Case Reports

A gram-negative bacillus of the Enterobacteriaceae family, Serratia marcescens is an organism known to cause bacteremia, pneumonia, urinary tract infection, endocarditis, meningitis, and septic arthritis.¹ Unusual cases of cellulitis and necrotizing fasciitis (NF) caused by S marcescens also have been reported.^2,3 This entity has been initially described in immunocompromised and nonimmunocompromised patients.⁴ Both community and nosocomial cases also have been reported.³

Case Report

A 68-year-old morbidly obese woman with high blood pressure, diabetes mellitus, chronic renal insufficiency, chronic venous insufficiency, and left leg lymphoedema was referred to our emergency unit. She had pain and circumferential erythema with multiple abscesses of the left leg of 2 weeks’ duration. No history of trauma, ulcer, injection, or animal bite was noted. At the time of presentation she had no fever and vital parameters were normal. Empirical treatment with oral amoxicillin (6 g daily) and amoxicillin-clavulanate (375 mg daily) was started. Forty-eight hours later, inflammation, pain, and abscesses worsened (Figure 1A). Laboratory tests showed an elevated white blood cell count (15.9×10⁹⁄L with 86% neutrophils [reference range, 4.5–11.0×10⁹⁄L]) and an elevated C-reactive protein level (322 mg/L [reference range, <2 mg/L]). Human immunodeficiency virus serology was negative. Needle aspiration of an abscess yielded S marcescens. A second aspiration confirmed the presence of the same organism, wild-type S marcescens, which was resistant to amoxicillin and clavulanic acid, first-generation cephalosporin, and tobramycin but sensitive to piperacillin, third-generation cephalosporins, amikacin, ciprofloxacin, and co-trimoxazole. Intravenous cefepime, a third-generation cephalosporin, was started. During the next 48 hours the patient developed severe sepsis with confusion, acute renal failure (creatinine: 231 µmol/L vs 138 µmol/L at baseline [reference range, 53–106 µmol/L), and worsening of skin lesions. Blood cultures were negative and amikacin was added. Magnetic resonance imaging showed a diffuse inflammatory process involving the skin and subcutaneous tissue that extended to the soleus fascia with no other muscle involvement or deep collection (Figure 2). Surgical debridement of infected tissues was performed (Figure 1B). Histologic examination revealed spreading suppurative inflammation involving the dermis and subcutaneous tissues. Clinical healing was obtained after 21 days of antimicrobial therapy. The debrided area required skin grafting 2 months later (Figure 1C).

Figure 1. Erythema with multiple abscesses on the left ankle and leg at presentation (A), day 1 following surgical debridement of infected tissues (B), and 2 months later with complete healing following a skin graft (C).

Comment

The most common causative bacteria of cellulitis are Staphylococcus aureus and group A β-hemolytic streptococci. Serratia marcescens is a rare but increasingly recognized pathogen of skin and soft tissue infections.⁵ The proposed pathogenic mechanism for skin necrosis during S marcescens infection is the bacterial production of large proteases (eg, deoxyribonuclease, lipase, gelatinase).⁶ Injection of purified proteinase from S marcescens into rat skin leads to increased vascular permeability, necrosis of epidermal tissue, dermal inflammation and edema, and infiltration of polymorphonuclear leukocytes into the subcutaneous fat and muscle.⁷Serratia marcescens is ubiquitous in soil and water and it also may colonize the respiratory, urinary, and digestive tracts in humans. Cellulitis due to S marcescens secondary to iguana bites^8,9 and snake bites¹⁰ or leech-borne cellulitis¹¹ suggest that the oral cavity of these animals may be colonized. To date, 49 cases of severe S marcescens skin infections have been described, according to a search of PubMed articles indexed for MEDLINE using the terms Serratia marcescens and skin, cutaneous, soft tissue, and cellulitis or necrotizing fasciitis: 20 cases with NF^3,12-28 and 29 non-NF cases^8-11,29-46 (typical cellulitis presentation [n=8]^{9,11,35-38,40}; abscesses, gumma, or pyoderma gangrenosum–like lesions associated with chronic granulomatous disease in childhood [n=7]^29,44,45; painful nodules with secondary abscesses [n=6]^31-34,46; acute bullous cellulitis [n=4]^8,10,30; secondary infections of ulcers [n=2]^35,40; abscesses in immunocompetent patient [n=1]⁴¹; and necrotizing skin ulceration [n=1]³⁶). Lower extremities were frequently involved (NF cases, n=13; non-NF cases, n=16). Underlying immunosuppression was observed in 14 NF cases and in 17 non-NF cases. Predisposing immunologic factors are summarized in the Table. Local risk factors, including chronic leg edema, trauma, surgical wound, filler injection, and ulcer, were frequently reported in NF and non-NF cases,^{16,20,26-28,31,32,34,35,37,38,40,46} including our case. Surgery was required in 19 NF cases and in 7 non-NF cases. Serratia marcescens–mediated NF led to higher mortality (n=12) than non-NF cases (n=1). Other nonsevere clinical manifestations of S marcescens infection reported in the literature included disseminated papular eruptions with human immunodeficiency virus infection⁴² and trunk folliculitis.⁴³ Our patient had many risk factors, including chronic edema, diabetes mellitus, chronic renal insufficiency, and chronic venous insufficiency. The potential presence of abscesses and necrotic tissue hinders antibiotic penetration at the infection site, and surgery should be systematically considered as early as possible in view of the high mortality rate of S marcescens cellulitis.

Conclusion

Although uncommon, an S marcescens skin infection may be suspected in cases of cellulitis in immunocompromised patients, especially when conventional antibiotics are not effective. Serratia marcescens naturally produces a cephalosporinase that confers resistance to amoxicillin and to amoxicillin associated with clavulanic acid. Broad-spectrum antibiotics such as third-generation cephalosporins, fluoroquinolones, or imipenem-cilastatin are indicated in cases of S marcescens skin infections, and surgery should be promptly considered if appropriate antibiotic therapy does not lead to rapid clinical improvement.

A gram-negative bacillus of the Enterobacteriaceae family, Serratia marcescens is an organism known to cause bacteremia, pneumonia, urinary tract infection, endocarditis, meningitis, and septic arthritis.¹ Unusual cases of cellulitis and necrotizing fasciitis (NF) caused by S marcescens also have been reported.^2,3 This entity has been initially described in immunocompromised and nonimmunocompromised patients.⁴ Both community and nosocomial cases also have been reported.³

Case Report

A 68-year-old morbidly obese woman with high blood pressure, diabetes mellitus, chronic renal insufficiency, chronic venous insufficiency, and left leg lymphoedema was referred to our emergency unit. She had pain and circumferential erythema with multiple abscesses of the left leg of 2 weeks’ duration. No history of trauma, ulcer, injection, or animal bite was noted. At the time of presentation she had no fever and vital parameters were normal. Empirical treatment with oral amoxicillin (6 g daily) and amoxicillin-clavulanate (375 mg daily) was started. Forty-eight hours later, inflammation, pain, and abscesses worsened (Figure 1A). Laboratory tests showed an elevated white blood cell count (15.9×10⁹⁄L with 86% neutrophils [reference range, 4.5–11.0×10⁹⁄L]) and an elevated C-reactive protein level (322 mg/L [reference range, <2 mg/L]). Human immunodeficiency virus serology was negative. Needle aspiration of an abscess yielded S marcescens. A second aspiration confirmed the presence of the same organism, wild-type S marcescens, which was resistant to amoxicillin and clavulanic acid, first-generation cephalosporin, and tobramycin but sensitive to piperacillin, third-generation cephalosporins, amikacin, ciprofloxacin, and co-trimoxazole. Intravenous cefepime, a third-generation cephalosporin, was started. During the next 48 hours the patient developed severe sepsis with confusion, acute renal failure (creatinine: 231 µmol/L vs 138 µmol/L at baseline [reference range, 53–106 µmol/L), and worsening of skin lesions. Blood cultures were negative and amikacin was added. Magnetic resonance imaging showed a diffuse inflammatory process involving the skin and subcutaneous tissue that extended to the soleus fascia with no other muscle involvement or deep collection (Figure 2). Surgical debridement of infected tissues was performed (Figure 1B). Histologic examination revealed spreading suppurative inflammation involving the dermis and subcutaneous tissues. Clinical healing was obtained after 21 days of antimicrobial therapy. The debrided area required skin grafting 2 months later (Figure 1C).

Figure 1. Erythema with multiple abscesses on the left ankle and leg at presentation (A), day 1 following surgical debridement of infected tissues (B), and 2 months later with complete healing following a skin graft (C).

Comment

The most common causative bacteria of cellulitis are Staphylococcus aureus and group A β-hemolytic streptococci. Serratia marcescens is a rare but increasingly recognized pathogen of skin and soft tissue infections.⁵ The proposed pathogenic mechanism for skin necrosis during S marcescens infection is the bacterial production of large proteases (eg, deoxyribonuclease, lipase, gelatinase).⁶ Injection of purified proteinase from S marcescens into rat skin leads to increased vascular permeability, necrosis of epidermal tissue, dermal inflammation and edema, and infiltration of polymorphonuclear leukocytes into the subcutaneous fat and muscle.⁷Serratia marcescens is ubiquitous in soil and water and it also may colonize the respiratory, urinary, and digestive tracts in humans. Cellulitis due to S marcescens secondary to iguana bites^8,9 and snake bites¹⁰ or leech-borne cellulitis¹¹ suggest that the oral cavity of these animals may be colonized. To date, 49 cases of severe S marcescens skin infections have been described, according to a search of PubMed articles indexed for MEDLINE using the terms Serratia marcescens and skin, cutaneous, soft tissue, and cellulitis or necrotizing fasciitis: 20 cases with NF^3,12-28 and 29 non-NF cases^8-11,29-46 (typical cellulitis presentation [n=8]^{9,11,35-38,40}; abscesses, gumma, or pyoderma gangrenosum–like lesions associated with chronic granulomatous disease in childhood [n=7]^29,44,45; painful nodules with secondary abscesses [n=6]^31-34,46; acute bullous cellulitis [n=4]^8,10,30; secondary infections of ulcers [n=2]^35,40; abscesses in immunocompetent patient [n=1]⁴¹; and necrotizing skin ulceration [n=1]³⁶). Lower extremities were frequently involved (NF cases, n=13; non-NF cases, n=16). Underlying immunosuppression was observed in 14 NF cases and in 17 non-NF cases. Predisposing immunologic factors are summarized in the Table. Local risk factors, including chronic leg edema, trauma, surgical wound, filler injection, and ulcer, were frequently reported in NF and non-NF cases,^{16,20,26-28,31,32,34,35,37,38,40,46} including our case. Surgery was required in 19 NF cases and in 7 non-NF cases. Serratia marcescens–mediated NF led to higher mortality (n=12) than non-NF cases (n=1). Other nonsevere clinical manifestations of S marcescens infection reported in the literature included disseminated papular eruptions with human immunodeficiency virus infection⁴² and trunk folliculitis.⁴³ Our patient had many risk factors, including chronic edema, diabetes mellitus, chronic renal insufficiency, and chronic venous insufficiency. The potential presence of abscesses and necrotic tissue hinders antibiotic penetration at the infection site, and surgery should be systematically considered as early as possible in view of the high mortality rate of S marcescens cellulitis.

Conclusion

Although uncommon, an S marcescens skin infection may be suspected in cases of cellulitis in immunocompromised patients, especially when conventional antibiotics are not effective. Serratia marcescens naturally produces a cephalosporinase that confers resistance to amoxicillin and to amoxicillin associated with clavulanic acid. Broad-spectrum antibiotics such as third-generation cephalosporins, fluoroquinolones, or imipenem-cilastatin are indicated in cases of S marcescens skin infections, and surgery should be promptly considered if appropriate antibiotic therapy does not lead to rapid clinical improvement.

A gram-negative bacillus of the Enterobacteriaceae family, Serratia marcescens is an organism known to cause bacteremia, pneumonia, urinary tract infection, endocarditis, meningitis, and septic arthritis.¹ Unusual cases of cellulitis and necrotizing fasciitis (NF) caused by S marcescens also have been reported.^2,3 This entity has been initially described in immunocompromised and nonimmunocompromised patients.⁴ Both community and nosocomial cases also have been reported.³

Case Report

A 68-year-old morbidly obese woman with high blood pressure, diabetes mellitus, chronic renal insufficiency, chronic venous insufficiency, and left leg lymphoedema was referred to our emergency unit. She had pain and circumferential erythema with multiple abscesses of the left leg of 2 weeks’ duration. No history of trauma, ulcer, injection, or animal bite was noted. At the time of presentation she had no fever and vital parameters were normal. Empirical treatment with oral amoxicillin (6 g daily) and amoxicillin-clavulanate (375 mg daily) was started. Forty-eight hours later, inflammation, pain, and abscesses worsened (Figure 1A). Laboratory tests showed an elevated white blood cell count (15.9×10⁹⁄L with 86% neutrophils [reference range, 4.5–11.0×10⁹⁄L]) and an elevated C-reactive protein level (322 mg/L [reference range, <2 mg/L]). Human immunodeficiency virus serology was negative. Needle aspiration of an abscess yielded S marcescens. A second aspiration confirmed the presence of the same organism, wild-type S marcescens, which was resistant to amoxicillin and clavulanic acid, first-generation cephalosporin, and tobramycin but sensitive to piperacillin, third-generation cephalosporins, amikacin, ciprofloxacin, and co-trimoxazole. Intravenous cefepime, a third-generation cephalosporin, was started. During the next 48 hours the patient developed severe sepsis with confusion, acute renal failure (creatinine: 231 µmol/L vs 138 µmol/L at baseline [reference range, 53–106 µmol/L), and worsening of skin lesions. Blood cultures were negative and amikacin was added. Magnetic resonance imaging showed a diffuse inflammatory process involving the skin and subcutaneous tissue that extended to the soleus fascia with no other muscle involvement or deep collection (Figure 2). Surgical debridement of infected tissues was performed (Figure 1B). Histologic examination revealed spreading suppurative inflammation involving the dermis and subcutaneous tissues. Clinical healing was obtained after 21 days of antimicrobial therapy. The debrided area required skin grafting 2 months later (Figure 1C).

Figure 1. Erythema with multiple abscesses on the left ankle and leg at presentation (A), day 1 following surgical debridement of infected tissues (B), and 2 months later with complete healing following a skin graft (C).

