Clinical Care Conundrums

A 67‐year‐old male presented to an outside hospital with a 1‐day history of fevers up to 39.4C, bilateral upper extremity weakness, and confusion. Forty‐eight hours prior to his presentation he had undergone uncomplicated bilateral carpal tunnel release surgery for the complaint of bilateral upper extremity paresthesias.

Bilateral carpal tunnel syndrome should prompt consideration of systemic diseases that infiltrate or impinge both canals (eg, rheumatoid arthritis, acromegaly, hypothyroidism, amyloidosis), although it is most frequently explained by a bilateral repetitive stress (eg, workplace typing). The development of upper extremity weakness suggests that an alternative condition such as cervical myelopathy, bilateral radiculopathy, or a rapidly progressive peripheral neuropathy may be responsible for his paresthesias. It would be unusual for a central nervous system process to selectively cause bilateral upper extremity weakness. Occasionally, patients emerge from surgery with limb weakness caused by peripheral nerve injury sustained from malpositioning of the extremity, but this would have been evident immediately following the operation.

Postoperative fevers are frequently unexplained, but require a search for common healthcare‐associated infections, such as pneumonia, urinary tract infection, intravenous catheter thrombophlebitis, wound infection, or Clostridium difficile colitis. However, such complications are unlikely following an ambulatory procedure. Confusion and fever together point to a central nervous system infection (meningoencephalitis or brain abscess) or a systemic infection that has impaired cognition. Malignancies can cause fever and altered mental status, but these are typically asynchronous events.

His past medical history was notable for hypertension, dyslipidemia, gout, actinic keratosis, and gastroesophageal reflux. His surgical history included bilateral knee replacements, repair of a left rotator cuff injury, and a herniorrhaphy. He was a nonsmoker who consumed 4 to 6 beers daily. His medications included clonidine, colchicine, atorvastatin, extended release metoprolol, triamterene‐hydrochlorothiazide, probenecid, and as‐needed ibuprofen and omeprazole.

Upon presentation he was cooperative and in no distress. Temperature was 38.9C, pulse 119 beats per minute, blood pressure 140/90 mm Hg, and oxygen saturation 94% on room air. He was noted to have logical thinking but impaired concentration. His upper extremity movement was restricted because of postoperative discomfort and swelling rather than true weakness. The rest of the exam was normal.

Metabolic, infectious, structural (intracranial), and toxic disorders can cause altered mental status. His heavy alcohol use puts him at risk for alcohol withdrawal and infections (such as Listeria meningitis), both of which may explain his fever and altered mental status. Signs and symptoms of meningitis are absent at this time. His knee prostheses could have harbored an infection preoperatively and therefore warrant close examination. Patients sometimes have adverse reactions to medications they have been prescribed but are not exposed to until hospitalization, although his surgical procedure was likely done on an outpatient basis. Empiric thiamine should be administered early given his confusion and alcohol habits.

Basic laboratories revealed a hemoglobin of 11.2 g/dL, white blood cell (WBC) count of 6,900/mm³ with 75% neutrophils, platelets of 206,000/mm³. Mean corpuscular volume was 97 mm³. Serum albumin was 2.4 g/dl, sodium 134 mmol/L, potassium 3.9 mmol/L, blood urea nitrogen 12 mg/dL, and creatinine 0.9 mg/dL. The aspartate aminotransferase was 93 U/L, alanine aminotransferase 73 U/L, alkaline phosphatase 254 U/L, and total bilirubin 1.0 mg/dL. Urinalysis was normal. Over the next 16 days fevers and waxing and waning mentation continued. The following studies were normal or negative: blood and urine cultures; transthoracic echocardiogram, antinuclear antibodies, hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody; magnetic resonance imaging of the brain, electroencephalogram, and lower extremity venous ultrasound.

Hypoalbuminemia may signal chronic illness, hypoproduction from liver disease (caused by his heavy alcohol use), or losses from the kidney or gastrointestinal tract. His anemia may reflect chronic disease or point toward a specific underlying disorder. For example, fever and anemia could arise from hemolytic processes such as thrombotic thrombocytopenic purpura or clostridial infections.

An extensive workup has not revealed a cause for his prolonged fever (eg, infection, malignancy, autoimmune condition, or toxin). Likewise, an explanation for confusion is lacking. Because systemic illness and structural brain disease have not been uncovered, a lumbar puncture is indicated.

A lumbar puncture under fluoroscopic guidance revealed a cerebrospinal fluid (CSF) WBC count of 6/mm³, red blood cell count (RBC) 2255/mm³, protein 49 mg/dL, and glucose 54 mg/dL. The WBC differential was not reported. No growth was reported on bacterial cultures. Polymerase chain reactions for enterovirus and herpes simplex viruses 1 and 2 were negative. Cryptococcal antigen and Venereal Disease Research Laboratory serologies were also negative.

A CSF WBC count of 6 is out of the normal range, but could be explained by a traumatic tap given the elevated RBC; the protein and glucose are likewise at the border of normal. Collectively, these are nonspecific findings that could point to an infectious or noninfectious cause of intrathecal or paraspinous inflammation, but are not suggestive of bacterial meningitis.

The patient developed pneumonia, for which he received ertapenem. On hospital day 17 he was intubated for hypoxia and respiratory distress and was extubated after 4 days of mechanical ventilation. Increasing weakness in all extremities prompted magnetic resonance imaging of the spine, which revealed fluid and enhancement involving the soft tissues around C3‐C4 and C5‐C6, raising concerns for discitis and osteomyelitis. Possible septic arthritis at the C3‐C4 and C4‐C5 facets was noted. Ring enhancing fluid collections from T2‐T8 compatible with an epidural abscess with cord compression at T4‐T5 and T6‐T7 were seen. Enhancement and fluid involving the facet joints between T2‐T7 was also consistent with septic arthritis (Figure 1).

Figure 1

His pneumonia appears to have developed many days into his hospitalization, and therefore is unlikely to account for his initial fever and confusion. Blood cultures and echocardiogram have not suggested an endovascular infection that could account for such widespread vertebral and epidural deposition. A wide number of bacteria can cause epidural abscesses and septic arthritis, most commonly Staphylococcus aureus. Less common pathogens with a predilection for osteoarticular involvement, such as Brucella species, warrant consideration when there is appropriate epidemiologic risk.

Systemic bacterial infection remains a concern with his alcoholism rendering him partially immunosuppressed. However, a large number of adjacent spinal joints harboring a bacterial infection is unusual, and a working diagnosis of multilevel spinal infection, therefore, should prompt consideration of noninfectious processes. When a patient develops a swollen peripheral joint and fever in the postoperative setting, gout or pseudogout is a leading consideration. That same thinking should be applied to the vertebrae, where spinal gout can manifest. Surgery itself or associated changes in alcohol consumption patterns or changes in medications (at least 4 of which are relevant to goutcolchicine, hydrochlorothiazide, probenecid, and ibuprofen) could predispose him to a flare.

Aspiration of the epidural collection yielded a negative Gram stain and culture. He developed swelling in the bilateral proximal interphalangeal joints and was treated with steroids and colchicine for suspected gout flare. Vancomycin and piperacillin‐tazobactam were initiated, and on hospital day 22 the patient was transferred to another hospital for further evaluation by neurosurgery.

The negative Gram stain and culture argues against septic arthritis, but these are imperfect tests and will not detect atypical pathogens (eg, spinal tuberculosis). Reexamination of the aspirate for urate and calcium pyrophosphate crystals would be useful. Initiation of steroids in the setting of potentially undiagnosed infection requires a careful risk/benefit analysis. It may be reasonable to treat the patient with colchicine alone while withholding steroids and avoiding nonsteroidal agents in case invasive procedures are planned.

On exam his temperature was 36C, blood pressure 156/92 mm Hg, pulse 100 beats per minute, respirations 21 per minute, and oxygenation 97% on room air. He was not in acute distress and was only oriented to self. Bilateral 2+ lower extremity pitting edema up to the knees was noted. Examination of the heart and lungs was unremarkable. Gouty tophi were noted over both elbows. His joints were normal.

Cranial nerves IIXII were normal. Motor exam revealed normal muscle tone and bulk. Muscle strength was approximately 3/5 in the right upper extremity and 4+/5 in the left upper extremity. Bilateral lower extremity strength was 3/5 in hip flexion, knee flexion, and knee extension. Dorsiflexion and plantar flexion were approximately 2/5 bilaterally. Sensation was intact to light touch and pinprick, and proprioception was normal. Gait was not tested. A Foley catheter was in place.

This examination confirms ongoing encephalopathy and incomplete quadriplegia. The lower extremity weakness is nearly equal proximally and distally, which can be seen with an advanced peripheral neuropathy but is more characteristic of myelopathy. The expected concomitant sensory deficit of myelopathy is not present, although this may be difficult to detect in a confused patient. Reflex testing would help in distinguishing myelopathy (favored because of the imaging findings) from a rapid progressive peripheral motor neuropathy (eg, acute inflammatory demyelinating polyneuropathy or acute intermittent porphyria).

The pitting edema likely represents fluid overload, which can be nonspecific after prolonged immobility during hospitalization; hypoalbuminemia is oftentimes speculated to play a role when this develops. His alcohol use puts him at risk for heart failure (although there is no evidence of this on exam) and liver disease (which his liver function tests suggest). The tophi speak to the extent and chronicity of his hyperuricemia.

On arrival he reported recent onset diarrhea. Medications at transfer included metoprolol, omeprazole, prednisone, piperacillin/tazobactam, vancomycin, and colchicine; acetaminophen, bisacodyl, diphenhydramine, fentanyl, subcutaneous insulin, and labetalol were administered as needed. Laboratory studies included a hemoglobin of 9.5 g/dL, WBC count of 7,300/mm³ with 95% neutrophils, platelets 301,000/mm³, sodium 151 mmol/L, potassium 2.9 mmol/L, blood urea nitrogen 76 mg/dL, creatinine 2.0 mg/dL, aspartate aminotransferase 171 U/L, and alanine aminotransferase 127 U/L. Serum albumin was 1.7 g/dL.

At least 3 of his medicationsdiphenhydramine, fentanyl, and prednisonemay be contributing to his ongoing altered mental status, which may be further compounded by hypernatremia. Although his liver disease remains uncharacterized, hepatic encephalopathy may be contributing to his confusion as well.

Colchicine is likely responsible for his diarrhea, which would be the most readily available explanation for his hypernatremia, hypokalemia, and acute kidney injury (AKI). Acute kidney injury could result from progressive liver disease (hepatorenal syndrome), decreased arterial perfusion (suggested by third spacing or his diarrhea), acute tubular necrosis (from infection or medication), or urinary retention secondary to catheter obstruction. Acute hyperuricemia can also cause AKI (urate nephropathy).

Anemia has progressed and requires evaluation for blood loss as well as hemolysis. Hepatotoxicity from any of his medications (eg, acetaminophen) must be considered. Coagulation studies and review of the previous abdominal computed tomography would help determine the extent of his liver disease.

Neurosurgical consultation was obtained and the patient and his family elected to proceed with a thoracic laminectomy. Cheesy fluid was identified at the facet joints at T6‐T7, which was found to contain rare deposits of monosodium urate crystals. Surgical specimen cultures were sterile. His mental status and strength slowly improved to baseline following the surgery. He was discharged on postoperative day 7 to a rehabilitation facility. On the telephone follow‐up he reported that he has regained his strength completely.

The fluid analysis and clinical course confirms spinal gout. The presenting encephalopathy remains unexplained; I am unaware of gout leading to altered mental status.

COMMENTARY

Gout is an inflammatory condition triggered by the deposition of monosodium urate crystals in tissues in association with hyperuricemia.[1] Based on the 20072008 National Health and Nutrition Examination Survey, the prevalence of gout among US adults was 3.9% (8.3 million individuals).[2] These rates are increasing and are thought to be spurred by the aging population, increasing rates of obesity, and changing dietary habits including increases in the consumption of soft drinks and red meat.[3, 4, 5] The development of gout during hospitalization can prolong length of stay, and the implementation of a management protocol appears to help decrease treatment delays and the inappropriate discontinuation of gout prophylaxis.[6, 7] Surgery, with its associated physiologic stressors, can trigger gout, which is often polyarticular and presents with fever leading to testing and consultations for the febrile episode.[8]

Gout is an ancient disease that is familiar to most clinicians. In 1666, Daniel Sennert, a German physician, described gout as the physician's shame because of its infrequent recognition.[9] Clinical gout spans 3 stages: asymptomatic hyperuricemia, acute and intercritical gout, and chronic gouty arthritis. The typical acute presentation is monoarticular with the abrupt onset of pain, swelling, warmth, and erythema in a peripheral joint. It manifests most characteristically in the first metatarsophalangeal joint (podagra), but also frequently involves the midfoot, ankle, knee, and wrist and sometimes affects multiple joints simultaneously (polyarticular gout).[1, 10] The visualization of monosodium urate crystals either in synovial fluid or from a tophus is diagnostic of gout; however, guidelines recognize that a classic presentation of gout may be diagnosed based on clinical criteria alone.[11] Dual energy computerized tomography and ultrasonography are emerging as techniques for the visualization of monosodium urate crystals; however, they are not currently routinely recommended.[12]

There are many unusual presentations of gout, with an increase in such reports paralleling both the overall increase in the prevalence of gout and improvements in available imaging techniques.[13] Atypical presentations present diagnostic challenges and are often caused by tophaceous deposits in unusual locations. Reports of atypical gout have described entrapment neuropathies (eg, gouty deposits inducing carpal tunnel syndrome), ocular gout manifested as conjunctival deposits and uveitis, pancreatic gout presenting as a mass, and dermatologic manifestations including panniculitis.[13, 14]

Spinal gout (also known as axial gout) manifests when crystal‐induced inflammation, erosive arthritis, and tophaceous deposits occur along the spinal column. A cross‐sectional study of patients with poorly controlled gout reported the prevalence of spinal gout diagnosed by computerized tomography to be 35%. These radiographic findings were not consistently correlated with back pain.[15] Imaging features that are suggestive of spinal gout include intra‐articular and juxta‐articular erosions with sclerotic margins and density greater than the surrounding muscle. Periosteal new bone formation adjacent to bony destruction can form overhanging edges.[16] When retrospectively presented with the final diagnosis, the radiologist at our institution noted that the appearance was typical gout in an atypical location.

Spinal gout can be confused with spinal metastasis, infection, and stenosis. It can remain asymptomatic or present with back pain, radiculopathy, or cord compression. The lumbar spine is the most frequently affected site.[17, 18] Many patients with spinal gout have had chronic tophaceous gout with radiologic evidence of erosions in the peripheral joints.[15] Patients with spinal gout also have elevated urate levels and markers of inflammation.[18] Surgical decompression and stabilization is recommended when there is frank cord compression, progressive neurologic compromise, or lack of improvement with gout therapy alone.[18]

This patient's male gender, history of gout, hypertension, alcohol consumption, and thiazide diuretic use placed him at an increased risk of a gout attack.[19, 20] The possible interruption of urate‐lowering therapy for the surgical procedure and surgery itself further heightened his risk of suffering acute gouty arthritis in the perioperative period.[21] The patient's encephalopathy may have masked back pain and precluded an accurate neurologic exam. There is one case report to our knowledge describing encephalopathy that improved with colchicine and was possibly related to gout.[22] This patient's encephalopathy was deemed multifactorial and attributed to alcohol withdrawal, medications (including opioids and steroids), and infection (pneumonia).

Gout is best known for its peripheral arthritis and is rarely invoked in the consideration of spinal and myelopathic processes where more pressing competing diagnoses, such as infection and malignancy, are typically considered. In addition, when surgical specimens are submitted for examination for pathology in formaldehyde (rather than alcohol), monosodium urate crystals are dissolved and are thus difficult to identify in the specimen.

This case reminds us that gout remains a diagnostic challenge and should be considered in the differential of an inflammatory process. Recognition of the multifaceted nature of gout can allow for the earlier recognition and treatment of the less typical presentations of this ancient malady.

KEY TEACHING POINTS

1. Crystalline disease is a common cause of postoperative arthritis.
2. Gout (and pseudogout) should be considered in cases of focal inflammation (detected by examination or imaging) when the evidence or predisposition for infection is limited or nonexistent.
3. Spinal gout presents with back pain, radiculopathy, or cord compression and may be confused with spinal metastasis, infection, and stenosis.

A 67‐year‐old male presented to an outside hospital with a 1‐day history of fevers up to 39.4C, bilateral upper extremity weakness, and confusion. Forty‐eight hours prior to his presentation he had undergone uncomplicated bilateral carpal tunnel release surgery for the complaint of bilateral upper extremity paresthesias.

