Grand Rounds

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

Stones are caused by a deficiency of the liver enzyme alanine-­glyoxylate aminotransferase (AGXT), which ordinarily converts glyoxylate to glycine.^2,4 When AGXT is absent, glyoxylate is converted instead to oxalate, which forms insoluble salts that accumulate in the kidney as oxalate kidney stones. Most patients (ie, 80% to 90%) present in late childhood or early adolescence with systems of recurrent stones and urinary tract infections resulting from blockage.^5,6 The natural history of the disease is progression to kidney failure and death from end-stage renal disease unless dialysis is initiated. 

While testing of oxalate-to-creatinine molar ratio in a random urine sample may be helpful, this measurement does not stabilize until age 14 to 18—often after kidney damage has already occurred.⁷ Liver biopsy can confirm whether the enzyme AGXT is absent. Differentiation between PHO and type 2 hyperoxaluria can only be confirmed by genetic testing in which the AGXT gene is identified.⁸

There is an increased incidence of PHO in Tunisia and Kuwait^9-11 and in the Arab and Druze families of Israel¹² as a result of intermarriages in this population. Since AGXT is a recessive gene, the child of parents who are both carriers has a 25% chance of having the disease. If either parent carries the genetic variant, there is a 50% chance that the recessive gene will be passed on.

Diagnosis
Early diagnosis of PHO is critical. However, because the disease is so rare, more than 40% of affected patients do not receive a diagnosis until three years after symptoms develop, and 30% are diagnosed only upon presentation with end-stage renal disease.^2,13

If PHO is detected early, the key management goal is to minimize renal and skeletal oxalate deposition. Components of medical management are shown in the table.^2,14-17 It is important to note that these strategies are effective only if initiated early, that is, before the patient’s glomerular filtration rate drops below 25 mL/min.¹⁸

Treatment
Organ transplantation remains the only definitive treatment for PHO^14,19—to prevent severe systemic oxalosis or to manage the patient who has progressed to end-stage renal disease. Researchers from the Mayo Clinic in Rochester, Minnesota (where, it should be noted, a National Oxalosis and Hyperoxaluria Registry is maintained under the direction of Dawn S. Milliner, MD), recently published an observational study of outcomes in transplant graft survival among 203 PHO patients. Bergstralh et al²⁰ reported high rates of recurrent oxalosis in patients undergoing kidney transplantation alone, and significantly improved outcomes in patients who underwent both liver and kidney transplantation.

Before 1990, according to a report by the Rare Kidney Stone Consortium,¹⁸ the prognosis for PHO transplant patients in the United States was so poor that a donor kidney was considered wasted on these patients. Since the year 2000, however, survival after transplantation has improved greatly, with rates similar to those of all kidney transplant patients nationwide. The explanation for increased survival rates among PHO patients undergoing transplantation was twofold:

• Increased preoperative stone control

• Use of combined liver-kidney transplants.^21,22

Since the liver is responsible for the cascade of calcium oxalate stones, the native liver must be fully removed prior to transplantation of a new liver and kidney. Postoperatively, stones will also emerge from where they have lodged in the skeletal tissue to shower the new kidney. Thus, medical management of this cascade of new stones is vital if the transplanted grafts are to survive.²³ Calcium oxalate blood levels can remain high for one to two years posttransplantation,^2,24 so long-term medical management of oxalate is essential.

The Case Patient
Clinicians engaged in a discussion with the patient and her family regarding a possible diagnosis of PHO. Blood was drawn and sent to the Mayo Clinic for genetic analysis. It was found that the patient had an abnormality in the AGXT gene; with the diagnosis of type 1 hyperoxaluria confirmed, she was flown to Rochester for a full workup.

The patient was the only member of her family with the defective AGXT gene, and her genetic counselors considered this a single mutation. She was accepted for the liver/kidney transplantation list. 

Due to the increase in reported survival among patients if they undergo transplantation early in the natural history of stone deposition, the average wait time for PHO patients is only three to four months. The case patient returned to the dialysis unit in Virginia, where she was placed on a dialysis regimen of five-hour treatments, five times per week (nighttime and day); this was determined to be the peak treatment duration for most efficient stone removal, as determined by calcium oxalate measurement during her workup at the Mayo Clinic.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

Stones are caused by a deficiency of the liver enzyme alanine-­glyoxylate aminotransferase (AGXT), which ordinarily converts glyoxylate to glycine.^2,4 When AGXT is absent, glyoxylate is converted instead to oxalate, which forms insoluble salts that accumulate in the kidney as oxalate kidney stones. Most patients (ie, 80% to 90%) present in late childhood or early adolescence with systems of recurrent stones and urinary tract infections resulting from blockage.^5,6 The natural history of the disease is progression to kidney failure and death from end-stage renal disease unless dialysis is initiated. 

While testing of oxalate-to-creatinine molar ratio in a random urine sample may be helpful, this measurement does not stabilize until age 14 to 18—often after kidney damage has already occurred.⁷ Liver biopsy can confirm whether the enzyme AGXT is absent. Differentiation between PHO and type 2 hyperoxaluria can only be confirmed by genetic testing in which the AGXT gene is identified.⁸

There is an increased incidence of PHO in Tunisia and Kuwait^9-11 and in the Arab and Druze families of Israel¹² as a result of intermarriages in this population. Since AGXT is a recessive gene, the child of parents who are both carriers has a 25% chance of having the disease. If either parent carries the genetic variant, there is a 50% chance that the recessive gene will be passed on.

Diagnosis
Early diagnosis of PHO is critical. However, because the disease is so rare, more than 40% of affected patients do not receive a diagnosis until three years after symptoms develop, and 30% are diagnosed only upon presentation with end-stage renal disease.^2,13

If PHO is detected early, the key management goal is to minimize renal and skeletal oxalate deposition. Components of medical management are shown in the table.^2,14-17 It is important to note that these strategies are effective only if initiated early, that is, before the patient’s glomerular filtration rate drops below 25 mL/min.¹⁸

Treatment
Organ transplantation remains the only definitive treatment for PHO^14,19—to prevent severe systemic oxalosis or to manage the patient who has progressed to end-stage renal disease. Researchers from the Mayo Clinic in Rochester, Minnesota (where, it should be noted, a National Oxalosis and Hyperoxaluria Registry is maintained under the direction of Dawn S. Milliner, MD), recently published an observational study of outcomes in transplant graft survival among 203 PHO patients. Bergstralh et al²⁰ reported high rates of recurrent oxalosis in patients undergoing kidney transplantation alone, and significantly improved outcomes in patients who underwent both liver and kidney transplantation.

Before 1990, according to a report by the Rare Kidney Stone Consortium,¹⁸ the prognosis for PHO transplant patients in the United States was so poor that a donor kidney was considered wasted on these patients. Since the year 2000, however, survival after transplantation has improved greatly, with rates similar to those of all kidney transplant patients nationwide. The explanation for increased survival rates among PHO patients undergoing transplantation was twofold:

• Increased preoperative stone control

• Use of combined liver-kidney transplants.^21,22

Since the liver is responsible for the cascade of calcium oxalate stones, the native liver must be fully removed prior to transplantation of a new liver and kidney. Postoperatively, stones will also emerge from where they have lodged in the skeletal tissue to shower the new kidney. Thus, medical management of this cascade of new stones is vital if the transplanted grafts are to survive.²³ Calcium oxalate blood levels can remain high for one to two years posttransplantation,^2,24 so long-term medical management of oxalate is essential.

The Case Patient
Clinicians engaged in a discussion with the patient and her family regarding a possible diagnosis of PHO. Blood was drawn and sent to the Mayo Clinic for genetic analysis. It was found that the patient had an abnormality in the AGXT gene; with the diagnosis of type 1 hyperoxaluria confirmed, she was flown to Rochester for a full workup.

The patient was the only member of her family with the defective AGXT gene, and her genetic counselors considered this a single mutation. She was accepted for the liver/kidney transplantation list. 

Due to the increase in reported survival among patients if they undergo transplantation early in the natural history of stone deposition, the average wait time for PHO patients is only three to four months. The case patient returned to the dialysis unit in Virginia, where she was placed on a dialysis regimen of five-hour treatments, five times per week (nighttime and day); this was determined to be the peak treatment duration for most efficient stone removal, as determined by calcium oxalate measurement during her workup at the Mayo Clinic.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

Stones are caused by a deficiency of the liver enzyme alanine-­glyoxylate aminotransferase (AGXT), which ordinarily converts glyoxylate to glycine.^2,4 When AGXT is absent, glyoxylate is converted instead to oxalate, which forms insoluble salts that accumulate in the kidney as oxalate kidney stones. Most patients (ie, 80% to 90%) present in late childhood or early adolescence with systems of recurrent stones and urinary tract infections resulting from blockage.^5,6 The natural history of the disease is progression to kidney failure and death from end-stage renal disease unless dialysis is initiated. 