Comment

The most common causative bacteria of cellulitis are Staphylococcus aureus and group A β-hemolytic streptococci. Serratia marcescens is a rare but increasingly recognized pathogen of skin and soft tissue infections.⁵ The proposed pathogenic mechanism for skin necrosis during S marcescens infection is the bacterial production of large proteases (eg, deoxyribonuclease, lipase, gelatinase).⁶ Injection of purified proteinase from S marcescens into rat skin leads to increased vascular permeability, necrosis of epidermal tissue, dermal inflammation and edema, and infiltration of polymorphonuclear leukocytes into the subcutaneous fat and muscle.⁷Serratia marcescens is ubiquitous in soil and water and it also may colonize the respiratory, urinary, and digestive tracts in humans. Cellulitis due to S marcescens secondary to iguana bites^8,9 and snake bites¹⁰ or leech-borne cellulitis¹¹ suggest that the oral cavity of these animals may be colonized. To date, 49 cases of severe S marcescens skin infections have been described, according to a search of PubMed articles indexed for MEDLINE using the terms Serratia marcescens and skin, cutaneous, soft tissue, and cellulitis or necrotizing fasciitis: 20 cases with NF^3,12-28 and 29 non-NF cases^8-11,29-46 (typical cellulitis presentation [n=8]^{9,11,35-38,40}; abscesses, gumma, or pyoderma gangrenosum–like lesions associated with chronic granulomatous disease in childhood [n=7]^29,44,45; painful nodules with secondary abscesses [n=6]^31-34,46; acute bullous cellulitis [n=4]^8,10,30; secondary infections of ulcers [n=2]^35,40; abscesses in immunocompetent patient [n=1]⁴¹; and necrotizing skin ulceration [n=1]³⁶). Lower extremities were frequently involved (NF cases, n=13; non-NF cases, n=16). Underlying immunosuppression was observed in 14 NF cases and in 17 non-NF cases. Predisposing immunologic factors are summarized in the Table. Local risk factors, including chronic leg edema, trauma, surgical wound, filler injection, and ulcer, were frequently reported in NF and non-NF cases,^{16,20,26-28,31,32,34,35,37,38,40,46} including our case. Surgery was required in 19 NF cases and in 7 non-NF cases. Serratia marcescens–mediated NF led to higher mortality (n=12) than non-NF cases (n=1). Other nonsevere clinical manifestations of S marcescens infection reported in the literature included disseminated papular eruptions with human immunodeficiency virus infection⁴² and trunk folliculitis.⁴³ Our patient had many risk factors, including chronic edema, diabetes mellitus, chronic renal insufficiency, and chronic venous insufficiency. The potential presence of abscesses and necrotic tissue hinders antibiotic penetration at the infection site, and surgery should be systematically considered as early as possible in view of the high mortality rate of S marcescens cellulitis.

Conclusion

Although uncommon, an S marcescens skin infection may be suspected in cases of cellulitis in immunocompromised patients, especially when conventional antibiotics are not effective. Serratia marcescens naturally produces a cephalosporinase that confers resistance to amoxicillin and to amoxicillin associated with clavulanic acid. Broad-spectrum antibiotics such as third-generation cephalosporins, fluoroquinolones, or imipenem-cilastatin are indicated in cases of S marcescens skin infections, and surgery should be promptly considered if appropriate antibiotic therapy does not lead to rapid clinical improvement.

A number of adverse cutaneous effects may result from radiation therapy, including radiodermatitis, alopecia, and radiation-induced neoplasms. Radiation therapy rarely induces pemphigus or pemphigoid disease, but awareness of this disorder is of clinical importance because these cutaneous lesions may resemble other skin diseases, including recurrent underlying cancer. We report 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for in situ ductal carcinoma of the breast, cervical squamous cell carcinoma, and metastatic squamous cell carcinoma of unknown origin, respectively.

Case Reports

To identify all the patients with radiation-induced pemphigus, pemphigoid diseases, or both diagnosed and treated at Mayo Clinic (Rochester, Minnesota) from 1988 to 2009, we performed a computerized search of dermatology, laboratory medicine, and pathology medical records using the following keywords: radiation, pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, and blistering disease. Inclusion criteria were a history of radiation therapy and subsequent development of pemphigus or pemphigoid disease within the irradiated fields. Patients with a history of immunobullous disease preceding radiation therapy and patients with a diagnosis of paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome were excluded. The diagnoses were confirmed by routine pathology as well as direct and indirect immunofluorescence examinations.

We identified 3 patients with severe extensive radiation-associated pemphigus/pemphigoid disease that had developed within 14 months after they received radiation therapy for their underlying cancer. The identified patients’ medical records were reviewed for underlying malignancy, symptoms at the time of diagnosis, treatment course, and follow-up. The protocol was reviewed and approved by the Mayo Clinic institutional review board.

Patient 1—A 58-year-old woman was diagnosed with in situ ductal carcinoma of the right breast and underwent a lumpectomy with subsequent radiation therapy at an outside institution. Fourteen months after the final radiation treatment, she developed localized flaccid blisters and a superficial erosion on the right areola (Figure 1). Routine pathologic and direct immunofluorescence studies performed on shave biopsies in conjunction with serum analysis by indirect immunofluorescence confirmed the diagnosis of pemphigus vulgaris (Figure 2). Additionally, a deeper 4-mm punch biopsy ruled out metastatic breast carcinoma. The patient initially was treated with prednisone 60 mg and azathioprine 50 mg daily. The prednisone was tapered over 4 to 5 months to a dose of 5 mg every other day for another 4 to 5 months. Azathioprine was discontinued after a few months because of increased liver enzyme levels and a rapid clinical response of the pemphigus to this regimen.

Subsequently, she developed oral and ocular erosions that were compatible with pemphigus and were believed to be precipitated by trauma secondary to dental work and to the use of contact lenses. These flares were treated and stabilized with short courses of prednisone at higher doses that were successfully tapered to a maintenance dose of 5 mg every other day to control the pemphigus. With that prednisone dosage, her disease has remained clinically stable.

Patient 2—A 40-year-old woman was diagnosed with stage IIIB cervical squamous carcinoma with para-aortic adenopathy. She was initially treated with primary radiation therapy directed at the pelvis and para-aortic regions using a 4-field approach at our institution, and she received weekly cisplatin chemotherapy at another institution. Nine months later, the patient was admitted to our institution with persistent metastatic cervical carcinoma of the retroperitoneum. She was scheduled for intraoperative radiation therapy as well as aggressive surgical cytoreduction. The day before her surgery she presented to our dermatology clinic with a generalized pruritic rash of 1 month’s duration and occasional blistering without mucosal involvement. Biopsy specimens from the lower back and abdomen were sent for routine histologic studies and direct immunofluorescence. Serum was sent for analysis by indirect immunofluorescence. Pathology results were consistent with a diagnosis of bullous pemphigoid with an infiltrate of eosinophils in the papillary dermis; direct immunofluorescence revealed continuous strong linear deposition of C3, which also was consistent with pemphigoid.

At that time, we recommended application of topical clobetasol 0.05% twice daily to affected areas before initiating prednisone. Postoperatively, her rash improved dramatically with clobetasol monotherapy. However, 4 months after discharge from our hospital, her local dermatologist called us for a telephone consultation regarding clinical and laboratory evidence of pemphigoid relapse. A direct immunofluorescence study showed both linear IgG and C3 deposition. The patient had healed well from the surgery, and the metastatic cervical carcinoma was quiescent. Prednisone in combination with a second immunosuppressive agent was recommended, pending approval by her local oncologist. No further follow-up information is available at this time.

Patient 3—A 72-year-old woman presented with a blistering eruption that had developed on the neck, the upper part of the chest, and other body sites, including the oral mucosa, 6 months after radiation therapy for metastatic squamous cell carcinoma of unknown origin on the neck. On admission to the local hospital, she received a diagnosis of pemphigoid, although the outside biopsy specimens and reports were not available.

The patient was initially treated with prednisone, which was rapidly tapered because she was diabetic and her blood glucose levels were labile. Consequently, she was switched to azathioprine 50 mg 3 times daily and mycophenolate mofetil 500 mg 3 times daily. The patient was transferred to our institution with mild fatigue, dysphagia, weight loss, and generalized blistering involving the skin and lips. Otolaryngologic consultation and radiographic evaluation revealed no evidence of recurrent carcinoma. A shave biopsy was obtained for routine histologic evaluation and immunofluorescence and confirmed the diagnosis of bullous pemphigoid. The patient, however, also was found to have pancytopenia, most likely induced by the combination of azathioprine and mycophenolate mofetil. Her therapeutic regimen was switched to triamcinolone ointment 0.1% to be applied to the eroded areas twice daily and mupirocin ointment to be applied to the hemorrhagic scabs. Subsequently, her complete blood cell count returned to normal.

She continued to use topical corticosteroid therapy to control pemphigoid symptoms, but 6 months later the patient was found to have a lung mass and died secondary to respiratory failure.

Figure 2. Pathologic and immunofluorescence studies confirmed the diagnosis of pemphigus vulgaris. Intraepidermal acantholysis forming a suprabasal blister with a tombstone appearance was seen along the basal cell layer (A)(H&E, original magnification ×400). Intercellular IgG deposition involving the epidermis was noted with direct immunofluorescence (B)(original magnification ×600).

Comment

A wide range of cutaneous reactions are known to occur in conjunction with radiation therapy. Early or acute adverse effects on the skin, such as erythema, edema, and desquamation, can be observed during radiation therapy and for several weeks thereafter. They are usually followed by hair loss and postinflammatory hyperpigmentation. Pemphigus or pemphigoid disease is a rare complication of radiation therapy and has been reported in case reports and small case series.^1-17 These disorders include bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, bullous lupus erythematosus, and acquired epidermolysis bullosa.¹⁰

The mechanism by which radiation therapy induces pemphigus remains open to speculation. Ionizing radiation may alter the antigenicity of the keratinocyte surface by disrupting the sulfhydryl groups,¹³ thus changing the immunoreactivity of the desmogleins or unmasking certain epidermal antigens. Another possible explanation is immune surveillance interference by damaged T-suppressor cells, which are preferentially sensitive to radiation.⁸ Robbins et al¹² presented a patient with radiation-induced mucocutaneous pemphigus. They performed immunomapping of perilesional skin for the irradiated field, which illustrated altered expression of desmoglein (Dsg) 1, a commonly targeted antigen in pemphigus. Their study also suggested that radiation changed either the distribution or the expression of Dsg1 in the epidermis.¹²

Approximately half the reported cases we identified were associated with breast carcinoma,^1-4,8,14 as in the case of patient 1. The majority of patients initially experienced blistering confined to the irradiated area followed by a variable degree of dissemination to other sites, probably due to the epitope-spreading phenomenon.¹² During the months after radiation therapy, Aguado et al¹ documented that their patient, who was initially positive for only anti-Dsg3 antibody, developed anti-Dsg1 antibodies. Therefore, the unusual development of mucosal ulcers, other skin lesions, or both after radiation therapy should raise suspicion for this diagnosis.

Bullous pemphigoid primarily affects elderly patients with blister formation along the dermoepidermal junction. Various causes, such as drugs, trauma, UV light, and ionizing radiation, have been associated with this autoimmune blistering disorder. In a systemic literature review, Mul et al¹⁰ discovered 27 case reports of bullous pemphigoid that were associated with radiation. It has been suggested that the alteration of the antigenicity and damaged dermoepidermal junction by radiation is a disease-producing mechanism.^15,16 Another explanation is that the patients had subclinical pemphigoid and underwent radiation therapy, which damaged the basal layer sufficiently to produce subepidermal blister formation (triggered pemphigoid).¹⁷

The patients in this analysis had clinical presentations similar to those previously reported, with a blistering rash that usually began in the irradiated field, raising the possibility of acute radiation dermatitis. However, unlike acute radiation dermatitis, the lesions extended beyond the radiation fields in all 3 cases with mucosal involvement in patients 1 and 3. Although an onset of pemphigoid was previously observed after a minimum dose of 20 Gy,¹⁰ there was no definitive correlation observed between the extent and the severity of the cutaneous eruption and the radiation dose in prior studies. Unfortunately, we could not obtain exact radiation doses in our cases because all 3 patients were treated by radiation oncologists at other institutions. We did not, however, observe in our patients that the eruptions were more severe within the irradiated areas. Our analysis demonstrated that radiation-induced pemphigus or pemphigoid disease does not differ greatly from the endogenous form of the disease in its response to therapy or clinical course.

In summary, radiation-induced pemphigus or pemphigoid disease, a rare but serious adverse effect of radiation therapy, should be considered in patients with new-onset blistering or erosive skin disease who have recently undergone irradiation. The accurate diagnosis of pemphigus or pemphigoid disease is important because such diseases often require long-term immunosuppressive therapy. A thorough history and skin examination must be obtained from all patients who receive radiation therapy and subsequently have blisters or eruptions on the skin, mucous membranes, or both. Appropriate diagnostic studies, including routine biopsy for histologic evaluation and direct immunofluorescence, serum for indirect immunofluorescence, and enzyme-linked immunosorbent assay, should be performed to exclude pemphigus or pemphigoid disease.

A number of adverse cutaneous effects may result from radiation therapy, including radiodermatitis, alopecia, and radiation-induced neoplasms. Radiation therapy rarely induces pemphigus or pemphigoid disease, but awareness of this disorder is of clinical importance because these cutaneous lesions may resemble other skin diseases, including recurrent underlying cancer. We report 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for in situ ductal carcinoma of the breast, cervical squamous cell carcinoma, and metastatic squamous cell carcinoma of unknown origin, respectively.

Case Reports

To identify all the patients with radiation-induced pemphigus, pemphigoid diseases, or both diagnosed and treated at Mayo Clinic (Rochester, Minnesota) from 1988 to 2009, we performed a computerized search of dermatology, laboratory medicine, and pathology medical records using the following keywords: radiation, pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, and blistering disease. Inclusion criteria were a history of radiation therapy and subsequent development of pemphigus or pemphigoid disease within the irradiated fields. Patients with a history of immunobullous disease preceding radiation therapy and patients with a diagnosis of paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome were excluded. The diagnoses were confirmed by routine pathology as well as direct and indirect immunofluorescence examinations.

We identified 3 patients with severe extensive radiation-associated pemphigus/pemphigoid disease that had developed within 14 months after they received radiation therapy for their underlying cancer. The identified patients’ medical records were reviewed for underlying malignancy, symptoms at the time of diagnosis, treatment course, and follow-up. The protocol was reviewed and approved by the Mayo Clinic institutional review board.

