribed a tapered course of oral prednisone due to our patient’s imminent need for angioplasty.

Conclusion

This case of AGEP induced by ranolazine is notable. Given the potential widespread use of this antianginal medication and the severity of this potential adverse reaction, it is important for clinicians to recognize AGEP, discontinue ranolazine if determined to be a causative agent, and then initiate an appropriate alternative antianginal therapy.

THE CASE

A 76-year-old man with a history of coronary artery disease presented with a fever, headache, and malaise one week after returning from a big game hunting trip in South Africa. Five days after his return, he noticed lesions on his right leg that eventually scabbed over. He sought care at his local emergency department and with his primary care physician, and completed an empiric trial of azithromycin. His symptoms, however, persisted and he was referred to our institution for evaluation and treatment.

On exam, he had a temperature of 100.5° F, inguinal lymphadenopathy, and 2 eschars: a 1.5 cm one on his right groin and an identical one on the medial aspect of the right popliteal fossa (FIGURE 1).

THE DIAGNOSIS

Laboratory studies showed a white blood cell count of 3000/mcL, hemoglobin of 14.1 g/dL, and platelet count of 142,000/mcL; peripheral blood smear was normal. Blood and urine cultures showed no growth. A malaria smear and antibodies for Lyme disease, dengue fever, Chikungunya virus, and Q fever were also negative. A biopsy of the eschar demonstrated epidermal and dermal necrosis consistent with infectious vasculitis caused by rickettsial disease (FIGURE 2). A polymerase chain reaction (PCR) for the spotted fever group (R rickettsii, R akari, and R conorii) and typhus fever group of rickettsial agents (R typhi and R prowazekii) were negative. However, a PCR was positive for R africae, confirming the diagnosis of African tick-bite fever (ATBF).

DISCUSSION

Two common reasons patients returning from international travel seek medical attention are fever and rash.¹ Initial assessment should include a detailed travel history of urban and rural exposures and any possible exposure to ticks or fleas. The time course of symptoms is important because some tropical infections can have long incubation periods.²

Rickettsial diseases are the most common febrile illness in patients returning from international travel.¹ ATBF caused by R africae is the most common rickettsiosis among returning travelers¹ and may be the most widespread of all spotted fever group rickettsiae that are known to be pathogenic to humans.³R africae is endemic to South Africa. The risk of contracting R africae is 4 to 5 times higher than the risk of contracting malaria in South Africa.¹

The risk of contracting R africae is 4 to 5 times higher than the risk of contracting malaria in South Africa.

R africae is transmitted through cattle and game ticks (Amblyomma species),^1-7 and tends to cause mild illness with rare progression to complicated disease.³ The risk of infection is particularly high from November to April,⁷ and our patient had traveled during April.

Most patients with ATBF present with fever, headache, and malaise, and 50% develop a variable rash.^1,2 Local lymphadenopathy often develops, and marked neck stiffness can occur.² An eschar is present in 95% of cases.² The finding of an eschar is often indicative of rickettsial infection; however, not all rickettsioses show eschars, and the absence of an eschar does not exclude rickettsial infection.¹

ATBF is usually benign and self-limiting, and no fatalities have been reported.^2,4,8 Complications such as peripheral nerve involvement, encephalitis, and myocarditis are rare.^5,8 Since rickettsial diseases may be more severe in elderly patients with underlying diseases, empiric treatment with inpatient monitoring is justifiable.⁵

Don’t wait for lab confirmation to begin antibiotics

Laboratory findings in a patient with ATBF include pancytopenia, elevated serum C-reactive protein, and abnormal liver function tests.^2,4 A blood PCR detects R africae,^1,3 and if a rash or eschar is present, a biopsy can confirm the diagnosis.¹ However, confirming the diagnosis is difficult if seroconversion has not occurred and PCR is not readily available.¹ Also, antibodies may not be detected in patients who have a mild case of ATBF or those who are immunocompromised.⁵

If you suspect your patient has ATBF, don’t wait for laboratory confirmation; instead, initiate empiric treatment with doxycycline 100 mg bid twice daily for 5 to 7 days.^1,2,4

Preventive measures include repellant lotions, clothing, and gear

Since there are no vaccines or prophylactic treatments for ATBF, counsel travelers on preventive measures.⁹ Instruct patients who plan to visit an endemic area such as sub-Saharan Africa or the West Indies to wear long-sleeved shirts, long pants, and hats. Individuals should also tuck their shirts into their pants and their pants into socks, as well as wear closed-toe shoes. When possible, it’s advisable to avoid woody and brushy areas.

Over-the-counter repellant lotions that contain ≥20% DEET are effective at preventing tick bites for several hours after an application, but should be reapplied as directed.⁹ These lotions should be applied after sunscreen. Advise patients that they can purchase clothing and gear that have been treated with the pesticide permethrin, or they can treat clothing and gear themselves. Explain, however, that permethrin should not be applied directly to skin.

Finally, instruct travelers to perform daily tick inspections and shower or bathe as soon as possible after returning from the outdoors.⁹ Educate patients on the proper technique for tick removal, which is described on the Centers for Disease Control and Prevention’s Web site at http://www.cdc.gov/ticks/removing_a_tick.html.

Our patient completed a 2-week course of doxycycline 100 mg bid. His symptoms and laboratory abnormalities completely resolved.

THE TAKEAWAY

ATBF is the most common rickettsiosis among patients returning from international travel. Because patients may present with several nonspecific symptoms, maintain a high index of suspicion for rickettsial infection among patients returning from sub-Saharan Africa or the West Indies. Though the disease usually can be successfully managed in the outpatient setting with doxycycline, elderly patients or those with comorbid conditions may require inpatient care. Educate patients who plan to travel to an endemic area about measures they can take to prevent exposure to ticks and subsequent infection.

THE CASE

A 76-year-old man with a history of coronary artery disease presented with a fever, headache, and malaise one week after returning from a big game hunting trip in South Africa. Five days after his return, he noticed lesions on his right leg that eventually scabbed over. He sought care at his local emergency department and with his primary care physician, and completed an empiric trial of azithromycin. His symptoms, however, persisted and he was referred to our institution for evaluation and treatment.

On exam, he had a temperature of 100.5° F, inguinal lymphadenopathy, and 2 eschars: a 1.5 cm one on his right groin and an identical one on the medial aspect of the right popliteal fossa (FIGURE 1).

THE DIAGNOSIS

Laboratory studies showed a white blood cell count of 3000/mcL, hemoglobin of 14.1 g/dL, and platelet count of 142,000/mcL; peripheral blood smear was normal. Blood and urine cultures showed no growth. A malaria smear and antibodies for Lyme disease, dengue fever, Chikungunya virus, and Q fever were also negative. A biopsy of the eschar demonstrated epidermal and dermal necrosis consistent with infectious vasculitis caused by rickettsial disease (FIGURE 2). A polymerase chain reaction (PCR) for the spotted fever group (R rickettsii, R akari, and R conorii) and typhus fever group of rickettsial agents (R typhi and R prowazekii) were negative. However, a PCR was positive for R africae, confirming the diagnosis of African tick-bite fever (ATBF).

DISCUSSION

Two common reasons patients returning from international travel seek medical attention are fever and rash.¹ Initial assessment should include a detailed travel history of urban and rural exposures and any possible exposure to ticks or fleas. The time course of symptoms is important because some tropical infections can have long incubation periods.²

Rickettsial diseases are the most common febrile illness in patients returning from international travel.¹ ATBF caused by R africae is the most common rickettsiosis among returning travelers¹ and may be the most widespread of all spotted fever group rickettsiae that are known to be pathogenic to humans.³R africae is endemic to South Africa. The risk of contracting R africae is 4 to 5 times higher than the risk of contracting malaria in South Africa.¹

The risk of contracting R africae is 4 to 5 times higher than the risk of contracting malaria in South Africa.

R africae is transmitted through cattle and game ticks (Amblyomma species),^1-7 and tends to cause mild illness with rare progression to complicated disease.³ The risk of infection is particularly high from November to April,⁷ and our patient had traveled during April.

Most patients with ATBF present with fever, headache, and malaise, and 50% develop a variable rash.^1,2 Local lymphadenopathy often develops, and marked neck stiffness can occur.² An eschar is present in 95% of cases.² The finding of an eschar is often indicative of rickettsial infection; however, not all rickettsioses show eschars, and the absence of an eschar does not exclude rickettsial infection.¹

ATBF is usually benign and self-limiting, and no fatalities have been reported.^2,4,8 Complications such as peripheral nerve involvement, encephalitis, and myocarditis are rare.^5,8 Since rickettsial diseases may be more severe in elderly patients with underlying diseases, empiric treatment with inpatient monitoring is justifiable.⁵

Don’t wait for lab confirmation to begin antibiotics

Laboratory findings in a patient with ATBF include pancytopenia, elevated serum C-reactive protein, and abnormal liver function tests.^2,4 A blood PCR detects R africae,^1,3 and if a rash or eschar is present, a biopsy can confirm the diagnosis.¹ However, confirming the diagnosis is difficult if seroconversion has not occurred and PCR is not readily available.¹ Also, antibodies may not be detected in patients who have a mild case of ATBF or those who are immunocompromised.⁵

If you suspect your patient has ATBF, don’t wait for laboratory confirmation; instead, initiate empiric treatment with doxycycline 100 mg bid twice daily for 5 to 7 days.^1,2,4

Preventive measures include repellant lotions, clothing, and gear

Since there are no vaccines or prophylactic treatments for ATBF, counsel travelers on preventive measures.⁹ Instruct patients who plan to visit an endemic area such as sub-Saharan Africa or the West Indies to wear long-sleeved shirts, long pants, and hats. Individuals should also tuck their shirts into their pants and their pants into socks, as well as wear closed-toe shoes. When possible, it’s advisable to avoid woody and brushy areas.

Over-the-counter repellant lotions that contain ≥20% DEET are effective at preventing tick bites for several hours after an application, but should be reapplied as directed.⁹ These lotions should be applied after sunscreen. Advise patients that they can purchase clothing and gear that have been treated with the pesticide permethrin, or they can treat clothing and gear themselves. Explain, however, that permethrin should not be applied directly to skin.

Finally, instruct travelers to perform daily tick inspections and shower or bathe as soon as possible after returning from the outdoors.⁹ Educate patients on the proper technique for tick removal, which is described on the Centers for Disease Control and Prevention’s Web site at http://www.cdc.gov/ticks/removing_a_tick.html.

Our patient completed a 2-week course of doxycycline 100 mg bid. His symptoms and laboratory abnormalities completely resolved.

THE TAKEAWAY

ATBF is the most common rickettsiosis among patients returning from international travel. Because patients may present with several nonspecific symptoms, maintain a high index of suspicion for rickettsial infection among patients returning from sub-Saharan Africa or the West Indies. Though the disease usually can be successfully managed in the outpatient setting with doxycycline, elderly patients or those with comorbid conditions may require inpatient care. Educate patients who plan to travel to an endemic area about measures they can take to prevent exposure to ticks and subsequent infection.

THE CASE

A 76-year-old man with a history of coronary artery disease presented with a fever, headache, and malaise one week after returning from a big game hunting trip in South Africa. Five days after his return, he noticed lesions on his right leg that eventually scabbed over. He sought care at his local emergency department and with his primary care physician, and completed an empiric trial of azithromycin. His symptoms, however, persisted and he was referred to our institution for evaluation and treatment.

On exam, he had a temperature of 100.5° F, inguinal lymphadenopathy, and 2 eschars: a 1.5 cm one on his right groin and an identical one on the medial aspect of the right popliteal fossa (FIGURE 1).

THE DIAGNOSIS

Laboratory studies showed a white blood cell count of 3000/mcL, hemoglobin of 14.1 g/dL, and platelet count of 142,000/mcL; peripheral blood smear was normal. Blood and urine cultures showed no growth. A malaria smear and antibodies for Lyme disease, dengue fever, Chikungunya virus, and Q fever were also negative. A biopsy of the eschar demonstrated epidermal and dermal necrosis consistent with infectious vasculitis caused by rickettsial disease (FIGURE 2). A polymerase chain reaction (PCR) for the spotted fever group (R rickettsii, R akari, and R conorii) and typhus fever group of rickettsial agents (R typhi and R prowazekii) were negative. However, a PCR was positive for R africae, confirming the diagnosis of African tick-bite fever (ATBF).