Bilateral carpal tunnel syndrome should prompt consideration of systemic diseases that infiltrate or impinge both canals (eg, rheumatoid arthritis, acromegaly, hypothyroidism, amyloidosis), although it is most frequently explained by a bilateral repetitive stress (eg, workplace typing). The development of upper extremity weakness suggests that an alternative condition such as cervical myelopathy, bilateral radiculopathy, or a rapidly progressive peripheral neuropathy may be responsible for his paresthesias. It would be unusual for a central nervous system process to selectively cause bilateral upper extremity weakness. Occasionally, patients emerge from surgery with limb weakness caused by peripheral nerve injury sustained from malpositioning of the extremity, but this would have been evident immediately following the operation.

Postoperative fevers are frequently unexplained, but require a search for common healthcare‐associated infections, such as pneumonia, urinary tract infection, intravenous catheter thrombophlebitis, wound infection, or Clostridium difficile colitis. However, such complications are unlikely following an ambulatory procedure. Confusion and fever together point to a central nervous system infection (meningoencephalitis or brain abscess) or a systemic infection that has impaired cognition. Malignancies can cause fever and altered mental status, but these are typically asynchronous events.

His past medical history was notable for hypertension, dyslipidemia, gout, actinic keratosis, and gastroesophageal reflux. His surgical history included bilateral knee replacements, repair of a left rotator cuff injury, and a herniorrhaphy. He was a nonsmoker who consumed 4 to 6 beers daily. His medications included clonidine, colchicine, atorvastatin, extended release metoprolol, triamterene‐hydrochlorothiazide, probenecid, and as‐needed ibuprofen and omeprazole.

Upon presentation he was cooperative and in no distress. Temperature was 38.9C, pulse 119 beats per minute, blood pressure 140/90 mm Hg, and oxygen saturation 94% on room air. He was noted to have logical thinking but impaired concentration. His upper extremity movement was restricted because of postoperative discomfort and swelling rather than true weakness. The rest of the exam was normal.

Metabolic, infectious, structural (intracranial), and toxic disorders can cause altered mental status. His heavy alcohol use puts him at risk for alcohol withdrawal and infections (such as Listeria meningitis), both of which may explain his fever and altered mental status. Signs and symptoms of meningitis are absent at this time. His knee prostheses could have harbored an infection preoperatively and therefore warrant close examination. Patients sometimes have adverse reactions to medications they have been prescribed but are not exposed to until hospitalization, although his surgical procedure was likely done on an outpatient basis. Empiric thiamine should be administered early given his confusion and alcohol habits.

Basic laboratories revealed a hemoglobin of 11.2 g/dL, white blood cell (WBC) count of 6,900/mm³ with 75% neutrophils, platelets of 206,000/mm³. Mean corpuscular volume was 97 mm³. Serum albumin was 2.4 g/dl, sodium 134 mmol/L, potassium 3.9 mmol/L, blood urea nitrogen 12 mg/dL, and creatinine 0.9 mg/dL. The aspartate aminotransferase was 93 U/L, alanine aminotransferase 73 U/L, alkaline phosphatase 254 U/L, and total bilirubin 1.0 mg/dL. Urinalysis was normal. Over the next 16 days fevers and waxing and waning mentation continued. The following studies were normal or negative: blood and urine cultures; transthoracic echocardiogram, antinuclear antibodies, hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody; magnetic resonance imaging of the brain, electroencephalogram, and lower extremity venous ultrasound.

Hypoalbuminemia may signal chronic illness, hypoproduction from liver disease (caused by his heavy alcohol use), or losses from the kidney or gastrointestinal tract. His anemia may reflect chronic disease or point toward a specific underlying disorder. For example, fever and anemia could arise from hemolytic processes such as thrombotic thrombocytopenic purpura or clostridial infections.

An extensive workup has not revealed a cause for his prolonged fever (eg, infection, malignancy, autoimmune condition, or toxin). Likewise, an explanation for confusion is lacking. Because systemic illness and structural brain disease have not been uncovered, a lumbar puncture is indicated.

A lumbar puncture under fluoroscopic guidance revealed a cerebrospinal fluid (CSF) WBC count of 6/mm³, red blood cell count (RBC) 2255/mm³, protein 49 mg/dL, and glucose 54 mg/dL. The WBC differential was not reported. No growth was reported on bacterial cultures. Polymerase chain reactions for enterovirus and herpes simplex viruses 1 and 2 were negative. Cryptococcal antigen and Venereal Disease Research Laboratory serologies were also negative.

A CSF WBC count of 6 is out of the normal range, but could be explained by a traumatic tap given the elevated RBC; the protein and glucose are likewise at the border of normal. Collectively, these are nonspecific findings that could point to an infectious or noninfectious cause of intrathecal or paraspinous inflammation, but are not suggestive of bacterial meningitis.

The patient developed pneumonia, for which he received ertapenem. On hospital day 17 he was intubated for hypoxia and respiratory distress and was extubated after 4 days of mechanical ventilation. Increasing weakness in all extremities prompted magnetic resonance imaging of the spine, which revealed fluid and enhancement involving the soft tissues around C3‐C4 and C5‐C6, raising concerns for discitis and osteomyelitis. Possible septic arthritis at the C3‐C4 and C4‐C5 facets was noted. Ring enhancing fluid collections from T2‐T8 compatible with an epidural abscess with cord compression at T4‐T5 and T6‐T7 were seen. Enhancement and fluid involving the facet joints between T2‐T7 was also consistent with septic arthritis (Figure 1).

Figure 1

His pneumonia appears to have developed many days into his hospitalization, and therefore is unlikely to account for his initial fever and confusion. Blood cultures and echocardiogram have not suggested an endovascular infection that could account for such widespread vertebral and epidural deposition. A wide number of bacteria can cause epidural abscesses and septic arthritis, most commonly Staphylococcus aureus. Less common pathogens with a predilection for osteoarticular involvement, such as Brucella species, warrant consideration when there is appropriate epidemiologic risk.

Systemic bacterial infection remains a concern with his alcoholism rendering him partially immunosuppressed. However, a large number of adjacent spinal joints harboring a bacterial infection is unusual, and a working diagnosis of multilevel spinal infection, therefore, should prompt consideration of noninfectious processes. When a patient develops a swollen peripheral joint and fever in the postoperative setting, gout or pseudogout is a leading consideration. That same thinking should be applied to the vertebrae, where spinal gout can manifest. Surgery itself or associated changes in alcohol consumption patterns or changes in medications (at least 4 of which are relevant to goutcolchicine, hydrochlorothiazide, probenecid, and ibuprofen) could predispose him to a flare.

Aspiration of the epidural collection yielded a negative Gram stain and culture. He developed swelling in the bilateral proximal interphalangeal joints and was treated with steroids and colchicine for suspected gout flare. Vancomycin and piperacillin‐tazobactam were initiated, and on hospital day 22 the patient was transferred to another hospital for further evaluation by neurosurgery.

The negative Gram stain and culture argues against septic arthritis, but these are imperfect tests and will not detect atypical pathogens (eg, spinal tuberculosis). Reexamination of the aspirate for urate and calcium pyrophosphate crystals would be useful. Initiation of steroids in the setting of potentially undiagnosed infection requires a careful risk/benefit analysis. It may be reasonable to treat the patient with colchicine alone while withholding steroids and avoiding nonsteroidal agents in case invasive procedures are planned.

On exam his temperature was 36C, blood pressure 156/92 mm Hg, pulse 100 beats per minute, respirations 21 per minute, and oxygenation 97% on room air. He was not in acute distress and was only oriented to self. Bilateral 2+ lower extremity pitting edema up to the knees was noted. Examination of the heart and lungs was unremarkable. Gouty tophi were noted over both elbows. His joints were normal.

Cranial nerves IIXII were normal. Motor exam revealed normal muscle tone and bulk. Muscle strength was approximately 3/5 in the right upper extremity and 4+/5 in the left upper extremity. Bilateral lower extremity strength was 3/5 in hip flexion, knee flexion, and knee extension. Dorsiflexion and plantar flexion were approximately 2/5 bilaterally. Sensation was intact to light touch and pinprick, and proprioception was normal. Gait was not tested. A Foley catheter was in place.

This examination confirms ongoing encephalopathy and incomplete quadriplegia. The lower extremity weakness is nearly equal proximally and distally, which can be seen with an advanced peripheral neuropathy but is more characteristic of myelopathy. The expected concomitant sensory deficit of myelopathy is not present, although this may be difficult to detect in a confused patient. Reflex testing would help in distinguishing myelopathy (favored because of the imaging findings) from a rapid progressive peripheral motor neuropathy (eg, acute inflammatory demyelinating polyneuropathy or acute intermittent porphyria).

The pitting edema likely represents fluid overload, which can be nonspecific after prolonged immobility during hospitalization; hypoalbuminemia is oftentimes speculated to play a role when this develops. His alcohol use puts him at risk for heart failure (although there is no evidence of this on exam) and liver disease (which his liver function tests suggest). The tophi speak to the extent and chronicity of his hyperuricemia.

On arrival he reported recent onset diarrhea. Medications at transfer included metoprolol, omeprazole, prednisone, piperacillin/tazobactam, vancomycin, and colchicine; acetaminophen, bisacodyl, diphenhydramine, fentanyl, subcutaneous insulin, and labetalol were administered as needed. Laboratory studies included a hemoglobin of 9.5 g/dL, WBC count of 7,300/mm³ with 95% neutrophils, platelets 301,000/mm³, sodium 151 mmol/L, potassium 2.9 mmol/L, blood urea nitrogen 76 mg/dL, creatinine 2.0 mg/dL, aspartate aminotransferase 171 U/L, and alanine aminotransferase 127 U/L. Serum albumin was 1.7 g/dL.

At least 3 of his medicationsdiphenhydramine, fentanyl, and prednisonemay be contributing to his ongoing altered mental status, which may be further compounded by hypernatremia. Although his liver disease remains uncharacterized, hepatic encephalopathy may be contributing to his confusion as well.

Colchicine is likely responsible for his diarrhea, which would be the most readily available explanation for his hypernatremia, hypokalemia, and acute kidney injury (AKI). Acute kidney injury could result from progressive liver disease (hepatorenal syndrome), decreased arterial perfusion (suggested by third spacing or his diarrhea), acute tubular necrosis (from infection or medication), or urinary retention secondary to catheter obstruction. Acute hyperuricemia can also cause AKI (urate nephropathy).

Anemia has progressed and requires evaluation for blood loss as well as hemolysis. Hepatotoxicity from any of his medications (eg, acetaminophen) must be considered. Coagulation studies and review of the previous abdominal computed tomography would help determine the extent of his liver disease.

Neurosurgical consultation was obtained and the patient and his family elected to proceed with a thoracic laminectomy. Cheesy fluid was identified at the facet joints at T6‐T7, which was found to contain rare deposits of monosodium urate crystals. Surgical specimen cultures were sterile. His mental status and strength slowly improved to baseline following the surgery. He was discharged on postoperative day 7 to a rehabilitation facility. On the telephone follow‐up he reported that he has regained his strength completely.

The fluid analysis and clinical course confirms spinal gout. The presenting encephalopathy remains unexplained; I am unaware of gout leading to altered mental status.

COMMENTARY

Gout is an inflammatory condition triggered by the deposition of monosodium urate crystals in tissues in association with hyperuricemia.[1] Based on the 20072008 National Health and Nutrition Examination Survey, the prevalence of gout among US adults was 3.9% (8.3 million individuals).[2] These rates are increasing and are thought to be spurred by the aging population, increasing rates of obesity, and changing dietary habits including increases in the consumption of soft drinks and red meat.[3, 4, 5] The development of gout during hospitalization can prolong length of stay, and the implementation of a management protocol appears to help decrease treatment delays and the inappropriate discontinuation of gout prophylaxis.[6, 7] Surgery, with its associated physiologic stressors, can trigger gout, which is often polyarticular and presents with fever leading to testing and consultations for the febrile episode.[8]

Gout is an ancient disease that is familiar to most clinicians. In 1666, Daniel Sennert, a German physician, described gout as the physician's shame because of its infrequent recognition.[9] Clinical gout spans 3 stages: asymptomatic hyperuricemia, acute and intercritical gout, and chronic gouty arthritis. The typical acute presentation is monoarticular with the abrupt onset of pain, swelling, warmth, and erythema in a peripheral joint. It manifests most characteristically in the first metatarsophalangeal joint (podagra), but also frequently involves the midfoot, ankle, knee, and wrist and sometimes affects multiple joints simultaneously (polyarticular gout).[1, 10] The visualization of monosodium urate crystals either in synovial fluid or from a tophus is diagnostic of gout; however, guidelines recognize that a classic presentation of gout may be diagnosed based on clinical criteria alone.[11] Dual energy computerized tomography and ultrasonography are emerging as techniques for the visualization of monosodium urate crystals; however, they are not currently routinely recommended.[12]

There are many unusual presentations of gout, with an increase in such reports paralleling both the overall increase in the prevalence of gout and improvements in available imaging techniques.[13] Atypical presentations present diagnostic challenges and are often caused by tophaceous deposits in unusual locations. Reports of atypical gout have described entrapment neuropathies (eg, gouty deposits inducing carpal tunnel syndrome), ocular gout manifested as conjunctival deposits and uveitis, pancreatic gout presenting as a mass, and dermatologic manifestations including panniculitis.[13, 14]

Spinal gout (also known as axial gout) manifests when crystal‐induced inflammation, erosive arthritis, and tophaceous deposits occur along the spinal column. A cross‐sectional study of patients with poorly controlled gout reported the prevalence of spinal gout diagnosed by computerized tomography to be 35%. These radiographic findings were not consistently correlated with back pain.[15] Imaging features that are suggestive of spinal gout include intra‐articular and juxta‐articular erosions with sclerotic margins and density greater than the surrounding muscle. Periosteal new bone formation adjacent to bony destruction can form overhanging edges.[16] When retrospectively presented with the final diagnosis, the radiologist at our institution noted that the appearance was typical gout in an atypical location.

Spinal gout can be confused with spinal metastasis, infection, and stenosis. It can remain asymptomatic or present with back pain, radiculopathy, or cord compression. The lumbar spine is the most frequently affected site.[17, 18] Many patients with spinal gout have had chronic tophaceous gout with radiologic evidence of erosions in the peripheral joints.[15] Patients with spinal gout also have elevated urate levels and markers of inflammation.[18] Surgical decompression and stabilization is recommended when there is frank cord compression, progressive neurologic compromise, or lack of improvement with gout therapy alone.[18]

This patient's male gender, history of gout, hypertension, alcohol consumption, and thiazide diuretic use placed him at an increased risk of a gout attack.[19, 20] The possible interruption of urate‐lowering therapy for the surgical procedure and surgery itself further heightened his risk of suffering acute gouty arthritis in the perioperative period.[21] The patient's encephalopathy may have masked back pain and precluded an accurate neurologic exam. There is one case report to our knowledge describing encephalopathy that improved with colchicine and was possibly related to gout.[22] This patient's encephalopathy was deemed multifactorial and attributed to alcohol withdrawal, medications (including opioids and steroids), and infection (pneumonia).

Gout is best known for its peripheral arthritis and is rarely invoked in the consideration of spinal and myelopathic processes where more pressing competing diagnoses, such as infection and malignancy, are typically considered. In addition, when surgical specimens are submitted for examination for pathology in formaldehyde (rather than alcohol), monosodium urate crystals are dissolved and are thus difficult to identify in the specimen.

This case reminds us that gout remains a diagnostic challenge and should be considered in the differential of an inflammatory process. Recognition of the multifaceted nature of gout can allow for the earlier recognition and treatment of the less typical presentations of this ancient malady.

KEY TEACHING POINTS

1. Crystalline disease is a common cause of postoperative arthritis.
2. Gout (and pseudogout) should be considered in cases of focal inflammation (detected by examination or imaging) when the evidence or predisposition for infection is limited or nonexistent.
3. Spinal gout presents with back pain, radiculopathy, or cord compression and may be confused with spinal metastasis, infection, and stenosis.

A 67‐year‐old male presented to an outside hospital with a 1‐day history of fevers up to 39.4C, bilateral upper extremity weakness, and confusion. Forty‐eight hours prior to his presentation he had undergone uncomplicated bilateral carpal tunnel release surgery for the complaint of bilateral upper extremity paresthesias.