Patient 1—A 58-year-old woman was diagnosed with in situ ductal carcinoma of the right breast and underwent a lumpectomy with subsequent radiation therapy at an outside institution. Fourteen months after the final radiation treatment, she developed localized flaccid blisters and a superficial erosion on the right areola (Figure 1). Routine pathologic and direct immunofluorescence studies performed on shave biopsies in conjunction with serum analysis by indirect immunofluorescence confirmed the diagnosis of pemphigus vulgaris (Figure 2). Additionally, a deeper 4-mm punch biopsy ruled out metastatic breast carcinoma. The patient initially was treated with prednisone 60 mg and azathioprine 50 mg daily. The prednisone was tapered over 4 to 5 months to a dose of 5 mg every other day for another 4 to 5 months. Azathioprine was discontinued after a few months because of increased liver enzyme levels and a rapid clinical response of the pemphigus to this regimen.

Subsequently, she developed oral and ocular erosions that were compatible with pemphigus and were believed to be precipitated by trauma secondary to dental work and to the use of contact lenses. These flares were treated and stabilized with short courses of prednisone at higher doses that were successfully tapered to a maintenance dose of 5 mg every other day to control the pemphigus. With that prednisone dosage, her disease has remained clinically stable.

Patient 2—A 40-year-old woman was diagnosed with stage IIIB cervical squamous carcinoma with para-aortic adenopathy. She was initially treated with primary radiation therapy directed at the pelvis and para-aortic regions using a 4-field approach at our institution, and she received weekly cisplatin chemotherapy at another institution. Nine months later, the patient was admitted to our institution with persistent metastatic cervical carcinoma of the retroperitoneum. She was scheduled for intraoperative radiation therapy as well as aggressive surgical cytoreduction. The day before her surgery she presented to our dermatology clinic with a generalized pruritic rash of 1 month’s duration and occasional blistering without mucosal involvement. Biopsy specimens from the lower back and abdomen were sent for routine histologic studies and direct immunofluorescence. Serum was sent for analysis by indirect immunofluorescence. Pathology results were consistent with a diagnosis of bullous pemphigoid with an infiltrate of eosinophils in the papillary dermis; direct immunofluorescence revealed continuous strong linear deposition of C3, which also was consistent with pemphigoid.

At that time, we recommended application of topical clobetasol 0.05% twice daily to affected areas before initiating prednisone. Postoperatively, her rash improved dramatically with clobetasol monotherapy. However, 4 months after discharge from our hospital, her local dermatologist called us for a telephone consultation regarding clinical and laboratory evidence of pemphigoid relapse. A direct immunofluorescence study showed both linear IgG and C3 deposition. The patient had healed well from the surgery, and the metastatic cervical carcinoma was quiescent. Prednisone in combination with a second immunosuppressive agent was recommended, pending approval by her local oncologist. No further follow-up information is available at this time.

Patient 3—A 72-year-old woman presented with a blistering eruption that had developed on the neck, the upper part of the chest, and other body sites, including the oral mucosa, 6 months after radiation therapy for metastatic squamous cell carcinoma of unknown origin on the neck. On admission to the local hospital, she received a diagnosis of pemphigoid, although the outside biopsy specimens and reports were not available.

The patient was initially treated with prednisone, which was rapidly tapered because she was diabetic and her blood glucose levels were labile. Consequently, she was switched to azathioprine 50 mg 3 times daily and mycophenolate mofetil 500 mg 3 times daily. The patient was transferred to our institution with mild fatigue, dysphagia, weight loss, and generalized blistering involving the skin and lips. Otolaryngologic consultation and radiographic evaluation revealed no evidence of recurrent carcinoma. A shave biopsy was obtained for routine histologic evaluation and immunofluorescence and confirmed the diagnosis of bullous pemphigoid. The patient, however, also was found to have pancytopenia, most likely induced by the combination of azathioprine and mycophenolate mofetil. Her therapeutic regimen was switched to triamcinolone ointment 0.1% to be applied to the eroded areas twice daily and mupirocin ointment to be applied to the hemorrhagic scabs. Subsequently, her complete blood cell count returned to normal.

She continued to use topical corticosteroid therapy to control pemphigoid symptoms, but 6 months later the patient was found to have a lung mass and died secondary to respiratory failure.

Figure 2. Pathologic and immunofluorescence studies confirmed the diagnosis of pemphigus vulgaris. Intraepidermal acantholysis forming a suprabasal blister with a tombstone appearance was seen along the basal cell layer (A)(H&E, original magnification ×400). Intercellular IgG deposition involving the epidermis was noted with direct immunofluorescence (B)(original magnification ×600).

Comment

A wide range of cutaneous reactions are known to occur in conjunction with radiation therapy. Early or acute adverse effects on the skin, such as erythema, edema, and desquamation, can be observed during radiation therapy and for several weeks thereafter. They are usually followed by hair loss and postinflammatory hyperpigmentation. Pemphigus or pemphigoid disease is a rare complication of radiation therapy and has been reported in case reports and small case series.^1-17 These disorders include bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, bullous lupus erythematosus, and acquired epidermolysis bullosa.¹⁰

The mechanism by which radiation therapy induces pemphigus remains open to speculation. Ionizing radiation may alter the antigenicity of the keratinocyte surface by disrupting the sulfhydryl groups,¹³ thus changing the immunoreactivity of the desmogleins or unmasking certain epidermal antigens. Another possible explanation is immune surveillance interference by damaged T-suppressor cells, which are preferentially sensitive to radiation.⁸ Robbins et al¹² presented a patient with radiation-induced mucocutaneous pemphigus. They performed immunomapping of perilesional skin for the irradiated field, which illustrated altered expression of desmoglein (Dsg) 1, a commonly targeted antigen in pemphigus. Their study also suggested that radiation changed either the distribution or the expression of Dsg1 in the epidermis.¹²

Approximately half the reported cases we identified were associated with breast carcinoma,^1-4,8,14 as in the case of patient 1. The majority of patients initially experienced blistering confined to the irradiated area followed by a variable degree of dissemination to other sites, probably due to the epitope-spreading phenomenon.¹² During the months after radiation therapy, Aguado et al¹ documented that their patient, who was initially positive for only anti-Dsg3 antibody, developed anti-Dsg1 antibodies. Therefore, the unusual development of mucosal ulcers, other skin lesions, or both after radiation therapy should raise suspicion for this diagnosis.

Bullous pemphigoid primarily affects elderly patients with blister formation along the dermoepidermal junction. Various causes, such as drugs, trauma, UV light, and ionizing radiation, have been associated with this autoimmune blistering disorder. In a systemic literature review, Mul et al¹⁰ discovered 27 case reports of bullous pemphigoid that were associated with radiation. It has been suggested that the alteration of the antigenicity and damaged dermoepidermal junction by radiation is a disease-producing mechanism.^15,16 Another explanation is that the patients had subclinical pemphigoid and underwent radiation therapy, which damaged the basal layer sufficiently to produce subepidermal blister formation (triggered pemphigoid).¹⁷

The patients in this analysis had clinical presentations similar to those previously reported, with a blistering rash that usually began in the irradiated field, raising the possibility of acute radiation dermatitis. However, unlike acute radiation dermatitis, the lesions extended beyond the radiation fields in all 3 cases with mucosal involvement in patients 1 and 3. Although an onset of pemphigoid was previously observed after a minimum dose of 20 Gy,¹⁰ there was no definitive correlation observed between the extent and the severity of the cutaneous eruption and the radiation dose in prior studies. Unfortunately, we could not obtain exact radiation doses in our cases because all 3 patients were treated by radiation oncologists at other institutions. We did not, however, observe in our patients that the eruptions were more severe within the irradiated areas. Our analysis demonstrated that radiation-induced pemphigus or pemphigoid disease does not differ greatly from the endogenous form of the disease in its response to therapy or clinical course.

In summary, radiation-induced pemphigus or pemphigoid disease, a rare but serious adverse effect of radiation therapy, should be considered in patients with new-onset blistering or erosive skin disease who have recently undergone irradiation. The accurate diagnosis of pemphigus or pemphigoid disease is important because such diseases often require long-term immunosuppressive therapy. A thorough history and skin examination must be obtained from all patients who receive radiation therapy and subsequently have blisters or eruptions on the skin, mucous membranes, or both. Appropriate diagnostic studies, including routine biopsy for histologic evaluation and direct immunofluorescence, serum for indirect immunofluorescence, and enzyme-linked immunosorbent assay, should be performed to exclude pemphigus or pemphigoid disease.

A number of adverse cutaneous effects may result from radiation therapy, including radiodermatitis, alopecia, and radiation-induced neoplasms. Radiation therapy rarely induces pemphigus or pemphigoid disease, but awareness of this disorder is of clinical importance because these cutaneous lesions may resemble other skin diseases, including recurrent underlying cancer. We report 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for in situ ductal carcinoma of the breast, cervical squamous cell carcinoma, and metastatic squamous cell carcinoma of unknown origin, respectively.

Case Reports

To identify all the patients with radiation-induced pemphigus, pemphigoid diseases, or both diagnosed and treated at Mayo Clinic (Rochester, Minnesota) from 1988 to 2009, we performed a computerized search of dermatology, laboratory medicine, and pathology medical records using the following keywords: radiation, pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, and blistering disease. Inclusion criteria were a history of radiation therapy and subsequent development of pemphigus or pemphigoid disease within the irradiated fields. Patients with a history of immunobullous disease preceding radiation therapy and patients with a diagnosis of paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome were excluded. The diagnoses were confirmed by routine pathology as well as direct and indirect immunofluorescence examinations.

We identified 3 patients with severe extensive radiation-associated pemphigus/pemphigoid disease that had developed within 14 months after they received radiation therapy for their underlying cancer. The identified patients’ medical records were reviewed for underlying malignancy, symptoms at the time of diagnosis, treatment course, and follow-up. The protocol was reviewed and approved by the Mayo Clinic institutional review board.

Patient 1—A 58-year-old woman was diagnosed with in situ ductal carcinoma of the right breast and underwent a lumpectomy with subsequent radiation therapy at an outside institution. Fourteen months after the final radiation treatment, she developed localized flaccid blisters and a superficial erosion on the right areola (Figure 1). Routine pathologic and direct immunofluorescence studies performed on shave biopsies in conjunction with serum analysis by indirect immunofluorescence confirmed the diagnosis of pemphigus vulgaris (Figure 2). Additionally, a deeper 4-mm punch biopsy ruled out metastatic breast carcinoma. The patient initially was treated with prednisone 60 mg and azathioprine 50 mg daily. The prednisone was tapered over 4 to 5 months to a dose of 5 mg every other day for another 4 to 5 months. Azathioprine was discontinued after a few months because of increased liver enzyme levels and a rapid clinical response of the pemphigus to this regimen.

Subsequently, she developed oral and ocular erosions that were compatible with pemphigus and were believed to be precipitated by trauma secondary to dental work and to the use of contact lenses. These flares were treated and stabilized with short courses of prednisone at higher doses that were successfully tapered to a maintenance dose of 5 mg every other day to control the pemphigus. With that prednisone dosage, her disease has remained clinically stable.

Patient 2—A 40-year-old woman was diagnosed with stage IIIB cervical squamous carcinoma with para-aortic adenopathy. She was initially treated with primary radiation therapy directed at the pelvis and para-aortic regions using a 4-field approach at our institution, and she received weekly cisplatin chemotherapy at another institution. Nine months later, the patient was admitted to our institution with persistent metastatic cervical carcinoma of the retroperitoneum. She was scheduled for intraoperative radiation therapy as well as aggressive surgical cytoreduction. The day before her surgery she presented to our dermatology clinic with a generalized pruritic rash of 1 month’s duration and occasional blistering without mucosal involvement. Biopsy specimens from the lower back and abdomen were sent for routine histologic studies and direct immunofluorescence. Serum was sent for analysis by indirect immunofluorescence. Pathology results were consistent with a diagnosis of bullous pemphigoid with an infiltrate of eosinophils in the papillary dermis; direct immunofluorescence revealed continuous strong linear deposition of C3, which also was consistent with pemphigoid.

At that time, we recommended application of topical clobetasol 0.05% twice daily to affected areas before initiating prednisone. Postoperatively, her rash improved dramatically with clobetasol monotherapy. However, 4 months after discharge from our hospital, her local dermatologist called us for a telephone consultation regarding clinical and laboratory evidence of pemphigoid relapse. A direct immunofluorescence study showed both linear IgG and C3 deposition. The patient had healed well from the surgery, and the metastatic cervical carcinoma was quiescent. Prednisone in combination with a second immunosuppressive agent was recommended, pending approval by her local oncologist. No further follow-up information is available at this time.

Patient 3—A 72-year-old woman presented with a blistering eruption that had developed on the neck, the upper part of the chest, and other body sites, including the oral mucosa, 6 months after radiation therapy for metastatic squamous cell carcinoma of unknown origin on the neck. On admission to the local hospital, she received a diagnosis of pemphigoid, although the outside biopsy specimens and reports were not available.

The patient was initially treated with prednisone, which was rapidly tapered because she was diabetic and her blood glucose levels were labile. Consequently, she was switched to azathioprine 50 mg 3 times daily and mycophenolate mofetil 500 mg 3 times daily. The patient was transferred to our institution with mild fatigue, dysphagia, weight loss, and generalized blistering involving the skin and lips. Otolaryngologic consultation and radiographic evaluation revealed no evidence of recurrent carcinoma. A shave biopsy was obtained for routine histologic evaluation and immunofluorescence and confirmed the diagnosis of bullous pemphigoid. The patient, however, also was found to have pancytopenia, most likely induced by the combination of azathioprine and mycophenolate mofetil. Her therapeutic regimen was switched to triamcinolone ointment 0.1% to be applied to the eroded areas twice daily and mupirocin ointment to be applied to the hemorrhagic scabs. Subsequently, her complete blood cell count returned to normal.

She continued to use topical corticosteroid therapy to control pemphigoid symptoms, but 6 months later the patient was found to have a lung mass and died secondary to respiratory failure.

Figure 2. Pathologic and immunofluorescence studies confirmed the diagnosis of pemphigus vulgaris. Intraepidermal acantholysis forming a suprabasal blister with a tombstone appearance was seen along the basal cell layer (A)(H&E, original magnification ×400). Intercellular IgG deposition involving the epidermis was noted with direct immunofluorescence (B)(original magnification ×600).