DISCUSSION

Two common reasons patients returning from international travel seek medical attention are fever and rash.¹ Initial assessment should include a detailed travel history of urban and rural exposures and any possible exposure to ticks or fleas. The time course of symptoms is important because some tropical infections can have long incubation periods.²

Rickettsial diseases are the most common febrile illness in patients returning from international travel.¹ ATBF caused by R africae is the most common rickettsiosis among returning travelers¹ and may be the most widespread of all spotted fever group rickettsiae that are known to be pathogenic to humans.³R africae is endemic to South Africa. The risk of contracting R africae is 4 to 5 times higher than the risk of contracting malaria in South Africa.¹

The risk of contracting R africae is 4 to 5 times higher than the risk of contracting malaria in South Africa.

R africae is transmitted through cattle and game ticks (Amblyomma species),^1-7 and tends to cause mild illness with rare progression to complicated disease.³ The risk of infection is particularly high from November to April,⁷ and our patient had traveled during April.

Most patients with ATBF present with fever, headache, and malaise, and 50% develop a variable rash.^1,2 Local lymphadenopathy often develops, and marked neck stiffness can occur.² An eschar is present in 95% of cases.² The finding of an eschar is often indicative of rickettsial infection; however, not all rickettsioses show eschars, and the absence of an eschar does not exclude rickettsial infection.¹

ATBF is usually benign and self-limiting, and no fatalities have been reported.^2,4,8 Complications such as peripheral nerve involvement, encephalitis, and myocarditis are rare.^5,8 Since rickettsial diseases may be more severe in elderly patients with underlying diseases, empiric treatment with inpatient monitoring is justifiable.⁵

Don’t wait for lab confirmation to begin antibiotics

Laboratory findings in a patient with ATBF include pancytopenia, elevated serum C-reactive protein, and abnormal liver function tests.^2,4 A blood PCR detects R africae,^1,3 and if a rash or eschar is present, a biopsy can confirm the diagnosis.¹ However, confirming the diagnosis is difficult if seroconversion has not occurred and PCR is not readily available.¹ Also, antibodies may not be detected in patients who have a mild case of ATBF or those who are immunocompromised.⁵

If you suspect your patient has ATBF, don’t wait for laboratory confirmation; instead, initiate empiric treatment with doxycycline 100 mg bid twice daily for 5 to 7 days.^1,2,4

Preventive measures include repellant lotions, clothing, and gear

Since there are no vaccines or prophylactic treatments for ATBF, counsel travelers on preventive measures.⁹ Instruct patients who plan to visit an endemic area such as sub-Saharan Africa or the West Indies to wear long-sleeved shirts, long pants, and hats. Individuals should also tuck their shirts into their pants and their pants into socks, as well as wear closed-toe shoes. When possible, it’s advisable to avoid woody and brushy areas.

Over-the-counter repellant lotions that contain ≥20% DEET are effective at preventing tick bites for several hours after an application, but should be reapplied as directed.⁹ These lotions should be applied after sunscreen. Advise patients that they can purchase clothing and gear that have been treated with the pesticide permethrin, or they can treat clothing and gear themselves. Explain, however, that permethrin should not be applied directly to skin.

Finally, instruct travelers to perform daily tick inspections and shower or bathe as soon as possible after returning from the outdoors.⁹ Educate patients on the proper technique for tick removal, which is described on the Centers for Disease Control and Prevention’s Web site at http://www.cdc.gov/ticks/removing_a_tick.html.

Our patient completed a 2-week course of doxycycline 100 mg bid. His symptoms and laboratory abnormalities completely resolved.

THE TAKEAWAY

ATBF is the most common rickettsiosis among patients returning from international travel. Because patients may present with several nonspecific symptoms, maintain a high index of suspicion for rickettsial infection among patients returning from sub-Saharan Africa or the West Indies. Though the disease usually can be successfully managed in the outpatient setting with doxycycline, elderly patients or those with comorbid conditions may require inpatient care. Educate patients who plan to travel to an endemic area about measures they can take to prevent exposure to ticks and subsequent infection.

Gorham-Stout disease (GSD) is a rare condition characterized by spontaneous idiopathic resorption of bone with lymphovascular proliferation and an absence of malignant features. It was originally described by Jackson¹ in an 1838 report of a 36-year-old man whose “arm bone, between the shoulder and elbow” had completely vanished after 2 fractures. The disease was defined and its pathology characterized by Gorham and Stout² in 1955 in a series of 24 patients. Despite about 200 reported cases in the literature,³ its etiology remains unclear. Any bone in the skeleton may be affected by GSD, although there is a predilection for the skull, humerus, clavicle, ribs, pelvis, and femur.^4-6 It commonly manifests within the first 3 decades of life, but case reports range from as early as 2 months of age to the eighth decade.^5,7

Gorham-Stout disease is a diagnosis of exclusion that requires careful consideration of the clinical context, radiographic findings, and histopathology. Typical histopathologic findings include benign lymphatic or vascular proliferation, involution of adipose tissue within the bone marrow, and thinning of bony trabeculae.⁶ Fibrous tissue may replace vascular tissue after the initial vasoproliferative, osteolytic phase.⁶ Some authors describe the disease as having 2 phases, the first with massive osteolysis followed by relative dormancy and the second without progression or re-ossification.^8,9 Treatment remains controversial and is guided by management of the disease’s complications. Options range from careful observation and supportive management to aggressive surgical resection and reconstruction, with positive outcomes reported using many different modalities.¹⁰ Most treatment successes, however, hinge on halting bony resorption using medical and radiation therapy. Surgery is usually reserved as a salvage option for patients who have failed medical modalities and have residual symptoms or functional limitations.⁶

This case report describes the successful surgical management of a patient with pelvic GSD who had progressive pain and functional limitation despite exhaustive medical and radiation therapy. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A healthy 27-year-old man sought medical attention after a fall while mowing his lawn that resulted in difficulty ambulating. Radiographic studies showed discontinuous lytic lesions in the right periacetabular region and the right sacroiliac (SI) joint. Biopsy at an outside institution revealed an infiltration of thin-walled branching vascular channels involving intertrabecular marrow spaces and periosteal connective tissue. The vessels were devoid of a muscular coat and lined by flattened epithelium; these features were seen as consistent with GSD.

The patient was managed medically at the outside institution for approximately 2 years, with regimens consisting of zoledronate, denosumab, sorafenib, vincristine, sirolimus, and bevacizumab. Because there is no standard chemotherapy protocol for GSD, this broad regimen was likely an attempt by treating physicians to control disease progression before considering radiation or surgery. Zoledronate, a bisphosphonate, and denosumab, a monoclonal antibody against the receptor activator of nuclear factor κβ ligand (RANKL), both inhibit bone resorption, making them logical choices in treating an osteolytic disease. Sorafenib, vincristine, sirolimus, and bevacizumab may be of clinical benefit in GSD via inhibition of vascular proliferation, which is a key histologic feature in GSD. Sorafenib inhibits the vascular endothelial growth factor (VEGF) receptor, vincristine and sirolimus inhibit VEGF production, and bevacizumab is a monoclonal antibody targeting VEGF.

The patient’s disease continued to involve more of his right hemipelvis despite this extensive regimen of chemotherapy, and he experienced significant functional decline about 2 years after initial presentation, when he was no longer able to ambulate unassisted. Radiation therapy to the pelvis was attempted at the outside institution (6/15 MV photons, 5040 cGy, 28 fractions) without improvement. Three years after his initial injury, he presented to our clinic.

Now age 30 years, the patient ambulated only with crutches and endorsed minimal improvement in his pain over 3 years of treatment. Physical examination of the patient revealed that he was a tall, thin man in visible discomfort. Sensation was intact to light touch in the bilateral L1 to S1 nerve distributions. There was marked weakness of the right lower extremity, and his examination was limited by pain. He could not perform a straight leg raise on the right side. Right quadriceps strength was 4/5, and right hamstrings strength was 3/5. There was no weakness in the left leg. Reflexes were normal and symmetric bilaterally at the patellar and gastrocnemius soleus tendons. Distal circulatory status in both extremities was normal, and there were no deformities of the skin.

Figure 1 shows the patient’s computed tomography (CT) scan. Figures 1A and 1B reveal fragmentation of the posterior ilia and sacrum along both SI joints. Dislocation of the pubic symphysis is shown in Figures 1C and 1D, and discontinuous involvement of the ischium and posterior wall of the acetabulum is visible in Figure 1E.

Serum studies, including C-reactive protein, erythrocyte sedimentation rate, and a complete blood count, were within normal limits. A CT-guided core needle biopsy and aspiration of the right SI joint revealed no infection; pathology was nondiagnostic. Anesthetic injection of the hip joint resulted in no relief. As this man was severely functionally limited and had exhausted all medical and radiation treatment options, a collaborative decision was made to proceed with surgical management. Surgical options included spinopelvic fusion unilaterally or bilaterally, hip arthroplasty, or sacropelvic resection with or without reconstruction. The patient opted for intralesional surgery and spinopelvic fusion in place of more radical options.

Thirty-seven months after his initial presentation, he underwent posterior spinal fusion L5 to S1, SI fusion, and anterior locking plate fixation of the pubic symphysis, as seen in Figure 2. Pathology from surgical specimens, seen at original magnification ×20 and ×100 in Figures 3A and 3B, respectively, showed prominent vascular proliferation in the right ilium, with reactive bone changes in the left ilium and right sacrum. A lytic lesion showed fibrous tissue with an embedded fragment of necrotic bone.

Six weeks after surgery, the patient had substantial improvement in his pain and was partially weight-bearing. He was able to ambulate with crutches and returned to work. The patient’s overall clinical status continued to improve throughout the postoperative course. He developed low back pain 7 months after surgery and was found to have a sacrococcygeal abscess and coccygeal fracture anterior to the sacrum. He underwent irrigation and débridement of the abscess and distal coccygectomy and was treated with 6 weeks of intravenous cefazolin and long-term suppression with levofloxacin and rifampin for methicillin-sensitive Staphylococcus aureus hardware infection and osteomyelitis. The patient’s clinical course subsequently improved. At latest follow-up 16 months after the index operation, pain was reported as manageable and mostly an annoyance. He was prescribed up to 40 mg of oxycodone daily for pain. The patient returned to work, ambulates with a cane (no other assistive devices), and reports being able to get around without any difficulty.

Discussion

Gorham-Stout disease is an exceedingly rare condition resulting in spontaneous osteolysis. Approximately 200 cases have been reported with no apparent gender, race, or familial predilection or systemic symptoms differentiating it from other etiologies of idiopathic osteolysis.⁶ These patients often seek medical attention after sustaining a pathologic fracture,⁶ when a broad differential diagnosis narrows to GSD only after biopsy excludes other possibilities and demonstrates characteristic angiomatosis without malignant features.^2,4,6,8,10 Gorham-Stout disease appears more frequently at particular sites within the skeleton, and pelvic involvement is common—more than 20% of cases in 1 review.^5,10 Limitations in the patient’s ability to ambulate invariably result from osteolysis of the pelvis, which is concerning considering the young age at which GSD typically presents. A variety of treatment modalities have been described for pelvic GSD, but surgery has been undertaken in relatively few cases.⁵

The diagnosis is one of exclusion after considering the clinical context and radiologic and pathologic findings. In this case, a pathologic fracture was discovered with osteolytic lesions throughout the hemipelvis. Biopsy excluded malignancy and demonstrated the key hemangiomatous vascular proliferation with thin-walled vessels that is classic for GSD. While our patient initially appeared to have 2 sites of disease, the surgical specimen revealed a primary site of vascular proliferation in the right ilium from which 2 apparent foci had spread, consistent with the typical monocentric presentation of GSD.¹¹ A broad differential diagnosis must be considered at initial presentation, including osteomyelitis, metastatic disease, multiple myeloma, and primary bone sarcoma. Upon identifying a primary osteolytic process, several considerations besides GSD remain, such as Hajdu-Cheney syndrome, Winchester syndrome, multicentric osteolysis with nephropathy, familial osteolysis, Farber disease, and neurogenic osteolysis; most of these etiologies involve familial predispositions and/or systemic symptoms.

Treatment options for GSD include supportive care, medical therapy, radiation, and surgery. For pelvic GSD, numerous reports have demonstrated good outcomes with supportive management, since osteolysis often spontaneously arrests.^8,9,12 Others have had success with medical treatments in attempts to halt bone resorption.^6,13-15 Bisphosphonates are the cornerstone of medical therapy in GSD, as they appear to halt further osteoclastic bone breakdown. The levels of VEGF have been shown to be elevated in GSD,¹³ likely consistent with the vascular proliferation evident on pathology, and therapies such as bevacizumab and interferon α-2b have been used to target osteolysis via this pathway with good outcome.^13,14,16 External beam-radiation therapy has been shown to prevent local progression of osteolysis in up to 80% of cases.⁴ However, even with arrest of bone resorption, damage to affected bone may have progressed to the point of significant functional limitation. This may be especially true in the pelvis.