While testing of oxalate-to-creatinine molar ratio in a random urine sample may be helpful, this measurement does not stabilize until age 14 to 18—often after kidney damage has already occurred.⁷ Liver biopsy can confirm whether the enzyme AGXT is absent. Differentiation between PHO and type 2 hyperoxaluria can only be confirmed by genetic testing in which the AGXT gene is identified.⁸

There is an increased incidence of PHO in Tunisia and Kuwait^9-11 and in the Arab and Druze families of Israel¹² as a result of intermarriages in this population. Since AGXT is a recessive gene, the child of parents who are both carriers has a 25% chance of having the disease. If either parent carries the genetic variant, there is a 50% chance that the recessive gene will be passed on.

Diagnosis
Early diagnosis of PHO is critical. However, because the disease is so rare, more than 40% of affected patients do not receive a diagnosis until three years after symptoms develop, and 30% are diagnosed only upon presentation with end-stage renal disease.^2,13

If PHO is detected early, the key management goal is to minimize renal and skeletal oxalate deposition. Components of medical management are shown in the table.^2,14-17 It is important to note that these strategies are effective only if initiated early, that is, before the patient’s glomerular filtration rate drops below 25 mL/min.¹⁸

Treatment
Organ transplantation remains the only definitive treatment for PHO^14,19—to prevent severe systemic oxalosis or to manage the patient who has progressed to end-stage renal disease. Researchers from the Mayo Clinic in Rochester, Minnesota (where, it should be noted, a National Oxalosis and Hyperoxaluria Registry is maintained under the direction of Dawn S. Milliner, MD), recently published an observational study of outcomes in transplant graft survival among 203 PHO patients. Bergstralh et al²⁰ reported high rates of recurrent oxalosis in patients undergoing kidney transplantation alone, and significantly improved outcomes in patients who underwent both liver and kidney transplantation.

Before 1990, according to a report by the Rare Kidney Stone Consortium,¹⁸ the prognosis for PHO transplant patients in the United States was so poor that a donor kidney was considered wasted on these patients. Since the year 2000, however, survival after transplantation has improved greatly, with rates similar to those of all kidney transplant patients nationwide. The explanation for increased survival rates among PHO patients undergoing transplantation was twofold:

• Increased preoperative stone control

• Use of combined liver-kidney transplants.^21,22

Since the liver is responsible for the cascade of calcium oxalate stones, the native liver must be fully removed prior to transplantation of a new liver and kidney. Postoperatively, stones will also emerge from where they have lodged in the skeletal tissue to shower the new kidney. Thus, medical management of this cascade of new stones is vital if the transplanted grafts are to survive.²³ Calcium oxalate blood levels can remain high for one to two years posttransplantation,^2,24 so long-term medical management of oxalate is essential.

The Case Patient
Clinicians engaged in a discussion with the patient and her family regarding a possible diagnosis of PHO. Blood was drawn and sent to the Mayo Clinic for genetic analysis. It was found that the patient had an abnormality in the AGXT gene; with the diagnosis of type 1 hyperoxaluria confirmed, she was flown to Rochester for a full workup.

The patient was the only member of her family with the defective AGXT gene, and her genetic counselors considered this a single mutation. She was accepted for the liver/kidney transplantation list. 

Due to the increase in reported survival among patients if they undergo transplantation early in the natural history of stone deposition, the average wait time for PHO patients is only three to four months. The case patient returned to the dialysis unit in Virginia, where she was placed on a dialysis regimen of five-hour treatments, five times per week (nighttime and day); this was determined to be the peak treatment duration for most efficient stone removal, as determined by calcium oxalate measurement during her workup at the Mayo Clinic.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

A 6-year-old girl was brought to a pediatric emergency department (ED) in Atlanta by her mother. The mother stated that during the previous hour, she had noticed that her daughter’s face seemed weaker on the right side.

The night before, the child had said, “I can’t blink my eye”; when her mother asked her to demonstrate, the child seemed to be able to blink both eyes appropriately, and she had no further complaints. The next morning, the child complained of the light being too bright and asked to wear her mother’s sunglasses. In the course of the day, she continued to complain of eye discomfort, which she described as “stinging” and “sore.” The mother could see nothing abnormal, but by late afternoon noticed that her daughter’s smile and facial movements were asymmetrical. She immediately took her to the pediatric ED.

The child had no significant medical history and no surgical history. Her vaccination schedule was current, and she denied any recent illnesses. The mother could recall no exposures to infections or tick bites, no rashes, and no trauma to the face or head. The mother and child were visiting Atlanta from northeastern Florida.

The review of systems was negative for headache, fever, chills, rash, earache, sore throat, cough, rhinorrhea, vision changes, weight loss, or change in appetite or disposition. The child was afebrile, and the other vital signs were within normal limits. 

Physical examination revealed an alert child who was calm and conversant. Her height was 45” and weight, 43 lb. Otoscopic exam showed normal ears and tympanic membranes with no sign of otitis media or ear pathology. No throat redness, tonsillar enlargement, or lymphadenopathies were noted. Breath sounds were clear, and heart rhythm and rate were regular without murmur. 

The patient’s left eye appeared normal, and the right eye was mildly erythematic without drainage or swelling; since corneal abrasion was not suspected, a slit lamp examination was not performed. Upon neurologic examination, right eye ptosis with incomplete lid closure, asymmetrical mouth movement with smile, and a diminished nasal labial fold crease were noted on the right side. When the child was asked to raise her eyebrows and wrinkle her forehead, asymmetrical forehead creases were apparent. All other cranial nerve functions were intact, and motor and sensory responses, including gait and reflexes, were assessed as normal. Unilateral dysfunction of right-sided cranial nerve VII (CN VII), including forehead involvement, was confirmed, consistent with a grade of III to IV on the House-Brackmann (maximum, VI)^1,2 facial nerve grading scale.

Based on the rapid onset of unilateral facial nerve paresis (FNP) and an otherwise normal exam, the patient was diagnosed with Bell’s palsy. No further testing was done, and the child was given a dose of oral prednisolone 40 mg in the ED, with a prescription for four more days of oral prednisolone at 15 mg bid. The need for eye protection and lubrication was emphasized to the mother, who was given lubricating eye drops to administer. The mother was also instructed to follow up with the child’s primary care practitioner upon their return to Florida. 

The child was seen by her pediatrician three days later. Her facial paresis had not worsened in the interim, and the pediatrician declined to extend the course of corticosteroids or to add an antiviral medication. At the mother’s request, the child was referred to a pediatric otolaryngologist, who saw her the following day and adjusted the treatment plan. The child was prescribed prednisolone elixir 20 mg bid for one week, followed by a tapering dose for the second week. In addition, she was prescribed oral acyclovir 400 mg qid for 10 days. Her mother was instructed to return with the child in one week for audiometry testing.  

Discussion
Idiopathic FNP, commonly referred to as Bell’s palsy, is defined as an acute unilateral paresis of the facial nerve without detectable underlying cause.^3,4 It most commonly occurs among persons ages 15 to 45, with a prevalence rate of 15 to 30 cases per 100,000 persons. The peak incidence of Bell’s palsy is in the fourth decade of life. Diabetic patients and pregnant women are disproportionately affected by idiopathic FNP.^2,5 About 8% to 10% of patients will experience a recurrence of Bell’s palsy within 10 years.^2,6

Pediatric FNP can be congenital or acquired. Congenital FNP is most often associated with birth trauma and occurs at a rate of 2.1 cases per 1,000 births. Rare genetic syndromes can also manifest with FNP and will most often present with other syndromic anomalies noted at birth.⁷

Acquired FNP is two to four times less common in children than adults, with an estimated prevalence of 2.7 per 100,000 patients younger than 10. Children account for only a small proportion of subjects in published studies that address diagnosis and management of FNP.³ While the presentation of FNP is much the same in adults and children, some notable differences in etiology exist.^2,3,7-9 Infectious, traumatic, or neoplastic causes of FNP are more common among children than adults and must be distinguished from idiopathic FNP.^7,9-11

Decisions regarding diagnostic testing, pharmacologic treatment, and referral must be guided by the history and physical exam, neurologic exam, and clinical judgment. Being able to identify or exclude alarming causes of FNP, such as neoplasm, will aid the primary care practitioner in treatment and referral practices for this condition.