Comment

A wide range of cutaneous reactions are known to occur in conjunction with radiation therapy. Early or acute adverse effects on the skin, such as erythema, edema, and desquamation, can be observed during radiation therapy and for several weeks thereafter. They are usually followed by hair loss and postinflammatory hyperpigmentation. Pemphigus or pemphigoid disease is a rare complication of radiation therapy and has been reported in case reports and small case series.^1-17 These disorders include bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, bullous lupus erythematosus, and acquired epidermolysis bullosa.¹⁰

The mechanism by which radiation therapy induces pemphigus remains open to speculation. Ionizing radiation may alter the antigenicity of the keratinocyte surface by disrupting the sulfhydryl groups,¹³ thus changing the immunoreactivity of the desmogleins or unmasking certain epidermal antigens. Another possible explanation is immune surveillance interference by damaged T-suppressor cells, which are preferentially sensitive to radiation.⁸ Robbins et al¹² presented a patient with radiation-induced mucocutaneous pemphigus. They performed immunomapping of perilesional skin for the irradiated field, which illustrated altered expression of desmoglein (Dsg) 1, a commonly targeted antigen in pemphigus. Their study also suggested that radiation changed either the distribution or the expression of Dsg1 in the epidermis.¹²

Approximately half the reported cases we identified were associated with breast carcinoma,^1-4,8,14 as in the case of patient 1. The majority of patients initially experienced blistering confined to the irradiated area followed by a variable degree of dissemination to other sites, probably due to the epitope-spreading phenomenon.¹² During the months after radiation therapy, Aguado et al¹ documented that their patient, who was initially positive for only anti-Dsg3 antibody, developed anti-Dsg1 antibodies. Therefore, the unusual development of mucosal ulcers, other skin lesions, or both after radiation therapy should raise suspicion for this diagnosis.

Bullous pemphigoid primarily affects elderly patients with blister formation along the dermoepidermal junction. Various causes, such as drugs, trauma, UV light, and ionizing radiation, have been associated with this autoimmune blistering disorder. In a systemic literature review, Mul et al¹⁰ discovered 27 case reports of bullous pemphigoid that were associated with radiation. It has been suggested that the alteration of the antigenicity and damaged dermoepidermal junction by radiation is a disease-producing mechanism.^15,16 Another explanation is that the patients had subclinical pemphigoid and underwent radiation therapy, which damaged the basal layer sufficiently to produce subepidermal blister formation (triggered pemphigoid).¹⁷

The patients in this analysis had clinical presentations similar to those previously reported, with a blistering rash that usually began in the irradiated field, raising the possibility of acute radiation dermatitis. However, unlike acute radiation dermatitis, the lesions extended beyond the radiation fields in all 3 cases with mucosal involvement in patients 1 and 3. Although an onset of pemphigoid was previously observed after a minimum dose of 20 Gy,¹⁰ there was no definitive correlation observed between the extent and the severity of the cutaneous eruption and the radiation dose in prior studies. Unfortunately, we could not obtain exact radiation doses in our cases because all 3 patients were treated by radiation oncologists at other institutions. We did not, however, observe in our patients that the eruptions were more severe within the irradiated areas. Our analysis demonstrated that radiation-induced pemphigus or pemphigoid disease does not differ greatly from the endogenous form of the disease in its response to therapy or clinical course.

In summary, radiation-induced pemphigus or pemphigoid disease, a rare but serious adverse effect of radiation therapy, should be considered in patients with new-onset blistering or erosive skin disease who have recently undergone irradiation. The accurate diagnosis of pemphigus or pemphigoid disease is important because such diseases often require long-term immunosuppressive therapy. A thorough history and skin examination must be obtained from all patients who receive radiation therapy and subsequently have blisters or eruptions on the skin, mucous membranes, or both. Appropriate diagnostic studies, including routine biopsy for histologic evaluation and direct immunofluorescence, serum for indirect immunofluorescence, and enzyme-linked immunosorbent assay, should be performed to exclude pemphigus or pemphigoid disease.

The number of veterans aged ≥ 65 years is expected to increase steadily as the Vietnam-era cohort ages. In 2012, the number of veterans aged ≥ 85 years was expected to peak at nearly 1.4 million. Vietnam-era veterans comprise the largest cohort of veterans, and > 15% of male and > 8% of female Vietnam veterans receiving care in the VA system have been diagnosed with posttraumatic stress disorder (PTSD). These veterans are rapidly approaching age groups in which cognitive disorders increase exponentially in prevalence.

Combat exposure has been called a common but “hidden variable” in studies of aging and health.¹ Combat exposure may be even more hidden for Vietnam veterans who have pursued health care outside the VA system and less likely to announce their service to health care providers.

Even veterans who did not serve in traditional combat roles can experience chronic debilitation from the psychological stress of overseas deployment to a war zone. Indeed, cases of noncombat trauma have been presented in the context of cognitive decline and late-onset PTSD.² It is probable that survivors of sexual assault, child abuse, crime, and natural disaster are also vulnerable to a recurrence of trauma symptoms if they experience cognitive slippage. In this article the authors report a case of delayed onset PTSD symptoms, precipitated by cognitive decline.

Case Report

Mr. B was a 72-year-old Korean War veteran referred for neuropsychological evaluation to establish baseline cognitive status before elective cardiac surgery. Mr. B relied on his wife to fill in many details of his personal history. His wife reported that the patient’s memory problems had increased significantly over the previous 12 months. Mr. B had been treated with donepezil 10 mg daily for about 1 year, with no observed benefit. His wife described life at home as “tense” due to his increased irritability and poor insight into his condition. Mr. B reported that he was often afraid of noises at night and needed to go outside and look around. His wife reported that he was very afraid of “strangers coming into the house.”

Mr. B was born in Arizona and experienced significant physical abuse while under the care of an alcoholic foster parent. He dropped out of high school and enlisted in the U.S. Marine Corps. Upon his discharge from military service, he worked as a truck driver for 23 years. He retired after experiencing hip problems. He drank heavily for many years after the war and, according to his wife, was “very violent,” but stopped 27 years previously, after injuring his wife while intoxicated. The patient’s medical history included hospitalization about 1 year prior to the evaluation following a fall associated with altered level of consciousness and confusion, which lasted several hours. He was discharged the same day and was thought to have had a stroke. The patient also had hypertension, hyperlipidemia, and sciatica. A carotid ultrasound showed bilateral carotid stenosis > 50%.

Mr. B was married for 45 years and had 5 children and 12 grandchildren. He enlisted in the U.S. Marine Corps at age 19 and served as a tank gunner during the Korean War. He experienced extremely heavy combat, was wounded several times (including loss of consciousness due to an explosion), and was hospitalizedfor 4 m onths in Japan. When he returned to the frontline, he found that many of the men in his unit had been killed. He was promoted to staff sergeant and tank commander. Mr. B received an honorable discharge after the war and a 50% service-connected disability pension for PTSD. He reported having received group psychotherapy at a VA hospital soon after the war but no other psychiatric treatment. He avoided watching the news because the Gulf War news reminded him of Korea.

Mr. B was smiling, pleasant, and cooperative throughout the 2 hours of testing and interviewing. He wore a Korean War veteran baseball cap festooned with military pins and ribbons, including a Purple Heart ribbon that he proudly showed to the test administrators. Unbidden, he also presented for inspection an assortment of life membership cards in various veterans service organizations. Mr. B reported frequent nightmares, night sweats, and intrusive thoughts about his combat experiences. During testing, he was repeatedly triggered by innocuous items and launched into a discourse on his combat experiences. When asked to memorize a short list of words that included the word fire, he said, “You know what that reminds me of...we had to fire big guns, 90 millimeter, that’s what it was…killing and how to kill.” When shown an abstract design that resembled the number 44, he said, “You know what that is? It was the radio call sign of our tank—‘This is 44, come in, we need some help.’”

Mr. B’s memory problems were marked by rapid forgetting, impaired ability to learn new information, and impaired ability to recall previously learned information. Language problems were also present, including difficulty recognizing and naming common objects, impaired auditory comprehension, and problems with verbal associative fluency during timed tasks. He also showed difficulties with executive functioning, attention, and working memory. His mini-mental state examination score was 21/30. He stated the year was 2020, did not know the day of the week, registered 2/3 words and recalled 0/3, he counted 3/5 in serial 7s, and was unable to repeat the phrase, “no ifs, ands, or buts.”

Discussion

Posttraumatic stress symptoms were present during the immediate aftermath of the initial trauma exposure for this patient. He managed to lead a relatively successful and productive life, sustained a marriage, and raised a family. The onset of cognitive decline precipitated a recrudescence of PTSD symptomology. In fact, the effects of combat trauma seem more malignant and extreme at the time of the memory disorders evaluation than at any prior time in his life.

A number of case reports have been published in recent years that describe comorbid presentations of cognitive disorder and PTSD symptomatology.^3-6 A clinicalconsensus that cognitive decline can exacerbate previously well-managed symptoms of earlier psychological trauma seems to be emerging. Several published casestudies have noted that comorbid presentation of dementia and PTSD is often marked by violence, psychotic symptoms, and increased risk of hospitalization.^7-9

PTSD Research

Unfortunately, systematic investigation into the relationship between PTSD and cognitive decline is in its infancy. Previous authors have posited various mechanisms to explain the exacerbation of dormant PTSD symptoms after cognitive decline.^10,11 Some have attributed the phenomenon to an age-related failure of either repression or avoidance or to a compromised ability to actively focus their attention elsewhere.^2,12 A finding of preservative errors on neuropsychological tests has been associated with an inability to organize and inhibit intrusive thought.¹³ In one case, the effects of combat trauma were purported to be denied, repressed, and largely forgotten for 30 years until rekindled by the patient’s deteriorating health and loss of employment.¹⁴ Several case examples have been presented in which physical illness, interpersonal loss, retirement, or losses of social support were other factors.^15-18 Two major studies of veterans with PTSD, found that subjects were twice as likely to develop dementia.^3,4 There is a strong association between chronic psychological stress and later development
of dementia. In a study by Wilson and colleagues, subjects with higher baseline stress had twice the chance of developing Alzheimer disease.19 Similar findings of
accelerated or higher cognitive decline were found by other studies, too.^17,20

Hippocampal damage associated with prolonged, intense psychological stress has been cited as a possible contributor to PTSD symptom recrudescence in older adults.²¹ It is well known that emotional arousal leads to better-encoded memories. In the context of a cognitive disorder marked by gradual memory loss, traumatic memories might be the last to go.²² Another proposed biologic mechanism is a reduction in hippocampal volume and decreased inhibition of the amgydala, which results in preferential recall of the nondeclarative, amygdaloidal traumatic memories.⁸

Research on selective area damage in the hippocampus opens a new era of understanding of consequences of stress. The dentate gyrus (DG) is the main area of hippocampus that helps in neurogenesis and cornus ammonis 3 (CA3) for dendritic branching.^23-25 In recent studies by Wang and colleagues, PTSD has been found to be associated with selective volume loss of the CA3/DG subfields, consistent with animal studies.^24-28 Abundance of glucocorticoid receptors in the hippocampus, especially at CA3^,29,30 may make it more vulnerable to the neurotoxic effect of glucocorticoids, causing suppression of neurogenesis,²⁹ diminished dendritic branching,30 loss of synapses,^26,31 and eventually diminished neuroplasticity,32 because CA3/DG is the main target of neurotoxicity by glucocorticoid and inflammatory damage.

The results of neuroimaging studies suggest that decreased integration of the prefrontal cortex and the hippocampus results in impaired short-term memory and perhaps increasing the prominence of long-term distressing memories.³³ Clinical observation confirms that patients with PTSD experience vivid, intense, detailed, and realistic recollections of remote memories at a time when their ability to recall nontraumatic autobiographical detail is severely compromised.

Symptom Reemergence

Both prospective and retrospective studies have shown that PTSD symptoms can evolve, even after a 20-year long symptom-free period, and reemergence of PTSD
symptoms is not uncommon.^34,35 A longer delay usually presents with less severe symptoms.³⁶ The unavailability of complete information regarding a patient’s past adjustment to psychological trauma has encouraged some experts to label exacerbation of PTSD symptoms precipitated by cognitive disorder as delayed onset PTSD. In most cases, it seems that this is more accurately described as a recrudescence of symptoms that were better managed previously. The picture is clouded by the often bizarre and extreme manifestation of PTSD symptoms in patients with memory disorders. The course of PTSD often does involve a delay between the time of exposure to trauma and symptom manifestation. In addition, symptom intensity can fluctuate significantly over the course of this often chronic illness.

The suffering associated with PTSD is often personal and concealed. Family and other collateral sources may be able to report only on social and occupational functioning. The authors recommend increased attention to proper assessment of (1) remote trauma history in patients being evaluated for memory disorders; and (2) cognitive decline in patients with history of PTSD. The problem of underreported cognitive decline is well known, although its extent is not. Early detection may help to mitigate the combined effects of these conditions. Aggressive early treatment of symptoms during the onset of cognitive dysfunction may prolong patients’ ability to remain at home.

Patient Care

Mr. B’s case was marked by significant tension in the home. Education and support of caregivers is essential to maintaining care in the least restrictive setting, such as the patient’s home. Families might be utterly bewildered by a patient’s apparently sudden preoccupation with traumatic memories. For many, this might be the first time they have ever heard the patient speak at length about the traumatic events. Simple strategies to limit exposure to distressing stimuli, improve grounding, and understand the effects of trauma can be taught. Psychopharmacologic intervention to improve sleep, slow cognitive decline, and decrease behavioral disturbances may be indicated.

Behavioral disturbance is frequently encountered when treating patients with cognitive impairment. In the limited literature on the subject, patients with both PTSD and cognitive impairment do not seem to be more prone to behavioral disturbance than patients with cognitive impairment alone.⁹ However, the case reports cited here demonstrate a high incidence of violence or potential violence in these comorbid patients. Routine assessment of potential harm from firearms or other weapons should be conducted assiduously.

It is possible that Vietnam War veterans may be more likely than previous veterans to exhibit behavioral disturbances in the context of cognitive decline and PTSD. A higher incidence of aggression, violence, and resistance to authority has been documented in this group.³⁷ Substance abuse and dependence also occurs with higher frequency in this cohort and may complicate treatment of cognitive impairment and PTSD.^38,39 A large number of these veterans may initially present to non-VA health care providers and these clinicians may be unaware of a patient’s prior combat exposure and thus fail to accurately assess PTSD.