We present a case of a patient who continued to deteriorate after maximal medical and radiation therapy. Many reported cases of pelvic GSD have had good outcomes with some combination of conservative management, medical therapy, and radiation. However, in our patient, the pelvis and lumbosacral spine were unstable as a result of significant bone loss and fracture, and his clinical deterioration was dramatic. We considered reasonable surgical approaches, including local intralesional débridement and massive en bloc resection with structural allograft. We chose the less radical procedure given the patient’s age, minimal surgical history, and personal preference. Although structural pelvic allograft has been successful in a few cases, there remains a high risk of complications, such as fracture, resorption, or infection.¹⁷ We considered the addition of hip arthroplasty with either scenario, but we elected not to perform this component given his young age and lack of symptomatic improvement with diagnostic anesthetic hip injection. The key to this patient’s surgical reconstruction, aside from eliminating gross disease, was the stabilization of the spinopelvic junction and pelvic ring. His functional improvement as early as 6 weeks after surgery demonstrates that surgery can have an important role for patients with pelvic GSD who fail medical and radiation therapy.

Gorham-Stout disease (GSD) is a rare condition characterized by spontaneous idiopathic resorption of bone with lymphovascular proliferation and an absence of malignant features. It was originally described by Jackson¹ in an 1838 report of a 36-year-old man whose “arm bone, between the shoulder and elbow” had completely vanished after 2 fractures. The disease was defined and its pathology characterized by Gorham and Stout² in 1955 in a series of 24 patients. Despite about 200 reported cases in the literature,³ its etiology remains unclear. Any bone in the skeleton may be affected by GSD, although there is a predilection for the skull, humerus, clavicle, ribs, pelvis, and femur.^4-6 It commonly manifests within the first 3 decades of life, but case reports range from as early as 2 months of age to the eighth decade.^5,7

Gorham-Stout disease is a diagnosis of exclusion that requires careful consideration of the clinical context, radiographic findings, and histopathology. Typical histopathologic findings include benign lymphatic or vascular proliferation, involution of adipose tissue within the bone marrow, and thinning of bony trabeculae.⁶ Fibrous tissue may replace vascular tissue after the initial vasoproliferative, osteolytic phase.⁶ Some authors describe the disease as having 2 phases, the first with massive osteolysis followed by relative dormancy and the second without progression or re-ossification.^8,9 Treatment remains controversial and is guided by management of the disease’s complications. Options range from careful observation and supportive management to aggressive surgical resection and reconstruction, with positive outcomes reported using many different modalities.¹⁰ Most treatment successes, however, hinge on halting bony resorption using medical and radiation therapy. Surgery is usually reserved as a salvage option for patients who have failed medical modalities and have residual symptoms or functional limitations.⁶

This case report describes the successful surgical management of a patient with pelvic GSD who had progressive pain and functional limitation despite exhaustive medical and radiation therapy. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A healthy 27-year-old man sought medical attention after a fall while mowing his lawn that resulted in difficulty ambulating. Radiographic studies showed discontinuous lytic lesions in the right periacetabular region and the right sacroiliac (SI) joint. Biopsy at an outside institution revealed an infiltration of thin-walled branching vascular channels involving intertrabecular marrow spaces and periosteal connective tissue. The vessels were devoid of a muscular coat and lined by flattened epithelium; these features were seen as consistent with GSD.

The patient was managed medically at the outside institution for approximately 2 years, with regimens consisting of zoledronate, denosumab, sorafenib, vincristine, sirolimus, and bevacizumab. Because there is no standard chemotherapy protocol for GSD, this broad regimen was likely an attempt by treating physicians to control disease progression before considering radiation or surgery. Zoledronate, a bisphosphonate, and denosumab, a monoclonal antibody against the receptor activator of nuclear factor κβ ligand (RANKL), both inhibit bone resorption, making them logical choices in treating an osteolytic disease. Sorafenib, vincristine, sirolimus, and bevacizumab may be of clinical benefit in GSD via inhibition of vascular proliferation, which is a key histologic feature in GSD. Sorafenib inhibits the vascular endothelial growth factor (VEGF) receptor, vincristine and sirolimus inhibit VEGF production, and bevacizumab is a monoclonal antibody targeting VEGF.

The patient’s disease continued to involve more of his right hemipelvis despite this extensive regimen of chemotherapy, and he experienced significant functional decline about 2 years after initial presentation, when he was no longer able to ambulate unassisted. Radiation therapy to the pelvis was attempted at the outside institution (6/15 MV photons, 5040 cGy, 28 fractions) without improvement. Three years after his initial injury, he presented to our clinic.

Now age 30 years, the patient ambulated only with crutches and endorsed minimal improvement in his pain over 3 years of treatment. Physical examination of the patient revealed that he was a tall, thin man in visible discomfort. Sensation was intact to light touch in the bilateral L1 to S1 nerve distributions. There was marked weakness of the right lower extremity, and his examination was limited by pain. He could not perform a straight leg raise on the right side. Right quadriceps strength was 4/5, and right hamstrings strength was 3/5. There was no weakness in the left leg. Reflexes were normal and symmetric bilaterally at the patellar and gastrocnemius soleus tendons. Distal circulatory status in both extremities was normal, and there were no deformities of the skin.

Figure 1 shows the patient’s computed tomography (CT) scan. Figures 1A and 1B reveal fragmentation of the posterior ilia and sacrum along both SI joints. Dislocation of the pubic symphysis is shown in Figures 1C and 1D, and discontinuous involvement of the ischium and posterior wall of the acetabulum is visible in Figure 1E.

Serum studies, including C-reactive protein, erythrocyte sedimentation rate, and a complete blood count, were within normal limits. A CT-guided core needle biopsy and aspiration of the right SI joint revealed no infection; pathology was nondiagnostic. Anesthetic injection of the hip joint resulted in no relief. As this man was severely functionally limited and had exhausted all medical and radiation treatment options, a collaborative decision was made to proceed with surgical management. Surgical options included spinopelvic fusion unilaterally or bilaterally, hip arthroplasty, or sacropelvic resection with or without reconstruction. The patient opted for intralesional surgery and spinopelvic fusion in place of more radical options.

Thirty-seven months after his initial presentation, he underwent posterior spinal fusion L5 to S1, SI fusion, and anterior locking plate fixation of the pubic symphysis, as seen in Figure 2. Pathology from surgical specimens, seen at original magnification ×20 and ×100 in Figures 3A and 3B, respectively, showed prominent vascular proliferation in the right ilium, with reactive bone changes in the left ilium and right sacrum. A lytic lesion showed fibrous tissue with an embedded fragment of necrotic bone.

Six weeks after surgery, the patient had substantial improvement in his pain and was partially weight-bearing. He was able to ambulate with crutches and returned to work. The patient’s overall clinical status continued to improve throughout the postoperative course. He developed low back pain 7 months after surgery and was found to have a sacrococcygeal abscess and coccygeal fracture anterior to the sacrum. He underwent irrigation and débridement of the abscess and distal coccygectomy and was treated with 6 weeks of intravenous cefazolin and long-term suppression with levofloxacin and rifampin for methicillin-sensitive Staphylococcus aureus hardware infection and osteomyelitis. The patient’s clinical course subsequently improved. At latest follow-up 16 months after the index operation, pain was reported as manageable and mostly an annoyance. He was prescribed up to 40 mg of oxycodone daily for pain. The patient returned to work, ambulates with a cane (no other assistive devices), and reports being able to get around without any difficulty.

Discussion

Gorham-Stout disease is an exceedingly rare condition resulting in spontaneous osteolysis. Approximately 200 cases have been reported with no apparent gender, race, or familial predilection or systemic symptoms differentiating it from other etiologies of idiopathic osteolysis.⁶ These patients often seek medical attention after sustaining a pathologic fracture,⁶ when a broad differential diagnosis narrows to GSD only after biopsy excludes other possibilities and demonstrates characteristic angiomatosis without malignant features.^2,4,6,8,10 Gorham-Stout disease appears more frequently at particular sites within the skeleton, and pelvic involvement is common—more than 20% of cases in 1 review.^5,10 Limitations in the patient’s ability to ambulate invariably result from osteolysis of the pelvis, which is concerning considering the young age at which GSD typically presents. A variety of treatment modalities have been described for pelvic GSD, but surgery has been undertaken in relatively few cases.⁵

The diagnosis is one of exclusion after considering the clinical context and radiologic and pathologic findings. In this case, a pathologic fracture was discovered with osteolytic lesions throughout the hemipelvis. Biopsy excluded malignancy and demonstrated the key hemangiomatous vascular proliferation with thin-walled vessels that is classic for GSD. While our patient initially appeared to have 2 sites of disease, the surgical specimen revealed a primary site of vascular proliferation in the right ilium from which 2 apparent foci had spread, consistent with the typical monocentric presentation of GSD.¹¹ A broad differential diagnosis must be considered at initial presentation, including osteomyelitis, metastatic disease, multiple myeloma, and primary bone sarcoma. Upon identifying a primary osteolytic process, several considerations besides GSD remain, such as Hajdu-Cheney syndrome, Winchester syndrome, multicentric osteolysis with nephropathy, familial osteolysis, Farber disease, and neurogenic osteolysis; most of these etiologies involve familial predispositions and/or systemic symptoms.

Treatment options for GSD include supportive care, medical therapy, radiation, and surgery. For pelvic GSD, numerous reports have demonstrated good outcomes with supportive management, since osteolysis often spontaneously arrests.^8,9,12 Others have had success with medical treatments in attempts to halt bone resorption.^6,13-15 Bisphosphonates are the cornerstone of medical therapy in GSD, as they appear to halt further osteoclastic bone breakdown. The levels of VEGF have been shown to be elevated in GSD,¹³ likely consistent with the vascular proliferation evident on pathology, and therapies such as bevacizumab and interferon α-2b have been used to target osteolysis via this pathway with good outcome.^13,14,16 External beam-radiation therapy has been shown to prevent local progression of osteolysis in up to 80% of cases.⁴ However, even with arrest of bone resorption, damage to affected bone may have progressed to the point of significant functional limitation. This may be especially true in the pelvis.

We present a case of a patient who continued to deteriorate after maximal medical and radiation therapy. Many reported cases of pelvic GSD have had good outcomes with some combination of conservative management, medical therapy, and radiation. However, in our patient, the pelvis and lumbosacral spine were unstable as a result of significant bone loss and fracture, and his clinical deterioration was dramatic. We considered reasonable surgical approaches, including local intralesional débridement and massive en bloc resection with structural allograft. We chose the less radical procedure given the patient’s age, minimal surgical history, and personal preference. Although structural pelvic allograft has been successful in a few cases, there remains a high risk of complications, such as fracture, resorption, or infection.¹⁷ We considered the addition of hip arthroplasty with either scenario, but we elected not to perform this component given his young age and lack of symptomatic improvement with diagnostic anesthetic hip injection. The key to this patient’s surgical reconstruction, aside from eliminating gross disease, was the stabilization of the spinopelvic junction and pelvic ring. His functional improvement as early as 6 weeks after surgery demonstrates that surgery can have an important role for patients with pelvic GSD who fail medical and radiation therapy.

Gorham-Stout disease (GSD) is a rare condition characterized by spontaneous idiopathic resorption of bone with lymphovascular proliferation and an absence of malignant features. It was originally described by Jackson¹ in an 1838 report of a 36-year-old man whose “arm bone, between the shoulder and elbow” had completely vanished after 2 fractures. The disease was defined and its pathology characterized by Gorham and Stout² in 1955 in a series of 24 patients. Despite about 200 reported cases in the literature,³ its etiology remains unclear. Any bone in the skeleton may be affected by GSD, although there is a predilection for the skull, humerus, clavicle, ribs, pelvis, and femur.^4-6 It commonly manifests within the first 3 decades of life, but case reports range from as early as 2 months of age to the eighth decade.^5,7

Gorham-Stout disease is a diagnosis of exclusion that requires careful consideration of the clinical context, radiographic findings, and histopathology. Typical histopathologic findings include benign lymphatic or vascular proliferation, involution of adipose tissue within the bone marrow, and thinning of bony trabeculae.⁶ Fibrous tissue may replace vascular tissue after the initial vasoproliferative, osteolytic phase.⁶ Some authors describe the disease as having 2 phases, the first with massive osteolysis followed by relative dormancy and the second without progression or re-ossification.^8,9 Treatment remains controversial and is guided by management of the disease’s complications. Options range from careful observation and supportive management to aggressive surgical resection and reconstruction, with positive outcomes reported using many different modalities.¹⁰ Most treatment successes, however, hinge on halting bony resorption using medical and radiation therapy. Surgery is usually reserved as a salvage option for patients who have failed medical modalities and have residual symptoms or functional limitations.⁶

This case report describes the successful surgical management of a patient with pelvic GSD who had progressive pain and functional limitation despite exhaustive medical and radiation therapy. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A healthy 27-year-old man sought medical attention after a fall while mowing his lawn that resulted in difficulty ambulating. Radiographic studies showed discontinuous lytic lesions in the right periacetabular region and the right sacroiliac (SI) joint. Biopsy at an outside institution revealed an infiltration of thin-walled branching vascular channels involving intertrabecular marrow spaces and periosteal connective tissue. The vessels were devoid of a muscular coat and lined by flattened epithelium; these features were seen as consistent with GSD.