Bilateral carpal tunnel syndrome should prompt consideration of systemic diseases that infiltrate or impinge both canals (eg, rheumatoid arthritis, acromegaly, hypothyroidism, amyloidosis), although it is most frequently explained by a bilateral repetitive stress (eg, workplace typing). The development of upper extremity weakness suggests that an alternative condition such as cervical myelopathy, bilateral radiculopathy, or a rapidly progressive peripheral neuropathy may be responsible for his paresthesias. It would be unusual for a central nervous system process to selectively cause bilateral upper extremity weakness. Occasionally, patients emerge from surgery with limb weakness caused by peripheral nerve injury sustained from malpositioning of the extremity, but this would have been evident immediately following the operation.

Postoperative fevers are frequently unexplained, but require a search for common healthcare‐associated infections, such as pneumonia, urinary tract infection, intravenous catheter thrombophlebitis, wound infection, or Clostridium difficile colitis. However, such complications are unlikely following an ambulatory procedure. Confusion and fever together point to a central nervous system infection (meningoencephalitis or brain abscess) or a systemic infection that has impaired cognition. Malignancies can cause fever and altered mental status, but these are typically asynchronous events.

His past medical history was notable for hypertension, dyslipidemia, gout, actinic keratosis, and gastroesophageal reflux. His surgical history included bilateral knee replacements, repair of a left rotator cuff injury, and a herniorrhaphy. He was a nonsmoker who consumed 4 to 6 beers daily. His medications included clonidine, colchicine, atorvastatin, extended release metoprolol, triamterene‐hydrochlorothiazide, probenecid, and as‐needed ibuprofen and omeprazole.

Upon presentation he was cooperative and in no distress. Temperature was 38.9C, pulse 119 beats per minute, blood pressure 140/90 mm Hg, and oxygen saturation 94% on room air. He was noted to have logical thinking but impaired concentration. His upper extremity movement was restricted because of postoperative discomfort and swelling rather than true weakness. The rest of the exam was normal.

Metabolic, infectious, structural (intracranial), and toxic disorders can cause altered mental status. His heavy alcohol use puts him at risk for alcohol withdrawal and infections (such as Listeria meningitis), both of which may explain his fever and altered mental status. Signs and symptoms of meningitis are absent at this time. His knee prostheses could have harbored an infection preoperatively and therefore warrant close examination. Patients sometimes have adverse reactions to medications they have been prescribed but are not exposed to until hospitalization, although his surgical procedure was likely done on an outpatient basis. Empiric thiamine should be administered early given his confusion and alcohol habits.

Basic laboratories revealed a hemoglobin of 11.2 g/dL, white blood cell (WBC) count of 6,900/mm³ with 75% neutrophils, platelets of 206,000/mm³. Mean corpuscular volume was 97 mm³. Serum albumin was 2.4 g/dl, sodium 134 mmol/L, potassium 3.9 mmol/L, blood urea nitrogen 12 mg/dL, and creatinine 0.9 mg/dL. The aspartate aminotransferase was 93 U/L, alanine aminotransferase 73 U/L, alkaline phosphatase 254 U/L, and total bilirubin 1.0 mg/dL. Urinalysis was normal. Over the next 16 days fevers and waxing and waning mentation continued. The following studies were normal or negative: blood and urine cultures; transthoracic echocardiogram, antinuclear antibodies, hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody; magnetic resonance imaging of the brain, electroencephalogram, and lower extremity venous ultrasound.

Hypoalbuminemia may signal chronic illness, hypoproduction from liver disease (caused by his heavy alcohol use), or losses from the kidney or gastrointestinal tract. His anemia may reflect chronic disease or point toward a specific underlying disorder. For example, fever and anemia could arise from hemolytic processes such as thrombotic thrombocytopenic purpura or clostridial infections.

An extensive workup has not revealed a cause for his prolonged fever (eg, infection, malignancy, autoimmune condition, or toxin). Likewise, an explanation for confusion is lacking. Because systemic illness and structural brain disease have not been uncovered, a lumbar puncture is indicated.

A lumbar puncture under fluoroscopic guidance revealed a cerebrospinal fluid (CSF) WBC count of 6/mm³, red blood cell count (RBC) 2255/mm³, protein 49 mg/dL, and glucose 54 mg/dL. The WBC differential was not reported. No growth was reported on bacterial cultures. Polymerase chain reactions for enterovirus and herpes simplex viruses 1 and 2 were negative. Cryptococcal antigen and Venereal Disease Research Laboratory serologies were also negative.

A CSF WBC count of 6 is out of the normal range, but could be explained by a traumatic tap given the elevated RBC; the protein and glucose are likewise at the border of normal. Collectively, these are nonspecific findings that could point to an infectious or noninfectious cause of intrathecal or paraspinous inflammation, but are not suggestive of bacterial meningitis.

The patient developed pneumonia, for which he received ertapenem. On hospital day 17 he was intubated for hypoxia and respiratory distress and was extubated after 4 days of mechanical ventilation. Increasing weakness in all extremities prompted magnetic resonance imaging of the spine, which revealed fluid and enhancement involving the soft tissues around C3‐C4 and C5‐C6, raising concerns for discitis and osteomyelitis. Possible septic arthritis at the C3‐C4 and C4‐C5 facets was noted. Ring enhancing fluid collections from T2‐T8 compatible with an epidural abscess with cord compression at T4‐T5 and T6‐T7 were seen. Enhancement and fluid involving the facet joints between T2‐T7 was also consistent with septic arthritis (Figure 1).

Figure 1

His pneumonia appears to have developed many days into his hospitalization, and therefore is unlikely to account for his initial fever and confusion. Blood cultures and echocardiogram have not suggested an endovascular infection that could account for such widespread vertebral and epidural deposition. A wide number of bacteria can cause epidural abscesses and septic arthritis, most commonly Staphylococcus aureus. Less common pathogens with a predilection for osteoarticular involvement, such as Brucella species, warrant consideration when there is appropriate epidemiologic risk.

Systemic bacterial infection remains a concern with his alcoholism rendering him partially immunosuppressed. However, a large number of adjacent spinal joints harboring a bacterial infection is unusual, and a working diagnosis of multilevel spinal infection, therefore, should prompt consideration of noninfectious processes. When a patient develops a swollen peripheral joint and fever in the postoperative setting, gout or pseudogout is a leading consideration. That same thinking should be applied to the vertebrae, where spinal gout can manifest. Surgery itself or associated changes in alcohol consumption patterns or changes in medications (at least 4 of which are relevant to goutcolchicine, hydrochlorothiazide, probenecid, and ibuprofen) could predispose him to a flare.

Aspiration of the epidural collection yielded a negative Gram stain and culture. He developed swelling in the bilateral proximal interphalangeal joints and was treated with steroids and colchicine for suspected gout flare. Vancomycin and piperacillin‐tazobactam were initiated, and on hospital day 22 the patient was transferred to another hospital for further evaluation by neurosurgery.

The negative Gram stain and culture argues against septic arthritis, but these are imperfect tests and will not detect atypical pathogens (eg, spinal tuberculosis). Reexamination of the aspirate for urate and calcium pyrophosphate crystals would be useful. Initiation of steroids in the setting of potentially undiagnosed infection requires a careful risk/benefit analysis. It may be reasonable to treat the patient with colchicine alone while withholding steroids and avoiding nonsteroidal agents in case invasive procedures are planned.

On exam his temperature was 36C, blood pressure 156/92 mm Hg, pulse 100 beats per minute, respirations 21 per minute, and oxygenation 97% on room air. He was not in acute distress and was only oriented to self. Bilateral 2+ lower extremity pitting edema up to the knees was noted. Examination of the heart and lungs was unremarkable. Gouty tophi were noted over both elbows. His joints were normal.

Cranial nerves IIXII were normal. Motor exam revealed normal muscle tone and bulk. Muscle strength was approximately 3/5 in the right upper extremity and 4+/5 in the left upper extremity. Bilateral lower extremity strength was 3/5 in hip flexion, knee flexion, and knee extension. Dorsiflexion and plantar flexion were approximately 2/5 bilaterally. Sensation was intact to light touch and pinprick, and proprioception was normal. Gait was not tested. A Foley catheter was in place.

This examination confirms ongoing encephalopathy and incomplete quadriplegia. The lower extremity weakness is nearly equal proximally and distally, which can be seen with an advanced peripheral neuropathy but is more characteristic of myelopathy. The expected concomitant sensory deficit of myelopathy is not present, although this may be difficult to detect in a confused patient. Reflex testing would help in distinguishing myelopathy (favored because of the imaging findings) from a rapid progressive peripheral motor neuropathy (eg, acute inflammatory demyelinating polyneuropathy or acute intermittent porphyria).

The pitting edema likely represents fluid overload, which can be nonspecific after prolonged immobility during hospitalization; hypoalbuminemia is oftentimes speculated to play a role when this develops. His alcohol use puts him at risk for heart failure (although there is no evidence of this on exam) and liver disease (which his liver function tests suggest). The tophi speak to the extent and chronicity of his hyperuricemia.

On arrival he reported recent onset diarrhea. Medications at transfer included metoprolol, omeprazole, prednisone, piperacillin/tazobactam, vancomycin, and colchicine; acetaminophen, bisacodyl, diphenhydramine, fentanyl, subcutaneous insulin, and labetalol were administered as needed. Laboratory studies included a hemoglobin of 9.5 g/dL, WBC count of 7,300/mm³ with 95% neutrophils, platelets 301,000/mm³, sodium 151 mmol/L, potassium 2.9 mmol/L, blood urea nitrogen 76 mg/dL, creatinine 2.0 mg/dL, aspartate aminotransferase 171 U/L, and alanine aminotransferase 127 U/L. Serum albumin was 1.7 g/dL.

At least 3 of his medicationsdiphenhydramine, fentanyl, and prednisonemay be contributing to his ongoing altered mental status, which may be further compounded by hypernatremia. Although his liver disease remains uncharacterized, hepatic encephalopathy may be contributing to his confusion as well.

Colchicine is likely responsible for his diarrhea, which would be the most readily available explanation for his hypernatremia, hypokalemia, and acute kidney injury (AKI). Acute kidney injury could result from progressive liver disease (hepatorenal syndrome), decreased arterial perfusion (suggested by third spacing or his diarrhea), acute tubular necrosis (from infection or medication), or urinary retention secondary to catheter obstruction. Acute hyperuricemia can also cause AKI (urate nephropathy).

Anemia has progressed and requires evaluation for blood loss as well as hemolysis. Hepatotoxicity from any of his medications (eg, acetaminophen) must be considered. Coagulation studies and review of the previous abdominal computed tomography would help determine the extent of his liver disease.

Neurosurgical consultation was obtained and the patient and his family elected to proceed with a thoracic laminectomy. Cheesy fluid was identified at the facet joints at T6‐T7, which was found to contain rare deposits of monosodium urate crystals. Surgical specimen cultures were sterile. His mental status and strength slowly improved to baseline following the surgery. He was discharged on postoperative day 7 to a rehabilitation facility. On the telephone follow‐up he reported that he has regained his strength completely.

The fluid analysis and clinical course confirms spinal gout. The presenting encephalopathy remains unexplained; I am unaware of gout leading to altered mental status.

COMMENTARY

Gout is an inflammatory condition triggered by the deposition of monosodium urate crystals in tissues in association with hyperuricemia.[1] Based on the 20072008 National Health and Nutrition Examination Survey, the prevalence of gout among US adults was 3.9% (8.3 million individuals).[2] These rates are increasing and are thought to be spurred by the aging population, increasing rates of obesity, and changing dietary habits including increases in the consumption of soft drinks and red meat.[3, 4, 5] The development of gout during hospitalization can prolong length of stay, and the implementation of a management protocol appears to help decrease treatment delays and the inappropriate discontinuation of gout prophylaxis.[6, 7] Surgery, with its associated physiologic stressors, can trigger gout, which is often polyarticular and presents with fever leading to testing and consultations for the febrile episode.[8]

Gout is an ancient disease that is familiar to most clinicians. In 1666, Daniel Sennert, a German physician, described gout as the physician's shame because of its infrequent recognition.[9] Clinical gout spans 3 stages: asymptomatic hyperuricemia, acute and intercritical gout, and chronic gouty arthritis. The typical acute presentation is monoarticular with the abrupt onset of pain, swelling, warmth, and erythema in a peripheral joint. It manifests most characteristically in the first metatarsophalangeal joint (podagra), but also frequently involves the midfoot, ankle, knee, and wrist and sometimes affects multiple joints simultaneously (polyarticular gout).[1, 10] The visualization of monosodium urate crystals either in synovial fluid or from a tophus is diagnostic of gout; however, guidelines recognize that a classic presentation of gout may be diagnosed based on clinical criteria alone.[11] Dual energy computerized tomography and ultrasonography are emerging as techniques for the visualization of monosodium urate crystals; however, they are not currently routinely recommended.[12]

There are many unusual presentations of gout, with an increase in such reports paralleling both the overall increase in the prevalence of gout and improvements in available imaging techniques.[13] Atypical presentations present diagnostic challenges and are often caused by tophaceous deposits in unusual locations. Reports of atypical gout have described entrapment neuropathies (eg, gouty deposits inducing carpal tunnel syndrome), ocular gout manifested as conjunctival deposits and uveitis, pancreatic gout presenting as a mass, and dermatologic manifestations including panniculitis.[13, 14]

Spinal gout (also known as axial gout) manifests when crystal‐induced inflammation, erosive arthritis, and tophaceous deposits occur along the spinal column. A cross‐sectional study of patients with poorly controlled gout reported the prevalence of spinal gout diagnosed by computerized tomography to be 35%. These radiographic findings were not consistently correlated with back pain.[15] Imaging features that are suggestive of spinal gout include intra‐articular and juxta‐articular erosions with sclerotic margins and density greater than the surrounding muscle. Periosteal new bone formation adjacent to bony destruction can form overhanging edges.[16] When retrospectively presented with the final diagnosis, the radiologist at our institution noted that the appearance was typical gout in an atypical location.

Spinal gout can be confused with spinal metastasis, infection, and stenosis. It can remain asymptomatic or present with back pain, radiculopathy, or cord compression. The lumbar spine is the most frequently affected site.[17, 18] Many patients with spinal gout have had chronic tophaceous gout with radiologic evidence of erosions in the peripheral joints.[15] Patients with spinal gout also have elevated urate levels and markers of inflammation.[18] Surgical decompression and stabilization is recommended when there is frank cord compression, progressive neurologic compromise, or lack of improvement with gout therapy alone.[18]

This patient's male gender, history of gout, hypertension, alcohol consumption, and thiazide diuretic use placed him at an increased risk of a gout attack.[19, 20] The possible interruption of urate‐lowering therapy for the surgical procedure and surgery itself further heightened his risk of suffering acute gouty arthritis in the perioperative period.[21] The patient's encephalopathy may have masked back pain and precluded an accurate neurologic exam. There is one case report to our knowledge describing encephalopathy that improved with colchicine and was possibly related to gout.[22] This patient's encephalopathy was deemed multifactorial and attributed to alcohol withdrawal, medications (including opioids and steroids), and infection (pneumonia).

Gout is best known for its peripheral arthritis and is rarely invoked in the consideration of spinal and myelopathic processes where more pressing competing diagnoses, such as infection and malignancy, are typically considered. In addition, when surgical specimens are submitted for examination for pathology in formaldehyde (rather than alcohol), monosodium urate crystals are dissolved and are thus difficult to identify in the specimen.

This case reminds us that gout remains a diagnostic challenge and should be considered in the differential of an inflammatory process. Recognition of the multifaceted nature of gout can allow for the earlier recognition and treatment of the less typical presentations of this ancient malady.

KEY TEACHING POINTS

1. Crystalline disease is a common cause of postoperative arthritis.
2. Gout (and pseudogout) should be considered in cases of focal inflammation (detected by examination or imaging) when the evidence or predisposition for infection is limited or nonexistent.
3. Spinal gout presents with back pain, radiculopathy, or cord compression and may be confused with spinal metastasis, infection, and stenosis.

A 51‐year‐old man presented with severe pain and swelling in the lower anterior right thigh. He stated that the symptoms limited his movement, and began 4 days prior to this presentation. He rated the pain severity a 10 on a 10‐point scale. He denied fevers, chills, or history of trauma or weight loss.

Cellulitis of the lower extremity is the most likely possibility, but the presence of severe pain and swelling of an extremity in the absence of trauma should always make the clinician consider deep‐seated infections such as myositis or necrotizing fasciitis. An early clue for necrotizing fasciitis is severe pain that is disproportionate to the physical examination findings. Erythema, bullous lesions, or crepitus can develop later in the course. The absence of fever and chills also raises the possibility of noninfectious causes such as unrecognized trauma, deep vein thrombosis, or tumor.