Although the relation of PTSD and vulnerability to dementia has been well established, it is unknown how the presence of PTSD symptomatology impacts dementia symptoms or how the presence of dementia impacts PTSD symptoms. Posttraumatic stress disorder and dementia share similar risks like traumatic brain injury, low IQ, poor education, substance abuse, precipitated by stressful life events and impairment of coping, physical health and related risk factors. Unmasking PTSD symptoms resulting from dementia is a well-known phenomenon described in recent studies on late-onset stress symptomatology (LOSS).^5,10,40

Since PTSD is a major risk factor that doubles the chance of developing dementia, mandatory screening for dementia in older patients along with assessment of other risk factors as a standard of care may help physicians in the early detection and initiation of care. Recognition of LOSS may be an important milestone in the treatment of delayed onset PTSD, which is considered a normal aging process and a premorbid stage of PTSD.^10,40

Although there is no established treatment, early psychotherapeutic approaches like reminiscent therapy along with psychoeducation may be beneficial in patients with LOSS.^40-42 Effective treatments for PTSD with patients with dementia may be challenging, though dementia was not found to be a barrier to implement prolonged exposure therapy in patients with mild cognitive impairment.43 Patient aligned care teams can be an ideal approach for the care of these veterans.

Conclusion

Posttraumatic stress disorder and dementia are well studied and documented disorders, although PTSD has been studied far more extensively in younger populations. Accounts of comorbidity of the 2 disorders are limited in the literature. Individuals may exhibit PTSD symptoms prior to the onset of dementia. They also may develop or uncover long quiescent symptoms of the disease. The populations of patients with PTSD and dementia are recognized, but their characteristics are largely unstudied and thus unknown.

Although the authors believe this to be a phenomenon of unrecognized coexistence of the 2 disorders, a disproportionate number of patients may be found in certain populations, especially among veterans. There is good evidence to expect increased numbers of these patients in the VA system, especially given the relative frequency of PTSD symptoms in aging cohorts of VA patients.

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The number of veterans aged ≥ 65 years is expected to increase steadily as the Vietnam-era cohort ages. In 2012, the number of veterans aged ≥ 85 years was expected to peak at nearly 1.4 million. Vietnam-era veterans comprise the largest cohort of veterans, and > 15% of male and > 8% of female Vietnam veterans receiving care in the VA system have been diagnosed with posttraumatic stress disorder (PTSD). These veterans are rapidly approaching age groups in which cognitive disorders increase exponentially in prevalence.

Combat exposure has been called a common but “hidden variable” in studies of aging and health.¹ Combat exposure may be even more hidden for Vietnam veterans who have pursued health care outside the VA system and less likely to announce their service to health care providers.

Even veterans who did not serve in traditional combat roles can experience chronic debilitation from the psychological stress of overseas deployment to a war zone. Indeed, cases of noncombat trauma have been presented in the context of cognitive decline and late-onset PTSD.² It is probable that survivors of sexual assault, child abuse, crime, and natural disaster are also vulnerable to a recurrence of trauma symptoms if they experience cognitive slippage. In this article the authors report a case of delayed onset PTSD symptoms, precipitated by cognitive decline.

Case Report

Mr. B was a 72-year-old Korean War veteran referred for neuropsychological evaluation to establish baseline cognitive status before elective cardiac surgery. Mr. B relied on his wife to fill in many details of his personal history. His wife reported that the patient’s memory problems had increased significantly over the previous 12 months. Mr. B had been treated with donepezil 10 mg daily for about 1 year, with no observed benefit. His wife described life at home as “tense” due to his increased irritability and poor insight into his condition. Mr. B reported that he was often afraid of noises at night and needed to go outside and look around. His wife reported that he was very afraid of “strangers coming into the house.”

Mr. B was born in Arizona and experienced significant physical abuse while under the care of an alcoholic foster parent. He dropped out of high school and enlisted in the U.S. Marine Corps. Upon his discharge from military service, he worked as a truck driver for 23 years. He retired after experiencing hip problems. He drank heavily for many years after the war and, according to his wife, was “very violent,” but stopped 27 years previously, after injuring his wife while intoxicated. The patient’s medical history included hospitalization about 1 year prior to the evaluation following a fall associated with altered level of consciousness and confusion, which lasted several hours. He was discharged the same day and was thought to have had a stroke. The patient also had hypertension, hyperlipidemia, and sciatica. A carotid ultrasound showed bilateral carotid stenosis > 50%.

Mr. B was married for 45 years and had 5 children and 12 grandchildren. He enlisted in the U.S. Marine Corps at age 19 and served as a tank gunner during the Korean War. He experienced extremely heavy combat, was wounded several times (including loss of consciousness due to an explosion), and was hospitalizedfor 4 m onths in Japan. When he returned to the frontline, he found that many of the men in his unit had been killed. He was promoted to staff sergeant and tank commander. Mr. B received an honorable discharge after the war and a 50% service-connected disability pension for PTSD. He reported having received group psychotherapy at a VA hospital soon after the war but no other psychiatric treatment. He avoided watching the news because the Gulf War news reminded him of Korea.

Mr. B was smiling, pleasant, and cooperative throughout the 2 hours of testing and interviewing. He wore a Korean War veteran baseball cap festooned with military pins and ribbons, including a Purple Heart ribbon that he proudly showed to the test administrators. Unbidden, he also presented for inspection an assortment of life membership cards in various veterans service organizations. Mr. B reported frequent nightmares, night sweats, and intrusive thoughts about his combat experiences. During testing, he was repeatedly triggered by innocuous items and launched into a discourse on his combat experiences. When asked to memorize a short list of words that included the word fire, he said, “You know what that reminds me of...we had to fire big guns, 90 millimeter, that’s what it was…killing and how to kill.” When shown an abstract design that resembled the number 44, he said, “You know what that is? It was the radio call sign of our tank—‘This is 44, come in, we need some help.’”

Mr. B’s memory problems were marked by rapid forgetting, impaired ability to learn new information, and impaired ability to recall previously learned information. Language problems were also present, including difficulty recognizing and naming common objects, impaired auditory comprehension, and problems with verbal associative fluency during timed tasks. He also showed difficulties with executive functioning, attention, and working memory. His mini-mental state examination score was 21/30. He stated the year was 2020, did not know the day of the week, registered 2/3 words and recalled 0/3, he counted 3/5 in serial 7s, and was unable to repeat the phrase, “no ifs, ands, or buts.”

Discussion

Posttraumatic stress symptoms were present during the immediate aftermath of the initial trauma exposure for this patient. He managed to lead a relatively successful and productive life, sustained a marriage, and raised a family. The onset of cognitive decline precipitated a recrudescence of PTSD symptomology. In fact, the effects of combat trauma seem more malignant and extreme at the time of the memory disorders evaluation than at any prior time in his life.

A number of case reports have been published in recent years that describe comorbid presentations of cognitive disorder and PTSD symptomatology.^3-6 A clinicalconsensus that cognitive decline can exacerbate previously well-managed symptoms of earlier psychological trauma seems to be emerging. Several published casestudies have noted that comorbid presentation of dementia and PTSD is often marked by violence, psychotic symptoms, and increased risk of hospitalization.^7-9

PTSD Research

Unfortunately, systematic investigation into the relationship between PTSD and cognitive decline is in its infancy. Previous authors have posited various mechanisms to explain the exacerbation of dormant PTSD symptoms after cognitive decline.^10,11 Some have attributed the phenomenon to an age-related failure of either repression or avoidance or to a compromised ability to actively focus their attention elsewhere.^2,12 A finding of preservative errors on neuropsychological tests has been associated with an inability to organize and inhibit intrusive thought.¹³ In one case, the effects of combat trauma were purported to be denied, repressed, and largely forgotten for 30 years until rekindled by the patient’s deteriorating health and loss of employment.¹⁴ Several case examples have been presented in which physical illness, interpersonal loss, retirement, or losses of social support were other factors.^15-18 Two major studies of veterans with PTSD, found that subjects were twice as likely to develop dementia.^3,4 There is a strong association between chronic psychological stress and later development
of dementia. In a study by Wilson and colleagues, subjects with higher baseline stress had twice the chance of developing Alzheimer disease.19 Similar findings of
accelerated or higher cognitive decline were found by other studies, too.^17,20

Hippocampal damage associated with prolonged, intense psychological stress has been cited as a possible contributor to PTSD symptom recrudescence in older adults.²¹ It is well known that emotional arousal leads to better-encoded memories. In the context of a cognitive disorder marked by gradual memory loss, traumatic memories might be the last to go.²² Another proposed biologic mechanism is a reduction in hippocampal volume and decreased inhibition of the amgydala, which results in preferential recall of the nondeclarative, amygdaloidal traumatic memories.⁸

Research on selective area damage in the hippocampus opens a new era of understanding of consequences of stress. The dentate gyrus (DG) is the main area of hippocampus that helps in neurogenesis and cornus ammonis 3 (CA3) for dendritic branching.^23-25 In recent studies by Wang and colleagues, PTSD has been found to be associated with selective volume loss of the CA3/DG subfields, consistent with animal studies.^24-28 Abundance of glucocorticoid receptors in the hippocampus, especially at CA3^,29,30 may make it more vulnerable to the neurotoxic effect of glucocorticoids, causing suppression of neurogenesis,²⁹ diminished dendritic branching,30 loss of synapses,^26,31 and eventually diminished neuroplasticity,32 because CA3/DG is the main target of neurotoxicity by glucocorticoid and inflammatory damage.

The results of neuroimaging studies suggest that decreased integration of the prefrontal cortex and the hippocampus results in impaired short-term memory and perhaps increasing the prominence of long-term distressing memories.³³ Clinical observation confirms that patients with PTSD experience vivid, intense, detailed, and realistic recollections of remote memories at a time when their ability to recall nontraumatic autobiographical detail is severely compromised.

Symptom Reemergence

Both prospective and retrospective studies have shown that PTSD symptoms can evolve, even after a 20-year long symptom-free period, and reemergence of PTSD
symptoms is not uncommon.^34,35 A longer delay usually presents with less severe symptoms.³⁶ The unavailability of complete information regarding a patient’s past adjustment to psychological trauma has encouraged some experts to label exacerbation of PTSD symptoms precipitated by cognitive disorder as delayed onset PTSD. In most cases, it seems that this is more accurately described as a recrudescence of symptoms that were better managed previously. The picture is clouded by the often bizarre and extreme manifestation of PTSD symptoms in patients with memory disorders. The course of PTSD often does involve a delay between the time of exposure to trauma and symptom manifestation. In addition, symptom intensity can fluctuate significantly over the course of this often chronic illness.

The suffering associated with PTSD is often personal and concealed. Family and other collateral sources may be able to report only on social and occupational functioning. The authors recommend increased attention to proper assessment of (1) remote trauma history in patients being evaluated for memory disorders; and (2) cognitive decline in patients with history of PTSD. The problem of underreported cognitive decline is well known, although its extent is not. Early detection may help to mitigate the combined effects of these conditions. Aggressive early treatment of symptoms during the onset of cognitive dysfunction may prolong patients’ ability to remain at home.

Patient Care

Mr. B’s case was marked by significant tension in the home. Education and support of caregivers is essential to maintaining care in the least restrictive setting, such as the patient’s home. Families might be utterly bewildered by a patient’s apparently sudden preoccupation with traumatic memories. For many, this might be the first time they have ever heard the patient speak at length about the traumatic events. Simple strategies to limit exposure to distressing stimuli, improve grounding, and understand the effects of trauma can be taught. Psychopharmacologic intervention to improve sleep, slow cognitive decline, and decrease behavioral disturbances may be indicated.

Behavioral disturbance is frequently encountered when treating patients with cognitive impairment. In the limited literature on the subject, patients with both PTSD and cognitive impairment do not seem to be more prone to behavioral disturbance than patients with cognitive impairment alone.⁹ However, the case reports cited here demonstrate a high incidence of violence or potential violence in these comorbid patients. Routine assessment of potential harm from firearms or other weapons should be conducted assiduously.

It is possible that Vietnam War veterans may be more likely than previous veterans to exhibit behavioral disturbances in the context of cognitive decline and PTSD. A higher incidence of aggression, violence, and resistance to authority has been documented in this group.³⁷ Substance abuse and dependence also occurs with higher frequency in this cohort and may complicate treatment of cognitive impairment and PTSD.^38,39 A large number of these veterans may initially present to non-VA health care providers and these clinicians may be unaware of a patient’s prior combat exposure and thus fail to accurately assess PTSD.

Although the relation of PTSD and vulnerability to dementia has been well established, it is unknown how the presence of PTSD symptomatology impacts dementia symptoms or how the presence of dementia impacts PTSD symptoms. Posttraumatic stress disorder and dementia share similar risks like traumatic brain injury, low IQ, poor education, substance abuse, precipitated by stressful life events and impairment of coping, physical health and related risk factors. Unmasking PTSD symptoms resulting from dementia is a well-known phenomenon described in recent studies on late-onset stress symptomatology (LOSS).^5,10,40

Since PTSD is a major risk factor that doubles the chance of developing dementia, mandatory screening for dementia in older patients along with assessment of other risk factors as a standard of care may help physicians in the early detection and initiation of care. Recognition of LOSS may be an important milestone in the treatment of delayed onset PTSD, which is considered a normal aging process and a premorbid stage of PTSD.^10,40

Although there is no established treatment, early psychotherapeutic approaches like reminiscent therapy along with psychoeducation may be beneficial in patients with LOSS.^40-42 Effective treatments for PTSD with patients with dementia may be challenging, though dementia was not found to be a barrier to implement prolonged exposure therapy in patients with mild cognitive impairment.43 Patient aligned care teams can be an ideal approach for the care of these veterans.

Conclusion

Posttraumatic stress disorder and dementia are well studied and documented disorders, although PTSD has been studied far more extensively in younger populations. Accounts of comorbidity of the 2 disorders are limited in the literature. Individuals may exhibit PTSD symptoms prior to the onset of dementia. They also may develop or uncover long quiescent symptoms of the disease. The populations of patients with PTSD and dementia are recognized, but their characteristics are largely unstudied and thus unknown.

Although the authors believe this to be a phenomenon of unrecognized coexistence of the 2 disorders, a disproportionate number of patients may be found in certain populations, especially among veterans. There is good evidence to expect increased numbers of these patients in the VA system, especially given the relative frequency of PTSD symptoms in aging cohorts of VA patients.

Click here to continue reading.

The number of veterans aged ≥ 65 years is expected to increase steadily as the Vietnam-era cohort ages. In 2012, the number of veterans aged ≥ 85 years was expected to peak at nearly 1.4 million. Vietnam-era veterans comprise the largest cohort of veterans, and > 15% of male and > 8% of female Vietnam veterans receiving care in the VA system have been diagnosed with posttraumatic stress disorder (PTSD). These veterans are rapidly approaching age groups in which cognitive disorders increase exponentially in prevalence.

Combat exposure has been called a common but “hidden variable” in studies of aging and health.¹ Combat exposure may be even more hidden for Vietnam veterans who have pursued health care outside the VA system and less likely to announce their service to health care providers.