The patient was managed medically at the outside institution for approximately 2 years, with regimens consisting of zoledronate, denosumab, sorafenib, vincristine, sirolimus, and bevacizumab. Because there is no standard chemotherapy protocol for GSD, this broad regimen was likely an attempt by treating physicians to control disease progression before considering radiation or surgery. Zoledronate, a bisphosphonate, and denosumab, a monoclonal antibody against the receptor activator of nuclear factor κβ ligand (RANKL), both inhibit bone resorption, making them logical choices in treating an osteolytic disease. Sorafenib, vincristine, sirolimus, and bevacizumab may be of clinical benefit in GSD via inhibition of vascular proliferation, which is a key histologic feature in GSD. Sorafenib inhibits the vascular endothelial growth factor (VEGF) receptor, vincristine and sirolimus inhibit VEGF production, and bevacizumab is a monoclonal antibody targeting VEGF.

The patient’s disease continued to involve more of his right hemipelvis despite this extensive regimen of chemotherapy, and he experienced significant functional decline about 2 years after initial presentation, when he was no longer able to ambulate unassisted. Radiation therapy to the pelvis was attempted at the outside institution (6/15 MV photons, 5040 cGy, 28 fractions) without improvement. Three years after his initial injury, he presented to our clinic.

Now age 30 years, the patient ambulated only with crutches and endorsed minimal improvement in his pain over 3 years of treatment. Physical examination of the patient revealed that he was a tall, thin man in visible discomfort. Sensation was intact to light touch in the bilateral L1 to S1 nerve distributions. There was marked weakness of the right lower extremity, and his examination was limited by pain. He could not perform a straight leg raise on the right side. Right quadriceps strength was 4/5, and right hamstrings strength was 3/5. There was no weakness in the left leg. Reflexes were normal and symmetric bilaterally at the patellar and gastrocnemius soleus tendons. Distal circulatory status in both extremities was normal, and there were no deformities of the skin.

Figure 1 shows the patient’s computed tomography (CT) scan. Figures 1A and 1B reveal fragmentation of the posterior ilia and sacrum along both SI joints. Dislocation of the pubic symphysis is shown in Figures 1C and 1D, and discontinuous involvement of the ischium and posterior wall of the acetabulum is visible in Figure 1E.

Serum studies, including C-reactive protein, erythrocyte sedimentation rate, and a complete blood count, were within normal limits. A CT-guided core needle biopsy and aspiration of the right SI joint revealed no infection; pathology was nondiagnostic. Anesthetic injection of the hip joint resulted in no relief. As this man was severely functionally limited and had exhausted all medical and radiation treatment options, a collaborative decision was made to proceed with surgical management. Surgical options included spinopelvic fusion unilaterally or bilaterally, hip arthroplasty, or sacropelvic resection with or without reconstruction. The patient opted for intralesional surgery and spinopelvic fusion in place of more radical options.

Thirty-seven months after his initial presentation, he underwent posterior spinal fusion L5 to S1, SI fusion, and anterior locking plate fixation of the pubic symphysis, as seen in Figure 2. Pathology from surgical specimens, seen at original magnification ×20 and ×100 in Figures 3A and 3B, respectively, showed prominent vascular proliferation in the right ilium, with reactive bone changes in the left ilium and right sacrum. A lytic lesion showed fibrous tissue with an embedded fragment of necrotic bone.

Six weeks after surgery, the patient had substantial improvement in his pain and was partially weight-bearing. He was able to ambulate with crutches and returned to work. The patient’s overall clinical status continued to improve throughout the postoperative course. He developed low back pain 7 months after surgery and was found to have a sacrococcygeal abscess and coccygeal fracture anterior to the sacrum. He underwent irrigation and débridement of the abscess and distal coccygectomy and was treated with 6 weeks of intravenous cefazolin and long-term suppression with levofloxacin and rifampin for methicillin-sensitive Staphylococcus aureus hardware infection and osteomyelitis. The patient’s clinical course subsequently improved. At latest follow-up 16 months after the index operation, pain was reported as manageable and mostly an annoyance. He was prescribed up to 40 mg of oxycodone daily for pain. The patient returned to work, ambulates with a cane (no other assistive devices), and reports being able to get around without any difficulty.

Discussion

Gorham-Stout disease is an exceedingly rare condition resulting in spontaneous osteolysis. Approximately 200 cases have been reported with no apparent gender, race, or familial predilection or systemic symptoms differentiating it from other etiologies of idiopathic osteolysis.⁶ These patients often seek medical attention after sustaining a pathologic fracture,⁶ when a broad differential diagnosis narrows to GSD only after biopsy excludes other possibilities and demonstrates characteristic angiomatosis without malignant features.^2,4,6,8,10 Gorham-Stout disease appears more frequently at particular sites within the skeleton, and pelvic involvement is common—more than 20% of cases in 1 review.^5,10 Limitations in the patient’s ability to ambulate invariably result from osteolysis of the pelvis, which is concerning considering the young age at which GSD typically presents. A variety of treatment modalities have been described for pelvic GSD, but surgery has been undertaken in relatively few cases.⁵

The diagnosis is one of exclusion after considering the clinical context and radiologic and pathologic findings. In this case, a pathologic fracture was discovered with osteolytic lesions throughout the hemipelvis. Biopsy excluded malignancy and demonstrated the key hemangiomatous vascular proliferation with thin-walled vessels that is classic for GSD. While our patient initially appeared to have 2 sites of disease, the surgical specimen revealed a primary site of vascular proliferation in the right ilium from which 2 apparent foci had spread, consistent with the typical monocentric presentation of GSD.¹¹ A broad differential diagnosis must be considered at initial presentation, including osteomyelitis, metastatic disease, multiple myeloma, and primary bone sarcoma. Upon identifying a primary osteolytic process, several considerations besides GSD remain, such as Hajdu-Cheney syndrome, Winchester syndrome, multicentric osteolysis with nephropathy, familial osteolysis, Farber disease, and neurogenic osteolysis; most of these etiologies involve familial predispositions and/or systemic symptoms.

Treatment options for GSD include supportive care, medical therapy, radiation, and surgery. For pelvic GSD, numerous reports have demonstrated good outcomes with supportive management, since osteolysis often spontaneously arrests.^8,9,12 Others have had success with medical treatments in attempts to halt bone resorption.^6,13-15 Bisphosphonates are the cornerstone of medical therapy in GSD, as they appear to halt further osteoclastic bone breakdown. The levels of VEGF have been shown to be elevated in GSD,¹³ likely consistent with the vascular proliferation evident on pathology, and therapies such as bevacizumab and interferon α-2b have been used to target osteolysis via this pathway with good outcome.^13,14,16 External beam-radiation therapy has been shown to prevent local progression of osteolysis in up to 80% of cases.⁴ However, even with arrest of bone resorption, damage to affected bone may have progressed to the point of significant functional limitation. This may be especially true in the pelvis.

We present a case of a patient who continued to deteriorate after maximal medical and radiation therapy. Many reported cases of pelvic GSD have had good outcomes with some combination of conservative management, medical therapy, and radiation. However, in our patient, the pelvis and lumbosacral spine were unstable as a result of significant bone loss and fracture, and his clinical deterioration was dramatic. We considered reasonable surgical approaches, including local intralesional débridement and massive en bloc resection with structural allograft. We chose the less radical procedure given the patient’s age, minimal surgical history, and personal preference. Although structural pelvic allograft has been successful in a few cases, there remains a high risk of complications, such as fracture, resorption, or infection.¹⁷ We considered the addition of hip arthroplasty with either scenario, but we elected not to perform this component given his young age and lack of symptomatic improvement with diagnostic anesthetic hip injection. The key to this patient’s surgical reconstruction, aside from eliminating gross disease, was the stabilization of the spinopelvic junction and pelvic ring. His functional improvement as early as 6 weeks after surgery demonstrates that surgery can have an important role for patients with pelvic GSD who fail medical and radiation therapy.

First described in 1996, posterior reversible encephalopathy syndrome (PRES) exhibits a wide clinical spectrum and is definitively diagnosed through computed tomography (CT) and/or magnetic resonance imaging (MRI) studies of the brain.¹ Clinical presentation may include a spectrum of symptoms, including nausea, emesis, seizures, visual loss, paralysis, and headaches.^2,3 The most common imaging finding of PRES is bilateral foci of vasogenic edema located in the parieto-occipital white matter.^2-6 Other areas of the brain are frequently affected as well, with the frontal and temporal lobes and the basal or cortical ganglia showing signs of distinctly noncytotoxic edema in 12.5% to 54.2% of all cases.³ With the symptom of visual loss being present in 20% to 62.5% of patients with PRES, the syndrome constitutes a rare potential cause for postoperative visual loss (POVL) after spinal surgery, which has a generally good prognosis because most patients will completely regain their eyesight.^2,3

We present a unique account of 2 patients who underwent extensive spinal surgery and received a timely diagnosis and treatment of PRES at a single institution. We aim to elucidate the difference in clinical and radiographic presentation of PRES in relation to other known causes of POVL after spinal surgery. The patients provided written informed consent for print and electronic publication of these case reports.

Case Reports

Case 1

Clinical Presentation. A 78-year-old woman presented to the outpatient clinic with disability due to severe lower back pain. Her surgical history was significant for breast lumpectomy and cataract excision. Her medical history was significant for hypertension, obesity (body mass index, 31.5), hypercholesterolemia, emphysema, and anemia. She had undergone spinal surgery, specifically laminectomies from L2 to S1. The radiographic examination showed degenerative thoracolumbar scoliosis with severe spondylosis, disc space collapse, and ankylosis of L4-L5 (Figure 1).

Operative Procedure. The patient underwent transpsoas lumbar interbody fusion (XLIF, NuVasive) from L1 to L4 and posterior spinal fusion from T10 to pelvis (Expedium, Depuy Synthes) (Figure 2). Operative time was 553 minutes; estimated blood loss was 2000 mL due to intraoperative coagulopathy (platelets, 40,000/µL) near the end of the posterior portion of the procedure. Intraoperative hypotension was treated by volume resuscitation and transient use of vasopressor agents. She was transfused with 1700 mL of blood, 150 mL of saline solution, and 420 mL of Lactated Ringer’s solution. No intraoperative complications occurred. The patient was extubated uneventfully on postoperative day 1 and was at baseline neurologically with no visual disturbances.

Development and Diagnosis of PRES. The patient made significant progress with physical therapy and developed episodes of hypertension at night on postoperative days 4 to 6. Her mean peak systolic blood pressure was 180 mm Hg. This improved after oral beta-blocker therapy. On postoperative day 6, the patient was ambulating with physical therapy and the aid of a walker. She was found to be neurologically intact, was resting comfortable in a chair reading a book, and was cleared for transfer to a rehabilitation facility the next day. During the morning on postoperative day 7, she developed confusion and visual loss. The patient reported blurry vision followed by complete bilateral painless loss of vision aside from mild light perception. She was unable to identify any objects. She had extinction to double simultaneous stimuli and evidence of agraphesthesia in the left hand. Her neurologic examination was otherwise at baseline. Upon emergent imaging, head CT showed bilateral symmetric areas of hypodensity involving the cortical and subcortical white matter of both occipital lobes (Figure 3). MRI showed extensive bilateral cortical and subcortical signal hyperintensity involving the parietal and occipital lobes (Figure 4). No evidence of petechial or lobar hemorrhage was found.

Treatment and Clinical Course. The patient was transferred to the neurology intensive care unit for neurologic monitoring. She was treated aggressively for recurrent hypertensive episodes. Twenty-four hours after initial blood pressure optimization therapy, she partially recovered her eyesight. She exhibited complete recovery after 48 hours. The patient was discharged to a rehabilitation facility in stable condition on postoperative day 11.