Pathophysiology
CN VII, the facial nerve, has a broad scope of function that incorporates both sensory and motor pathways. The brachial nerve portion of CN VII controls the muscles of voluntary facial expression. CN VII also autonomically innervates the lacrimal gland and submandibular gland and governs sensation from part of the ear as well as taste from the anterior two-thirds of the tongue.⁴

The precise pathophysiology involved in FNP remains an area of continuing debate, but infectious, vascular, immunologic, and genetic causes have been hypothesized.^7,12 Inflammation and subsequent nerve damage along CN VII caused by an infectious process is thought to be the most likely explanation for the pathogenesis of acquired FNP in both adults and children.^5,13

Herpes simplex virus 1 (HSV-1) has been suggested as the virus most commonly linked to FNP in both adults and children, but it is unlikely to be the sole cause.^5,6,9 Data from a three-year prospective study of FNP cases in children support a relationship between pediatric FNP and HSV-1 infection.¹⁴ Other infectious causes implicated in pediatric FNP are Lyme disease, Epstein-Barr, varicella zoster virus, rubella, coxsackie virus, adenovirus, and otitis media.^4,7,9

Presentation, History, and Physical Exam
Most children with idiopathic FNP will present with sudden-onset facial asymmetry and may have decreased tearing, loss of the conjunctival reflex (leading to difficulty closing the eye), an inability to hold the lips tightly together, and difficulty keeping food in the mouth. Complaints of otalgia, speech disturbances, hyperacusis, and altered sense of taste are common.^2,7 Recent occurrence of an upper respiratory infection is often reported in the history of a pediatric patient with FNP.^3,7,15,16

Idiopathic FNP is essentially a diagnosis of exclusion.^3,5 A meticulous history must be conducted, including any recent illnesses, trauma to the face or head, vaccines, rashes, and travel. Assessment of the head, eyes, ears, nose, and throat, and a careful neurologic history must be conducted to identify nonidiopathic causes of FNP (see Table 1^5-7,9). Facial weakness can progress from mild palsy to complete paralysis over one to two weeks⁵; therefore, a careful history of the progression of facial weakness should be ascertained and documented.^5,17 

A full neurologic exam is essential. Cranial nerves I through XII should be evaluated; any malfunction of a cranial nerve other than CN VII could be indicative of a tumor or process other than idiopathic FNP. Assessment of facial nerve function is imperative, as this factor is the most important for predicting recovery; it can also aid in formulating a prognosis and directing treatment.^5,9,17

The House-Brackmann facial nerve grading system^1,2 is considered the gold standard for grading severity of facial paresis⁹ (see Table 2^1,2 ). A clear distinction between paresis (partial or incomplete palsy) and paralysis (complete palsy) must be made. Pediatric patients with an incomplete palsy have an improved chance of full recovery.^17,18

Any abnormalities in the peripheral neurologic exam should prompt further testing. FNP not involving the forehead musculature, gradual progression of paresis, and weakness in any extremity could be indicative of a central lesion. FNP has been the presenting symptom in various neoplastic processes, including leukemia, cholesteatoma, and astrocytoma.^3,7,9

Otitis media is a frequent cause of FNP among children.^9-11 Thus, a thorough examination of the ear canal, tympanic membrane, and hearing should be performed. The throat and oropharynx should be inspected, and the parotid gland palpated. Any swelling or abnormalities warrant further investigation.

Lyme disease presenting with FNP is more common in children than adults. This may be related to the increased likelihood for children to be bitten by ticks in the head and neck areas. Frequently, FNP associated with Lyme disease is bilateral—as often as 25% of the time.¹⁹ Headache, onset of symptoms during peak Lyme season, or bilateral FNP should raise the clinician’s suspicion for Lyme disease.^7,9,19

An accurate assessment of blood pressure is essential, as severe hypertension may be implicated in FNP in children.^3,5,7 One literature review reported that hypertension was the origin of FNP in 3% to 17% of affected children.²⁰ Vascular hemorrhage induced by hypertension is thought to cause nerve compression and subsequent FNP.⁷

A bilateral eye exam is also important. Irritation is likely, and the patient with any suspected corneal abrasion or damage should be referred to an ophthalmologist.^6,18

Laboratory Testing and Imaging
Diagnostic testing that facilitates the exclusion of known causes of FNP should be considered, as there is no specific laboratory test to confirm the diagnosis. A complete blood count, Lyme titers, cerebrospinal fluid analysis, CT, and/or MRI may be warranted, based on the clinical presentation.^7-9 In children in whom Lyme disease is suspected (ie, those living in tick-endemic areas or with recent tick bites), serologic testing should be performed. Lumbar puncture and an evaluation of cerebrospinal fluid may be necessary in cases in which meningitis cannot be excluded.^7,9

Specialized diagnostic tests are not routinely recommended for patients with paresis that is improving. Audiometry and evaluation of the stapedial reflex may help guide treatment decisions for patients whose condition is not improving. In children, the presence or return of the stapedial reflex within three weeks of disease onset is predictive of complete recovery.⁵ In patients who experience complete paralysis or unimproved paresis, results of electrodiagnostic testing (in particular, evoked facial nerve electroneuronography) can help forecast recovery of facial nerve function.^5,17

Treatment and Management
Treatment for FNP in adults is controversial, and even more so for the pediatric patient. Treatment decisions consist of eye care, corticosteroids, antiviral medications, and appropriate referrals.

Eye care. Eye lubrication and protection should be implemented immediately. Protecting the cornea is paramount; thorough lubrication of the eye is the mainstay of treatment.¹⁸ Artificial tears should be used frequently during the day, and an ointment should be applied to the eye at night. Use of eye patches is controversial, as they may actually cause corneal injury.^7,9 Taping the eye shut at night may prevent trauma during sleep, but this option must be considered carefully.^9,18

Corticosteroids. Early initiation of corticosteroids should be considered for all patients with FNP, including children.^2,7,9,17 Studies are inconclusive as to whether steroid therapy is beneficial in children with idiopathic FNP. However, two 2010 reviews of pediatric FNP recommend early initiation of steroids for children with acute-onset FNP, particularly when facial paresis is evaluated at a House-Brackmann grade V or VI.^7,9 The American Academy of Family Physicians (AAFP) recommends a tapering course of prednisone for all patients, begun as soon as possible.⁶ The prednisone dosage for pediatric patients is usually 1.0 mg/kg/d, split into two doses, for six days, followed by a tapering dose for four days.⁵

Antivirals and antibiotic therapy. When an infectious cause of FNP is known, appropriate antibiotic or antiviral therapy should begin. If the patient lives in or has traveled to an area endemic for Lyme disease, empiric treatment may be appropriate. When Ramsay Hunt syndrome is diagnosed or herpetic lesions are visible, antiviral treatment should be initiated.⁷

Antiviral therapy for idiopathic FNP is the most controversial of the treatment decisions. In 2001, the American Academy of Neurology concluded that no clear benefit from acyclovir could be ascertained, although it might be effective.¹³ This was affirmed in a recently updated Cochrane review of antiviral therapy for idiopathic FNP.¹² Antiviral therapy alone showed no benefit, compared with placebo; however, combined antiviral and corticosteroid therapy was more effective than placebo alone in recovery outcomes. Antivirals may benefit pediatric patients and should be considered early when the cause of FNP is viral or idiopathic.^7,9

Referrals. Initial presentation and course of paresis should guide referral patterns for the pediatric patient presenting with FNP. The American Academy of Pediatrics (AAP) recommends referral to an otolaryngologist for any infant or child with FNP.²¹ The AAFP recommends referral to a specialist for any patient who does not show improvement within two weeks.⁶

In patients with complete paralysis, early surgical intervention may be considered, and referral should be made promptly for electrodiagnostic testing and surgical consult. In cases in which otitis media causes FNP, myringotomy and tube insertion are indicated, and appropriate referral should be made.^7,9

Outcomes
|The prognosis in children with FNP is good, and most will recover completely.^2,9-11,22 Idiopathic and infectious etiologies of FNP seem to have the greatest likelihood for complete recovery.^10,11,16,17 Recovery appears to be affected by etiology, degree of paresis, and treatment. How these factors coalesce is not fully understood, and up to 20% of children may have mild to moderate residual facial nerve dysfunction.^10,11,19,22

The Case Patient
The child’s facial nerve function gradually returned over a three-week period, with no residual deficit (see Figures 1a, 1b, and 1c). Results of the audiometry screening on day 10 were normal, showing a positive stapedial reflex. An MRI, performed four months after the initial paralysis to rule out any tumors, yielded normal results. 