Even veterans who did not serve in traditional combat roles can experience chronic debilitation from the psychological stress of overseas deployment to a war zone. Indeed, cases of noncombat trauma have been presented in the context of cognitive decline and late-onset PTSD.² It is probable that survivors of sexual assault, child abuse, crime, and natural disaster are also vulnerable to a recurrence of trauma symptoms if they experience cognitive slippage. In this article the authors report a case of delayed onset PTSD symptoms, precipitated by cognitive decline.

Case Report

Mr. B was a 72-year-old Korean War veteran referred for neuropsychological evaluation to establish baseline cognitive status before elective cardiac surgery. Mr. B relied on his wife to fill in many details of his personal history. His wife reported that the patient’s memory problems had increased significantly over the previous 12 months. Mr. B had been treated with donepezil 10 mg daily for about 1 year, with no observed benefit. His wife described life at home as “tense” due to his increased irritability and poor insight into his condition. Mr. B reported that he was often afraid of noises at night and needed to go outside and look around. His wife reported that he was very afraid of “strangers coming into the house.”

Mr. B was born in Arizona and experienced significant physical abuse while under the care of an alcoholic foster parent. He dropped out of high school and enlisted in the U.S. Marine Corps. Upon his discharge from military service, he worked as a truck driver for 23 years. He retired after experiencing hip problems. He drank heavily for many years after the war and, according to his wife, was “very violent,” but stopped 27 years previously, after injuring his wife while intoxicated. The patient’s medical history included hospitalization about 1 year prior to the evaluation following a fall associated with altered level of consciousness and confusion, which lasted several hours. He was discharged the same day and was thought to have had a stroke. The patient also had hypertension, hyperlipidemia, and sciatica. A carotid ultrasound showed bilateral carotid stenosis > 50%.

Mr. B was married for 45 years and had 5 children and 12 grandchildren. He enlisted in the U.S. Marine Corps at age 19 and served as a tank gunner during the Korean War. He experienced extremely heavy combat, was wounded several times (including loss of consciousness due to an explosion), and was hospitalizedfor 4 m onths in Japan. When he returned to the frontline, he found that many of the men in his unit had been killed. He was promoted to staff sergeant and tank commander. Mr. B received an honorable discharge after the war and a 50% service-connected disability pension for PTSD. He reported having received group psychotherapy at a VA hospital soon after the war but no other psychiatric treatment. He avoided watching the news because the Gulf War news reminded him of Korea.

Mr. B was smiling, pleasant, and cooperative throughout the 2 hours of testing and interviewing. He wore a Korean War veteran baseball cap festooned with military pins and ribbons, including a Purple Heart ribbon that he proudly showed to the test administrators. Unbidden, he also presented for inspection an assortment of life membership cards in various veterans service organizations. Mr. B reported frequent nightmares, night sweats, and intrusive thoughts about his combat experiences. During testing, he was repeatedly triggered by innocuous items and launched into a discourse on his combat experiences. When asked to memorize a short list of words that included the word fire, he said, “You know what that reminds me of...we had to fire big guns, 90 millimeter, that’s what it was…killing and how to kill.” When shown an abstract design that resembled the number 44, he said, “You know what that is? It was the radio call sign of our tank—‘This is 44, come in, we need some help.’”

Mr. B’s memory problems were marked by rapid forgetting, impaired ability to learn new information, and impaired ability to recall previously learned information. Language problems were also present, including difficulty recognizing and naming common objects, impaired auditory comprehension, and problems with verbal associative fluency during timed tasks. He also showed difficulties with executive functioning, attention, and working memory. His mini-mental state examination score was 21/30. He stated the year was 2020, did not know the day of the week, registered 2/3 words and recalled 0/3, he counted 3/5 in serial 7s, and was unable to repeat the phrase, “no ifs, ands, or buts.”

Discussion

Posttraumatic stress symptoms were present during the immediate aftermath of the initial trauma exposure for this patient. He managed to lead a relatively successful and productive life, sustained a marriage, and raised a family. The onset of cognitive decline precipitated a recrudescence of PTSD symptomology. In fact, the effects of combat trauma seem more malignant and extreme at the time of the memory disorders evaluation than at any prior time in his life.

A number of case reports have been published in recent years that describe comorbid presentations of cognitive disorder and PTSD symptomatology.^3-6 A clinicalconsensus that cognitive decline can exacerbate previously well-managed symptoms of earlier psychological trauma seems to be emerging. Several published casestudies have noted that comorbid presentation of dementia and PTSD is often marked by violence, psychotic symptoms, and increased risk of hospitalization.^7-9

PTSD Research

Unfortunately, systematic investigation into the relationship between PTSD and cognitive decline is in its infancy. Previous authors have posited various mechanisms to explain the exacerbation of dormant PTSD symptoms after cognitive decline.^10,11 Some have attributed the phenomenon to an age-related failure of either repression or avoidance or to a compromised ability to actively focus their attention elsewhere.^2,12 A finding of preservative errors on neuropsychological tests has been associated with an inability to organize and inhibit intrusive thought.¹³ In one case, the effects of combat trauma were purported to be denied, repressed, and largely forgotten for 30 years until rekindled by the patient’s deteriorating health and loss of employment.¹⁴ Several case examples have been presented in which physical illness, interpersonal loss, retirement, or losses of social support were other factors.^15-18 Two major studies of veterans with PTSD, found that subjects were twice as likely to develop dementia.^3,4 There is a strong association between chronic psychological stress and later development
of dementia. In a study by Wilson and colleagues, subjects with higher baseline stress had twice the chance of developing Alzheimer disease.19 Similar findings of
accelerated or higher cognitive decline were found by other studies, too.^17,20

Hippocampal damage associated with prolonged, intense psychological stress has been cited as a possible contributor to PTSD symptom recrudescence in older adults.²¹ It is well known that emotional arousal leads to better-encoded memories. In the context of a cognitive disorder marked by gradual memory loss, traumatic memories might be the last to go.²² Another proposed biologic mechanism is a reduction in hippocampal volume and decreased inhibition of the amgydala, which results in preferential recall of the nondeclarative, amygdaloidal traumatic memories.⁸

Research on selective area damage in the hippocampus opens a new era of understanding of consequences of stress. The dentate gyrus (DG) is the main area of hippocampus that helps in neurogenesis and cornus ammonis 3 (CA3) for dendritic branching.^23-25 In recent studies by Wang and colleagues, PTSD has been found to be associated with selective volume loss of the CA3/DG subfields, consistent with animal studies.^24-28 Abundance of glucocorticoid receptors in the hippocampus, especially at CA3^,29,30 may make it more vulnerable to the neurotoxic effect of glucocorticoids, causing suppression of neurogenesis,²⁹ diminished dendritic branching,30 loss of synapses,^26,31 and eventually diminished neuroplasticity,32 because CA3/DG is the main target of neurotoxicity by glucocorticoid and inflammatory damage.

The results of neuroimaging studies suggest that decreased integration of the prefrontal cortex and the hippocampus results in impaired short-term memory and perhaps increasing the prominence of long-term distressing memories.³³ Clinical observation confirms that patients with PTSD experience vivid, intense, detailed, and realistic recollections of remote memories at a time when their ability to recall nontraumatic autobiographical detail is severely compromised.

Symptom Reemergence

Both prospective and retrospective studies have shown that PTSD symptoms can evolve, even after a 20-year long symptom-free period, and reemergence of PTSD
symptoms is not uncommon.^34,35 A longer delay usually presents with less severe symptoms.³⁶ The unavailability of complete information regarding a patient’s past adjustment to psychological trauma has encouraged some experts to label exacerbation of PTSD symptoms precipitated by cognitive disorder as delayed onset PTSD. In most cases, it seems that this is more accurately described as a recrudescence of symptoms that were better managed previously. The picture is clouded by the often bizarre and extreme manifestation of PTSD symptoms in patients with memory disorders. The course of PTSD often does involve a delay between the time of exposure to trauma and symptom manifestation. In addition, symptom intensity can fluctuate significantly over the course of this often chronic illness.

The suffering associated with PTSD is often personal and concealed. Family and other collateral sources may be able to report only on social and occupational functioning. The authors recommend increased attention to proper assessment of (1) remote trauma history in patients being evaluated for memory disorders; and (2) cognitive decline in patients with history of PTSD. The problem of underreported cognitive decline is well known, although its extent is not. Early detection may help to mitigate the combined effects of these conditions. Aggressive early treatment of symptoms during the onset of cognitive dysfunction may prolong patients’ ability to remain at home.

Patient Care

Mr. B’s case was marked by significant tension in the home. Education and support of caregivers is essential to maintaining care in the least restrictive setting, such as the patient’s home. Families might be utterly bewildered by a patient’s apparently sudden preoccupation with traumatic memories. For many, this might be the first time they have ever heard the patient speak at length about the traumatic events. Simple strategies to limit exposure to distressing stimuli, improve grounding, and understand the effects of trauma can be taught. Psychopharmacologic intervention to improve sleep, slow cognitive decline, and decrease behavioral disturbances may be indicated.

Behavioral disturbance is frequently encountered when treating patients with cognitive impairment. In the limited literature on the subject, patients with both PTSD and cognitive impairment do not seem to be more prone to behavioral disturbance than patients with cognitive impairment alone.⁹ However, the case reports cited here demonstrate a high incidence of violence or potential violence in these comorbid patients. Routine assessment of potential harm from firearms or other weapons should be conducted assiduously.

It is possible that Vietnam War veterans may be more likely than previous veterans to exhibit behavioral disturbances in the context of cognitive decline and PTSD. A higher incidence of aggression, violence, and resistance to authority has been documented in this group.³⁷ Substance abuse and dependence also occurs with higher frequency in this cohort and may complicate treatment of cognitive impairment and PTSD.^38,39 A large number of these veterans may initially present to non-VA health care providers and these clinicians may be unaware of a patient’s prior combat exposure and thus fail to accurately assess PTSD.

Although the relation of PTSD and vulnerability to dementia has been well established, it is unknown how the presence of PTSD symptomatology impacts dementia symptoms or how the presence of dementia impacts PTSD symptoms. Posttraumatic stress disorder and dementia share similar risks like traumatic brain injury, low IQ, poor education, substance abuse, precipitated by stressful life events and impairment of coping, physical health and related risk factors. Unmasking PTSD symptoms resulting from dementia is a well-known phenomenon described in recent studies on late-onset stress symptomatology (LOSS).^5,10,40

Since PTSD is a major risk factor that doubles the chance of developing dementia, mandatory screening for dementia in older patients along with assessment of other risk factors as a standard of care may help physicians in the early detection and initiation of care. Recognition of LOSS may be an important milestone in the treatment of delayed onset PTSD, which is considered a normal aging process and a premorbid stage of PTSD.^10,40

Although there is no established treatment, early psychotherapeutic approaches like reminiscent therapy along with psychoeducation may be beneficial in patients with LOSS.^40-42 Effective treatments for PTSD with patients with dementia may be challenging, though dementia was not found to be a barrier to implement prolonged exposure therapy in patients with mild cognitive impairment.43 Patient aligned care teams can be an ideal approach for the care of these veterans.

Conclusion

Posttraumatic stress disorder and dementia are well studied and documented disorders, although PTSD has been studied far more extensively in younger populations. Accounts of comorbidity of the 2 disorders are limited in the literature. Individuals may exhibit PTSD symptoms prior to the onset of dementia. They also may develop or uncover long quiescent symptoms of the disease. The populations of patients with PTSD and dementia are recognized, but their characteristics are largely unstudied and thus unknown.

Although the authors believe this to be a phenomenon of unrecognized coexistence of the 2 disorders, a disproportionate number of patients may be found in certain populations, especially among veterans. There is good evidence to expect increased numbers of these patients in the VA system, especially given the relative frequency of PTSD symptoms in aging cohorts of VA patients.

Click here to continue reading.

Case

A 34-year-old woman presented to the ED with severe, persistent abdominal pain that had begun 18 days earlier. She was 7 weeks pregnant and had been seen in the same ED the day before. During that visit, ultrasound had shown a single pregnancy of doubtful viability. Abdominal magnetic resonance imaging was normal. She was given multiple doses of hydromorphone. The discharge diagnosis was “missed abortion.”

Since the onset of her pain, she had been hospitalized twice elsewhere, with no clear diagnosis to explain her pain. Treatment consisted of repeat doses of hydromorphone. During the second hospitalization, a sodium level of 109 mEq/L had been corrected with hypertonic saline, and a urinary tract infection (UTI) had been treated with cephalexin.

Our patient had never experienced similar abdominal pain. Her medical history included depression and asthma. Her family history was notable for an aunt who had died of lung cancer.

On this ED visit, the patient’s vital signs were normal. On examination, she was moaning in pain and clutching her abdomen. The abdomen was tender in both lower quadrants, with guarding but no rebound. Her sodium level was 125 mEq/L; the day before it had been 132 mEq/L.

Urine dipstick testing showed 2+ glucose and 2+ bilirubin; both had been within normal range (negative) the day before. An abdominal/pelvic computed tomography scan with intravenous (IV) and oral contrast did not reveal any potential cause of the patient’s pain. Multiple doses of IV hydromorphone were given, but her pain persisted.

We revisited our patient’s family history. With prompting, she remembered that as a teenager, her mother had had an illness that caused “problems with her nerves and blood vessels and turned her urine red.” When reached by phone, the patient’s mother, who lives outside the United States, said she was familiar with the term “porphyria,” but curiously, she did not state she carried the diagnosis, and had not advised her children they could be at risk.

The patient was admitted to the intensive care unit (ICU) for treatment of hyponatremia. Her mother’s history led us to suspect porphyria, so we sent a urine sample from the ED for porphobilinogen (PBG) testing. Her urine was not red at that time (on further questioning, she remembered she had had an episode of “red urine” recently). Two days later, after the PBG result came back positive, treatment was initiated for porphyria. With further stool and serum testing, the diagnosis of acute intermittent porphyria (AIP) was made.

The patient was treated with glucose loading and hemin therapy. In the ICU, 2 ampules of 50% dextrose in water solution (D50W) was administered, and she was transferred to the hematology-oncology service for hemin therapy. Soon after, she underwent a dilation and curettage. Three weeks later, she was discharged in good condition.

Discussion

The unifying diagnostic concept is that toxins damage all components of the nervous system: intestinal, central, peripheral, and autonomic. Hence, any combination of abdominal pain, vomiting, psychiatric symptoms, vital sign instability, weakness, or sensory loss may occur.¹ To further confuse the diagnostician, the constellation of symptoms may vary with each episode.