Case 2

Clinical Presentation. A 51-year-old woman presented to the outpatient clinic with progressive low back pain and decompensation due to degenerative adult scoliosis. Her surgical history was significant for an uneventful Caesarean section. Her medical history was significant for borderline hypertension and obesity (body mass index, 34.4). The radiographic examination showed an S-shaped thoracolumbar curve from T4 to L4 (Figure 5).

Operative Procedure. After discussions about the risks and benefits of the procedure, the patient underwent posterior spinal fusion from T3 to pelvis (Mesa, K2M) and interbody fusion from L4 to S1 via a presacral approach using the AxiaLIF system (TranS1) (Figure 6). The operation spanned 507 minutes. The patient lost approximately 2200 mL of blood. She was transfused with 1690 mL of blood, 1250 mL of Lactated Ringer’s solution, and 1 unit (50 mL) of albumin. No intraoperative complications occurred.

Development and Diagnosis of PRES. The patient was ambulatory with physical therapy and a walker on postoperative day 1. Her albumin levels were noted to be decreased postoperatively (28 mg/mL; normal, >35 mg/mL). She developed intermittent hypertensive episodes and experienced transient peripheral vision loss. After her ophthalmologic symptoms cleared, she was discharged and transferred to a rehabilitation facility on postoperative day 9. Eleven days later, the patient was emergently readmitted for a deep spine wound infection after an onset of wound swelling and fever. She underwent irrigation and débridement of the spine wound with an estimated blood loss of 400 mL. The patient continued to have fevers and was placed on ciprofloxacin and vancomycin, which was changed to levofloxacin on postoperative day 5. Elevated creatinine was noted, and the patient was diagnosed with acute renal failure. On postoperative day 7, oxacillin therapy was commenced. After her cultures grew methicillin-resistant Staphylococcus aureus, a peripherally inserted central catheter line was placed on postoperative day 9. As a result of nausea and constipation, the patient received feeding tubes on postoperative day 11. Additionally, she was diagnosed with a pleural effusion on postoperative day 14. Although her creatinine levels were decreasing, she continued to experience intermittent hypertensive episodes with a mean peak systolic blood pressure of 148 mm Hg. On postoperative day 15, she had a seizure and again developed visual loss. The patient was lethargic and followed only simple commands. She moved all extremities and withdrew symmetrically to noxious stimuli. Upon emergent imaging, head CT showed posterior subcortical white matter hypodensity within the occipital and parietal lobes bilaterally (Figure 7). MRI showed focal regions of symmetric hemispheric edema involving the parietal and occipital lobes in a predominantly subcortical white-matter distribution. Additionally, extensive involvement of the splenium and of the corpus callosum, left greater than right, was observed (Figure 8).

Treatment and Clinical Course. The patient was transferred to the intensive care unit for neuromonitoring. Her hypokalemia and hypertension were treated aggressively to normalize her potassium levels and blood pressure. Her oxacillin therapy was changed to daptomycin. On postoperative day 17, the patient was transferred to another institution for further medical management after achieving full recovery of her eyesight after electrolyte and blood pressure corrections.

Discussion

Posterior reversible encephalopathy syndrome is a rare but frequently devastating complication of spinal surgery, with an estimated incidence of 0.094% to 0.2%.^7,8  Pediatric patients, as well as patients undergoing deformity correction surgery and posterior lumbar fusion, which necessitate prone positioning, have a significantly increased risk of POVL after spinal surgery.⁹ There are several causes of POVL after spinal surgery, each with a unique pathophysiology, clinical presentation, and prognosis.

The most common cause of POVL, accounting for 89% of all cases, is ischemic neuropathy.¹⁰ Ischemic neuropathy refers to a hypoperfusion or infarction of the anterior or posterior portion of the optic nerve and presents as painless bilateral vision loss or complete blindness on waking from the surgical procedure.¹¹ Risk factors associated with anterior ischemic neuropathy are primarily diabetes mellitus, prone positioning, nocturnal hypotension, and blood loss.¹¹ Posterior ischemic neuropathy has been most strongly correlated with anemia and hypotension.¹² The exact etiology of this complication has not been established, although the prognosis is generally unfavorable, with most vision loss being permanent.^10-12 

Another potential cause of POVL after spinal surgery is retinal artery occlusion. It is most commonly observed in patients who were improperly positioned, resulting in compression of an orbit on the surface of the headrest or the operating table.¹³ Retinal artery occlusion characteristically presents as an irreversible unilateral complete loss of vision with a red spot on the macula and an afferent pupillary defect.¹⁴

Cortical blindness, another possible common cause of POVL, results from the hypoperfusion of the occipital cortex and has a slightly better prognosis. Cortical blindness generally results from an embolic event that can be visualized through neuroimaging and may be unilateral or bilateral, ranging from mild peripheral vision loss to complete blindness.¹⁵

Posterior reversible encephalopathy syndrome, the cause of POVL diagnosed in the 2 patients in this case report, is a neurologic syndrome that differs significantly in its clinical presentation and pathophysiology from the more well-known etiologies. The precise pathophysiologic mechanism of the syndrome is yet to be elucidated. One theory revolves around the failure of cerebral vascular autoregulation. It postulates that intracerebellar hypertension leads to the extravasation of proteins and fluid, resulting in the characteristic vasogenic edema.^16,17 The other equally discussed theory postulates that cerebellar vasospasm and subsequent hypoperfusion leading to cellular hypoxemia and ischemia may be responsible.^18-20 Posterior reversible encephalopathy syndrome has been reported with increasing frequency, particularly in connection with hypertension, acute renal failure associated with malignancy, cytotoxicity, and corticosteroids, as well as preeclampsia, eclampsia, and autoimmune disorders.^1-3,21-23 Traditionally, patients display a combination of different symptoms, including vision changes ranging from slightly decreased perception to complete blindness. Unlike retinal artery occlusion and ischemic optic neuropathy, the onset of vision loss often does not happen immediately after surgery and may occur several hours to days after surgery. Visual disturbance may progressively worsen if the medical cause for the syndrome is not determined and corrected.^2,3 In contrast to other known etiologies of POVL, PRES has a relatively favorable prognosis if managed appropriately. Reported case series determined a resolution of the characteristic parieto-occipital vasogenic edema in 83% to 88% of all patients in follow-up neuroimaging after aggressive control of seizures and arterial hypertension.^2-3 

Both patients undergoing spinal deformity surgery in this report suffered from intermittent hypertensive episodes in the postoperative period. One patient also developed acute renal failure during her hospital stay, and demonstrated low albumin levels postoperatively, which has also been associated with PRES.²⁴ Through the immediate diagnosis and primary control of hypertension, both patients achieved complete neurologic recovery after a mean of 1.5 days (range, 1-2 days); this compares to a recovery period of an average 6.2 days (range, 1-14 days) reported by Ni and colleagues.³ The catastrophic effects of a misdiagnosis and incorrect or untimely treatment were well described in this case report. Several patients who were incorrectly diagnosed with demyelinating disorders or lupus encephalopathy received high doses of immunosuppressants and corticosteroids, known risk factors for the development of PRES.³ The patients subsequently rapidly deteriorated; no patients had a full recovery of their preoperative eyesight, and 1 patient developed complete permanent blindness.³ Optimized multidisciplinary collaboration allowing for a rapid neuro-ophthalmic examination and appropriate neuroimaging will permit an accurate and rapid diagnosis, leading to timely intervention and restoration of vision.

Conclusion

Temporary POVL is a potentially devastating complication of spinal surgery and general anesthesia. The more frequent causes such as ischemic optic neuropathy, retinal artery occlusion, and cortical blindness have very limited effective options for treatment and an overall poor prognosis. The inclusion of PRES in the differential diagnosis of POVL may allow early detection, management, and restoration of vision.

First described in 1996, posterior reversible encephalopathy syndrome (PRES) exhibits a wide clinical spectrum and is definitively diagnosed through computed tomography (CT) and/or magnetic resonance imaging (MRI) studies of the brain.¹ Clinical presentation may include a spectrum of symptoms, including nausea, emesis, seizures, visual loss, paralysis, and headaches.^2,3 The most common imaging finding of PRES is bilateral foci of vasogenic edema located in the parieto-occipital white matter.^2-6 Other areas of the brain are frequently affected as well, with the frontal and temporal lobes and the basal or cortical ganglia showing signs of distinctly noncytotoxic edema in 12.5% to 54.2% of all cases.³ With the symptom of visual loss being present in 20% to 62.5% of patients with PRES, the syndrome constitutes a rare potential cause for postoperative visual loss (POVL) after spinal surgery, which has a generally good prognosis because most patients will completely regain their eyesight.^2,3

We present a unique account of 2 patients who underwent extensive spinal surgery and received a timely diagnosis and treatment of PRES at a single institution. We aim to elucidate the difference in clinical and radiographic presentation of PRES in relation to other known causes of POVL after spinal surgery. The patients provided written informed consent for print and electronic publication of these case reports.

Case Reports

Case 1

Clinical Presentation. A 78-year-old woman presented to the outpatient clinic with disability due to severe lower back pain. Her surgical history was significant for breast lumpectomy and cataract excision. Her medical history was significant for hypertension, obesity (body mass index, 31.5), hypercholesterolemia, emphysema, and anemia. She had undergone spinal surgery, specifically laminectomies from L2 to S1. The radiographic examination showed degenerative thoracolumbar scoliosis with severe spondylosis, disc space collapse, and ankylosis of L4-L5 (Figure 1).

Operative Procedure. The patient underwent transpsoas lumbar interbody fusion (XLIF, NuVasive) from L1 to L4 and posterior spinal fusion from T10 to pelvis (Expedium, Depuy Synthes) (Figure 2). Operative time was 553 minutes; estimated blood loss was 2000 mL due to intraoperative coagulopathy (platelets, 40,000/µL) near the end of the posterior portion of the procedure. Intraoperative hypotension was treated by volume resuscitation and transient use of vasopressor agents. She was transfused with 1700 mL of blood, 150 mL of saline solution, and 420 mL of Lactated Ringer’s solution. No intraoperative complications occurred. The patient was extubated uneventfully on postoperative day 1 and was at baseline neurologically with no visual disturbances.

Development and Diagnosis of PRES. The patient made significant progress with physical therapy and developed episodes of hypertension at night on postoperative days 4 to 6. Her mean peak systolic blood pressure was 180 mm Hg. This improved after oral beta-blocker therapy. On postoperative day 6, the patient was ambulating with physical therapy and the aid of a walker. She was found to be neurologically intact, was resting comfortable in a chair reading a book, and was cleared for transfer to a rehabilitation facility the next day. During the morning on postoperative day 7, she developed confusion and visual loss. The patient reported blurry vision followed by complete bilateral painless loss of vision aside from mild light perception. She was unable to identify any objects. She had extinction to double simultaneous stimuli and evidence of agraphesthesia in the left hand. Her neurologic examination was otherwise at baseline. Upon emergent imaging, head CT showed bilateral symmetric areas of hypodensity involving the cortical and subcortical white matter of both occipital lobes (Figure 3). MRI showed extensive bilateral cortical and subcortical signal hyperintensity involving the parietal and occipital lobes (Figure 4). No evidence of petechial or lobar hemorrhage was found.

Treatment and Clinical Course. The patient was transferred to the neurology intensive care unit for neurologic monitoring. She was treated aggressively for recurrent hypertensive episodes. Twenty-four hours after initial blood pressure optimization therapy, she partially recovered her eyesight. She exhibited complete recovery after 48 hours. The patient was discharged to a rehabilitation facility in stable condition on postoperative day 11.

Case 2

Clinical Presentation. A 51-year-old woman presented to the outpatient clinic with progressive low back pain and decompensation due to degenerative adult scoliosis. Her surgical history was significant for an uneventful Caesarean section. Her medical history was significant for borderline hypertension and obesity (body mass index, 34.4). The radiographic examination showed an S-shaped thoracolumbar curve from T4 to L4 (Figure 5).

Operative Procedure. After discussions about the risks and benefits of the procedure, the patient underwent posterior spinal fusion from T3 to pelvis (Mesa, K2M) and interbody fusion from L4 to S1 via a presacral approach using the AxiaLIF system (TranS1) (Figure 6). The operation spanned 507 minutes. The patient lost approximately 2200 mL of blood. She was transfused with 1690 mL of blood, 1250 mL of Lactated Ringer’s solution, and 1 unit (50 mL) of albumin. No intraoperative complications occurred.