This case highlights the differing management of pediatric Bell’s palsy among emergency, pediatric, and specialized providers. This child was managed more aggressively under the care of an otolaryngologist with a two-week course of steroids, antiviral medication for 10 days, and a follow-up MRI to rule out any evidence of a tumor. The need for further research to guide practice in the pediatric patient with Bell’s palsy is apparent.

Conclusion
FNP in the pediatric population is rare and more likely to have an identifiable cause than among adults. Careful examination should reveal differential diagnoses that warrant treatment and referrals. The main causes of FNP that should not be missed are otitis media, hypertension, varicella zoster virus (Ramsay Hunt syndrome), neoplastic processes, and Lyme disease.

Practitioners should have a high index of suspicion for nonidiopathic causes of FNP when a child has a neurologic exam that includes facial paresis of gradual onset, abnormal function of other cranial nerves, lack of forehead muscle weakness, or peripheral abnormalities. In addition to the history and exam, blood work and radiologic imaging can aid the practitioner in ruling in or out nonidiopathic causes of FNP. 

Grading of facial palsy severity using the House-Brackmann scale helps guide prognosis and referral choices. Referral to a specialist in otolaryngology is appropriate and recommended by the AAP. Referral should be made to an ophthalmologist if any suspicion of corneal abrasion exists. 

Treatment in children should consist of eye care and steroids. Antiviral therapy should be considered on an individualized basis and when evidence of HSV or varicella exists. Parents should be advised about the importance of eye care in a child with FNP (see Table 3^{5-7,9,17,18,22}).

The emotional stress associated with FNP can be significant for both children and adults; fear of lifelong facial deformity can be psychologically debilitating. Yet a favorable prognosis for recovery of facial nerve function can be relayed to anxious parents.

A 6-year-old girl was brought to a pediatric emergency department (ED) in Atlanta by her mother. The mother stated that during the previous hour, she had noticed that her daughter’s face seemed weaker on the right side.

The night before, the child had said, “I can’t blink my eye”; when her mother asked her to demonstrate, the child seemed to be able to blink both eyes appropriately, and she had no further complaints. The next morning, the child complained of the light being too bright and asked to wear her mother’s sunglasses. In the course of the day, she continued to complain of eye discomfort, which she described as “stinging” and “sore.” The mother could see nothing abnormal, but by late afternoon noticed that her daughter’s smile and facial movements were asymmetrical. She immediately took her to the pediatric ED.

The child had no significant medical history and no surgical history. Her vaccination schedule was current, and she denied any recent illnesses. The mother could recall no exposures to infections or tick bites, no rashes, and no trauma to the face or head. The mother and child were visiting Atlanta from northeastern Florida.

The review of systems was negative for headache, fever, chills, rash, earache, sore throat, cough, rhinorrhea, vision changes, weight loss, or change in appetite or disposition. The child was afebrile, and the other vital signs were within normal limits. 

Physical examination revealed an alert child who was calm and conversant. Her height was 45” and weight, 43 lb. Otoscopic exam showed normal ears and tympanic membranes with no sign of otitis media or ear pathology. No throat redness, tonsillar enlargement, or lymphadenopathies were noted. Breath sounds were clear, and heart rhythm and rate were regular without murmur. 

The patient’s left eye appeared normal, and the right eye was mildly erythematic without drainage or swelling; since corneal abrasion was not suspected, a slit lamp examination was not performed. Upon neurologic examination, right eye ptosis with incomplete lid closure, asymmetrical mouth movement with smile, and a diminished nasal labial fold crease were noted on the right side. When the child was asked to raise her eyebrows and wrinkle her forehead, asymmetrical forehead creases were apparent. All other cranial nerve functions were intact, and motor and sensory responses, including gait and reflexes, were assessed as normal. Unilateral dysfunction of right-sided cranial nerve VII (CN VII), including forehead involvement, was confirmed, consistent with a grade of III to IV on the House-Brackmann (maximum, VI)^1,2 facial nerve grading scale.

Based on the rapid onset of unilateral facial nerve paresis (FNP) and an otherwise normal exam, the patient was diagnosed with Bell’s palsy. No further testing was done, and the child was given a dose of oral prednisolone 40 mg in the ED, with a prescription for four more days of oral prednisolone at 15 mg bid. The need for eye protection and lubrication was emphasized to the mother, who was given lubricating eye drops to administer. The mother was also instructed to follow up with the child’s primary care practitioner upon their return to Florida. 

The child was seen by her pediatrician three days later. Her facial paresis had not worsened in the interim, and the pediatrician declined to extend the course of corticosteroids or to add an antiviral medication. At the mother’s request, the child was referred to a pediatric otolaryngologist, who saw her the following day and adjusted the treatment plan. The child was prescribed prednisolone elixir 20 mg bid for one week, followed by a tapering dose for the second week. In addition, she was prescribed oral acyclovir 400 mg qid for 10 days. Her mother was instructed to return with the child in one week for audiometry testing.  

Discussion
Idiopathic FNP, commonly referred to as Bell’s palsy, is defined as an acute unilateral paresis of the facial nerve without detectable underlying cause.^3,4 It most commonly occurs among persons ages 15 to 45, with a prevalence rate of 15 to 30 cases per 100,000 persons. The peak incidence of Bell’s palsy is in the fourth decade of life. Diabetic patients and pregnant women are disproportionately affected by idiopathic FNP.^2,5 About 8% to 10% of patients will experience a recurrence of Bell’s palsy within 10 years.^2,6

Pediatric FNP can be congenital or acquired. Congenital FNP is most often associated with birth trauma and occurs at a rate of 2.1 cases per 1,000 births. Rare genetic syndromes can also manifest with FNP and will most often present with other syndromic anomalies noted at birth.⁷

Acquired FNP is two to four times less common in children than adults, with an estimated prevalence of 2.7 per 100,000 patients younger than 10. Children account for only a small proportion of subjects in published studies that address diagnosis and management of FNP.³ While the presentation of FNP is much the same in adults and children, some notable differences in etiology exist.^2,3,7-9 Infectious, traumatic, or neoplastic causes of FNP are more common among children than adults and must be distinguished from idiopathic FNP.^7,9-11

Decisions regarding diagnostic testing, pharmacologic treatment, and referral must be guided by the history and physical exam, neurologic exam, and clinical judgment. Being able to identify or exclude alarming causes of FNP, such as neoplasm, will aid the primary care practitioner in treatment and referral practices for this condition.

Pathophysiology
CN VII, the facial nerve, has a broad scope of function that incorporates both sensory and motor pathways. The brachial nerve portion of CN VII controls the muscles of voluntary facial expression. CN VII also autonomically innervates the lacrimal gland and submandibular gland and governs sensation from part of the ear as well as taste from the anterior two-thirds of the tongue.⁴

The precise pathophysiology involved in FNP remains an area of continuing debate, but infectious, vascular, immunologic, and genetic causes have been hypothesized.^7,12 Inflammation and subsequent nerve damage along CN VII caused by an infectious process is thought to be the most likely explanation for the pathogenesis of acquired FNP in both adults and children.^5,13

Herpes simplex virus 1 (HSV-1) has been suggested as the virus most commonly linked to FNP in both adults and children, but it is unlikely to be the sole cause.^5,6,9 Data from a three-year prospective study of FNP cases in children support a relationship between pediatric FNP and HSV-1 infection.¹⁴ Other infectious causes implicated in pediatric FNP are Lyme disease, Epstein-Barr, varicella zoster virus, rubella, coxsackie virus, adenovirus, and otitis media.^4,7,9

Presentation, History, and Physical Exam
Most children with idiopathic FNP will present with sudden-onset facial asymmetry and may have decreased tearing, loss of the conjunctival reflex (leading to difficulty closing the eye), an inability to hold the lips tightly together, and difficulty keeping food in the mouth. Complaints of otalgia, speech disturbances, hyperacusis, and altered sense of taste are common.^2,7 Recent occurrence of an upper respiratory infection is often reported in the history of a pediatric patient with FNP.^3,7,15,16