Two critical laboratory clues are red urine—which often is mistaken for a UTI or hematuria—and hyponatremia.¹ Another porphyria hallmark is triggers. These include drugs, carbohydrate deprivation, smoking, and stress. Common chemical inciters include alcohol, ketamine, etomidate, macrodantin, nifedipine, progesterone, and phenytoin.¹ The Atkins diet (zero carbohydrates) reportedly caused an uptick in new porphyria cases.¹

Attacks usually start after puberty. Women tend to experience flares during the luteal (progesterone) phase of the menstrual cycle.¹ Acute intermittent porphyria can mimic Guillain-Barré syndrome and psychosis.² Delayed diagnosis may lead to irreversible neurological damage or death.²

Despite AIP’s complexity, initial diagnostic testing is simple: a urinary PBG level obtained during an attack is virtually 100% sensitive and specific for AIP and two other acute porphyrias: hereditary coproporphyria (HCP), and variegate porphyria (VP). A positive urine PBG mandates immediate treatment—even while awaiting porphyrin and GK delta-aminolevulinic acid (ALA) levels in stool and serum to identify which porphyria (AIP, HCP, or VP) is present. The fourth (and least common) acute porphyria, ALA dehydratase porphyria (ADP), may produce no PBG elevation and requires separate porphyrin and ALA testing to make the diagnosis.

Treatment

Treatment targets runaway heme precursor synthesis at its start and finish (Figure). Glucose-loading suppresses the initial enzyme, ALA synthase. Since the absence of normal end-product (heme) drives the enzymatic cascade, addition of IV hemin provides the substrate—and negative feedback—to stop it.

Conclusion

This case represents an example of AIP in which a patient presented with the characteristic abdominal pain and hyponatremia, complicated by the fact that she was pregnant and her urine was not red.

Intractable abdominal pain with negative imaging must prompt a search for red urine, neurological symptoms, porphyria medication triggers, and a family history of porphyria. Any constellation of findings should prompt immediate urine PBG testing.

In the appropriate clinical setting, it may be prudent to glucose-load a patient while waiting for confirmatory testing (which can take 1-2 days). Hemin therapy is best instituted by the hematology service after high urine PBG levels are confirmed.

Case

A 34-year-old woman presented to the ED with severe, persistent abdominal pain that had begun 18 days earlier. She was 7 weeks pregnant and had been seen in the same ED the day before. During that visit, ultrasound had shown a single pregnancy of doubtful viability. Abdominal magnetic resonance imaging was normal. She was given multiple doses of hydromorphone. The discharge diagnosis was “missed abortion.”

Since the onset of her pain, she had been hospitalized twice elsewhere, with no clear diagnosis to explain her pain. Treatment consisted of repeat doses of hydromorphone. During the second hospitalization, a sodium level of 109 mEq/L had been corrected with hypertonic saline, and a urinary tract infection (UTI) had been treated with cephalexin.

Our patient had never experienced similar abdominal pain. Her medical history included depression and asthma. Her family history was notable for an aunt who had died of lung cancer.

On this ED visit, the patient’s vital signs were normal. On examination, she was moaning in pain and clutching her abdomen. The abdomen was tender in both lower quadrants, with guarding but no rebound. Her sodium level was 125 mEq/L; the day before it had been 132 mEq/L.

Urine dipstick testing showed 2+ glucose and 2+ bilirubin; both had been within normal range (negative) the day before. An abdominal/pelvic computed tomography scan with intravenous (IV) and oral contrast did not reveal any potential cause of the patient’s pain. Multiple doses of IV hydromorphone were given, but her pain persisted.

We revisited our patient’s family history. With prompting, she remembered that as a teenager, her mother had had an illness that caused “problems with her nerves and blood vessels and turned her urine red.” When reached by phone, the patient’s mother, who lives outside the United States, said she was familiar with the term “porphyria,” but curiously, she did not state she carried the diagnosis, and had not advised her children they could be at risk.

The patient was admitted to the intensive care unit (ICU) for treatment of hyponatremia. Her mother’s history led us to suspect porphyria, so we sent a urine sample from the ED for porphobilinogen (PBG) testing. Her urine was not red at that time (on further questioning, she remembered she had had an episode of “red urine” recently). Two days later, after the PBG result came back positive, treatment was initiated for porphyria. With further stool and serum testing, the diagnosis of acute intermittent porphyria (AIP) was made.

The patient was treated with glucose loading and hemin therapy. In the ICU, 2 ampules of 50% dextrose in water solution (D50W) was administered, and she was transferred to the hematology-oncology service for hemin therapy. Soon after, she underwent a dilation and curettage. Three weeks later, she was discharged in good condition.

Discussion

The unifying diagnostic concept is that toxins damage all components of the nervous system: intestinal, central, peripheral, and autonomic. Hence, any combination of abdominal pain, vomiting, psychiatric symptoms, vital sign instability, weakness, or sensory loss may occur.¹ To further confuse the diagnostician, the constellation of symptoms may vary with each episode.

Two critical laboratory clues are red urine—which often is mistaken for a UTI or hematuria—and hyponatremia.¹ Another porphyria hallmark is triggers. These include drugs, carbohydrate deprivation, smoking, and stress. Common chemical inciters include alcohol, ketamine, etomidate, macrodantin, nifedipine, progesterone, and phenytoin.¹ The Atkins diet (zero carbohydrates) reportedly caused an uptick in new porphyria cases.¹

Attacks usually start after puberty. Women tend to experience flares during the luteal (progesterone) phase of the menstrual cycle.¹ Acute intermittent porphyria can mimic Guillain-Barré syndrome and psychosis.² Delayed diagnosis may lead to irreversible neurological damage or death.²

Despite AIP’s complexity, initial diagnostic testing is simple: a urinary PBG level obtained during an attack is virtually 100% sensitive and specific for AIP and two other acute porphyrias: hereditary coproporphyria (HCP), and variegate porphyria (VP). A positive urine PBG mandates immediate treatment—even while awaiting porphyrin and GK delta-aminolevulinic acid (ALA) levels in stool and serum to identify which porphyria (AIP, HCP, or VP) is present. The fourth (and least common) acute porphyria, ALA dehydratase porphyria (ADP), may produce no PBG elevation and requires separate porphyrin and ALA testing to make the diagnosis.

Treatment

Treatment targets runaway heme precursor synthesis at its start and finish (Figure). Glucose-loading suppresses the initial enzyme, ALA synthase. Since the absence of normal end-product (heme) drives the enzymatic cascade, addition of IV hemin provides the substrate—and negative feedback—to stop it.

Conclusion

This case represents an example of AIP in which a patient presented with the characteristic abdominal pain and hyponatremia, complicated by the fact that she was pregnant and her urine was not red.

Intractable abdominal pain with negative imaging must prompt a search for red urine, neurological symptoms, porphyria medication triggers, and a family history of porphyria. Any constellation of findings should prompt immediate urine PBG testing.

In the appropriate clinical setting, it may be prudent to glucose-load a patient while waiting for confirmatory testing (which can take 1-2 days). Hemin therapy is best instituted by the hematology service after high urine PBG levels are confirmed.

Case

A 34-year-old woman presented to the ED with severe, persistent abdominal pain that had begun 18 days earlier. She was 7 weeks pregnant and had been seen in the same ED the day before. During that visit, ultrasound had shown a single pregnancy of doubtful viability. Abdominal magnetic resonance imaging was normal. She was given multiple doses of hydromorphone. The discharge diagnosis was “missed abortion.”

Since the onset of her pain, she had been hospitalized twice elsewhere, with no clear diagnosis to explain her pain. Treatment consisted of repeat doses of hydromorphone. During the second hospitalization, a sodium level of 109 mEq/L had been corrected with hypertonic saline, and a urinary tract infection (UTI) had been treated with cephalexin.

Our patient had never experienced similar abdominal pain. Her medical history included depression and asthma. Her family history was notable for an aunt who had died of lung cancer.

On this ED visit, the patient’s vital signs were normal. On examination, she was moaning in pain and clutching her abdomen. The abdomen was tender in both lower quadrants, with guarding but no rebound. Her sodium level was 125 mEq/L; the day before it had been 132 mEq/L.

Urine dipstick testing showed 2+ glucose and 2+ bilirubin; both had been within normal range (negative) the day before. An abdominal/pelvic computed tomography scan with intravenous (IV) and oral contrast did not reveal any potential cause of the patient’s pain. Multiple doses of IV hydromorphone were given, but her pain persisted.

We revisited our patient’s family history. With prompting, she remembered that as a teenager, her mother had had an illness that caused “problems with her nerves and blood vessels and turned her urine red.” When reached by phone, the patient’s mother, who lives outside the United States, said she was familiar with the term “porphyria,” but curiously, she did not state she carried the diagnosis, and had not advised her children they could be at risk.

The patient was admitted to the intensive care unit (ICU) for treatment of hyponatremia. Her mother’s history led us to suspect porphyria, so we sent a urine sample from the ED for porphobilinogen (PBG) testing. Her urine was not red at that time (on further questioning, she remembered she had had an episode of “red urine” recently). Two days later, after the PBG result came back positive, treatment was initiated for porphyria. With further stool and serum testing, the diagnosis of acute intermittent porphyria (AIP) was made.

The patient was treated with glucose loading and hemin therapy. In the ICU, 2 ampules of 50% dextrose in water solution (D50W) was administered, and she was transferred to the hematology-oncology service for hemin therapy. Soon after, she underwent a dilation and curettage. Three weeks later, she was discharged in good condition.

Discussion

The unifying diagnostic concept is that toxins damage all components of the nervous system: intestinal, central, peripheral, and autonomic. Hence, any combination of abdominal pain, vomiting, psychiatric symptoms, vital sign instability, weakness, or sensory loss may occur.¹ To further confuse the diagnostician, the constellation of symptoms may vary with each episode.

Two critical laboratory clues are red urine—which often is mistaken for a UTI or hematuria—and hyponatremia.¹ Another porphyria hallmark is triggers. These include drugs, carbohydrate deprivation, smoking, and stress. Common chemical inciters include alcohol, ketamine, etomidate, macrodantin, nifedipine, progesterone, and phenytoin.¹ The Atkins diet (zero carbohydrates) reportedly caused an uptick in new porphyria cases.¹

Attacks usually start after puberty. Women tend to experience flares during the luteal (progesterone) phase of the menstrual cycle.¹ Acute intermittent porphyria can mimic Guillain-Barré syndrome and psychosis.² Delayed diagnosis may lead to irreversible neurological damage or death.²

Despite AIP’s complexity, initial diagnostic testing is simple: a urinary PBG level obtained during an attack is virtually 100% sensitive and specific for AIP and two other acute porphyrias: hereditary coproporphyria (HCP), and variegate porphyria (VP). A positive urine PBG mandates immediate treatment—even while awaiting porphyrin and GK delta-aminolevulinic acid (ALA) levels in stool and serum to identify which porphyria (AIP, HCP, or VP) is present. The fourth (and least common) acute porphyria, ALA dehydratase porphyria (ADP), may produce no PBG elevation and requires separate porphyrin and ALA testing to make the diagnosis.

Treatment

Treatment targets runaway heme precursor synthesis at its start and finish (Figure). Glucose-loading suppresses the initial enzyme, ALA synthase. Since the absence of normal end-product (heme) drives the enzymatic cascade, addition of IV hemin provides the substrate—and negative feedback—to stop it.

Conclusion

This case represents an example of AIP in which a patient presented with the characteristic abdominal pain and hyponatremia, complicated by the fact that she was pregnant and her urine was not red.

Intractable abdominal pain with negative imaging must prompt a search for red urine, neurological symptoms, porphyria medication triggers, and a family history of porphyria. Any constellation of findings should prompt immediate urine PBG testing.

In the appropriate clinical setting, it may be prudent to glucose-load a patient while waiting for confirmatory testing (which can take 1-2 days). Hemin therapy is best instituted by the hematology service after high urine PBG levels are confirmed.

Intra-articular corticosteroid injections (CSIs) have been a common treatment for osteoarthritis since the 1950s and continue to be an option for patients who prefer nonoperative management.¹ Although CSIs may improve pain secondary to osteoarthritis temporarily, they do not slow articular cartilage degradation, and many patients request multiple CSIs before total joint arthroplasty ultimately is required.^1,2 Therefore, acute and chronic side effects of CSI must be considered when repeatedly administering corticosteroids.

A postinjection flare, the most common acute side effect of intra-articular CSI, is characterized by a localized inflammatory response that can last 2 to 3 days. The flare occurs in 2% to 25% of CSI cases.^3-5 Symptoms can range from mild joint effusion to disabling pain.⁶ In the present case, a severe postinjection flare occurred after intra-articular administration of triamcinolone acetonide (Kenalog). This case is novel in that its acuity of onset, severity of symptoms, and synovial fluid analysis mimicked septic arthritis, which was ultimately ruled out with negative cultures and confirmation of triamcinolone acetonide crystals in the synovial aspirate, viewed by polarized light microscopy. To date, only one other case of an immediate (<2 hours) and severe postinjection flare in response to triamcinolone has been reported.⁷ As CSIs are often used in the nonoperative treatment of osteoarthritis, it is imperative for the treating physician to be aware of this potential side effect in order to appropriately inform the patient of this risk and guide treatment should the scenario arise. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old woman with a history of hypertension, hypothyroidism, and moderate bilateral knee osteoarthritis presented with left knee pain. She had been receiving annual hylan injections for 5 years and had no adverse reactions, but the pain gradually worsened over the past 3 months. She was given an intra-articular injection of 2 mL of 1% lidocaine and 2 mL (40 mg) of triamcinolone acetonide in the left knee.

Two hours later, she experienced swelling and intense pain in the knee and was unable to ambulate. Physical examination revealed she was afebrile but was having severe pain in the knee through all range of motion. The knee had no appreciable erythema or warmth. Laboratory data were significant: White blood cell (WBC) count was 14,600, and erythrocyte sedimentation rate was 1 mm/h. The knee was aspirated with a return of 25 mL of “butterscotch”-colored fluid (Figure 1). The patient was admitted to rule out iatrogenic septic arthritis, or chronic, indolent septic arthritis acutely worsened by CSI, until synovial fluid analysis and cultures could be performed (Table 1).

She was treated overnight with a compressive wrap, elevation, ice, and nonsteroidal anti-inflammatory drugs, which provided significant pain relief. Polarized light microscopy revealed polymorphic intracellular and extracellular crystals with crystal morphology consistent with the injection of triamcinolone ester (Figure 2). Gram stain showed many WBCs but no organisms. These findings were thought to represent an exogenous crystal-induced acute inflammatory response. Given the patient’s improving clinical course, she was discharged the next morning.