Development and Diagnosis of PRES. The patient was ambulatory with physical therapy and a walker on postoperative day 1. Her albumin levels were noted to be decreased postoperatively (28 mg/mL; normal, >35 mg/mL). She developed intermittent hypertensive episodes and experienced transient peripheral vision loss. After her ophthalmologic symptoms cleared, she was discharged and transferred to a rehabilitation facility on postoperative day 9. Eleven days later, the patient was emergently readmitted for a deep spine wound infection after an onset of wound swelling and fever. She underwent irrigation and débridement of the spine wound with an estimated blood loss of 400 mL. The patient continued to have fevers and was placed on ciprofloxacin and vancomycin, which was changed to levofloxacin on postoperative day 5. Elevated creatinine was noted, and the patient was diagnosed with acute renal failure. On postoperative day 7, oxacillin therapy was commenced. After her cultures grew methicillin-resistant Staphylococcus aureus, a peripherally inserted central catheter line was placed on postoperative day 9. As a result of nausea and constipation, the patient received feeding tubes on postoperative day 11. Additionally, she was diagnosed with a pleural effusion on postoperative day 14. Although her creatinine levels were decreasing, she continued to experience intermittent hypertensive episodes with a mean peak systolic blood pressure of 148 mm Hg. On postoperative day 15, she had a seizure and again developed visual loss. The patient was lethargic and followed only simple commands. She moved all extremities and withdrew symmetrically to noxious stimuli. Upon emergent imaging, head CT showed posterior subcortical white matter hypodensity within the occipital and parietal lobes bilaterally (Figure 7). MRI showed focal regions of symmetric hemispheric edema involving the parietal and occipital lobes in a predominantly subcortical white-matter distribution. Additionally, extensive involvement of the splenium and of the corpus callosum, left greater than right, was observed (Figure 8).

Treatment and Clinical Course. The patient was transferred to the intensive care unit for neuromonitoring. Her hypokalemia and hypertension were treated aggressively to normalize her potassium levels and blood pressure. Her oxacillin therapy was changed to daptomycin. On postoperative day 17, the patient was transferred to another institution for further medical management after achieving full recovery of her eyesight after electrolyte and blood pressure corrections.

Discussion

Posterior reversible encephalopathy syndrome is a rare but frequently devastating complication of spinal surgery, with an estimated incidence of 0.094% to 0.2%.^7,8  Pediatric patients, as well as patients undergoing deformity correction surgery and posterior lumbar fusion, which necessitate prone positioning, have a significantly increased risk of POVL after spinal surgery.⁹ There are several causes of POVL after spinal surgery, each with a unique pathophysiology, clinical presentation, and prognosis.

The most common cause of POVL, accounting for 89% of all cases, is ischemic neuropathy.¹⁰ Ischemic neuropathy refers to a hypoperfusion or infarction of the anterior or posterior portion of the optic nerve and presents as painless bilateral vision loss or complete blindness on waking from the surgical procedure.¹¹ Risk factors associated with anterior ischemic neuropathy are primarily diabetes mellitus, prone positioning, nocturnal hypotension, and blood loss.¹¹ Posterior ischemic neuropathy has been most strongly correlated with anemia and hypotension.¹² The exact etiology of this complication has not been established, although the prognosis is generally unfavorable, with most vision loss being permanent.^10-12 

Another potential cause of POVL after spinal surgery is retinal artery occlusion. It is most commonly observed in patients who were improperly positioned, resulting in compression of an orbit on the surface of the headrest or the operating table.¹³ Retinal artery occlusion characteristically presents as an irreversible unilateral complete loss of vision with a red spot on the macula and an afferent pupillary defect.¹⁴

Cortical blindness, another possible common cause of POVL, results from the hypoperfusion of the occipital cortex and has a slightly better prognosis. Cortical blindness generally results from an embolic event that can be visualized through neuroimaging and may be unilateral or bilateral, ranging from mild peripheral vision loss to complete blindness.¹⁵

Posterior reversible encephalopathy syndrome, the cause of POVL diagnosed in the 2 patients in this case report, is a neurologic syndrome that differs significantly in its clinical presentation and pathophysiology from the more well-known etiologies. The precise pathophysiologic mechanism of the syndrome is yet to be elucidated. One theory revolves around the failure of cerebral vascular autoregulation. It postulates that intracerebellar hypertension leads to the extravasation of proteins and fluid, resulting in the characteristic vasogenic edema.^16,17 The other equally discussed theory postulates that cerebellar vasospasm and subsequent hypoperfusion leading to cellular hypoxemia and ischemia may be responsible.^18-20 Posterior reversible encephalopathy syndrome has been reported with increasing frequency, particularly in connection with hypertension, acute renal failure associated with malignancy, cytotoxicity, and corticosteroids, as well as preeclampsia, eclampsia, and autoimmune disorders.^1-3,21-23 Traditionally, patients display a combination of different symptoms, including vision changes ranging from slightly decreased perception to complete blindness. Unlike retinal artery occlusion and ischemic optic neuropathy, the onset of vision loss often does not happen immediately after surgery and may occur several hours to days after surgery. Visual disturbance may progressively worsen if the medical cause for the syndrome is not determined and corrected.^2,3 In contrast to other known etiologies of POVL, PRES has a relatively favorable prognosis if managed appropriately. Reported case series determined a resolution of the characteristic parieto-occipital vasogenic edema in 83% to 88% of all patients in follow-up neuroimaging after aggressive control of seizures and arterial hypertension.^2-3 

Both patients undergoing spinal deformity surgery in this report suffered from intermittent hypertensive episodes in the postoperative period. One patient also developed acute renal failure during her hospital stay, and demonstrated low albumin levels postoperatively, which has also been associated with PRES.²⁴ Through the immediate diagnosis and primary control of hypertension, both patients achieved complete neurologic recovery after a mean of 1.5 days (range, 1-2 days); this compares to a recovery period of an average 6.2 days (range, 1-14 days) reported by Ni and colleagues.³ The catastrophic effects of a misdiagnosis and incorrect or untimely treatment were well described in this case report. Several patients who were incorrectly diagnosed with demyelinating disorders or lupus encephalopathy received high doses of immunosuppressants and corticosteroids, known risk factors for the development of PRES.³ The patients subsequently rapidly deteriorated; no patients had a full recovery of their preoperative eyesight, and 1 patient developed complete permanent blindness.³ Optimized multidisciplinary collaboration allowing for a rapid neuro-ophthalmic examination and appropriate neuroimaging will permit an accurate and rapid diagnosis, leading to timely intervention and restoration of vision.

Conclusion

Temporary POVL is a potentially devastating complication of spinal surgery and general anesthesia. The more frequent causes such as ischemic optic neuropathy, retinal artery occlusion, and cortical blindness have very limited effective options for treatment and an overall poor prognosis. The inclusion of PRES in the differential diagnosis of POVL may allow early detection, management, and restoration of vision.

First described in 1996, posterior reversible encephalopathy syndrome (PRES) exhibits a wide clinical spectrum and is definitively diagnosed through computed tomography (CT) and/or magnetic resonance imaging (MRI) studies of the brain.¹ Clinical presentation may include a spectrum of symptoms, including nausea, emesis, seizures, visual loss, paralysis, and headaches.^2,3 The most common imaging finding of PRES is bilateral foci of vasogenic edema located in the parieto-occipital white matter.^2-6 Other areas of the brain are frequently affected as well, with the frontal and temporal lobes and the basal or cortical ganglia showing signs of distinctly noncytotoxic edema in 12.5% to 54.2% of all cases.³ With the symptom of visual loss being present in 20% to 62.5% of patients with PRES, the syndrome constitutes a rare potential cause for postoperative visual loss (POVL) after spinal surgery, which has a generally good prognosis because most patients will completely regain their eyesight.^2,3

We present a unique account of 2 patients who underwent extensive spinal surgery and received a timely diagnosis and treatment of PRES at a single institution. We aim to elucidate the difference in clinical and radiographic presentation of PRES in relation to other known causes of POVL after spinal surgery. The patients provided written informed consent for print and electronic publication of these case reports.

Case Reports

Case 1

Clinical Presentation. A 78-year-old woman presented to the outpatient clinic with disability due to severe lower back pain. Her surgical history was significant for breast lumpectomy and cataract excision. Her medical history was significant for hypertension, obesity (body mass index, 31.5), hypercholesterolemia, emphysema, and anemia. She had undergone spinal surgery, specifically laminectomies from L2 to S1. The radiographic examination showed degenerative thoracolumbar scoliosis with severe spondylosis, disc space collapse, and ankylosis of L4-L5 (Figure 1).

Operative Procedure. The patient underwent transpsoas lumbar interbody fusion (XLIF, NuVasive) from L1 to L4 and posterior spinal fusion from T10 to pelvis (Expedium, Depuy Synthes) (Figure 2). Operative time was 553 minutes; estimated blood loss was 2000 mL due to intraoperative coagulopathy (platelets, 40,000/µL) near the end of the posterior portion of the procedure. Intraoperative hypotension was treated by volume resuscitation and transient use of vasopressor agents. She was transfused with 1700 mL of blood, 150 mL of saline solution, and 420 mL of Lactated Ringer’s solution. No intraoperative complications occurred. The patient was extubated uneventfully on postoperative day 1 and was at baseline neurologically with no visual disturbances.

Development and Diagnosis of PRES. The patient made significant progress with physical therapy and developed episodes of hypertension at night on postoperative days 4 to 6. Her mean peak systolic blood pressure was 180 mm Hg. This improved after oral beta-blocker therapy. On postoperative day 6, the patient was ambulating with physical therapy and the aid of a walker. She was found to be neurologically intact, was resting comfortable in a chair reading a book, and was cleared for transfer to a rehabilitation facility the next day. During the morning on postoperative day 7, she developed confusion and visual loss. The patient reported blurry vision followed by complete bilateral painless loss of vision aside from mild light perception. She was unable to identify any objects. She had extinction to double simultaneous stimuli and evidence of agraphesthesia in the left hand. Her neurologic examination was otherwise at baseline. Upon emergent imaging, head CT showed bilateral symmetric areas of hypodensity involving the cortical and subcortical white matter of both occipital lobes (Figure 3). MRI showed extensive bilateral cortical and subcortical signal hyperintensity involving the parietal and occipital lobes (Figure 4). No evidence of petechial or lobar hemorrhage was found.

Treatment and Clinical Course. The patient was transferred to the neurology intensive care unit for neurologic monitoring. She was treated aggressively for recurrent hypertensive episodes. Twenty-four hours after initial blood pressure optimization therapy, she partially recovered her eyesight. She exhibited complete recovery after 48 hours. The patient was discharged to a rehabilitation facility in stable condition on postoperative day 11.

Case 2

Clinical Presentation. A 51-year-old woman presented to the outpatient clinic with progressive low back pain and decompensation due to degenerative adult scoliosis. Her surgical history was significant for an uneventful Caesarean section. Her medical history was significant for borderline hypertension and obesity (body mass index, 34.4). The radiographic examination showed an S-shaped thoracolumbar curve from T4 to L4 (Figure 5).

Operative Procedure. After discussions about the risks and benefits of the procedure, the patient underwent posterior spinal fusion from T3 to pelvis (Mesa, K2M) and interbody fusion from L4 to S1 via a presacral approach using the AxiaLIF system (TranS1) (Figure 6). The operation spanned 507 minutes. The patient lost approximately 2200 mL of blood. She was transfused with 1690 mL of blood, 1250 mL of Lactated Ringer’s solution, and 1 unit (50 mL) of albumin. No intraoperative complications occurred.

Development and Diagnosis of PRES. The patient was ambulatory with physical therapy and a walker on postoperative day 1. Her albumin levels were noted to be decreased postoperatively (28 mg/mL; normal, >35 mg/mL). She developed intermittent hypertensive episodes and experienced transient peripheral vision loss. After her ophthalmologic symptoms cleared, she was discharged and transferred to a rehabilitation facility on postoperative day 9. Eleven days later, the patient was emergently readmitted for a deep spine wound infection after an onset of wound swelling and fever. She underwent irrigation and débridement of the spine wound with an estimated blood loss of 400 mL. The patient continued to have fevers and was placed on ciprofloxacin and vancomycin, which was changed to levofloxacin on postoperative day 5. Elevated creatinine was noted, and the patient was diagnosed with acute renal failure. On postoperative day 7, oxacillin therapy was commenced. After her cultures grew methicillin-resistant Staphylococcus aureus, a peripherally inserted central catheter line was placed on postoperative day 9. As a result of nausea and constipation, the patient received feeding tubes on postoperative day 11. Additionally, she was diagnosed with a pleural effusion on postoperative day 14. Although her creatinine levels were decreasing, she continued to experience intermittent hypertensive episodes with a mean peak systolic blood pressure of 148 mm Hg. On postoperative day 15, she had a seizure and again developed visual loss. The patient was lethargic and followed only simple commands. She moved all extremities and withdrew symmetrically to noxious stimuli. Upon emergent imaging, head CT showed posterior subcortical white matter hypodensity within the occipital and parietal lobes bilaterally (Figure 7). MRI showed focal regions of symmetric hemispheric edema involving the parietal and occipital lobes in a predominantly subcortical white-matter distribution. Additionally, extensive involvement of the splenium and of the corpus callosum, left greater than right, was observed (Figure 8).