Idiopathic FNP is essentially a diagnosis of exclusion.^3,5 A meticulous history must be conducted, including any recent illnesses, trauma to the face or head, vaccines, rashes, and travel. Assessment of the head, eyes, ears, nose, and throat, and a careful neurologic history must be conducted to identify nonidiopathic causes of FNP (see Table 1^5-7,9). Facial weakness can progress from mild palsy to complete paralysis over one to two weeks⁵; therefore, a careful history of the progression of facial weakness should be ascertained and documented.^5,17 

A full neurologic exam is essential. Cranial nerves I through XII should be evaluated; any malfunction of a cranial nerve other than CN VII could be indicative of a tumor or process other than idiopathic FNP. Assessment of facial nerve function is imperative, as this factor is the most important for predicting recovery; it can also aid in formulating a prognosis and directing treatment.^5,9,17

The House-Brackmann facial nerve grading system^1,2 is considered the gold standard for grading severity of facial paresis⁹ (see Table 2^1,2 ). A clear distinction between paresis (partial or incomplete palsy) and paralysis (complete palsy) must be made. Pediatric patients with an incomplete palsy have an improved chance of full recovery.^17,18

Any abnormalities in the peripheral neurologic exam should prompt further testing. FNP not involving the forehead musculature, gradual progression of paresis, and weakness in any extremity could be indicative of a central lesion. FNP has been the presenting symptom in various neoplastic processes, including leukemia, cholesteatoma, and astrocytoma.^3,7,9

Otitis media is a frequent cause of FNP among children.^9-11 Thus, a thorough examination of the ear canal, tympanic membrane, and hearing should be performed. The throat and oropharynx should be inspected, and the parotid gland palpated. Any swelling or abnormalities warrant further investigation.

Lyme disease presenting with FNP is more common in children than adults. This may be related to the increased likelihood for children to be bitten by ticks in the head and neck areas. Frequently, FNP associated with Lyme disease is bilateral—as often as 25% of the time.¹⁹ Headache, onset of symptoms during peak Lyme season, or bilateral FNP should raise the clinician’s suspicion for Lyme disease.^7,9,19

An accurate assessment of blood pressure is essential, as severe hypertension may be implicated in FNP in children.^3,5,7 One literature review reported that hypertension was the origin of FNP in 3% to 17% of affected children.²⁰ Vascular hemorrhage induced by hypertension is thought to cause nerve compression and subsequent FNP.⁷

A bilateral eye exam is also important. Irritation is likely, and the patient with any suspected corneal abrasion or damage should be referred to an ophthalmologist.^6,18

Laboratory Testing and Imaging
Diagnostic testing that facilitates the exclusion of known causes of FNP should be considered, as there is no specific laboratory test to confirm the diagnosis. A complete blood count, Lyme titers, cerebrospinal fluid analysis, CT, and/or MRI may be warranted, based on the clinical presentation.^7-9 In children in whom Lyme disease is suspected (ie, those living in tick-endemic areas or with recent tick bites), serologic testing should be performed. Lumbar puncture and an evaluation of cerebrospinal fluid may be necessary in cases in which meningitis cannot be excluded.^7,9

Specialized diagnostic tests are not routinely recommended for patients with paresis that is improving. Audiometry and evaluation of the stapedial reflex may help guide treatment decisions for patients whose condition is not improving. In children, the presence or return of the stapedial reflex within three weeks of disease onset is predictive of complete recovery.⁵ In patients who experience complete paralysis or unimproved paresis, results of electrodiagnostic testing (in particular, evoked facial nerve electroneuronography) can help forecast recovery of facial nerve function.^5,17

Treatment and Management
Treatment for FNP in adults is controversial, and even more so for the pediatric patient. Treatment decisions consist of eye care, corticosteroids, antiviral medications, and appropriate referrals.

Eye care. Eye lubrication and protection should be implemented immediately. Protecting the cornea is paramount; thorough lubrication of the eye is the mainstay of treatment.¹⁸ Artificial tears should be used frequently during the day, and an ointment should be applied to the eye at night. Use of eye patches is controversial, as they may actually cause corneal injury.^7,9 Taping the eye shut at night may prevent trauma during sleep, but this option must be considered carefully.^9,18

Corticosteroids. Early initiation of corticosteroids should be considered for all patients with FNP, including children.^2,7,9,17 Studies are inconclusive as to whether steroid therapy is beneficial in children with idiopathic FNP. However, two 2010 reviews of pediatric FNP recommend early initiation of steroids for children with acute-onset FNP, particularly when facial paresis is evaluated at a House-Brackmann grade V or VI.^7,9 The American Academy of Family Physicians (AAFP) recommends a tapering course of prednisone for all patients, begun as soon as possible.⁶ The prednisone dosage for pediatric patients is usually 1.0 mg/kg/d, split into two doses, for six days, followed by a tapering dose for four days.⁵

Antivirals and antibiotic therapy. When an infectious cause of FNP is known, appropriate antibiotic or antiviral therapy should begin. If the patient lives in or has traveled to an area endemic for Lyme disease, empiric treatment may be appropriate. When Ramsay Hunt syndrome is diagnosed or herpetic lesions are visible, antiviral treatment should be initiated.⁷

Antiviral therapy for idiopathic FNP is the most controversial of the treatment decisions. In 2001, the American Academy of Neurology concluded that no clear benefit from acyclovir could be ascertained, although it might be effective.¹³ This was affirmed in a recently updated Cochrane review of antiviral therapy for idiopathic FNP.¹² Antiviral therapy alone showed no benefit, compared with placebo; however, combined antiviral and corticosteroid therapy was more effective than placebo alone in recovery outcomes. Antivirals may benefit pediatric patients and should be considered early when the cause of FNP is viral or idiopathic.^7,9

Referrals. Initial presentation and course of paresis should guide referral patterns for the pediatric patient presenting with FNP. The American Academy of Pediatrics (AAP) recommends referral to an otolaryngologist for any infant or child with FNP.²¹ The AAFP recommends referral to a specialist for any patient who does not show improvement within two weeks.⁶

In patients with complete paralysis, early surgical intervention may be considered, and referral should be made promptly for electrodiagnostic testing and surgical consult. In cases in which otitis media causes FNP, myringotomy and tube insertion are indicated, and appropriate referral should be made.^7,9

Outcomes
|The prognosis in children with FNP is good, and most will recover completely.^2,9-11,22 Idiopathic and infectious etiologies of FNP seem to have the greatest likelihood for complete recovery.^10,11,16,17 Recovery appears to be affected by etiology, degree of paresis, and treatment. How these factors coalesce is not fully understood, and up to 20% of children may have mild to moderate residual facial nerve dysfunction.^10,11,19,22

The Case Patient
The child’s facial nerve function gradually returned over a three-week period, with no residual deficit (see Figures 1a, 1b, and 1c). Results of the audiometry screening on day 10 were normal, showing a positive stapedial reflex. An MRI, performed four months after the initial paralysis to rule out any tumors, yielded normal results. 

This case highlights the differing management of pediatric Bell’s palsy among emergency, pediatric, and specialized providers. This child was managed more aggressively under the care of an otolaryngologist with a two-week course of steroids, antiviral medication for 10 days, and a follow-up MRI to rule out any evidence of a tumor. The need for further research to guide practice in the pediatric patient with Bell’s palsy is apparent.

Conclusion
FNP in the pediatric population is rare and more likely to have an identifiable cause than among adults. Careful examination should reveal differential diagnoses that warrant treatment and referrals. The main causes of FNP that should not be missed are otitis media, hypertension, varicella zoster virus (Ramsay Hunt syndrome), neoplastic processes, and Lyme disease.

Practitioners should have a high index of suspicion for nonidiopathic causes of FNP when a child has a neurologic exam that includes facial paresis of gradual onset, abnormal function of other cranial nerves, lack of forehead muscle weakness, or peripheral abnormalities. In addition to the history and exam, blood work and radiologic imaging can aid the practitioner in ruling in or out nonidiopathic causes of FNP. 

Grading of facial palsy severity using the House-Brackmann scale helps guide prognosis and referral choices. Referral to a specialist in otolaryngology is appropriate and recommended by the AAP. Referral should be made to an ophthalmologist if any suspicion of corneal abrasion exists. 

Treatment in children should consist of eye care and steroids. Antiviral therapy should be considered on an individualized basis and when evidence of HSV or varicella exists. Parents should be advised about the importance of eye care in a child with FNP (see Table 3^{5-7,9,17,18,22}).