The patient had a 15‐year history of type 2 diabetes complicated by end‐stage renal disease secondary to diabetic nephropathy for which he had been on hemodialysis for 5 months, proliferative diabetic retinopathy that rendered him legally blind, hypertension, and anemia. He stated that his diabetes had been poorly controlled, especially after he started dialysis.

A history of poorly controlled diabetes mellitus certainly increases the risk of the infectious disorders mentioned above. The patient's long‐standing history of diabetes mellitus with secondary nephropathy and retinopathy puts him at higher risk of atherosclerosis and vascular insufficiency, which consequently increase his risk for ischemic myonecrosis. Diabetic amyotrophy (diabetic lumbosacral plexopathy) is also a possibility, as it usually manifests with acute, unilateral, and focal tenderness followed by weakness involving a proximal leg. However, it typically occurs in patients who have been recently diagnosed with type 2 diabetes mellitus or whose disease has been under fairly good control and usually is associated with significant weight loss.

The patient was on oral medications for his diabetes until 1year before his presentation, at which point he was switched to insulin therapy. His other medications were amlodipine, lisinopril, aspirin, sevelamer, calcitriol, and calcium and iron supplements. He denied using alcohol, tobacco, or illicit drugs. He lives in Chicago and denies a recent travel history. His family history was significant for type 2 diabetes in multiple family members.

The absence of drugs, tobacco, and alcohol lowers the risk of some infectious and ischemic conditions. Patients with alcoholic liver disease who live in the southern United States are predisposed to developing Vibrio vulnificus myositis and fasciitis after ingesting contaminated oysters during the summer months. However, the clinical presentation of Vibrio usually includes septic shock and bullous lesions on the lower extremity. Also, the patient denies any recent travel to the southern United States, which makes Vibrio myositis and fasciitis less likely. Tobacco abuse increases the risk of atherosclerosis, peripheral vascular insufficiency, and ischemic myonecrosis.

The patient had a temperature of 99.1F, blood pressure of 139/85 mm Hg, pulse of 97 beats/minute, and respiratory rate of 18 breaths/minute. His body mass index was 31 kg/m². Physical examination revealed a firm, warm, severely tender area of swelling in the inferomedial aspect of the right thigh. The knee was also swollen, and effusion could not be ruled out. The range of motion of the knee was markedly limited by pain. The skin overlying the swelling was erythematous but not broken. No crepitus was noted. The strength of the right lower extremity muscles could not be accurately assessed because of the patient's excruciating pain, but the patient was able to move his foot and toes against gravity. Sensation was absent in most of the tested points in the feet but was normal in the legs. The deep tendon reflexes in both ankles were normal. The pedal pulses were mildly decreased in both feet. He also had extremely decreased visual acuity, which has been chronic. The rest of the physical examination was unremarkable.

The absence of fever does not rule out a serious infection in a diabetic patient but does raise the possibility of a noninfectious cause. Also, over‐the‐counter acetaminophen or nonsteroidal anti‐inflammatory drugs could mask a fever. The patient's physical examination was significant for obesity, a risk factor for developing deep‐seated infections, and a firm and severely tender area of swelling near the right knee that limited range of motion. Septic arthritis of the knee is one possibility; arthrocentesis should be performed as soon as possible. The absence of crepitus, because it is a late physical examination finding, does not rule out myositis or necrotizing fasciitis. The presence of unilateral lower extremity swelling also raises the suspicion for a deep vein thrombosis, which warrants compression ultrasonography. The localized tenderness and the lack of dermatological manifestations, such as Gottron's papules, makes an inflammatory myositis such as dermatomyositis much less likely.

Laboratory studies demonstrated a hemoglobin A1C of 13.0% (reference range, 4.36.1%), fasting blood glucose level of 224 mg/dL (reference range, 7099 mg/dL), white blood cell count of 8300 cells/mm³ (reference range, 450011,000 cells/mm³) without band forms, erythrocyte sedimentation rate of 81 mm/hr (reference range, <14 mm/hr), and creatinine kinase level of 582 IU/L (reference range, 30200 IU/L). Routine chemistries were normal otherwise. An x‐ray of the right knee revealed soft tissue edema. The right knee was aspirated, and fluid analysis revealed a white blood cell count of 106 cells/mm³ (reference range, <200 cell/mm³). Compression ultrasonography of the right lower extremity did not reveal thrombosis.

Poor glycemic control, as evidenced by a high hemoglobin A1C level, is associated with a higher probability of infectious complications. An elevated sedimentation rate is compatible with an infection, and an increased creatinine kinase intensifies suspicion of myositis or myonecrosis. A normal white blood cell count decreases, but does not eliminate, the likelihood of a serious bacterial infection. The fluid analysis rules out septic arthritis, and the compression ultrasonography findings make deep vein thrombosis very unlikely. However, the differential diagnosis still includes myositis, clostridial myonecrosis, cellulitis, and necrotizing fasciitis. The patient should undergo magnetic resonance imaging (MRI) of the lower extremity, and a surgical consultation should be obtained to consider the possibility of surgical exploration.

Blood and the aspirated fluids were sent for culturing, and the patient was started on empiric antibiotics. MRI of his right thigh revealed extensive edema involving the vastus medialis and lateralis of the quadriceps as well as subcutaneous edema without fascial enhancement or gas (Figure 1).

Figure 1

The absence of gas and fascial enhancement makes clostridial myonecrosis or necrotizing fasciitis less likely. The absence of a fluid collection in the muscle makes pyomyositis due to Staphylococci unlikely. Broad‐spectrum antibiotic coverage (usually vancomycin and either piperacillin/tazobactam or a carbapenem) targeting methicillin‐resistant Staphylococcus aureus, anaerobes, Streptococci, and Enterobacteriaceae should be empirically started as soon as cultures are obtained. Clindamycin should be part of the empiric antibiotic regimen to block toxin production in the event that Streptococcus pyogenes is responsible.

Surgical biopsy of the right vastus medialis muscle was performed, and tissue was sent for Gram staining, culture, and routine histopathological analysis. Gram staining was negative, and histopathological analysis revealed ischemic skeletal muscle fibers with areas of necrosis (Figure 2). Cultures from blood, fluid from the right knee, and muscular tissue samples did not grow any bacteria.

Figure 2

The muscle biopsy results are consistent with myonecrosis. Clostridial myonecrosis is possible but usually is associated with gas in tissues or occurs in the setting of intra‐abdominal pathology or severe trauma, and tissue culture was negative. Ischemic myonecrosis due to severe vascular insufficiency would be unlikely given the presence of pedal pulses and the absence of toes or forefoot cyanosis. A vasculitis syndrome is also unlikely because of the focal nature of the findings and the absence of weight loss, muscle weakness, and chronic joint pain in the patient's history. Calciphylaxis (calcific uremic arteriolopathy) might be considered in a patient with end‐stage renal disease who presents with a thigh pain; however, this condition is usually characterized by areas of ischemic necrosis that develop in the dermis and/or subcutaneous fat and infrequently involve muscles. The absence of the painful subcutaneous nodules typical of calciphylaxis makes it an unlikely diagnosis.

A diagnosis of diabetic myonecrosis was made. Antibiotics were discontinued, and the patient was treated symptomatically. His symptoms improved during the next few days. The patient was discharged from the hospital, and conservative management with bed rest and analgesics for 4 weeks was prescribed. Four months later, however, the patient returned with similar symptoms in the contralateral thigh. The patient was diagnosed with recurrent diabetic myonecrosis by MRI and muscle biopsy findings. Conservative management was advised, and the patient became pain‐free in a few weeks.

DISCUSSION

Diabetic myonecrosis (also known as diabetic muscle infarction) is a rare disorder initially described in 1965[1] that typically presents spontaneously as an acute, localized, severely painful swelling that limits the mobility of the affected extremity, usually without systemic signs of infection. It affects the thighs in 83% of patients and the calves in 17% of patients.[2, 3] Bilateral involvement, which is usually asynchronous, occurs in one‐third of patients.[4] The upper limbs are rarely involved. Diabetic myonecrosis affects patients who have a relatively longstanding history of diabetes. It is commonly associated with the microvascular complications of diabetes, including nephropathy (80% of patients), retinopathy (60% of patents), and/or neuropathy (64% of patients).[3, 5] The pathogenesis of diabetic myonecrosis is unclear, but the disease is likely due to a diffuse microangiopathy and atherosclerosis.[2, 5] Some authors have suggested that abnormalities in the clotting or fibrinolytic pathways play a role in the etiology of the disorder.[6]

Clinical and MRI findings can be used to make the diagnosis with reasonable certainty.[3, 5] Although both ultrasonography and MRI have been used to assess patients with diabetic myonecrosis, MRI with intravenous contrast enhancement appears to be the most useful diagnostic technique. It demonstrates extensive edema within the muscle(s), muscle enlargement, subcutaneous and interfascial edema, a patchwork pattern of involvement, and a high signal intensity on T2‐weighted images.[4, 7] Gadolinium enhancement may reveal an enhanced margin of the infarcted muscle with a central nonenhancing area of necrotic tissue.[4, 5] Muscle biopsy is not typically indicated because it may prolong recovery time and lead to infections.[8, 9, 10, 11] When performed, however, muscle biopsy reveals ischemic muscle fibers in different stages of degeneration and regeneration, with areas of necrosis and edema. Occlusion of arterioles and capillaries by fibrin could also be seen.[1] Although the patient underwent a muscle biopsy because infection could not be excluded definitively on clinical grounds, we believe that repeating the biopsy 4 months later was inappropriate.

Diabetic myonecrosis should be considered in a diabetic patient who presents with severe localized muscle pain and swelling of an extremity, especially if the clinical features favoring infection are absent. The differential diagnosis should include infection (eg, clostridial myonecrosis, myositis, cellulitis, abscess, necrotizing fasciitis, osteomyelitis), trauma (eg, hematoma, muscle rupture, myositis ossificans), peripheral neuropathy (particularly lumbosacral plexopathy), vascular disorders (deep vein thrombosis, and compartment syndrome), tumors, inflammatory muscle diseases, and drug‐related myositis.

No evidence‐based recommendations regarding the management of diabetic myonecrosis are available, although the findings of one retrospective analysis support conservative management with bed rest, leg elevation, and analgesics.[12] Physiotherapy may cause the condition to worsen,[13, 14] but routine daily activity, although often painful, is not harmful.[14] Some authors suggest a cautious use of antiplatelet or anti‐inflammatory medications.[12] We would also recommend achieving good glycemic control during the illness. Owing to the rarity of the disease, however, no studies have definitively shown that this hastens recovery or prevents recurrent diabetic myonecrosis. Surgery may prolong the recovery period; one study found that the recovery period of patients with diabetic myonecrosis who underwent surgery was longer than that of those who were treated conservatively (13 weeks vs 5.5 weeks).[12] Patients with diabetic myonecrosis have a good short‐term prognosis. Longer‐term, however, they have a poor prognosis; their recurrence rate is as high as 40%, and their 2‐year mortality rate is 10%, even after one episode of the disease. Death in these patients is mainly due to macrovascular events.[12]

TEACHING POINTS

1. Diabetic myonecrosis is a rare complication of longstanding and poorly controlled diabetes. It usually presents with acute localized muscular pain in the lower extremities.
2. Although a definitive diagnosis of diabetic myonecrosis is histopathologic, a clinical diagnosis can be made with reasonable certainty for patients with compatible MRI findings and no clinical or laboratory features suggesting infection.
3. Conservative management with bed rest, analgesics, and antiplatelets is recommended. Surgery should be avoided, as it may prolong recovery.

Disclosure

Nothing to report.

A 51‐year‐old man presented with severe pain and swelling in the lower anterior right thigh. He stated that the symptoms limited his movement, and began 4 days prior to this presentation. He rated the pain severity a 10 on a 10‐point scale. He denied fevers, chills, or history of trauma or weight loss.

Cellulitis of the lower extremity is the most likely possibility, but the presence of severe pain and swelling of an extremity in the absence of trauma should always make the clinician consider deep‐seated infections such as myositis or necrotizing fasciitis. An early clue for necrotizing fasciitis is severe pain that is disproportionate to the physical examination findings. Erythema, bullous lesions, or crepitus can develop later in the course. The absence of fever and chills also raises the possibility of noninfectious causes such as unrecognized trauma, deep vein thrombosis, or tumor.

The patient had a 15‐year history of type 2 diabetes complicated by end‐stage renal disease secondary to diabetic nephropathy for which he had been on hemodialysis for 5 months, proliferative diabetic retinopathy that rendered him legally blind, hypertension, and anemia. He stated that his diabetes had been poorly controlled, especially after he started dialysis.

A history of poorly controlled diabetes mellitus certainly increases the risk of the infectious disorders mentioned above. The patient's long‐standing history of diabetes mellitus with secondary nephropathy and retinopathy puts him at higher risk of atherosclerosis and vascular insufficiency, which consequently increase his risk for ischemic myonecrosis. Diabetic amyotrophy (diabetic lumbosacral plexopathy) is also a possibility, as it usually manifests with acute, unilateral, and focal tenderness followed by weakness involving a proximal leg. However, it typically occurs in patients who have been recently diagnosed with type 2 diabetes mellitus or whose disease has been under fairly good control and usually is associated with significant weight loss.

The patient was on oral medications for his diabetes until 1year before his presentation, at which point he was switched to insulin therapy. His other medications were amlodipine, lisinopril, aspirin, sevelamer, calcitriol, and calcium and iron supplements. He denied using alcohol, tobacco, or illicit drugs. He lives in Chicago and denies a recent travel history. His family history was significant for type 2 diabetes in multiple family members.

The absence of drugs, tobacco, and alcohol lowers the risk of some infectious and ischemic conditions. Patients with alcoholic liver disease who live in the southern United States are predisposed to developing Vibrio vulnificus myositis and fasciitis after ingesting contaminated oysters during the summer months. However, the clinical presentation of Vibrio usually includes septic shock and bullous lesions on the lower extremity. Also, the patient denies any recent travel to the southern United States, which makes Vibrio myositis and fasciitis less likely. Tobacco abuse increases the risk of atherosclerosis, peripheral vascular insufficiency, and ischemic myonecrosis.

The patient had a temperature of 99.1F, blood pressure of 139/85 mm Hg, pulse of 97 beats/minute, and respiratory rate of 18 breaths/minute. His body mass index was 31 kg/m². Physical examination revealed a firm, warm, severely tender area of swelling in the inferomedial aspect of the right thigh. The knee was also swollen, and effusion could not be ruled out. The range of motion of the knee was markedly limited by pain. The skin overlying the swelling was erythematous but not broken. No crepitus was noted. The strength of the right lower extremity muscles could not be accurately assessed because of the patient's excruciating pain, but the patient was able to move his foot and toes against gravity. Sensation was absent in most of the tested points in the feet but was normal in the legs. The deep tendon reflexes in both ankles were normal. The pedal pulses were mildly decreased in both feet. He also had extremely decreased visual acuity, which has been chronic. The rest of the physical examination was unremarkable.

The absence of fever does not rule out a serious infection in a diabetic patient but does raise the possibility of a noninfectious cause. Also, over‐the‐counter acetaminophen or nonsteroidal anti‐inflammatory drugs could mask a fever. The patient's physical examination was significant for obesity, a risk factor for developing deep‐seated infections, and a firm and severely tender area of swelling near the right knee that limited range of motion. Septic arthritis of the knee is one possibility; arthrocentesis should be performed as soon as possible. The absence of crepitus, because it is a late physical examination finding, does not rule out myositis or necrotizing fasciitis. The presence of unilateral lower extremity swelling also raises the suspicion for a deep vein thrombosis, which warrants compression ultrasonography. The localized tenderness and the lack of dermatological manifestations, such as Gottron's papules, makes an inflammatory myositis such as dermatomyositis much less likely.

Laboratory studies demonstrated a hemoglobin A1C of 13.0% (reference range, 4.36.1%), fasting blood glucose level of 224 mg/dL (reference range, 7099 mg/dL), white blood cell count of 8300 cells/mm³ (reference range, 450011,000 cells/mm³) without band forms, erythrocyte sedimentation rate of 81 mm/hr (reference range, <14 mm/hr), and creatinine kinase level of 582 IU/L (reference range, 30200 IU/L). Routine chemistries were normal otherwise. An x‐ray of the right knee revealed soft tissue edema. The right knee was aspirated, and fluid analysis revealed a white blood cell count of 106 cells/mm³ (reference range, <200 cell/mm³). Compression ultrasonography of the right lower extremity did not reveal thrombosis.