Treatment and Clinical Course. The patient was transferred to the intensive care unit for neuromonitoring. Her hypokalemia and hypertension were treated aggressively to normalize her potassium levels and blood pressure. Her oxacillin therapy was changed to daptomycin. On postoperative day 17, the patient was transferred to another institution for further medical management after achieving full recovery of her eyesight after electrolyte and blood pressure corrections.

Discussion

Posterior reversible encephalopathy syndrome is a rare but frequently devastating complication of spinal surgery, with an estimated incidence of 0.094% to 0.2%.^7,8  Pediatric patients, as well as patients undergoing deformity correction surgery and posterior lumbar fusion, which necessitate prone positioning, have a significantly increased risk of POVL after spinal surgery.⁹ There are several causes of POVL after spinal surgery, each with a unique pathophysiology, clinical presentation, and prognosis.

The most common cause of POVL, accounting for 89% of all cases, is ischemic neuropathy.¹⁰ Ischemic neuropathy refers to a hypoperfusion or infarction of the anterior or posterior portion of the optic nerve and presents as painless bilateral vision loss or complete blindness on waking from the surgical procedure.¹¹ Risk factors associated with anterior ischemic neuropathy are primarily diabetes mellitus, prone positioning, nocturnal hypotension, and blood loss.¹¹ Posterior ischemic neuropathy has been most strongly correlated with anemia and hypotension.¹² The exact etiology of this complication has not been established, although the prognosis is generally unfavorable, with most vision loss being permanent.^10-12 

Another potential cause of POVL after spinal surgery is retinal artery occlusion. It is most commonly observed in patients who were improperly positioned, resulting in compression of an orbit on the surface of the headrest or the operating table.¹³ Retinal artery occlusion characteristically presents as an irreversible unilateral complete loss of vision with a red spot on the macula and an afferent pupillary defect.¹⁴

Cortical blindness, another possible common cause of POVL, results from the hypoperfusion of the occipital cortex and has a slightly better prognosis. Cortical blindness generally results from an embolic event that can be visualized through neuroimaging and may be unilateral or bilateral, ranging from mild peripheral vision loss to complete blindness.¹⁵

Posterior reversible encephalopathy syndrome, the cause of POVL diagnosed in the 2 patients in this case report, is a neurologic syndrome that differs significantly in its clinical presentation and pathophysiology from the more well-known etiologies. The precise pathophysiologic mechanism of the syndrome is yet to be elucidated. One theory revolves around the failure of cerebral vascular autoregulation. It postulates that intracerebellar hypertension leads to the extravasation of proteins and fluid, resulting in the characteristic vasogenic edema.^16,17 The other equally discussed theory postulates that cerebellar vasospasm and subsequent hypoperfusion leading to cellular hypoxemia and ischemia may be responsible.^18-20 Posterior reversible encephalopathy syndrome has been reported with increasing frequency, particularly in connection with hypertension, acute renal failure associated with malignancy, cytotoxicity, and corticosteroids, as well as preeclampsia, eclampsia, and autoimmune disorders.^1-3,21-23 Traditionally, patients display a combination of different symptoms, including vision changes ranging from slightly decreased perception to complete blindness. Unlike retinal artery occlusion and ischemic optic neuropathy, the onset of vision loss often does not happen immediately after surgery and may occur several hours to days after surgery. Visual disturbance may progressively worsen if the medical cause for the syndrome is not determined and corrected.^2,3 In contrast to other known etiologies of POVL, PRES has a relatively favorable prognosis if managed appropriately. Reported case series determined a resolution of the characteristic parieto-occipital vasogenic edema in 83% to 88% of all patients in follow-up neuroimaging after aggressive control of seizures and arterial hypertension.^2-3 

Both patients undergoing spinal deformity surgery in this report suffered from intermittent hypertensive episodes in the postoperative period. One patient also developed acute renal failure during her hospital stay, and demonstrated low albumin levels postoperatively, which has also been associated with PRES.²⁴ Through the immediate diagnosis and primary control of hypertension, both patients achieved complete neurologic recovery after a mean of 1.5 days (range, 1-2 days); this compares to a recovery period of an average 6.2 days (range, 1-14 days) reported by Ni and colleagues.³ The catastrophic effects of a misdiagnosis and incorrect or untimely treatment were well described in this case report. Several patients who were incorrectly diagnosed with demyelinating disorders or lupus encephalopathy received high doses of immunosuppressants and corticosteroids, known risk factors for the development of PRES.³ The patients subsequently rapidly deteriorated; no patients had a full recovery of their preoperative eyesight, and 1 patient developed complete permanent blindness.³ Optimized multidisciplinary collaboration allowing for a rapid neuro-ophthalmic examination and appropriate neuroimaging will permit an accurate and rapid diagnosis, leading to timely intervention and restoration of vision.

Conclusion

Temporary POVL is a potentially devastating complication of spinal surgery and general anesthesia. The more frequent causes such as ischemic optic neuropathy, retinal artery occlusion, and cortical blindness have very limited effective options for treatment and an overall poor prognosis. The inclusion of PRES in the differential diagnosis of POVL may allow early detection, management, and restoration of vision.

The literature on extensor tendon rupture and even chronic flexor tendon rupture after volar plating and distal radius fracture malunion is ubiquitous. However, acute and subacute flexor tendon ruptures caused by distal radius fractures have been reported only in limited case reports. These rare injuries may involve multiple tendons and are associated with high-energy mechanisms. This case report details the involvement of multiple flexor tendon injuries associated with a Gustilo-Anderson type II distal radius fracture and the development of acute carpal tunnel syndrome (CTS) after a motor vehicle collision. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

The patient is a 46-year-old woman who was involved in a motor vehicle collision. She was triaged as a trauma patient via Advanced Trauma Life Support protocol, and treated with antibiotic and tetanus prophylaxis. Radiographs showed an open, comminuted, displaced intra-articular distal radius fracture on the right side (Figures 1A, 1B). The fracture was closed reduced and splinted in the emergency department (Figures 2A, 2B). On initial examination, the patient had diffuse paresthesias in the digits that were most pronounced in the median nerve distribution. Motor examination was limited secondary to pain; however, she demonstrated gentle flexion and extension of the digits. The hand was well perfused, and a palpable radial pulse was present. 

After clearance was obtained, she was taken urgently to the operating room. The wound was volar and transverse, approximately 2 cm in length, and approximately 4 cm proximal to the wrist crease. The wound was extended proximally and distally for a standard volar (Henry) approach. The flexor carpi radialis tendon was found to be partially lacerated, comprising 60% of the tendon. The fracture was readily identified because the deep fascia and the pronator quadratus were disrupted. No deep tendon lacerations were identified. The median nerve was found to be in continuity. After satisfactory débridement of the fracture and the wound, reduction and fixation was achieved with a volar locking plate and a single Kirschner wire. The flexor carpi radialis tendon was repaired with a modified Kessler stitch and epitenon repair. The wound was closed primarily in layers (Figures 3A, 3B).

The patient’s immediate postoperative neurologic examination was compromised secondary to the patient having a supraclavicular nerve block for anesthesia. Regional anesthesia was chosen because the patient’s pulmonologist recommended avoiding general anesthesia owing to her history of severe asthma that frequently required corticosteroid treatment. Once the block wore off, she complained of persistent paresthesias in all digits but most pronounced in the median nerve distribution. She was able to flex the interphalangeal joint to the index finger but could not flex the interphalangeal joint to the thumb. Over the course of the night, she was also noted to have worsening pain out of proportion to her injury.

As the paresthesias became denser in the median nerve distribution, she was diagnosed with acute CTS and was taken urgently back to the operating room under general anesthesia. After releasing the carpal tunnel through a separate incision, the original wound was reopened and explored. The median nerve was again visualized and found to be in continuity. All 4 tendons to both the flexor digitorum superficialis and flexor digitorum profundus were identified. The flexor pollicis longus (FPL) was not visualized in the wound. The distal portion of the FPL was retracted in the thumb tendon sheath and retrieved blindly with a tendon passer. The proximal portion was retracted to the mid-forearm. The laceration occurred distal to the musculotendinous junction. The tendon was repaired with a modified Kessler stitch as well as a box suture, resulting in 4 core strands across the tendon. The hand and the wrist were splinted in a thumb spica cast, and the patient was started on a modified Duran protocol 1 week after surgery. Median nerve function improved postoperatively. 

Discussion

The rupture of the extensor pollicis longus tendon in nondisplaced distal radius fractures is not uncommon, but occurs in fewer than 5% of nondisplaced distal radius fractures.¹ Although less common, chronic complications with flexor tendon rupture after distal radius fracture are well described.^1-6 Flexor tendon rupture after distal radius malunion or volar plating is a known complication and is thought to be the result of attritional tendon wear because the flexors rub against protruding bone or plate;^3,4,7 however, the initial tendon injury may play a role in those tendons that rupture more quickly.³ When secondary to volar plating, the rupture typically occurs within 1 year of injury,⁷ but, in both plating and malunion, it has been characterized as a late complication up to 10 years and even 20 years after injury.^3,4 Similar to other reports, this rupture was encountered during a volar wrist approach. It has been suggested that, as the incidence of volar plating rises, more acute flexor tendon injuries may be diagnosed because of anatomic exposure,² but this has not been reported in the literature. 

Acute and subacute flexor tendon ruptures are rarely reported in the literature. To our knowledge, there are only 2 other reports of acute flexor tendon rupture^2,5 after a distal radius fracture, neither of which involved the FPL. These cases, which involved ruptures of the flexor digitorum superficialis and flexor carpi radialis, were thought to be the result of tendon laceration by a volar bone spike. There is also one report of subacute FPL and flexor digitorum profundus rupture approximately 4 weeks after closed reduction of a distal radius fracture.⁶ Although sparse, the literature regarding flexor tendon rupture and distal radius fractures suggests that involvement of the flexor digitorum superficialis and the flexor digitorum profundus tendons is most common and that the rupture typically occurs in 1 to 4 months.¹

We report a rare case of 2 acute flexor tendon lacerations after a Gustilo-Anderson type II open distal radius fracture, likely caused by the volar spike of bone that created the open injury. This case also was complicated by the development of acute CTS. 

To our knowledge, despite a rate of acute CTS reported as high as 5.4% in operatively treated distal radius fractures, there are no established associations between acute CTS and flexor tendon rupture in the setting of distal radius fracture.^8,9 In a 2008 retrospective case–control study by Dyer and colleagues,⁸ fracture translation is the most important risk factor for the development of acute CTS associated with fracture of the distal radius. Although not statistically significant, ipsilateral upper extremity trauma, higher-energy injuries, younger age, and male sex were also associated with the development of acute CTS. Open injuries occurred in only 3 of 50 cases of acute CTS.⁸

In agreement with published reports, the probability and the timing of tendon rupture are likely related to the severity of the deforming forces applied during the initial insult rather than the resultant stresses.¹ Clinicians should have a high suspicion of acute CTS and possible tendon injuries after a high-energy injury with a significantly displaced open distal radius fracture and median nerve paresthesias. A thoughtful and complete preoperative examination of the flexor tendons may prevent the need for reoperation. Concerns for flexor injury and acute CTS should be elevated with the observation of a disrupted pronator. For patients with a volarly displaced fragment after fracture reduction, this concern should be even more elevated.⁹ Preoperative median nerve symptoms in the setting of the severely displaced fracture should necessitate an acute carpal tunnel release. If 1 flexor tendon is injured, the surgeon should remember that multiple flexor tendons may be involved. We recommend that any injured tendons be repaired primarily, if possible, and the patient started on appropriate rehabilitation.