The emotional stress associated with FNP can be significant for both children and adults; fear of lifelong facial deformity can be psychologically debilitating. Yet a favorable prognosis for recovery of facial nerve function can be relayed to anxious parents.

A 6-year-old girl was brought to a pediatric emergency department (ED) in Atlanta by her mother. The mother stated that during the previous hour, she had noticed that her daughter’s face seemed weaker on the right side.

The night before, the child had said, “I can’t blink my eye”; when her mother asked her to demonstrate, the child seemed to be able to blink both eyes appropriately, and she had no further complaints. The next morning, the child complained of the light being too bright and asked to wear her mother’s sunglasses. In the course of the day, she continued to complain of eye discomfort, which she described as “stinging” and “sore.” The mother could see nothing abnormal, but by late afternoon noticed that her daughter’s smile and facial movements were asymmetrical. She immediately took her to the pediatric ED.

The child had no significant medical history and no surgical history. Her vaccination schedule was current, and she denied any recent illnesses. The mother could recall no exposures to infections or tick bites, no rashes, and no trauma to the face or head. The mother and child were visiting Atlanta from northeastern Florida.

The review of systems was negative for headache, fever, chills, rash, earache, sore throat, cough, rhinorrhea, vision changes, weight loss, or change in appetite or disposition. The child was afebrile, and the other vital signs were within normal limits. 

Physical examination revealed an alert child who was calm and conversant. Her height was 45” and weight, 43 lb. Otoscopic exam showed normal ears and tympanic membranes with no sign of otitis media or ear pathology. No throat redness, tonsillar enlargement, or lymphadenopathies were noted. Breath sounds were clear, and heart rhythm and rate were regular without murmur. 

The patient’s left eye appeared normal, and the right eye was mildly erythematic without drainage or swelling; since corneal abrasion was not suspected, a slit lamp examination was not performed. Upon neurologic examination, right eye ptosis with incomplete lid closure, asymmetrical mouth movement with smile, and a diminished nasal labial fold crease were noted on the right side. When the child was asked to raise her eyebrows and wrinkle her forehead, asymmetrical forehead creases were apparent. All other cranial nerve functions were intact, and motor and sensory responses, including gait and reflexes, were assessed as normal. Unilateral dysfunction of right-sided cranial nerve VII (CN VII), including forehead involvement, was confirmed, consistent with a grade of III to IV on the House-Brackmann (maximum, VI)^1,2 facial nerve grading scale.

Based on the rapid onset of unilateral facial nerve paresis (FNP) and an otherwise normal exam, the patient was diagnosed with Bell’s palsy. No further testing was done, and the child was given a dose of oral prednisolone 40 mg in the ED, with a prescription for four more days of oral prednisolone at 15 mg bid. The need for eye protection and lubrication was emphasized to the mother, who was given lubricating eye drops to administer. The mother was also instructed to follow up with the child’s primary care practitioner upon their return to Florida. 

The child was seen by her pediatrician three days later. Her facial paresis had not worsened in the interim, and the pediatrician declined to extend the course of corticosteroids or to add an antiviral medication. At the mother’s request, the child was referred to a pediatric otolaryngologist, who saw her the following day and adjusted the treatment plan. The child was prescribed prednisolone elixir 20 mg bid for one week, followed by a tapering dose for the second week. In addition, she was prescribed oral acyclovir 400 mg qid for 10 days. Her mother was instructed to return with the child in one week for audiometry testing.  

Discussion
Idiopathic FNP, commonly referred to as Bell’s palsy, is defined as an acute unilateral paresis of the facial nerve without detectable underlying cause.^3,4 It most commonly occurs among persons ages 15 to 45, with a prevalence rate of 15 to 30 cases per 100,000 persons. The peak incidence of Bell’s palsy is in the fourth decade of life. Diabetic patients and pregnant women are disproportionately affected by idiopathic FNP.^2,5 About 8% to 10% of patients will experience a recurrence of Bell’s palsy within 10 years.^2,6

Pediatric FNP can be congenital or acquired. Congenital FNP is most often associated with birth trauma and occurs at a rate of 2.1 cases per 1,000 births. Rare genetic syndromes can also manifest with FNP and will most often present with other syndromic anomalies noted at birth.⁷

Acquired FNP is two to four times less common in children than adults, with an estimated prevalence of 2.7 per 100,000 patients younger than 10. Children account for only a small proportion of subjects in published studies that address diagnosis and management of FNP.³ While the presentation of FNP is much the same in adults and children, some notable differences in etiology exist.^2,3,7-9 Infectious, traumatic, or neoplastic causes of FNP are more common among children than adults and must be distinguished from idiopathic FNP.^7,9-11

Decisions regarding diagnostic testing, pharmacologic treatment, and referral must be guided by the history and physical exam, neurologic exam, and clinical judgment. Being able to identify or exclude alarming causes of FNP, such as neoplasm, will aid the primary care practitioner in treatment and referral practices for this condition.

Pathophysiology
CN VII, the facial nerve, has a broad scope of function that incorporates both sensory and motor pathways. The brachial nerve portion of CN VII controls the muscles of voluntary facial expression. CN VII also autonomically innervates the lacrimal gland and submandibular gland and governs sensation from part of the ear as well as taste from the anterior two-thirds of the tongue.⁴

The precise pathophysiology involved in FNP remains an area of continuing debate, but infectious, vascular, immunologic, and genetic causes have been hypothesized.^7,12 Inflammation and subsequent nerve damage along CN VII caused by an infectious process is thought to be the most likely explanation for the pathogenesis of acquired FNP in both adults and children.^5,13

Herpes simplex virus 1 (HSV-1) has been suggested as the virus most commonly linked to FNP in both adults and children, but it is unlikely to be the sole cause.^5,6,9 Data from a three-year prospective study of FNP cases in children support a relationship between pediatric FNP and HSV-1 infection.¹⁴ Other infectious causes implicated in pediatric FNP are Lyme disease, Epstein-Barr, varicella zoster virus, rubella, coxsackie virus, adenovirus, and otitis media.^4,7,9

Presentation, History, and Physical Exam
Most children with idiopathic FNP will present with sudden-onset facial asymmetry and may have decreased tearing, loss of the conjunctival reflex (leading to difficulty closing the eye), an inability to hold the lips tightly together, and difficulty keeping food in the mouth. Complaints of otalgia, speech disturbances, hyperacusis, and altered sense of taste are common.^2,7 Recent occurrence of an upper respiratory infection is often reported in the history of a pediatric patient with FNP.^3,7,15,16

Idiopathic FNP is essentially a diagnosis of exclusion.^3,5 A meticulous history must be conducted, including any recent illnesses, trauma to the face or head, vaccines, rashes, and travel. Assessment of the head, eyes, ears, nose, and throat, and a careful neurologic history must be conducted to identify nonidiopathic causes of FNP (see Table 1^5-7,9). Facial weakness can progress from mild palsy to complete paralysis over one to two weeks⁵; therefore, a careful history of the progression of facial weakness should be ascertained and documented.^5,17 

A full neurologic exam is essential. Cranial nerves I through XII should be evaluated; any malfunction of a cranial nerve other than CN VII could be indicative of a tumor or process other than idiopathic FNP. Assessment of facial nerve function is imperative, as this factor is the most important for predicting recovery; it can also aid in formulating a prognosis and directing treatment.^5,9,17

The House-Brackmann facial nerve grading system^1,2 is considered the gold standard for grading severity of facial paresis⁹ (see Table 2^1,2 ). A clear distinction between paresis (partial or incomplete palsy) and paralysis (complete palsy) must be made. Pediatric patients with an incomplete palsy have an improved chance of full recovery.^17,18

Any abnormalities in the peripheral neurologic exam should prompt further testing. FNP not involving the forehead musculature, gradual progression of paresis, and weakness in any extremity could be indicative of a central lesion. FNP has been the presenting symptom in various neoplastic processes, including leukemia, cholesteatoma, and astrocytoma.^3,7,9

Otitis media is a frequent cause of FNP among children.^9-11 Thus, a thorough examination of the ear canal, tympanic membrane, and hearing should be performed. The throat and oropharynx should be inspected, and the parotid gland palpated. Any swelling or abnormalities warrant further investigation.