Poor glycemic control, as evidenced by a high hemoglobin A1C level, is associated with a higher probability of infectious complications. An elevated sedimentation rate is compatible with an infection, and an increased creatinine kinase intensifies suspicion of myositis or myonecrosis. A normal white blood cell count decreases, but does not eliminate, the likelihood of a serious bacterial infection. The fluid analysis rules out septic arthritis, and the compression ultrasonography findings make deep vein thrombosis very unlikely. However, the differential diagnosis still includes myositis, clostridial myonecrosis, cellulitis, and necrotizing fasciitis. The patient should undergo magnetic resonance imaging (MRI) of the lower extremity, and a surgical consultation should be obtained to consider the possibility of surgical exploration.

Blood and the aspirated fluids were sent for culturing, and the patient was started on empiric antibiotics. MRI of his right thigh revealed extensive edema involving the vastus medialis and lateralis of the quadriceps as well as subcutaneous edema without fascial enhancement or gas (Figure 1).

Figure 1

The absence of gas and fascial enhancement makes clostridial myonecrosis or necrotizing fasciitis less likely. The absence of a fluid collection in the muscle makes pyomyositis due to Staphylococci unlikely. Broad‐spectrum antibiotic coverage (usually vancomycin and either piperacillin/tazobactam or a carbapenem) targeting methicillin‐resistant Staphylococcus aureus, anaerobes, Streptococci, and Enterobacteriaceae should be empirically started as soon as cultures are obtained. Clindamycin should be part of the empiric antibiotic regimen to block toxin production in the event that Streptococcus pyogenes is responsible.

Surgical biopsy of the right vastus medialis muscle was performed, and tissue was sent for Gram staining, culture, and routine histopathological analysis. Gram staining was negative, and histopathological analysis revealed ischemic skeletal muscle fibers with areas of necrosis (Figure 2). Cultures from blood, fluid from the right knee, and muscular tissue samples did not grow any bacteria.

Figure 2

The muscle biopsy results are consistent with myonecrosis. Clostridial myonecrosis is possible but usually is associated with gas in tissues or occurs in the setting of intra‐abdominal pathology or severe trauma, and tissue culture was negative. Ischemic myonecrosis due to severe vascular insufficiency would be unlikely given the presence of pedal pulses and the absence of toes or forefoot cyanosis. A vasculitis syndrome is also unlikely because of the focal nature of the findings and the absence of weight loss, muscle weakness, and chronic joint pain in the patient's history. Calciphylaxis (calcific uremic arteriolopathy) might be considered in a patient with end‐stage renal disease who presents with a thigh pain; however, this condition is usually characterized by areas of ischemic necrosis that develop in the dermis and/or subcutaneous fat and infrequently involve muscles. The absence of the painful subcutaneous nodules typical of calciphylaxis makes it an unlikely diagnosis.

A diagnosis of diabetic myonecrosis was made. Antibiotics were discontinued, and the patient was treated symptomatically. His symptoms improved during the next few days. The patient was discharged from the hospital, and conservative management with bed rest and analgesics for 4 weeks was prescribed. Four months later, however, the patient returned with similar symptoms in the contralateral thigh. The patient was diagnosed with recurrent diabetic myonecrosis by MRI and muscle biopsy findings. Conservative management was advised, and the patient became pain‐free in a few weeks.

DISCUSSION

Diabetic myonecrosis (also known as diabetic muscle infarction) is a rare disorder initially described in 1965[1] that typically presents spontaneously as an acute, localized, severely painful swelling that limits the mobility of the affected extremity, usually without systemic signs of infection. It affects the thighs in 83% of patients and the calves in 17% of patients.[2, 3] Bilateral involvement, which is usually asynchronous, occurs in one‐third of patients.[4] The upper limbs are rarely involved. Diabetic myonecrosis affects patients who have a relatively longstanding history of diabetes. It is commonly associated with the microvascular complications of diabetes, including nephropathy (80% of patients), retinopathy (60% of patents), and/or neuropathy (64% of patients).[3, 5] The pathogenesis of diabetic myonecrosis is unclear, but the disease is likely due to a diffuse microangiopathy and atherosclerosis.[2, 5] Some authors have suggested that abnormalities in the clotting or fibrinolytic pathways play a role in the etiology of the disorder.[6]

Clinical and MRI findings can be used to make the diagnosis with reasonable certainty.[3, 5] Although both ultrasonography and MRI have been used to assess patients with diabetic myonecrosis, MRI with intravenous contrast enhancement appears to be the most useful diagnostic technique. It demonstrates extensive edema within the muscle(s), muscle enlargement, subcutaneous and interfascial edema, a patchwork pattern of involvement, and a high signal intensity on T2‐weighted images.[4, 7] Gadolinium enhancement may reveal an enhanced margin of the infarcted muscle with a central nonenhancing area of necrotic tissue.[4, 5] Muscle biopsy is not typically indicated because it may prolong recovery time and lead to infections.[8, 9, 10, 11] When performed, however, muscle biopsy reveals ischemic muscle fibers in different stages of degeneration and regeneration, with areas of necrosis and edema. Occlusion of arterioles and capillaries by fibrin could also be seen.[1] Although the patient underwent a muscle biopsy because infection could not be excluded definitively on clinical grounds, we believe that repeating the biopsy 4 months later was inappropriate.

Diabetic myonecrosis should be considered in a diabetic patient who presents with severe localized muscle pain and swelling of an extremity, especially if the clinical features favoring infection are absent. The differential diagnosis should include infection (eg, clostridial myonecrosis, myositis, cellulitis, abscess, necrotizing fasciitis, osteomyelitis), trauma (eg, hematoma, muscle rupture, myositis ossificans), peripheral neuropathy (particularly lumbosacral plexopathy), vascular disorders (deep vein thrombosis, and compartment syndrome), tumors, inflammatory muscle diseases, and drug‐related myositis.

No evidence‐based recommendations regarding the management of diabetic myonecrosis are available, although the findings of one retrospective analysis support conservative management with bed rest, leg elevation, and analgesics.[12] Physiotherapy may cause the condition to worsen,[13, 14] but routine daily activity, although often painful, is not harmful.[14] Some authors suggest a cautious use of antiplatelet or anti‐inflammatory medications.[12] We would also recommend achieving good glycemic control during the illness. Owing to the rarity of the disease, however, no studies have definitively shown that this hastens recovery or prevents recurrent diabetic myonecrosis. Surgery may prolong the recovery period; one study found that the recovery period of patients with diabetic myonecrosis who underwent surgery was longer than that of those who were treated conservatively (13 weeks vs 5.5 weeks).[12] Patients with diabetic myonecrosis have a good short‐term prognosis. Longer‐term, however, they have a poor prognosis; their recurrence rate is as high as 40%, and their 2‐year mortality rate is 10%, even after one episode of the disease. Death in these patients is mainly due to macrovascular events.[12]

TEACHING POINTS

1. Diabetic myonecrosis is a rare complication of longstanding and poorly controlled diabetes. It usually presents with acute localized muscular pain in the lower extremities.
2. Although a definitive diagnosis of diabetic myonecrosis is histopathologic, a clinical diagnosis can be made with reasonable certainty for patients with compatible MRI findings and no clinical or laboratory features suggesting infection.
3. Conservative management with bed rest, analgesics, and antiplatelets is recommended. Surgery should be avoided, as it may prolong recovery.

Disclosure

Nothing to report.

A 51‐year‐old man presented with severe pain and swelling in the lower anterior right thigh. He stated that the symptoms limited his movement, and began 4 days prior to this presentation. He rated the pain severity a 10 on a 10‐point scale. He denied fevers, chills, or history of trauma or weight loss.

Cellulitis of the lower extremity is the most likely possibility, but the presence of severe pain and swelling of an extremity in the absence of trauma should always make the clinician consider deep‐seated infections such as myositis or necrotizing fasciitis. An early clue for necrotizing fasciitis is severe pain that is disproportionate to the physical examination findings. Erythema, bullous lesions, or crepitus can develop later in the course. The absence of fever and chills also raises the possibility of noninfectious causes such as unrecognized trauma, deep vein thrombosis, or tumor.

The patient had a 15‐year history of type 2 diabetes complicated by end‐stage renal disease secondary to diabetic nephropathy for which he had been on hemodialysis for 5 months, proliferative diabetic retinopathy that rendered him legally blind, hypertension, and anemia. He stated that his diabetes had been poorly controlled, especially after he started dialysis.

A history of poorly controlled diabetes mellitus certainly increases the risk of the infectious disorders mentioned above. The patient's long‐standing history of diabetes mellitus with secondary nephropathy and retinopathy puts him at higher risk of atherosclerosis and vascular insufficiency, which consequently increase his risk for ischemic myonecrosis. Diabetic amyotrophy (diabetic lumbosacral plexopathy) is also a possibility, as it usually manifests with acute, unilateral, and focal tenderness followed by weakness involving a proximal leg. However, it typically occurs in patients who have been recently diagnosed with type 2 diabetes mellitus or whose disease has been under fairly good control and usually is associated with significant weight loss.

The patient was on oral medications for his diabetes until 1year before his presentation, at which point he was switched to insulin therapy. His other medications were amlodipine, lisinopril, aspirin, sevelamer, calcitriol, and calcium and iron supplements. He denied using alcohol, tobacco, or illicit drugs. He lives in Chicago and denies a recent travel history. His family history was significant for type 2 diabetes in multiple family members.

The absence of drugs, tobacco, and alcohol lowers the risk of some infectious and ischemic conditions. Patients with alcoholic liver disease who live in the southern United States are predisposed to developing Vibrio vulnificus myositis and fasciitis after ingesting contaminated oysters during the summer months. However, the clinical presentation of Vibrio usually includes septic shock and bullous lesions on the lower extremity. Also, the patient denies any recent travel to the southern United States, which makes Vibrio myositis and fasciitis less likely. Tobacco abuse increases the risk of atherosclerosis, peripheral vascular insufficiency, and ischemic myonecrosis.

The patient had a temperature of 99.1F, blood pressure of 139/85 mm Hg, pulse of 97 beats/minute, and respiratory rate of 18 breaths/minute. His body mass index was 31 kg/m². Physical examination revealed a firm, warm, severely tender area of swelling in the inferomedial aspect of the right thigh. The knee was also swollen, and effusion could not be ruled out. The range of motion of the knee was markedly limited by pain. The skin overlying the swelling was erythematous but not broken. No crepitus was noted. The strength of the right lower extremity muscles could not be accurately assessed because of the patient's excruciating pain, but the patient was able to move his foot and toes against gravity. Sensation was absent in most of the tested points in the feet but was normal in the legs. The deep tendon reflexes in both ankles were normal. The pedal pulses were mildly decreased in both feet. He also had extremely decreased visual acuity, which has been chronic. The rest of the physical examination was unremarkable.

The absence of fever does not rule out a serious infection in a diabetic patient but does raise the possibility of a noninfectious cause. Also, over‐the‐counter acetaminophen or nonsteroidal anti‐inflammatory drugs could mask a fever. The patient's physical examination was significant for obesity, a risk factor for developing deep‐seated infections, and a firm and severely tender area of swelling near the right knee that limited range of motion. Septic arthritis of the knee is one possibility; arthrocentesis should be performed as soon as possible. The absence of crepitus, because it is a late physical examination finding, does not rule out myositis or necrotizing fasciitis. The presence of unilateral lower extremity swelling also raises the suspicion for a deep vein thrombosis, which warrants compression ultrasonography. The localized tenderness and the lack of dermatological manifestations, such as Gottron's papules, makes an inflammatory myositis such as dermatomyositis much less likely.

Laboratory studies demonstrated a hemoglobin A1C of 13.0% (reference range, 4.36.1%), fasting blood glucose level of 224 mg/dL (reference range, 7099 mg/dL), white blood cell count of 8300 cells/mm³ (reference range, 450011,000 cells/mm³) without band forms, erythrocyte sedimentation rate of 81 mm/hr (reference range, <14 mm/hr), and creatinine kinase level of 582 IU/L (reference range, 30200 IU/L). Routine chemistries were normal otherwise. An x‐ray of the right knee revealed soft tissue edema. The right knee was aspirated, and fluid analysis revealed a white blood cell count of 106 cells/mm³ (reference range, <200 cell/mm³). Compression ultrasonography of the right lower extremity did not reveal thrombosis.

Poor glycemic control, as evidenced by a high hemoglobin A1C level, is associated with a higher probability of infectious complications. An elevated sedimentation rate is compatible with an infection, and an increased creatinine kinase intensifies suspicion of myositis or myonecrosis. A normal white blood cell count decreases, but does not eliminate, the likelihood of a serious bacterial infection. The fluid analysis rules out septic arthritis, and the compression ultrasonography findings make deep vein thrombosis very unlikely. However, the differential diagnosis still includes myositis, clostridial myonecrosis, cellulitis, and necrotizing fasciitis. The patient should undergo magnetic resonance imaging (MRI) of the lower extremity, and a surgical consultation should be obtained to consider the possibility of surgical exploration.

Blood and the aspirated fluids were sent for culturing, and the patient was started on empiric antibiotics. MRI of his right thigh revealed extensive edema involving the vastus medialis and lateralis of the quadriceps as well as subcutaneous edema without fascial enhancement or gas (Figure 1).

Figure 1

The absence of gas and fascial enhancement makes clostridial myonecrosis or necrotizing fasciitis less likely. The absence of a fluid collection in the muscle makes pyomyositis due to Staphylococci unlikely. Broad‐spectrum antibiotic coverage (usually vancomycin and either piperacillin/tazobactam or a carbapenem) targeting methicillin‐resistant Staphylococcus aureus, anaerobes, Streptococci, and Enterobacteriaceae should be empirically started as soon as cultures are obtained. Clindamycin should be part of the empiric antibiotic regimen to block toxin production in the event that Streptococcus pyogenes is responsible.

Surgical biopsy of the right vastus medialis muscle was performed, and tissue was sent for Gram staining, culture, and routine histopathological analysis. Gram staining was negative, and histopathological analysis revealed ischemic skeletal muscle fibers with areas of necrosis (Figure 2). Cultures from blood, fluid from the right knee, and muscular tissue samples did not grow any bacteria.

Figure 2

The muscle biopsy results are consistent with myonecrosis. Clostridial myonecrosis is possible but usually is associated with gas in tissues or occurs in the setting of intra‐abdominal pathology or severe trauma, and tissue culture was negative. Ischemic myonecrosis due to severe vascular insufficiency would be unlikely given the presence of pedal pulses and the absence of toes or forefoot cyanosis. A vasculitis syndrome is also unlikely because of the focal nature of the findings and the absence of weight loss, muscle weakness, and chronic joint pain in the patient's history. Calciphylaxis (calcific uremic arteriolopathy) might be considered in a patient with end‐stage renal disease who presents with a thigh pain; however, this condition is usually characterized by areas of ischemic necrosis that develop in the dermis and/or subcutaneous fat and infrequently involve muscles. The absence of the painful subcutaneous nodules typical of calciphylaxis makes it an unlikely diagnosis.

A diagnosis of diabetic myonecrosis was made. Antibiotics were discontinued, and the patient was treated symptomatically. His symptoms improved during the next few days. The patient was discharged from the hospital, and conservative management with bed rest and analgesics for 4 weeks was prescribed. Four months later, however, the patient returned with similar symptoms in the contralateral thigh. The patient was diagnosed with recurrent diabetic myonecrosis by MRI and muscle biopsy findings. Conservative management was advised, and the patient became pain‐free in a few weeks.

DISCUSSION

Diabetic myonecrosis (also known as diabetic muscle infarction) is a rare disorder initially described in 1965[1] that typically presents spontaneously as an acute, localized, severely painful swelling that limits the mobility of the affected extremity, usually without systemic signs of infection. It affects the thighs in 83% of patients and the calves in 17% of patients.[2, 3] Bilateral involvement, which is usually asynchronous, occurs in one‐third of patients.[4] The upper limbs are rarely involved. Diabetic myonecrosis affects patients who have a relatively longstanding history of diabetes. It is commonly associated with the microvascular complications of diabetes, including nephropathy (80% of patients), retinopathy (60% of patents), and/or neuropathy (64% of patients).[3, 5] The pathogenesis of diabetic myonecrosis is unclear, but the disease is likely due to a diffuse microangiopathy and atherosclerosis.[2, 5] Some authors have suggested that abnormalities in the clotting or fibrinolytic pathways play a role in the etiology of the disorder.[6]

Clinical and MRI findings can be used to make the diagnosis with reasonable certainty.[3, 5] Although both ultrasonography and MRI have been used to assess patients with diabetic myonecrosis, MRI with intravenous contrast enhancement appears to be the most useful diagnostic technique. It demonstrates extensive edema within the muscle(s), muscle enlargement, subcutaneous and interfascial edema, a patchwork pattern of involvement, and a high signal intensity on T2‐weighted images.[4, 7] Gadolinium enhancement may reveal an enhanced margin of the infarcted muscle with a central nonenhancing area of necrotic tissue.[4, 5] Muscle biopsy is not typically indicated because it may prolong recovery time and lead to infections.[8, 9, 10, 11] When performed, however, muscle biopsy reveals ischemic muscle fibers in different stages of degeneration and regeneration, with areas of necrosis and edema. Occlusion of arterioles and capillaries by fibrin could also be seen.[1] Although the patient underwent a muscle biopsy because infection could not be excluded definitively on clinical grounds, we believe that repeating the biopsy 4 months later was inappropriate.