The literature on extensor tendon rupture and even chronic flexor tendon rupture after volar plating and distal radius fracture malunion is ubiquitous. However, acute and subacute flexor tendon ruptures caused by distal radius fractures have been reported only in limited case reports. These rare injuries may involve multiple tendons and are associated with high-energy mechanisms. This case report details the involvement of multiple flexor tendon injuries associated with a Gustilo-Anderson type II distal radius fracture and the development of acute carpal tunnel syndrome (CTS) after a motor vehicle collision. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

The patient is a 46-year-old woman who was involved in a motor vehicle collision. She was triaged as a trauma patient via Advanced Trauma Life Support protocol, and treated with antibiotic and tetanus prophylaxis. Radiographs showed an open, comminuted, displaced intra-articular distal radius fracture on the right side (Figures 1A, 1B). The fracture was closed reduced and splinted in the emergency department (Figures 2A, 2B). On initial examination, the patient had diffuse paresthesias in the digits that were most pronounced in the median nerve distribution. Motor examination was limited secondary to pain; however, she demonstrated gentle flexion and extension of the digits. The hand was well perfused, and a palpable radial pulse was present. 

After clearance was obtained, she was taken urgently to the operating room. The wound was volar and transverse, approximately 2 cm in length, and approximately 4 cm proximal to the wrist crease. The wound was extended proximally and distally for a standard volar (Henry) approach. The flexor carpi radialis tendon was found to be partially lacerated, comprising 60% of the tendon. The fracture was readily identified because the deep fascia and the pronator quadratus were disrupted. No deep tendon lacerations were identified. The median nerve was found to be in continuity. After satisfactory débridement of the fracture and the wound, reduction and fixation was achieved with a volar locking plate and a single Kirschner wire. The flexor carpi radialis tendon was repaired with a modified Kessler stitch and epitenon repair. The wound was closed primarily in layers (Figures 3A, 3B).

The patient’s immediate postoperative neurologic examination was compromised secondary to the patient having a supraclavicular nerve block for anesthesia. Regional anesthesia was chosen because the patient’s pulmonologist recommended avoiding general anesthesia owing to her history of severe asthma that frequently required corticosteroid treatment. Once the block wore off, she complained of persistent paresthesias in all digits but most pronounced in the median nerve distribution. She was able to flex the interphalangeal joint to the index finger but could not flex the interphalangeal joint to the thumb. Over the course of the night, she was also noted to have worsening pain out of proportion to her injury.

As the paresthesias became denser in the median nerve distribution, she was diagnosed with acute CTS and was taken urgently back to the operating room under general anesthesia. After releasing the carpal tunnel through a separate incision, the original wound was reopened and explored. The median nerve was again visualized and found to be in continuity. All 4 tendons to both the flexor digitorum superficialis and flexor digitorum profundus were identified. The flexor pollicis longus (FPL) was not visualized in the wound. The distal portion of the FPL was retracted in the thumb tendon sheath and retrieved blindly with a tendon passer. The proximal portion was retracted to the mid-forearm. The laceration occurred distal to the musculotendinous junction. The tendon was repaired with a modified Kessler stitch as well as a box suture, resulting in 4 core strands across the tendon. The hand and the wrist were splinted in a thumb spica cast, and the patient was started on a modified Duran protocol 1 week after surgery. Median nerve function improved postoperatively. 

Discussion

The rupture of the extensor pollicis longus tendon in nondisplaced distal radius fractures is not uncommon, but occurs in fewer than 5% of nondisplaced distal radius fractures.¹ Although less common, chronic complications with flexor tendon rupture after distal radius fracture are well described.^1-6 Flexor tendon rupture after distal radius malunion or volar plating is a known complication and is thought to be the result of attritional tendon wear because the flexors rub against protruding bone or plate;^3,4,7 however, the initial tendon injury may play a role in those tendons that rupture more quickly.³ When secondary to volar plating, the rupture typically occurs within 1 year of injury,⁷ but, in both plating and malunion, it has been characterized as a late complication up to 10 years and even 20 years after injury.^3,4 Similar to other reports, this rupture was encountered during a volar wrist approach. It has been suggested that, as the incidence of volar plating rises, more acute flexor tendon injuries may be diagnosed because of anatomic exposure,² but this has not been reported in the literature. 

Acute and subacute flexor tendon ruptures are rarely reported in the literature. To our knowledge, there are only 2 other reports of acute flexor tendon rupture^2,5 after a distal radius fracture, neither of which involved the FPL. These cases, which involved ruptures of the flexor digitorum superficialis and flexor carpi radialis, were thought to be the result of tendon laceration by a volar bone spike. There is also one report of subacute FPL and flexor digitorum profundus rupture approximately 4 weeks after closed reduction of a distal radius fracture.⁶ Although sparse, the literature regarding flexor tendon rupture and distal radius fractures suggests that involvement of the flexor digitorum superficialis and the flexor digitorum profundus tendons is most common and that the rupture typically occurs in 1 to 4 months.¹

We report a rare case of 2 acute flexor tendon lacerations after a Gustilo-Anderson type II open distal radius fracture, likely caused by the volar spike of bone that created the open injury. This case also was complicated by the development of acute CTS. 

To our knowledge, despite a rate of acute CTS reported as high as 5.4% in operatively treated distal radius fractures, there are no established associations between acute CTS and flexor tendon rupture in the setting of distal radius fracture.^8,9 In a 2008 retrospective case–control study by Dyer and colleagues,⁸ fracture translation is the most important risk factor for the development of acute CTS associated with fracture of the distal radius. Although not statistically significant, ipsilateral upper extremity trauma, higher-energy injuries, younger age, and male sex were also associated with the development of acute CTS. Open injuries occurred in only 3 of 50 cases of acute CTS.⁸

In agreement with published reports, the probability and the timing of tendon rupture are likely related to the severity of the deforming forces applied during the initial insult rather than the resultant stresses.¹ Clinicians should have a high suspicion of acute CTS and possible tendon injuries after a high-energy injury with a significantly displaced open distal radius fracture and median nerve paresthesias. A thoughtful and complete preoperative examination of the flexor tendons may prevent the need for reoperation. Concerns for flexor injury and acute CTS should be elevated with the observation of a disrupted pronator. For patients with a volarly displaced fragment after fracture reduction, this concern should be even more elevated.⁹ Preoperative median nerve symptoms in the setting of the severely displaced fracture should necessitate an acute carpal tunnel release. If 1 flexor tendon is injured, the surgeon should remember that multiple flexor tendons may be involved. We recommend that any injured tendons be repaired primarily, if possible, and the patient started on appropriate rehabilitation.

The literature on extensor tendon rupture and even chronic flexor tendon rupture after volar plating and distal radius fracture malunion is ubiquitous. However, acute and subacute flexor tendon ruptures caused by distal radius fractures have been reported only in limited case reports. These rare injuries may involve multiple tendons and are associated with high-energy mechanisms. This case report details the involvement of multiple flexor tendon injuries associated with a Gustilo-Anderson type II distal radius fracture and the development of acute carpal tunnel syndrome (CTS) after a motor vehicle collision. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

The patient is a 46-year-old woman who was involved in a motor vehicle collision. She was triaged as a trauma patient via Advanced Trauma Life Support protocol, and treated with antibiotic and tetanus prophylaxis. Radiographs showed an open, comminuted, displaced intra-articular distal radius fracture on the right side (Figures 1A, 1B). The fracture was closed reduced and splinted in the emergency department (Figures 2A, 2B). On initial examination, the patient had diffuse paresthesias in the digits that were most pronounced in the median nerve distribution. Motor examination was limited secondary to pain; however, she demonstrated gentle flexion and extension of the digits. The hand was well perfused, and a palpable radial pulse was present. 

After clearance was obtained, she was taken urgently to the operating room. The wound was volar and transverse, approximately 2 cm in length, and approximately 4 cm proximal to the wrist crease. The wound was extended proximally and distally for a standard volar (Henry) approach. The flexor carpi radialis tendon was found to be partially lacerated, comprising 60% of the tendon. The fracture was readily identified because the deep fascia and the pronator quadratus were disrupted. No deep tendon lacerations were identified. The median nerve was found to be in continuity. After satisfactory débridement of the fracture and the wound, reduction and fixation was achieved with a volar locking plate and a single Kirschner wire. The flexor carpi radialis tendon was repaired with a modified Kessler stitch and epitenon repair. The wound was closed primarily in layers (Figures 3A, 3B).

The patient’s immediate postoperative neurologic examination was compromised secondary to the patient having a supraclavicular nerve block for anesthesia. Regional anesthesia was chosen because the patient’s pulmonologist recommended avoiding general anesthesia owing to her history of severe asthma that frequently required corticosteroid treatment. Once the block wore off, she complained of persistent paresthesias in all digits but most pronounced in the median nerve distribution. She was able to flex the interphalangeal joint to the index finger but could not flex the interphalangeal joint to the thumb. Over the course of the night, she was also noted to have worsening pain out of proportion to her injury.

As the paresthesias became denser in the median nerve distribution, she was diagnosed with acute CTS and was taken urgently back to the operating room under general anesthesia. After releasing the carpal tunnel through a separate incision, the original wound was reopened and explored. The median nerve was again visualized and found to be in continuity. All 4 tendons to both the flexor digitorum superficialis and flexor digitorum profundus were identified. The flexor pollicis longus (FPL) was not visualized in the wound. The distal portion of the FPL was retracted in the thumb tendon sheath and retrieved blindly with a tendon passer. The proximal portion was retracted to the mid-forearm. The laceration occurred distal to the musculotendinous junction. The tendon was repaired with a modified Kessler stitch as well as a box suture, resulting in 4 core strands across the tendon. The hand and the wrist were splinted in a thumb spica cast, and the patient was started on a modified Duran protocol 1 week after surgery. Median nerve function improved postoperatively. 

Discussion

The rupture of the extensor pollicis longus tendon in nondisplaced distal radius fractures is not uncommon, but occurs in fewer than 5% of nondisplaced distal radius fractures.¹ Although less common, chronic complications with flexor tendon rupture after distal radius fracture are well described.^1-6 Flexor tendon rupture after distal radius malunion or volar plating is a known complication and is thought to be the result of attritional tendon wear because the flexors rub against protruding bone or plate;^3,4,7 however, the initial tendon injury may play a role in those tendons that rupture more quickly.³ When secondary to volar plating, the rupture typically occurs within 1 year of injury,⁷ but, in both plating and malunion, it has been characterized as a late complication up to 10 years and even 20 years after injury.^3,4 Similar to other reports, this rupture was encountered during a volar wrist approach. It has been suggested that, as the incidence of volar plating rises, more acute flexor tendon injuries may be diagnosed because of anatomic exposure,² but this has not been reported in the literature. 

Acute and subacute flexor tendon ruptures are rarely reported in the literature. To our knowledge, there are only 2 other reports of acute flexor tendon rupture^2,5 after a distal radius fracture, neither of which involved the FPL. These cases, which involved ruptures of the flexor digitorum superficialis and flexor carpi radialis, were thought to be the result of tendon laceration by a volar bone spike. There is also one report of subacute FPL and flexor digitorum profundus rupture approximately 4 weeks after closed reduction of a distal radius fracture.⁶ Although sparse, the literature regarding flexor tendon rupture and distal radius fractures suggests that involvement of the flexor digitorum superficialis and the flexor digitorum profundus tendons is most common and that the rupture typically occurs in 1 to 4 months.¹

We report a rare case of 2 acute flexor tendon lacerations after a Gustilo-Anderson type II open distal radius fracture, likely caused by the volar spike of bone that created the open injury. This case also was complicated by the development of acute CTS. 

To our knowledge, despite a rate of acute CTS reported as high as 5.4% in operatively treated distal radius fractures, there are no established associations between acute CTS and flexor tendon rupture in the setting of distal radius fracture.^8,9 In a 2008 retrospective case–control study by Dyer and colleagues,⁸ fracture translation is the most important risk factor for the development of acute CTS associated with fracture of the distal radius. Although not statistically significant, ipsilateral upper extremity trauma, higher-energy injuries, younger age, and male sex were also associated with the development of acute CTS. Open injuries occurred in only 3 of 50 cases of acute CTS.⁸

In agreement with published reports, the probability and the timing of tendon rupture are likely related to the severity of the deforming forces applied during the initial insult rather than the resultant stresses.¹ Clinicians should have a high suspicion of acute CTS and possible tendon injuries after a high-energy injury with a significantly displaced open distal radius fracture and median nerve paresthesias. A thoughtful and complete preoperative examination of the flexor tendons may prevent the need for reoperation. Concerns for flexor injury and acute CTS should be elevated with the observation of a disrupted pronator. For patients with a volarly displaced fragment after fracture reduction, this concern should be even more elevated.⁹ Preoperative median nerve symptoms in the setting of the severely displaced fracture should necessitate an acute carpal tunnel release. If 1 flexor tendon is injured, the surgeon should remember that multiple flexor tendons may be involved. We recommend that any injured tendons be repaired primarily, if possible, and the patient started on appropriate rehabilitation.