Lyme disease presenting with FNP is more common in children than adults. This may be related to the increased likelihood for children to be bitten by ticks in the head and neck areas. Frequently, FNP associated with Lyme disease is bilateral—as often as 25% of the time.¹⁹ Headache, onset of symptoms during peak Lyme season, or bilateral FNP should raise the clinician’s suspicion for Lyme disease.^7,9,19

An accurate assessment of blood pressure is essential, as severe hypertension may be implicated in FNP in children.^3,5,7 One literature review reported that hypertension was the origin of FNP in 3% to 17% of affected children.²⁰ Vascular hemorrhage induced by hypertension is thought to cause nerve compression and subsequent FNP.⁷

A bilateral eye exam is also important. Irritation is likely, and the patient with any suspected corneal abrasion or damage should be referred to an ophthalmologist.^6,18

Laboratory Testing and Imaging
Diagnostic testing that facilitates the exclusion of known causes of FNP should be considered, as there is no specific laboratory test to confirm the diagnosis. A complete blood count, Lyme titers, cerebrospinal fluid analysis, CT, and/or MRI may be warranted, based on the clinical presentation.^7-9 In children in whom Lyme disease is suspected (ie, those living in tick-endemic areas or with recent tick bites), serologic testing should be performed. Lumbar puncture and an evaluation of cerebrospinal fluid may be necessary in cases in which meningitis cannot be excluded.^7,9

Specialized diagnostic tests are not routinely recommended for patients with paresis that is improving. Audiometry and evaluation of the stapedial reflex may help guide treatment decisions for patients whose condition is not improving. In children, the presence or return of the stapedial reflex within three weeks of disease onset is predictive of complete recovery.⁵ In patients who experience complete paralysis or unimproved paresis, results of electrodiagnostic testing (in particular, evoked facial nerve electroneuronography) can help forecast recovery of facial nerve function.^5,17

Treatment and Management
Treatment for FNP in adults is controversial, and even more so for the pediatric patient. Treatment decisions consist of eye care, corticosteroids, antiviral medications, and appropriate referrals.

Eye care. Eye lubrication and protection should be implemented immediately. Protecting the cornea is paramount; thorough lubrication of the eye is the mainstay of treatment.¹⁸ Artificial tears should be used frequently during the day, and an ointment should be applied to the eye at night. Use of eye patches is controversial, as they may actually cause corneal injury.^7,9 Taping the eye shut at night may prevent trauma during sleep, but this option must be considered carefully.^9,18

Corticosteroids. Early initiation of corticosteroids should be considered for all patients with FNP, including children.^2,7,9,17 Studies are inconclusive as to whether steroid therapy is beneficial in children with idiopathic FNP. However, two 2010 reviews of pediatric FNP recommend early initiation of steroids for children with acute-onset FNP, particularly when facial paresis is evaluated at a House-Brackmann grade V or VI.^7,9 The American Academy of Family Physicians (AAFP) recommends a tapering course of prednisone for all patients, begun as soon as possible.⁶ The prednisone dosage for pediatric patients is usually 1.0 mg/kg/d, split into two doses, for six days, followed by a tapering dose for four days.⁵

Antivirals and antibiotic therapy. When an infectious cause of FNP is known, appropriate antibiotic or antiviral therapy should begin. If the patient lives in or has traveled to an area endemic for Lyme disease, empiric treatment may be appropriate. When Ramsay Hunt syndrome is diagnosed or herpetic lesions are visible, antiviral treatment should be initiated.⁷

Antiviral therapy for idiopathic FNP is the most controversial of the treatment decisions. In 2001, the American Academy of Neurology concluded that no clear benefit from acyclovir could be ascertained, although it might be effective.¹³ This was affirmed in a recently updated Cochrane review of antiviral therapy for idiopathic FNP.¹² Antiviral therapy alone showed no benefit, compared with placebo; however, combined antiviral and corticosteroid therapy was more effective than placebo alone in recovery outcomes. Antivirals may benefit pediatric patients and should be considered early when the cause of FNP is viral or idiopathic.^7,9

Referrals. Initial presentation and course of paresis should guide referral patterns for the pediatric patient presenting with FNP. The American Academy of Pediatrics (AAP) recommends referral to an otolaryngologist for any infant or child with FNP.²¹ The AAFP recommends referral to a specialist for any patient who does not show improvement within two weeks.⁶

In patients with complete paralysis, early surgical intervention may be considered, and referral should be made promptly for electrodiagnostic testing and surgical consult. In cases in which otitis media causes FNP, myringotomy and tube insertion are indicated, and appropriate referral should be made.^7,9

Outcomes
|The prognosis in children with FNP is good, and most will recover completely.^2,9-11,22 Idiopathic and infectious etiologies of FNP seem to have the greatest likelihood for complete recovery.^10,11,16,17 Recovery appears to be affected by etiology, degree of paresis, and treatment. How these factors coalesce is not fully understood, and up to 20% of children may have mild to moderate residual facial nerve dysfunction.^10,11,19,22

The Case Patient
The child’s facial nerve function gradually returned over a three-week period, with no residual deficit (see Figures 1a, 1b, and 1c). Results of the audiometry screening on day 10 were normal, showing a positive stapedial reflex. An MRI, performed four months after the initial paralysis to rule out any tumors, yielded normal results. 

This case highlights the differing management of pediatric Bell’s palsy among emergency, pediatric, and specialized providers. This child was managed more aggressively under the care of an otolaryngologist with a two-week course of steroids, antiviral medication for 10 days, and a follow-up MRI to rule out any evidence of a tumor. The need for further research to guide practice in the pediatric patient with Bell’s palsy is apparent.

Conclusion
FNP in the pediatric population is rare and more likely to have an identifiable cause than among adults. Careful examination should reveal differential diagnoses that warrant treatment and referrals. The main causes of FNP that should not be missed are otitis media, hypertension, varicella zoster virus (Ramsay Hunt syndrome), neoplastic processes, and Lyme disease.

Practitioners should have a high index of suspicion for nonidiopathic causes of FNP when a child has a neurologic exam that includes facial paresis of gradual onset, abnormal function of other cranial nerves, lack of forehead muscle weakness, or peripheral abnormalities. In addition to the history and exam, blood work and radiologic imaging can aid the practitioner in ruling in or out nonidiopathic causes of FNP. 

Grading of facial palsy severity using the House-Brackmann scale helps guide prognosis and referral choices. Referral to a specialist in otolaryngology is appropriate and recommended by the AAP. Referral should be made to an ophthalmologist if any suspicion of corneal abrasion exists. 

Treatment in children should consist of eye care and steroids. Antiviral therapy should be considered on an individualized basis and when evidence of HSV or varicella exists. Parents should be advised about the importance of eye care in a child with FNP (see Table 3^{5-7,9,17,18,22}).

The emotional stress associated with FNP can be significant for both children and adults; fear of lifelong facial deformity can be psychologically debilitating. Yet a favorable prognosis for recovery of facial nerve function can be relayed to anxious parents.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

A 72-year-old man presented to his primary care provider’s office with complaints of peeling skin on his penis and frequent, burning urination. He said he had first noticed redness on his penis about four days earlier, adding that it was growing worse. He was unsure whether he was truly experiencing frequent urination or just more aware of urinating because of the burning pain. He reported no attempts to treat himself, stating that he was “just keeping an eye on it and hoping it would go away.”

The patient’s medical history was limited to hypertension, for which he was taking valsartan, and allergies, for which he took fexofenadine. His surgical history included a tonsillectomy and appendectomy during his early teens. He had no known allergies to any medications.

The patient was married and retired after an executive career. He and his wife split their residence between New York and Florida during seasonal changes and were living in Florida at the time. He reported social drinking (“on rare occasions, these days”) and smoking an occasional cigar. He reported that he showers only once or twice weekly because of dry skin.

The following vital signs were recorded: blood pressure, 110/72 mm Hg; heart rate, 68 beats/min; respirations, 15/min; temperature, 97.8°F; and O2 saturation, 99% on room air. He was 73” tall and weighed 197 lb, with a BMI of 26.

The patient was alert and oriented. His physical exam was overall unremarkable, with the exception of an uncircumcised penis with redness and inflammation on the glans penis and no discharge noted. The reddened area was bright and shiny with a moist appearance and well-defined borders. The man denied any risk for sexually transmitted disease (STD) and denied any penile discharge. He also denied fever, chills, or arthritis.

Urinalysis performed in the office was negative for a urinary tract infection or for elevated glucose. A laboratory report from six months earlier was reviewed; all findings were within normal range, including the blood glucose level, with special attention paid for possible underlying cause; and the prostate-specific antigen (PSA) level, obtained for possible prostatitis or prostate cancer.