Diabetic myonecrosis should be considered in a diabetic patient who presents with severe localized muscle pain and swelling of an extremity, especially if the clinical features favoring infection are absent. The differential diagnosis should include infection (eg, clostridial myonecrosis, myositis, cellulitis, abscess, necrotizing fasciitis, osteomyelitis), trauma (eg, hematoma, muscle rupture, myositis ossificans), peripheral neuropathy (particularly lumbosacral plexopathy), vascular disorders (deep vein thrombosis, and compartment syndrome), tumors, inflammatory muscle diseases, and drug‐related myositis.

No evidence‐based recommendations regarding the management of diabetic myonecrosis are available, although the findings of one retrospective analysis support conservative management with bed rest, leg elevation, and analgesics.[12] Physiotherapy may cause the condition to worsen,[13, 14] but routine daily activity, although often painful, is not harmful.[14] Some authors suggest a cautious use of antiplatelet or anti‐inflammatory medications.[12] We would also recommend achieving good glycemic control during the illness. Owing to the rarity of the disease, however, no studies have definitively shown that this hastens recovery or prevents recurrent diabetic myonecrosis. Surgery may prolong the recovery period; one study found that the recovery period of patients with diabetic myonecrosis who underwent surgery was longer than that of those who were treated conservatively (13 weeks vs 5.5 weeks).[12] Patients with diabetic myonecrosis have a good short‐term prognosis. Longer‐term, however, they have a poor prognosis; their recurrence rate is as high as 40%, and their 2‐year mortality rate is 10%, even after one episode of the disease. Death in these patients is mainly due to macrovascular events.[12]

TEACHING POINTS

1. Diabetic myonecrosis is a rare complication of longstanding and poorly controlled diabetes. It usually presents with acute localized muscular pain in the lower extremities.
2. Although a definitive diagnosis of diabetic myonecrosis is histopathologic, a clinical diagnosis can be made with reasonable certainty for patients with compatible MRI findings and no clinical or laboratory features suggesting infection.
3. Conservative management with bed rest, analgesics, and antiplatelets is recommended. Surgery should be avoided, as it may prolong recovery.

Disclosure

Nothing to report.

A 40‐year‐old man with human immunodeficiency virus (HIV) infection and a CD4 count of 58 cells/L was admitted to the hospital with 1 month of fevers, night sweats, a 5‐kg weight loss, several weeks of progressive dyspnea on exertion, and a nonproductive cough. He denied headaches, vision changes, odynophagia, diarrhea, or rash. He had no history of opportunistic infections, HIV‐associated neoplasms, or other relevant past medical history. He was diagnosed with HIV 3 years ago and had been off antiretroviral therapy (ART) for the last 10 months. Two weeks prior to this presentation, he was seen in clinic but did not report his symptoms. He was prescribed trimethoprim/sulfamethoxazole (TMP/SMX) for prophylaxis against Pneumocystis jirovecii pneumonia (PCP). He had recently moved from New York City to San Francisco, had quit smoking within the last month, and denied alcohol or illicit drug use.

At a CD4 cell count of 58 cells/L, the patient is at risk for the entire spectrum of HIV‐associated opportunistic infections and neoplasms. The presence of fevers, night sweats, and weight loss suggests the possibility of a disseminated infection, although a neoplastic process with accompanying B symptoms should also be considered. Dyspnea and nonproductive cough indicate cardiopulmonary involvement. The duration of these complaints is more suggestive of a nonbacterial infectious etiology (e.g., PCP, mycobacterial or fungal disease) than a bacterial etiology (e.g., Streptococcus pneumoniae). Irrespective of CD4 count, patients with HIV are at increased risk for cardiovascular events and pulmonary arterial hypertension, although the time course and presence of constitutional symptoms makes these diagnoses less likely. Similarly, patients with HIV are at increased risk for chronic obstructive pulmonary disease (COPD), and the patient does have a history of cigarette smoking, but the clinical history and systemic involvement make COPD unlikely.

On physical examination, the patient was in no acute distress. The temperature was 36C, the blood pressure 117/68 mm Hg, the heart rate 106 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 100% on ambient air. No oral lesions were noted, and his neck was supple with nontender bilateral cervical lymphadenopathy measuring up to 1.5 cm. There was no jugular venous distension or peripheral edema. The cardiovascular exam revealed tachycardia with a regular rhythm and no murmurs or gallops. His lungs were clear to auscultation. The spleen tipwas palpable. No rashes were identified. The neurological examination, including mental status, was normal.

The white blood cell count was 2400/mm³, the hemoglobin 7 g/dL with mean corpuscular volume of 86 fL, and the platelet count 162,000/mm³. Basic chemistry, liver, and glucose‐6‐phosphate dehydrogenase (G6PD) tests were within the laboratory's normal range. The HIV viral load was 150,000 copies/mL. Chest radiography revealed bibasilar hazy opacities, and computerized tomography (CT) of the chest revealed a focal nodular consolidation in the right middle lobe along with subcentimeter bilateral axillary and mediastinal lymphadenopathy. There were no ground‐glass opacities.

The patient's physical examination does not support a cardiac disorder. Lymphadenopathy is nonspecific, but it is consistent with a potential infectious or neoplastic process. Leukopenia and anemia suggest potential bone‐marrow infiltration or suppression by TMP/SMX. Although the pulmonary exam was nonfocal, chest imaging is the cornerstone of the evaluation of suspected pulmonary disease in persons with HIV. The focal nodular consolidation on chest CT is nonspecific but is more characteristic of typical or atypical bacterial pneumonia, mycobacterial disease such as tuberculosis, or fungal pneumonia than PCP or viral pneumonia. A lack of ground‐glass opacities also makes PCP and interstitial lung diseases less likely.

The patient was treated for community‐acquired pneumonia with ceftriaxone and doxycycline with improvement in dyspnea. Antiretroviral therapy with darunavir, ritonavir, tenofovir, and emtricitabine was initiated. Azithromycin was started for prophylaxis against Mycobacterium avium complex (MAC). The TMP/SMX was changed to dapsone, given concern for bone‐marrow suppression. Blood cultures for bacteria, fungi, and mycobacteria were negative. Polymerase chain reaction from pharyngeal swab for influenza A and B, parainfluenza types 13, rhinovirus, and respiratory syncytial virus were negative. Several attempts to obtain sputum for acid‐fast bacillus staining and culture were unsuccessful because the patient was unable to expectorate sputum. Serum interferon‐gamma release assay for M. tuberculosis and thefollowing serologic studies were also negative: cytomegalovirus, Epstein‐Barr virus, parvovirus, Bartonella species, Coccidioides immitis, and Cryptococcus neoformans antigen. Given his improvement, the patient was discharged from the hospital on ART, doxycycline for community‐acquired pneumonia, and prophylactic azithromycin and dapsone with scheduled outpatient follow‐up.

Ten days later, he was seen in clinic. Though his dyspnea had improved after completing the doxycycline, he noted a persistent dry cough and daily fevers to 40C. The physical exam was unchanged, including persistent cervical lymphadenopathy. Laboratories revealed a white blood cell count of 2400/mm³, hemoglobin of 4.8 g/dL, and a platelet count of 122,000/mm³. The absolute reticulocyte count was 21,000/L (normal value, 20,000100,000/L). A peripheral blood smear was unremarkable, and serum lactate dehydrogenase (LDH) was within normal limits. The direct antiglobulin test (DAT) was negative. The patient was readmitted to the hospital.

The initial improvement in dyspnea but persistent fevers and cough and worsening pancytopenia are suggestive of multiple processes occurring simultaneously. Dapsone can cause both hemolytic anemia and aplastic anemia, although the peripheral smear, normal LDH and G6PD, and negative DAT are not consistent with the former. Bone‐marrow suppression from a combination of ART medications and dapsone cannot be ruled out. An infiltrative process involving the bone marrow, including tuberculosis, MAC, disseminated fungal infection, or malignancy, remains a possibility. Repeat chest imaging is warranted to assess the prior right middle lobe consolidation and to further evaluate the persistent respiratory complaints.

Prophylaxis of PCP with dapsone was switched to atovaquone due to persistent anemia. A repeat CT of the chest and a concurrent abdominal CT revealed interval enlargement of mediastinal lymph nodes with multiple periportal, retroperitoneal, and hilar nodes not present on prior chest imaging, in addition to new bilateral centrilobular nodules and interval development of small bilateral pleural effusions. The abdominal CT also showed hepatosplenomegaly with splenic‐vein engorgement. Empiric treatment for disseminated MAC infection with clarithromycin and ethambutol was initiated in addition to vancomycin and cefepime for possible healthcare‐associated pneumonia. Over the next several days, the patient continued to have daily fevers up to 39.8C. A repeat CD4 count 3 weeks after starting ART was 121 cells/L. The HIV RNA level had decreased to 854 copies/mL.

The patient has developed progressive, generalized lymphadenopathy, worsening pancytopenia, and persistent fevers in the setting of negative cultures and serologic studies and despite treatment for MAC. This constellation, along with the radiographic findings of hilar lymphadenopathy and pleural effusions, is suggestive of non‐Hodgkin lymphoma (NHL). Alternatively, Kaposi sarcoma (KS) or tuberculosis can have a similar radiographic and clinical presentation, although pancytopenia from KS seems unusual. The lymphadenopathy could be consistent with multicentric Castleman disease or bacillary angiomatosis (BA), although the latter diagnosis would be unlikely given recent antibiotic therapy. At this time, a careful search for other manifestations and reasonable targets for biopsy is warranted. An appropriate suppression of the HIV viral load after initiation of ART, with improvement in CD4 count, is the proper context for the immune reconstitution inflammatory syndrome (IRIS), which is characterized by paradoxical worsening or unmasking of a disseminated process.

A bone‐marrow biopsy revealed marked dysmegakaryopoiesis and mild dyserythropoiesis, but no other abnormalities. Flow cytometry and histoimmunochemical staining did not show evidence of lymphoproliferative disorder in the marrow. Smears and cultures of the bone marrow for bacteria, acid‐fast bacilli, and fungi were negative. A right cervical lymph node biopsy was performed, with multiple fine‐needle aspiration and core samples taken. Bacterial, fungal, and acid‐fast bacilli tissue cultures were without growth, and initial pathology results were concerning for high‐grade lymphoma. A monoclonal proliferation of lymphocytes was noted on flow cytometry of the tissue sample. The patient developed progressive dyspnea, tachypnea, and hypoxemia. A chest x‐ray revealed worsening perihilar and basilar opacities.

The possibility of bone‐marrow sampling error must be considered in a patient that has such a high pretest probability for lymphoma or infection, but staining, immunological assays, cultures, and direct assessment by pathologists generally give some suggestion of an alternative diagnosis. The bone‐marrow findings are compatible with HIV‐related changes, but continued vigilance for infection and malignancy is warranted. Although the diagnosis of NHL based on the cervical biopsy result is only preliminary, the patient's rapidly deteriorating clinical status warrants initiation of treatment with steroids while awaiting definitive results, particularly given his poor response to aggressive management of potential infectious causes. A bronchoscopy should be considered given the predominance of pulmonary symptoms and his rapid respiratory decline.

Approximately 1 week after admission, high‐dose systemic corticosteroids were administered for presumed aggressive lymphoma. Over the next 48 hours, the patient's hypoxemia worsened, and he was intubated for hypoxemic respiratory failure. A repeat chest CT (see Fig. 1) showed bilateral peribronchovascular patchy consolidations and pleural effusions without evidence of pulmonary embolism. The patient was also noted to have a single, discrete violaceous nodule on the hard palate as well as a nodule with similar appearance on his upper chest (neither lesion was present on admission). A skin biopsy was obtained. Despite steroids, antibiotic therapy, and aggressive critical‐care management, severe acidosis, progressive acute kidney injury, and anuria ensued. Continuous venovenous hemodialysis was initiated.

Figure 1

Discrete violaceous nodules with mucocutaneous localization in the context of AIDS are virtually pathognomonic for KS. Rarely, BA may be misdiagnosed as KS, or they may occur concurrently. The patient's current clinical deterioration, radiographic findings, and development of new skin lesions in the setting of response to ART are concerning for KS‐related IRIS with visceral involvement. It is likely that systemic corticosteroids are potentiating KS‐related IRIS. At this point, there is compelling evidence of 2 distinct systemic disease processes: lymphoma and KS‐related IRIS, both of which may be contributing to respiratory failure. Steroids can be highly effective in the treatment of high‐grade lymphoma but can be harmful in patients with KS, where they have been shown to potentially exacerbate underlying disease. Given the patient's worsening respiratory status, discontinuation of corticosteroids and initiation of chemotherapy against both opportunistic malignancies should be considered.

The patient's condition deteriorated with progressive acidosis and hypoxemia, and he died shortly after being transitioned to comfort‐care measures. Review of the skin biopsy revealed KS. Autopsy revealed disseminated KS involving the skin, lymph nodes, and lungs, and high‐grade anaplastic plasmablastic lymphoma infiltrating multiple lymph nodes and organs, including the lungs (see Fig. 2). There was no evidence of infection.

Figure 2

COMMENTARY

This case demonstrates the simultaneous fatal progression of 2 treatable HIV‐associated malignancies in an era in which the end‐stage manifestations of untreated HIV are becoming less common, particularly in developed countries. Modern ARTthe centerpiece of progress with HIVhas yielded dramatic improvements in prognosis, but in this case, by precipitating KS‐IRIS, ART paradoxically contributed to this patient's demise. Similarly, high‐dose systemic corticosteroids, which were deemed necessary to stabilize the progression of his high‐grade lymphoma, likely accelerated his KS. This corticosteroid‐mediated worsening appears to be unique to KS given that corticosteroids are often recommended to treat severe presentations of IRIS in other diseases (eg, tuberculosis, MAC, PCP).

Immune reconstitution inflammatory syndrome is the paradoxical worsening of well‐controlled disease or progression of previously occult disease after initiation of ART.1

Although infectious diseasesincluding mycobacteria, cytomegalovirus, cryptococcosis, or PCPare best known for their ability to recrudesce or manifest with a recovering immune system, opportunistic malignancies such as KS can do the same. Risk factors for development of IRIS are low pre‐ART CD4 count, high pre‐ART viral load, and rapid response to ART.2 In 1 large series, the median time to diagnosis of IRIS was 33 days.2 Immune reconstitution inflammatory syndrome is a clinical diagnosis without specific pathologic findings. Because IRIS is a diagnosis of exclusion, other explanations for worsening disease, including drug resistance, drug reactions (eg, abacavir hypersensitivity syndrome), and poor adherence to medications, should be ruled out before making the diagnosis.