Twelve days later, at clinic follow-up, she was still experiencing pain above her baseline level. Given the continued effusion, 8 mL of synovial fluid was aspirated, which appeared clear and only slightly blood-tinged. Synovial analysis showed resolution of leukocytosis, confirming a severe postinjection flare in response to triamcinolone acetonide.

Discussion

Although rare, side effects from repeated intra-articular CSIs include hypothalamic-pituitary-adrenal axis dysfunction and steroid-induced myopathy.^8,9 Acute side effects are more common and include postinjection flare, iatrogenic septic arthritis, local tissue atrophy, cartilage damage, tendon rupture, nerve atrophy, increased blood glucose, and osteonecrosis.^10,11 The present case report describes an extreme example of a postinjection flare in response to triamcinolone acetonide and summarizes the characteristics of injections that cause flares.

The physical properties of corticosteroids have a significant impact on their efficacy and on their potential for adverse events. Corticosteroid preparations can be water-soluble or water-insoluble. Most commonly, water-insoluble preparations that contain insoluble corticosteroid esters (eg, triamcinolone, methylprednisolone) are used in intra-articular injections. These form microcrystalline aggregates in solution, which require the patient’s own hydrolytic enzymes (esterases) to release the active moiety and thus have a longer duration of action. However, they are more commonly associated with postinjection flares compared with their more soluble and faster- acting counterparts (eg. dexamethasone, betamethasone).¹⁰ Microcrystalline aggregates, which are larger in size, induce a stronger inflammatory response, and in a dose-dependent manner.6A sterile inflammatory reaction to hydrocortisone, cortisone, dexamethasone, triamcinolone, and prednisolone crystals in normal joints has been previously described,6,12,13 and crystals of the various preparations have been demonstrated within leukocytes by both polarized light and electron microscopy.^12,13 Table 2 summarizes previous synovial fluid analyses after intra-articular injections of various corticosteroid preparations in normal healthy joints and in patients experiencing a postinjection flare. To date, there have been no reports of an immediate (<2 hours) and severe postinjection flare in response to triamcinolone acetonide, though there was a report of a postinjection flare in response to triamcinolone hexacetonide (Aristospan),⁷ and here the synovial fluid WBC count (30,000) was much lower.

Although many cases of corticosteroid hypersensitivity have been reported, in rare cases intra-articular administration of triamcinolone has caused anaphylactic reactions and shock.^14,15 Multiple case studies have determined that the specific excipient carboxymethylcellulose (found in many triamcinolone preparations), and not the corticosteroid itself, can cause an immunoglobulin E–mediated anaphylactic reaction.^16-18 Therefore, performing skin-prick tests for potential corticosteroids and their excipients in patients with known postinjection flares might help prevent serious adverse reactions.^18,19

The present case involved an extreme postinjection flare in response to intra-articular administration of triamcinolone acetonide. Postinjection flares are rare but significant events, and physicians using CSIs in the treatment of arthritis need to be aware of this potential reaction in order to appropriately inform patients of this risk and guide treatment should the scenario arise.

Intra-articular corticosteroid injections (CSIs) have been a common treatment for osteoarthritis since the 1950s and continue to be an option for patients who prefer nonoperative management.¹ Although CSIs may improve pain secondary to osteoarthritis temporarily, they do not slow articular cartilage degradation, and many patients request multiple CSIs before total joint arthroplasty ultimately is required.^1,2 Therefore, acute and chronic side effects of CSI must be considered when repeatedly administering corticosteroids.

A postinjection flare, the most common acute side effect of intra-articular CSI, is characterized by a localized inflammatory response that can last 2 to 3 days. The flare occurs in 2% to 25% of CSI cases.^3-5 Symptoms can range from mild joint effusion to disabling pain.⁶ In the present case, a severe postinjection flare occurred after intra-articular administration of triamcinolone acetonide (Kenalog). This case is novel in that its acuity of onset, severity of symptoms, and synovial fluid analysis mimicked septic arthritis, which was ultimately ruled out with negative cultures and confirmation of triamcinolone acetonide crystals in the synovial aspirate, viewed by polarized light microscopy. To date, only one other case of an immediate (<2 hours) and severe postinjection flare in response to triamcinolone has been reported.⁷ As CSIs are often used in the nonoperative treatment of osteoarthritis, it is imperative for the treating physician to be aware of this potential side effect in order to appropriately inform the patient of this risk and guide treatment should the scenario arise. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old woman with a history of hypertension, hypothyroidism, and moderate bilateral knee osteoarthritis presented with left knee pain. She had been receiving annual hylan injections for 5 years and had no adverse reactions, but the pain gradually worsened over the past 3 months. She was given an intra-articular injection of 2 mL of 1% lidocaine and 2 mL (40 mg) of triamcinolone acetonide in the left knee.

Two hours later, she experienced swelling and intense pain in the knee and was unable to ambulate. Physical examination revealed she was afebrile but was having severe pain in the knee through all range of motion. The knee had no appreciable erythema or warmth. Laboratory data were significant: White blood cell (WBC) count was 14,600, and erythrocyte sedimentation rate was 1 mm/h. The knee was aspirated with a return of 25 mL of “butterscotch”-colored fluid (Figure 1). The patient was admitted to rule out iatrogenic septic arthritis, or chronic, indolent septic arthritis acutely worsened by CSI, until synovial fluid analysis and cultures could be performed (Table 1).

She was treated overnight with a compressive wrap, elevation, ice, and nonsteroidal anti-inflammatory drugs, which provided significant pain relief. Polarized light microscopy revealed polymorphic intracellular and extracellular crystals with crystal morphology consistent with the injection of triamcinolone ester (Figure 2). Gram stain showed many WBCs but no organisms. These findings were thought to represent an exogenous crystal-induced acute inflammatory response. Given the patient’s improving clinical course, she was discharged the next morning.

Twelve days later, at clinic follow-up, she was still experiencing pain above her baseline level. Given the continued effusion, 8 mL of synovial fluid was aspirated, which appeared clear and only slightly blood-tinged. Synovial analysis showed resolution of leukocytosis, confirming a severe postinjection flare in response to triamcinolone acetonide.

Discussion

Although rare, side effects from repeated intra-articular CSIs include hypothalamic-pituitary-adrenal axis dysfunction and steroid-induced myopathy.^8,9 Acute side effects are more common and include postinjection flare, iatrogenic septic arthritis, local tissue atrophy, cartilage damage, tendon rupture, nerve atrophy, increased blood glucose, and osteonecrosis.^10,11 The present case report describes an extreme example of a postinjection flare in response to triamcinolone acetonide and summarizes the characteristics of injections that cause flares.

The physical properties of corticosteroids have a significant impact on their efficacy and on their potential for adverse events. Corticosteroid preparations can be water-soluble or water-insoluble. Most commonly, water-insoluble preparations that contain insoluble corticosteroid esters (eg, triamcinolone, methylprednisolone) are used in intra-articular injections. These form microcrystalline aggregates in solution, which require the patient’s own hydrolytic enzymes (esterases) to release the active moiety and thus have a longer duration of action. However, they are more commonly associated with postinjection flares compared with their more soluble and faster- acting counterparts (eg. dexamethasone, betamethasone).¹⁰ Microcrystalline aggregates, which are larger in size, induce a stronger inflammatory response, and in a dose-dependent manner.6A sterile inflammatory reaction to hydrocortisone, cortisone, dexamethasone, triamcinolone, and prednisolone crystals in normal joints has been previously described,6,12,13 and crystals of the various preparations have been demonstrated within leukocytes by both polarized light and electron microscopy.^12,13 Table 2 summarizes previous synovial fluid analyses after intra-articular injections of various corticosteroid preparations in normal healthy joints and in patients experiencing a postinjection flare. To date, there have been no reports of an immediate (<2 hours) and severe postinjection flare in response to triamcinolone acetonide, though there was a report of a postinjection flare in response to triamcinolone hexacetonide (Aristospan),⁷ and here the synovial fluid WBC count (30,000) was much lower.

Although many cases of corticosteroid hypersensitivity have been reported, in rare cases intra-articular administration of triamcinolone has caused anaphylactic reactions and shock.^14,15 Multiple case studies have determined that the specific excipient carboxymethylcellulose (found in many triamcinolone preparations), and not the corticosteroid itself, can cause an immunoglobulin E–mediated anaphylactic reaction.^16-18 Therefore, performing skin-prick tests for potential corticosteroids and their excipients in patients with known postinjection flares might help prevent serious adverse reactions.^18,19

The present case involved an extreme postinjection flare in response to intra-articular administration of triamcinolone acetonide. Postinjection flares are rare but significant events, and physicians using CSIs in the treatment of arthritis need to be aware of this potential reaction in order to appropriately inform patients of this risk and guide treatment should the scenario arise.

Intra-articular corticosteroid injections (CSIs) have been a common treatment for osteoarthritis since the 1950s and continue to be an option for patients who prefer nonoperative management.¹ Although CSIs may improve pain secondary to osteoarthritis temporarily, they do not slow articular cartilage degradation, and many patients request multiple CSIs before total joint arthroplasty ultimately is required.^1,2 Therefore, acute and chronic side effects of CSI must be considered when repeatedly administering corticosteroids.

A postinjection flare, the most common acute side effect of intra-articular CSI, is characterized by a localized inflammatory response that can last 2 to 3 days. The flare occurs in 2% to 25% of CSI cases.^3-5 Symptoms can range from mild joint effusion to disabling pain.⁶ In the present case, a severe postinjection flare occurred after intra-articular administration of triamcinolone acetonide (Kenalog). This case is novel in that its acuity of onset, severity of symptoms, and synovial fluid analysis mimicked septic arthritis, which was ultimately ruled out with negative cultures and confirmation of triamcinolone acetonide crystals in the synovial aspirate, viewed by polarized light microscopy. To date, only one other case of an immediate (<2 hours) and severe postinjection flare in response to triamcinolone has been reported.⁷ As CSIs are often used in the nonoperative treatment of osteoarthritis, it is imperative for the treating physician to be aware of this potential side effect in order to appropriately inform the patient of this risk and guide treatment should the scenario arise. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old woman with a history of hypertension, hypothyroidism, and moderate bilateral knee osteoarthritis presented with left knee pain. She had been receiving annual hylan injections for 5 years and had no adverse reactions, but the pain gradually worsened over the past 3 months. She was given an intra-articular injection of 2 mL of 1% lidocaine and 2 mL (40 mg) of triamcinolone acetonide in the left knee.

Two hours later, she experienced swelling and intense pain in the knee and was unable to ambulate. Physical examination revealed she was afebrile but was having severe pain in the knee through all range of motion. The knee had no appreciable erythema or warmth. Laboratory data were significant: White blood cell (WBC) count was 14,600, and erythrocyte sedimentation rate was 1 mm/h. The knee was aspirated with a return of 25 mL of “butterscotch”-colored fluid (Figure 1). The patient was admitted to rule out iatrogenic septic arthritis, or chronic, indolent septic arthritis acutely worsened by CSI, until synovial fluid analysis and cultures could be performed (Table 1).

She was treated overnight with a compressive wrap, elevation, ice, and nonsteroidal anti-inflammatory drugs, which provided significant pain relief. Polarized light microscopy revealed polymorphic intracellular and extracellular crystals with crystal morphology consistent with the injection of triamcinolone ester (Figure 2). Gram stain showed many WBCs but no organisms. These findings were thought to represent an exogenous crystal-induced acute inflammatory response. Given the patient’s improving clinical course, she was discharged the next morning.

Twelve days later, at clinic follow-up, she was still experiencing pain above her baseline level. Given the continued effusion, 8 mL of synovial fluid was aspirated, which appeared clear and only slightly blood-tinged. Synovial analysis showed resolution of leukocytosis, confirming a severe postinjection flare in response to triamcinolone acetonide.

Discussion

Although rare, side effects from repeated intra-articular CSIs include hypothalamic-pituitary-adrenal axis dysfunction and steroid-induced myopathy.^8,9 Acute side effects are more common and include postinjection flare, iatrogenic septic arthritis, local tissue atrophy, cartilage damage, tendon rupture, nerve atrophy, increased blood glucose, and osteonecrosis.^10,11 The present case report describes an extreme example of a postinjection flare in response to triamcinolone acetonide and summarizes the characteristics of injections that cause flares.

The physical properties of corticosteroids have a significant impact on their efficacy and on their potential for adverse events. Corticosteroid preparations can be water-soluble or water-insoluble. Most commonly, water-insoluble preparations that contain insoluble corticosteroid esters (eg, triamcinolone, methylprednisolone) are used in intra-articular injections. These form microcrystalline aggregates in solution, which require the patient’s own hydrolytic enzymes (esterases) to release the active moiety and thus have a longer duration of action. However, they are more commonly associated with postinjection flares compared with their more soluble and faster- acting counterparts (eg. dexamethasone, betamethasone).¹⁰ Microcrystalline aggregates, which are larger in size, induce a stronger inflammatory response, and in a dose-dependent manner.6A sterile inflammatory reaction to hydrocortisone, cortisone, dexamethasone, triamcinolone, and prednisolone crystals in normal joints has been previously described,6,12,13 and crystals of the various preparations have been demonstrated within leukocytes by both polarized light and electron microscopy.^12,13 Table 2 summarizes previous synovial fluid analyses after intra-articular injections of various corticosteroid preparations in normal healthy joints and in patients experiencing a postinjection flare. To date, there have been no reports of an immediate (<2 hours) and severe postinjection flare in response to triamcinolone acetonide, though there was a report of a postinjection flare in response to triamcinolone hexacetonide (Aristospan),⁷ and here the synovial fluid WBC count (30,000) was much lower.

Although many cases of corticosteroid hypersensitivity have been reported, in rare cases intra-articular administration of triamcinolone has caused anaphylactic reactions and shock.^14,15 Multiple case studies have determined that the specific excipient carboxymethylcellulose (found in many triamcinolone preparations), and not the corticosteroid itself, can cause an immunoglobulin E–mediated anaphylactic reaction.^16-18 Therefore, performing skin-prick tests for potential corticosteroids and their excipients in patients with known postinjection flares might help prevent serious adverse reactions.^18,19

The present case involved an extreme postinjection flare in response to intra-articular administration of triamcinolone acetonide. Postinjection flares are rare but significant events, and physicians using CSIs in the treatment of arthritis need to be aware of this potential reaction in order to appropriately inform patients of this risk and guide treatment should the scenario arise.