Kaposi sarcoma is a vascular tumor associated with infection by human herpesvirus 8 (HHV‐8). The incidence of AIDS‐related KS has declined substantially in the post‐ART era.2, 4 The classic radiographic presentation of pulmonary KS includes central bilateral opacities with a peribronchovascular distribution as well as pulmonary nodules, intraseptal thickening, mediastinal lymphadenopathy, and associated pleural effusions.5, 6 Kaposi sarcomarelated IRIS has been described as developing within weeks of ART initiation and is associated with substantial morbidity and mortality, particularly in the context of pulmonary involvement, with 1 recent series showing 100% mortality in patients who did not receive chemotherapy.79

Human immunodeficiency virusassociated KS can respond well to ART alone. Indications for systemic chemotherapy for KS include extensive mucocutaneous disease, symptomatic visceral disease, or KS‐related IRIS.10 The main chemotherapeutic agents used systemically for KS are liposomal anthracyclines such as doxorubicin or daunorubicin, or taxanes such as paclitaxel.11 An association between corticosteroids and progression of KS has been previously described, even as early as several days after steroid administration.1214 Recently, revised diagnostic criteria for corticosteroid‐associated KS‐IRIS have been proposed; this patient met those criteria.15

Plasmablastic lymphoma is a highly aggressive systemic NHL seen predominantly in HIV‐positive patients. There is a strong association with Epstein‐Barr virus; HHV‐8 is more variably associated and is of unclear significance.16 Most HIV‐infected patients have extranodal involvement at diagnosis; in a series of 53 HIV‐positive patients, the oral cavity was the most frequent site, and lung involvement was seen in 12%. The prognosis is poor, with a mean survival of approximately 1 year.17

Treatment for systemic NHL in HIV‐positive patients generally consists of a chemotherapy regimen while ART is continued or initiated.18 The most commonly used chemotherapy combination is cyclophosphamide, doxorubicin, vincristine, and prednisone, often supplemented with the anti‐CD20 monoclonal antibody rituximab. In the case of aggressive systemic NHL, more intensive treatment regimens are often utilized, though it remains unclear if they are associated with improved outcomes.17, 19 Antiretroviral therapy is continued, as it has been shown to reduce the rate of opportunistic infections and decrease mortality.20

Despite the remarkable progress that has been made in the past 30 years, HIV/AIDS remains a devastating and remarkably complex disease. As the landscape of HIV/AIDS evolves, clinicians will continue to be faced with new challenging and vexing decisions. Perhaps no greater challenge exists than the presence of 2 simultaneous, rapidly fatal malignancies with directly competing therapeutic strategies, as in this case, where the ART and steroids employed to address NHL fostered widespread KS‐IRIS. This case reminds us that a single unifying diagnosis can often be the exception rather than the rule in the care of patients with advanced HIV. It also illustrates how the mainstay of HIV treatment, ART, can be a double‐edged sword.

KEY TEACHING POINTS

• In HIV/AIDS patients receiving ART who become paradoxically more ill despite improvements in their CD4 counts, consider IRIS.

• Though corticosteroids are a hallmark of treatment for most types of IRIS‐and for aggressive lymphomas‐they can worsen KS.

A 40‐year‐old man with human immunodeficiency virus (HIV) infection and a CD4 count of 58 cells/L was admitted to the hospital with 1 month of fevers, night sweats, a 5‐kg weight loss, several weeks of progressive dyspnea on exertion, and a nonproductive cough. He denied headaches, vision changes, odynophagia, diarrhea, or rash. He had no history of opportunistic infections, HIV‐associated neoplasms, or other relevant past medical history. He was diagnosed with HIV 3 years ago and had been off antiretroviral therapy (ART) for the last 10 months. Two weeks prior to this presentation, he was seen in clinic but did not report his symptoms. He was prescribed trimethoprim/sulfamethoxazole (TMP/SMX) for prophylaxis against Pneumocystis jirovecii pneumonia (PCP). He had recently moved from New York City to San Francisco, had quit smoking within the last month, and denied alcohol or illicit drug use.

At a CD4 cell count of 58 cells/L, the patient is at risk for the entire spectrum of HIV‐associated opportunistic infections and neoplasms. The presence of fevers, night sweats, and weight loss suggests the possibility of a disseminated infection, although a neoplastic process with accompanying B symptoms should also be considered. Dyspnea and nonproductive cough indicate cardiopulmonary involvement. The duration of these complaints is more suggestive of a nonbacterial infectious etiology (e.g., PCP, mycobacterial or fungal disease) than a bacterial etiology (e.g., Streptococcus pneumoniae). Irrespective of CD4 count, patients with HIV are at increased risk for cardiovascular events and pulmonary arterial hypertension, although the time course and presence of constitutional symptoms makes these diagnoses less likely. Similarly, patients with HIV are at increased risk for chronic obstructive pulmonary disease (COPD), and the patient does have a history of cigarette smoking, but the clinical history and systemic involvement make COPD unlikely.

On physical examination, the patient was in no acute distress. The temperature was 36C, the blood pressure 117/68 mm Hg, the heart rate 106 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 100% on ambient air. No oral lesions were noted, and his neck was supple with nontender bilateral cervical lymphadenopathy measuring up to 1.5 cm. There was no jugular venous distension or peripheral edema. The cardiovascular exam revealed tachycardia with a regular rhythm and no murmurs or gallops. His lungs were clear to auscultation. The spleen tipwas palpable. No rashes were identified. The neurological examination, including mental status, was normal.

The white blood cell count was 2400/mm³, the hemoglobin 7 g/dL with mean corpuscular volume of 86 fL, and the platelet count 162,000/mm³. Basic chemistry, liver, and glucose‐6‐phosphate dehydrogenase (G6PD) tests were within the laboratory's normal range. The HIV viral load was 150,000 copies/mL. Chest radiography revealed bibasilar hazy opacities, and computerized tomography (CT) of the chest revealed a focal nodular consolidation in the right middle lobe along with subcentimeter bilateral axillary and mediastinal lymphadenopathy. There were no ground‐glass opacities.

The patient's physical examination does not support a cardiac disorder. Lymphadenopathy is nonspecific, but it is consistent with a potential infectious or neoplastic process. Leukopenia and anemia suggest potential bone‐marrow infiltration or suppression by TMP/SMX. Although the pulmonary exam was nonfocal, chest imaging is the cornerstone of the evaluation of suspected pulmonary disease in persons with HIV. The focal nodular consolidation on chest CT is nonspecific but is more characteristic of typical or atypical bacterial pneumonia, mycobacterial disease such as tuberculosis, or fungal pneumonia than PCP or viral pneumonia. A lack of ground‐glass opacities also makes PCP and interstitial lung diseases less likely.

The patient was treated for community‐acquired pneumonia with ceftriaxone and doxycycline with improvement in dyspnea. Antiretroviral therapy with darunavir, ritonavir, tenofovir, and emtricitabine was initiated. Azithromycin was started for prophylaxis against Mycobacterium avium complex (MAC). The TMP/SMX was changed to dapsone, given concern for bone‐marrow suppression. Blood cultures for bacteria, fungi, and mycobacteria were negative. Polymerase chain reaction from pharyngeal swab for influenza A and B, parainfluenza types 13, rhinovirus, and respiratory syncytial virus were negative. Several attempts to obtain sputum for acid‐fast bacillus staining and culture were unsuccessful because the patient was unable to expectorate sputum. Serum interferon‐gamma release assay for M. tuberculosis and thefollowing serologic studies were also negative: cytomegalovirus, Epstein‐Barr virus, parvovirus, Bartonella species, Coccidioides immitis, and Cryptococcus neoformans antigen. Given his improvement, the patient was discharged from the hospital on ART, doxycycline for community‐acquired pneumonia, and prophylactic azithromycin and dapsone with scheduled outpatient follow‐up.

Ten days later, he was seen in clinic. Though his dyspnea had improved after completing the doxycycline, he noted a persistent dry cough and daily fevers to 40C. The physical exam was unchanged, including persistent cervical lymphadenopathy. Laboratories revealed a white blood cell count of 2400/mm³, hemoglobin of 4.8 g/dL, and a platelet count of 122,000/mm³. The absolute reticulocyte count was 21,000/L (normal value, 20,000100,000/L). A peripheral blood smear was unremarkable, and serum lactate dehydrogenase (LDH) was within normal limits. The direct antiglobulin test (DAT) was negative. The patient was readmitted to the hospital.

The initial improvement in dyspnea but persistent fevers and cough and worsening pancytopenia are suggestive of multiple processes occurring simultaneously. Dapsone can cause both hemolytic anemia and aplastic anemia, although the peripheral smear, normal LDH and G6PD, and negative DAT are not consistent with the former. Bone‐marrow suppression from a combination of ART medications and dapsone cannot be ruled out. An infiltrative process involving the bone marrow, including tuberculosis, MAC, disseminated fungal infection, or malignancy, remains a possibility. Repeat chest imaging is warranted to assess the prior right middle lobe consolidation and to further evaluate the persistent respiratory complaints.

Prophylaxis of PCP with dapsone was switched to atovaquone due to persistent anemia. A repeat CT of the chest and a concurrent abdominal CT revealed interval enlargement of mediastinal lymph nodes with multiple periportal, retroperitoneal, and hilar nodes not present on prior chest imaging, in addition to new bilateral centrilobular nodules and interval development of small bilateral pleural effusions. The abdominal CT also showed hepatosplenomegaly with splenic‐vein engorgement. Empiric treatment for disseminated MAC infection with clarithromycin and ethambutol was initiated in addition to vancomycin and cefepime for possible healthcare‐associated pneumonia. Over the next several days, the patient continued to have daily fevers up to 39.8C. A repeat CD4 count 3 weeks after starting ART was 121 cells/L. The HIV RNA level had decreased to 854 copies/mL.

The patient has developed progressive, generalized lymphadenopathy, worsening pancytopenia, and persistent fevers in the setting of negative cultures and serologic studies and despite treatment for MAC. This constellation, along with the radiographic findings of hilar lymphadenopathy and pleural effusions, is suggestive of non‐Hodgkin lymphoma (NHL). Alternatively, Kaposi sarcoma (KS) or tuberculosis can have a similar radiographic and clinical presentation, although pancytopenia from KS seems unusual. The lymphadenopathy could be consistent with multicentric Castleman disease or bacillary angiomatosis (BA), although the latter diagnosis would be unlikely given recent antibiotic therapy. At this time, a careful search for other manifestations and reasonable targets for biopsy is warranted. An appropriate suppression of the HIV viral load after initiation of ART, with improvement in CD4 count, is the proper context for the immune reconstitution inflammatory syndrome (IRIS), which is characterized by paradoxical worsening or unmasking of a disseminated process.

A bone‐marrow biopsy revealed marked dysmegakaryopoiesis and mild dyserythropoiesis, but no other abnormalities. Flow cytometry and histoimmunochemical staining did not show evidence of lymphoproliferative disorder in the marrow. Smears and cultures of the bone marrow for bacteria, acid‐fast bacilli, and fungi were negative. A right cervical lymph node biopsy was performed, with multiple fine‐needle aspiration and core samples taken. Bacterial, fungal, and acid‐fast bacilli tissue cultures were without growth, and initial pathology results were concerning for high‐grade lymphoma. A monoclonal proliferation of lymphocytes was noted on flow cytometry of the tissue sample. The patient developed progressive dyspnea, tachypnea, and hypoxemia. A chest x‐ray revealed worsening perihilar and basilar opacities.

The possibility of bone‐marrow sampling error must be considered in a patient that has such a high pretest probability for lymphoma or infection, but staining, immunological assays, cultures, and direct assessment by pathologists generally give some suggestion of an alternative diagnosis. The bone‐marrow findings are compatible with HIV‐related changes, but continued vigilance for infection and malignancy is warranted. Although the diagnosis of NHL based on the cervical biopsy result is only preliminary, the patient's rapidly deteriorating clinical status warrants initiation of treatment with steroids while awaiting definitive results, particularly given his poor response to aggressive management of potential infectious causes. A bronchoscopy should be considered given the predominance of pulmonary symptoms and his rapid respiratory decline.

Approximately 1 week after admission, high‐dose systemic corticosteroids were administered for presumed aggressive lymphoma. Over the next 48 hours, the patient's hypoxemia worsened, and he was intubated for hypoxemic respiratory failure. A repeat chest CT (see Fig. 1) showed bilateral peribronchovascular patchy consolidations and pleural effusions without evidence of pulmonary embolism. The patient was also noted to have a single, discrete violaceous nodule on the hard palate as well as a nodule with similar appearance on his upper chest (neither lesion was present on admission). A skin biopsy was obtained. Despite steroids, antibiotic therapy, and aggressive critical‐care management, severe acidosis, progressive acute kidney injury, and anuria ensued. Continuous venovenous hemodialysis was initiated.

Figure 1

Discrete violaceous nodules with mucocutaneous localization in the context of AIDS are virtually pathognomonic for KS. Rarely, BA may be misdiagnosed as KS, or they may occur concurrently. The patient's current clinical deterioration, radiographic findings, and development of new skin lesions in the setting of response to ART are concerning for KS‐related IRIS with visceral involvement. It is likely that systemic corticosteroids are potentiating KS‐related IRIS. At this point, there is compelling evidence of 2 distinct systemic disease processes: lymphoma and KS‐related IRIS, both of which may be contributing to respiratory failure. Steroids can be highly effective in the treatment of high‐grade lymphoma but can be harmful in patients with KS, where they have been shown to potentially exacerbate underlying disease. Given the patient's worsening respiratory status, discontinuation of corticosteroids and initiation of chemotherapy against both opportunistic malignancies should be considered.

The patient's condition deteriorated with progressive acidosis and hypoxemia, and he died shortly after being transitioned to comfort‐care measures. Review of the skin biopsy revealed KS. Autopsy revealed disseminated KS involving the skin, lymph nodes, and lungs, and high‐grade anaplastic plasmablastic lymphoma infiltrating multiple lymph nodes and organs, including the lungs (see Fig. 2). There was no evidence of infection.

Figure 2

COMMENTARY

This case demonstrates the simultaneous fatal progression of 2 treatable HIV‐associated malignancies in an era in which the end‐stage manifestations of untreated HIV are becoming less common, particularly in developed countries. Modern ARTthe centerpiece of progress with HIVhas yielded dramatic improvements in prognosis, but in this case, by precipitating KS‐IRIS, ART paradoxically contributed to this patient's demise. Similarly, high‐dose systemic corticosteroids, which were deemed necessary to stabilize the progression of his high‐grade lymphoma, likely accelerated his KS. This corticosteroid‐mediated worsening appears to be unique to KS given that corticosteroids are often recommended to treat severe presentations of IRIS in other diseases (eg, tuberculosis, MAC, PCP).

Immune reconstitution inflammatory syndrome is the paradoxical worsening of well‐controlled disease or progression of previously occult disease after initiation of ART.1

Although infectious diseasesincluding mycobacteria, cytomegalovirus, cryptococcosis, or PCPare best known for their ability to recrudesce or manifest with a recovering immune system, opportunistic malignancies such as KS can do the same. Risk factors for development of IRIS are low pre‐ART CD4 count, high pre‐ART viral load, and rapid response to ART.2 In 1 large series, the median time to diagnosis of IRIS was 33 days.2 Immune reconstitution inflammatory syndrome is a clinical diagnosis without specific pathologic findings. Because IRIS is a diagnosis of exclusion, other explanations for worsening disease, including drug resistance, drug reactions (eg, abacavir hypersensitivity syndrome), and poor adherence to medications, should be ruled out before making the diagnosis.

Kaposi sarcoma is a vascular tumor associated with infection by human herpesvirus 8 (HHV‐8). The incidence of AIDS‐related KS has declined substantially in the post‐ART era.2, 4 The classic radiographic presentation of pulmonary KS includes central bilateral opacities with a peribronchovascular distribution as well as pulmonary nodules, intraseptal thickening, mediastinal lymphadenopathy, and associated pleural effusions.5, 6 Kaposi sarcomarelated IRIS has been described as developing within weeks of ART initiation and is associated with substantial morbidity and mortality, particularly in the context of pulmonary involvement, with 1 recent series showing 100% mortality in patients who did not receive chemotherapy.79

Human immunodeficiency virusassociated KS can respond well to ART alone. Indications for systemic chemotherapy for KS include extensive mucocutaneous disease, symptomatic visceral disease, or KS‐related IRIS.10 The main chemotherapeutic agents used systemically for KS are liposomal anthracyclines such as doxorubicin or daunorubicin, or taxanes such as paclitaxel.11 An association between corticosteroids and progression of KS has been previously described, even as early as several days after steroid administration.1214 Recently, revised diagnostic criteria for corticosteroid‐associated KS‐IRIS have been proposed; this patient met those criteria.15

Plasmablastic lymphoma is a highly aggressive systemic NHL seen predominantly in HIV‐positive patients. There is a strong association with Epstein‐Barr virus; HHV‐8 is more variably associated and is of unclear significance.16 Most HIV‐infected patients have extranodal involvement at diagnosis; in a series of 53 HIV‐positive patients, the oral cavity was the most frequent site, and lung involvement was seen in 12%. The prognosis is poor, with a mean survival of approximately 1 year.17

Treatment for systemic NHL in HIV‐positive patients generally consists of a chemotherapy regimen while ART is continued or initiated.18 The most commonly used chemotherapy combination is cyclophosphamide, doxorubicin, vincristine, and prednisone, often supplemented with the anti‐CD20 monoclonal antibody rituximab. In the case of aggressive systemic NHL, more intensive treatment regimens are often utilized, though it remains unclear if they are associated with improved outcomes.17, 19 Antiretroviral therapy is continued, as it has been shown to reduce the rate of opportunistic infections and decrease mortality.20

Despite the remarkable progress that has been made in the past 30 years, HIV/AIDS remains a devastating and remarkably complex disease. As the landscape of HIV/AIDS evolves, clinicians will continue to be faced with new challenging and vexing decisions. Perhaps no greater challenge exists than the presence of 2 simultaneous, rapidly fatal malignancies with directly competing therapeutic strategies, as in this case, where the ART and steroids employed to address NHL fostered widespread KS‐IRIS. This case reminds us that a single unifying diagnosis can often be the exception rather than the rule in the care of patients with advanced HIV. It also illustrates how the mainstay of HIV treatment, ART, can be a double‐edged sword.

KEY TEACHING POINTS

• In HIV/AIDS patients receiving ART who become paradoxically more ill despite improvements in their CD4 counts, consider IRIS.

• Though corticosteroids are a hallmark of treatment for most types of IRIS‐and for aggressive lymphomas‐they can worsen KS.

A 40‐year‐old man with human immunodeficiency virus (HIV) infection and a CD4 count of 58 cells/L was admitted to the hospital with 1 month of fevers, night sweats, a 5‐kg weight loss, several weeks of progressive dyspnea on exertion, and a nonproductive cough. He denied headaches, vision changes, odynophagia, diarrhea, or rash. He had no history of opportunistic infections, HIV‐associated neoplasms, or other relevant past medical history. He was diagnosed with HIV 3 years ago and had been off antiretroviral therapy (ART) for the last 10 months. Two weeks prior to this presentation, he was seen in clinic but did not report his symptoms. He was prescribed trimethoprim/sulfamethoxazole (TMP/SMX) for prophylaxis against Pneumocystis jirovecii pneumonia (PCP). He had recently moved from New York City to San Francisco, had quit smoking within the last month, and denied alcohol or illicit drug use.

At a CD4 cell count of 58 cells/L, the patient is at risk for the entire spectrum of HIV‐associated opportunistic infections and neoplasms. The presence of fevers, night sweats, and weight loss suggests the possibility of a disseminated infection, although a neoplastic process with accompanying B symptoms should also be considered. Dyspnea and nonproductive cough indicate cardiopulmonary involvement. The duration of these complaints is more suggestive of a nonbacterial infectious etiology (e.g., PCP, mycobacterial or fungal disease) than a bacterial etiology (e.g., Streptococcus pneumoniae). Irrespective of CD4 count, patients with HIV are at increased risk for cardiovascular events and pulmonary arterial hypertension, although the time course and presence of constitutional symptoms makes these diagnoses less likely. Similarly, patients with HIV are at increased risk for chronic obstructive pulmonary disease (COPD), and the patient does have a history of cigarette smoking, but the clinical history and systemic involvement make COPD unlikely.

On physical examination, the patient was in no acute distress. The temperature was 36C, the blood pressure 117/68 mm Hg, the heart rate 106 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 100% on ambient air. No oral lesions were noted, and his neck was supple with nontender bilateral cervical lymphadenopathy measuring up to 1.5 cm. There was no jugular venous distension or peripheral edema. The cardiovascular exam revealed tachycardia with a regular rhythm and no murmurs or gallops. His lungs were clear to auscultation. The spleen tipwas palpable. No rashes were identified. The neurological examination, including mental status, was normal.

The white blood cell count was 2400/mm³, the hemoglobin 7 g/dL with mean corpuscular volume of 86 fL, and the platelet count 162,000/mm³. Basic chemistry, liver, and glucose‐6‐phosphate dehydrogenase (G6PD) tests were within the laboratory's normal range. The HIV viral load was 150,000 copies/mL. Chest radiography revealed bibasilar hazy opacities, and computerized tomography (CT) of the chest revealed a focal nodular consolidation in the right middle lobe along with subcentimeter bilateral axillary and mediastinal lymphadenopathy. There were no ground‐glass opacities.

The patient's physical examination does not support a cardiac disorder. Lymphadenopathy is nonspecific, but it is consistent with a potential infectious or neoplastic process. Leukopenia and anemia suggest potential bone‐marrow infiltration or suppression by TMP/SMX. Although the pulmonary exam was nonfocal, chest imaging is the cornerstone of the evaluation of suspected pulmonary disease in persons with HIV. The focal nodular consolidation on chest CT is nonspecific but is more characteristic of typical or atypical bacterial pneumonia, mycobacterial disease such as tuberculosis, or fungal pneumonia than PCP or viral pneumonia. A lack of ground‐glass opacities also makes PCP and interstitial lung diseases less likely.

The patient was treated for community‐acquired pneumonia with ceftriaxone and doxycycline with improvement in dyspnea. Antiretroviral therapy with darunavir, ritonavir, tenofovir, and emtricitabine was initiated. Azithromycin was started for prophylaxis against Mycobacterium avium complex (MAC). The TMP/SMX was changed to dapsone, given concern for bone‐marrow suppression. Blood cultures for bacteria, fungi, and mycobacteria were negative. Polymerase chain reaction from pharyngeal swab for influenza A and B, parainfluenza types 13, rhinovirus, and respiratory syncytial virus were negative. Several attempts to obtain sputum for acid‐fast bacillus staining and culture were unsuccessful because the patient was unable to expectorate sputum. Serum interferon‐gamma release assay for M. tuberculosis and thefollowing serologic studies were also negative: cytomegalovirus, Epstein‐Barr virus, parvovirus, Bartonella species, Coccidioides immitis, and Cryptococcus neoformans antigen. Given his improvement, the patient was discharged from the hospital on ART, doxycycline for community‐acquired pneumonia, and prophylactic azithromycin and dapsone with scheduled outpatient follow‐up.

Ten days later, he was seen in clinic. Though his dyspnea had improved after completing the doxycycline, he noted a persistent dry cough and daily fevers to 40C. The physical exam was unchanged, including persistent cervical lymphadenopathy. Laboratories revealed a white blood cell count of 2400/mm³, hemoglobin of 4.8 g/dL, and a platelet count of 122,000/mm³. The absolute reticulocyte count was 21,000/L (normal value, 20,000100,000/L). A peripheral blood smear was unremarkable, and serum lactate dehydrogenase (LDH) was within normal limits. The direct antiglobulin test (DAT) was negative. The patient was readmitted to the hospital.

The initial improvement in dyspnea but persistent fevers and cough and worsening pancytopenia are suggestive of multiple processes occurring simultaneously. Dapsone can cause both hemolytic anemia and aplastic anemia, although the peripheral smear, normal LDH and G6PD, and negative DAT are not consistent with the former. Bone‐marrow suppression from a combination of ART medications and dapsone cannot be ruled out. An infiltrative process involving the bone marrow, including tuberculosis, MAC, disseminated fungal infection, or malignancy, remains a possibility. Repeat chest imaging is warranted to assess the prior right middle lobe consolidation and to further evaluate the persistent respiratory complaints.

Prophylaxis of PCP with dapsone was switched to atovaquone due to persistent anemia. A repeat CT of the chest and a concurrent abdominal CT revealed interval enlargement of mediastinal lymph nodes with multiple periportal, retroperitoneal, and hilar nodes not present on prior chest imaging, in addition to new bilateral centrilobular nodules and interval development of small bilateral pleural effusions. The abdominal CT also showed hepatosplenomegaly with splenic‐vein engorgement. Empiric treatment for disseminated MAC infection with clarithromycin and ethambutol was initiated in addition to vancomycin and cefepime for possible healthcare‐associated pneumonia. Over the next several days, the patient continued to have daily fevers up to 39.8C. A repeat CD4 count 3 weeks after starting ART was 121 cells/L. The HIV RNA level had decreased to 854 copies/mL.

The patient has developed progressive, generalized lymphadenopathy, worsening pancytopenia, and persistent fevers in the setting of negative cultures and serologic studies and despite treatment for MAC. This constellation, along with the radiographic findings of hilar lymphadenopathy and pleural effusions, is suggestive of non‐Hodgkin lymphoma (NHL). Alternatively, Kaposi sarcoma (KS) or tuberculosis can have a similar radiographic and clinical presentation, although pancytopenia from KS seems unusual. The lymphadenopathy could be consistent with multicentric Castleman disease or bacillary angiomatosis (BA), although the latter diagnosis would be unlikely given recent antibiotic therapy. At this time, a careful search for other manifestations and reasonable targets for biopsy is warranted. An appropriate suppression of the HIV viral load after initiation of ART, with improvement in CD4 count, is the proper context for the immune reconstitution inflammatory syndrome (IRIS), which is characterized by paradoxical worsening or unmasking of a disseminated process.

A bone‐marrow biopsy revealed marked dysmegakaryopoiesis and mild dyserythropoiesis, but no other abnormalities. Flow cytometry and histoimmunochemical staining did not show evidence of lymphoproliferative disorder in the marrow. Smears and cultures of the bone marrow for bacteria, acid‐fast bacilli, and fungi were negative. A right cervical lymph node biopsy was performed, with multiple fine‐needle aspiration and core samples taken. Bacterial, fungal, and acid‐fast bacilli tissue cultures were without growth, and initial pathology results were concerning for high‐grade lymphoma. A monoclonal proliferation of lymphocytes was noted on flow cytometry of the tissue sample. The patient developed progressive dyspnea, tachypnea, and hypoxemia. A chest x‐ray revealed worsening perihilar and basilar opacities.

The possibility of bone‐marrow sampling error must be considered in a patient that has such a high pretest probability for lymphoma or infection, but staining, immunological assays, cultures, and direct assessment by pathologists generally give some suggestion of an alternative diagnosis. The bone‐marrow findings are compatible with HIV‐related changes, but continued vigilance for infection and malignancy is warranted. Although the diagnosis of NHL based on the cervical biopsy result is only preliminary, the patient's rapidly deteriorating clinical status warrants initiation of treatment with steroids while awaiting definitive results, particularly given his poor response to aggressive management of potential infectious causes. A bronchoscopy should be considered given the predominance of pulmonary symptoms and his rapid respiratory decline.

Approximately 1 week after admission, high‐dose systemic corticosteroids were administered for presumed aggressive lymphoma. Over the next 48 hours, the patient's hypoxemia worsened, and he was intubated for hypoxemic respiratory failure. A repeat chest CT (see Fig. 1) showed bilateral peribronchovascular patchy consolidations and pleural effusions without evidence of pulmonary embolism. The patient was also noted to have a single, discrete violaceous nodule on the hard palate as well as a nodule with similar appearance on his upper chest (neither lesion was present on admission). A skin biopsy was obtained. Despite steroids, antibiotic therapy, and aggressive critical‐care management, severe acidosis, progressive acute kidney injury, and anuria ensued. Continuous venovenous hemodialysis was initiated.

Figure 1

Discrete violaceous nodules with mucocutaneous localization in the context of AIDS are virtually pathognomonic for KS. Rarely, BA may be misdiagnosed as KS, or they may occur concurrently. The patient's current clinical deterioration, radiographic findings, and development of new skin lesions in the setting of response to ART are concerning for KS‐related IRIS with visceral involvement. It is likely that systemic corticosteroids are potentiating KS‐related IRIS. At this point, there is compelling evidence of 2 distinct systemic disease processes: lymphoma and KS‐related IRIS, both of which may be contributing to respiratory failure. Steroids can be highly effective in the treatment of high‐grade lymphoma but can be harmful in patients with KS, where they have been shown to potentially exacerbate underlying disease. Given the patient's worsening respiratory status, discontinuation of corticosteroids and initiation of chemotherapy against both opportunistic malignancies should be considered.

The patient's condition deteriorated with progressive acidosis and hypoxemia, and he died shortly after being transitioned to comfort‐care measures. Review of the skin biopsy revealed KS. Autopsy revealed disseminated KS involving the skin, lymph nodes, and lungs, and high‐grade anaplastic plasmablastic lymphoma infiltrating multiple lymph nodes and organs, including the lungs (see Fig. 2). There was no evidence of infection.

Figure 2

COMMENTARY

This case demonstrates the simultaneous fatal progression of 2 treatable HIV‐associated malignancies in an era in which the end‐stage manifestations of untreated HIV are becoming less common, particularly in developed countries. Modern ARTthe centerpiece of progress with HIVhas yielded dramatic improvements in prognosis, but in this case, by precipitating KS‐IRIS, ART paradoxically contributed to this patient's demise. Similarly, high‐dose systemic corticosteroids, which were deemed necessary to stabilize the progression of his high‐grade lymphoma, likely accelerated his KS. This corticosteroid‐mediated worsening appears to be unique to KS given that corticosteroids are often recommended to treat severe presentations of IRIS in other diseases (eg, tuberculosis, MAC, PCP).

Immune reconstitution inflammatory syndrome is the paradoxical worsening of well‐controlled disease or progression of previously occult disease after initiation of ART.1

Although infectious diseasesincluding mycobacteria, cytomegalovirus, cryptococcosis, or PCPare best known for their ability to recrudesce or manifest with a recovering immune system, opportunistic malignancies such as KS can do the same. Risk factors for development of IRIS are low pre‐ART CD4 count, high pre‐ART viral load, and rapid response to ART.2 In 1 large series, the median time to diagnosis of IRIS was 33 days.2 Immune reconstitution inflammatory syndrome is a clinical diagnosis without specific pathologic findings. Because IRIS is a diagnosis of exclusion, other explanations for worsening disease, including drug resistance, drug reactions (eg, abacavir hypersensitivity syndrome), and poor adherence to medications, should be ruled out before making the diagnosis.

Kaposi sarcoma is a vascular tumor associated with infection by human herpesvirus 8 (HHV‐8). The incidence of AIDS‐related KS has declined substantially in the post‐ART era.2, 4 The classic radiographic presentation of pulmonary KS includes central bilateral opacities with a peribronchovascular distribution as well as pulmonary nodules, intraseptal thickening, mediastinal lymphadenopathy, and associated pleural effusions.5, 6 Kaposi sarcomarelated IRIS has been described as developing within weeks of ART initiation and is associated with substantial morbidity and mortality, particularly in the context of pulmonary involvement, with 1 recent series showing 100% mortality in patients who did not receive chemotherapy.79

Human immunodeficiency virusassociated KS can respond well to ART alone. Indications for systemic chemotherapy for KS include extensive mucocutaneous disease, symptomatic visceral disease, or KS‐related IRIS.10 The main chemotherapeutic agents used systemically for KS are liposomal anthracyclines such as doxorubicin or daunorubicin, or taxanes such as paclitaxel.11 An association between corticosteroids and progression of KS has been previously described, even as early as several days after steroid administration.1214 Recently, revised diagnostic criteria for corticosteroid‐associated KS‐IRIS have been proposed; this patient met those criteria.15

Plasmablastic lymphoma is a highly aggressive systemic NHL seen predominantly in HIV‐positive patients. There is a strong association with Epstein‐Barr virus; HHV‐8 is more variably associated and is of unclear significance.16 Most HIV‐infected patients have extranodal involvement at diagnosis; in a series of 53 HIV‐positive patients, the oral cavity was the most frequent site, and lung involvement was seen in 12%. The prognosis is poor, with a mean survival of approximately 1 year.17

Treatment for systemic NHL in HIV‐positive patients generally consists of a chemotherapy regimen while ART is continued or initiated.18 The most commonly used chemotherapy combination is cyclophosphamide, doxorubicin, vincristine, and prednisone, often supplemented with the anti‐CD20 monoclonal antibody rituximab. In the case of aggressive systemic NHL, more intensive treatment regimens are often utilized, though it remains unclear if they are associated with improved outcomes.17, 19 Antiretroviral therapy is continued, as it has been shown to reduce the rate of opportunistic infections and decrease mortality.20

Despite the remarkable progress that has been made in the past 30 years, HIV/AIDS remains a devastating and remarkably complex disease. As the landscape of HIV/AIDS evolves, clinicians will continue to be faced with new challenging and vexing decisions. Perhaps no greater challenge exists than the presence of 2 simultaneous, rapidly fatal malignancies with directly competing therapeutic strategies, as in this case, where the ART and steroids employed to address NHL fostered widespread KS‐IRIS. This case reminds us that a single unifying diagnosis can often be the exception rather than the rule in the care of patients with advanced HIV. It also illustrates how the mainstay of HIV treatment, ART, can be a double‐edged sword.

KEY TEACHING POINTS

• In HIV/AIDS patients receiving ART who become paradoxically more ill despite improvements in their CD4 counts, consider IRIS.

• Though corticosteroids are a hallmark of treatment for most types of IRIS‐and for aggressive lymphomas‐they can worsen KS.