The differential diagnosis included eczema or psoriasis, Zoon’s balanitis, penile cancer, balanitis xerotica obliterans (lichen sclerosus), candidiasis balanitis, and circinate balanitis (as occurs in patients with Reiter’s disease; see table^1-5). The absence of circumcision and the patient’s report of infrequent bathing raised concern for a hygiene-related etiology; the final diagnosis, made empirically, was candidiasis balanitis. Regarding an underlying cause, the laboratory order included a urine culture, fasting complete blood count, chemistry panel, and PSA level.

The patient was given instructions to wash the affected area twice daily for one week with a lukewarm weak saline solution (1 tablespoon salt/L water),^5,6 gently retracting the foreskin; he was also given a topical antifungal cream⁷ (ketoconazole 2%, although other choices are discussed below), to be applied two to three times daily until his symptoms resolved.⁶ He was advised to return in one week if the condition did not improve or grew worse⁵; referral to dermatology would then be considered. The patient was also advised that in the case of a recurrent episode, dermatology would be consulted. The possibility of circumcision was discussed,⁸ and the patient was given information about the procedure, with referral to a urologist in the area.

Discussion

Balanitis is an inflammation of the glans penis; balanoposthitis involves the foreskin and prepuce.^9-11 Balanitis can occur in men of any age, with etiologies varying with a patient’s age. Typical signs and symptoms include redness and swelling of the glans penis or foreskin, itching and/or pain, urethral discharge, phimosis, swollen lymph nodes, ulceration or plaque appearance, and pain on urination.¹²

In addition to the differential diagnoses mentioned, several additional conditions can be considered in a man with penile lesions. In older men, it is particularly important to investigate such lesions thoroughly, following the patient until the underlying cause is determined and the best treatment choice is selected. Specialists in dermatology and urology can best identify persistent or chronic lesions and make appropriate treatment recommendations, including possible circumcision.

The condition is commonly associated with absence of circumcision, poor hygiene, and phimosis (the inability to retract the foreskin from the glans penis). Accumulation of glandular secretions (smegma) and sloughed epithelial cells under the foreskin can lead to irritation and subsequent infection.

Uncontrolled or poorly controlled diabetes can be implicated in candidiasis infections.¹ Other causes and contributing factors include chemical irritants (eg, soaps, lubricating jelly), edematous conditions (including congestive heart failure, cirrhosis, and nephrosis), drug allergies, morbid obesity, and a number of viruses and other pathogens, including those associated with STDs.¹²

A more detailed laboratory work-up might include the following:

• Serum glucose test (as part of a diabetes screening; in older men, this inflammatory condition can be a presenting sign of diabetes mellitus⁶)

• Culture of discharge, if any is present

• Serology test for STDs

• Wet mount with potassium hydroxide (for Candida albicans infection)

• Ultrasound, in severe cases or when urinary obstruction is suspected.

Additionally, in chronic cases, the patient should be referred to dermatology or urology for biopsy.^5,9 Testing for anaerobes should also be considered for the patient and his sexual partner; if results are positive, treatment with oral metronidazole (400 mg tid for 10 days) is advised.⁶

In this patient’s case, the test that would best support an in-office diagnosis of candidiasis balanitis is a wet mount with potassium hydroxide. This was not performed at the time of the case patient’s visit, however; the diagnosis was empirically determined.

Management, Including Patient Education

Treatment of candidiasis balanitis involves routinely cleaning the penis and foreskin, as the case patient was instructed; use of soap, an irritant, should be avoided until the condition is resolved.^7,10 Appropriate topical antifungal creams include nystatin, ketoconazole, miconazole, clotrimazole, econazole, and terbinafine, applied two to three times daily for at least 10 days; a cream combining an imidazole with 1% hydrocortisone may be effective for patients with significant inflammation.^5,6,8,10,13

The patient should be instructed to:

• Keep the area clean and dry

• Wash twice daily with weak saline solution after removing residual medication and before applying fresh medication

• Wear loose cotton underwear

• Avoid sharing towels or cleaning cloths

• Wash personal items and surfaces, if possible, with disinfectant

• Notify sexual partner(s) that they may need treatment

• Discontinue sexual intercourse until infection is resolved

• Continue treatment for 10 to 14 days, even though relief may occur early

• Follow up with the clinician if no improvement is seen within one week

• Consider circumcision, in case of chronic infection.^1,2,8,12

Conclusion

It is important to diagnose balanitis correctly, as this condition can affect sexual and urinary function, and its effects should not be underestimated in older men. Differentiating between infectious, noninfectious, premalignant, and malignant lesions will lead to appropriate care and allow early diagnosis or prevention of curable malignancies.

While waiting to cross a street, a 30-year-old woman was suddenly struck by an oncoming vehicle, which crushed her legs against a parked automobile. She sustained a life-threatening traumatic injury and nearly exsanguinated at the scene. Nearby pedestrians assisted her, including a man who applied his belt to the woman’s left thigh to prevent complete exsanguination following the crush. She was emergently transported to an adult regional trauma center and admitted to the ICU.

The patient was given multiple transfusions of packed red blood cells, platelets, and frozen plasma in attempts to restore hemostasis. She underwent emergent surgery for a complete washout, debridement, and compartment fasciotomy on the right leg. The left leg required an above-knee amputation. Following surgery, full-thickness and split-thickness wounds were present on both extremities.

Before the accident, the woman had a history of hypertension controlled with a single antihypertensive. She was obese, with a BMI of 31.9. She had no surgical history. She denied excessive alcohol consumption, illicit drug use, or smoking. She was unaware of having any food or drug allergies.

The woman was married and had a 6-month-old baby. Until her accident, she was employed full-time as an investment accountant. She expressed contentment regarding her home, family, work, and busy lifestyle.

Once the patient’s condition was stabilized and hemostasis achieved in the trauma ICU, the bilateral lower-extremity wounds were managed by application of foam dressings via negative-pressure therapy. The dressings were changed on the patient’s lower-extremity wounds three times per week for about three weeks. When the wounds’ depth decreased and granulation was achieved, split-thickness skin grafts (STSGs) harvested from the right anterior thigh were applied to the open wounds (see Figure 1) in the operating room.

Following application of the STSGs and hemostasis of the patient’s donor site, silver silicone foam dressings were applied directly over the right lower-extremity graft and the donor site in the operating room. The dressings remained in place for four days (see Figure 2). A nonadherent, petrolatum-based contact layer was then applied to the left lower-extremity amputation graft site, followed by a negative-pressure foam dressing.

The negative-pressure pump was programmed for 75 mm Hg continuous therapy for four days. The silver silicone foam and negative-pressure foam dressings were removed from the respective graft sites on the fourth postpostoperative day. The grafts were viable and intact (see Figures 3 and 4). The silver silicone foam was reapplied to the lower-extremity STSGs and donor site and changed every four days.

When a few pinpoint dehisced areas were noted on the grafts, a silver-coated absorbent antimicrobial dressing was applied. A nonadherent, petrolatum-based contact layer, followed by wide-mesh stretch gauze, was secured as an exterior dressing over the graft sites. Both lower-extremity dressings were layered with elastic wraps to prevent edema. The dressings were changed daily for two weeks.

On postoperative Day 4, the silver silicone foam was removed from the donor site. A nonadherent contact layer of bismuth tribromophenate petrolatum, followed by the silver silicone foam, was selected for placement over the donor site. Gauze and an elastic wrap were secured as an exterior dressing and removed three days later.

The donor site dressing was reduced to a layer of bismuth tribromophenate petrolatum and left open to air. As the edges of the nonadherent contact layer dried, they were trimmed with scissors (see Figure 5). A moisturizing cocoa butter–based lotion was applied daily to the exposed areas of the donor site.

During the patient’s third postoperative week at the trauma center, as she underwent a continuum of aggressive rehabilitation and wound care, the donor and STSG sites were pronounced healed (see Figures 6, 7, and 8). The donor site was left open to air, with daily use of cocoa butter lotion. Maintenance care of the graft sites included daily application of cocoa butter lotion, stretch gauze, and elastic wraps. The patient was discharged from the rehabilitation unit to home, where she awaited a prosthetic fitting.

Throughout the patient’s hospitalization and rehabilitation, surgical, medical, pain, and nutrition management were monitored on a continuum, as were laboratory values. Her vital signs remained within reasonable limits. The patient remained infection free and experienced neither medical nor surgical complications during the course of her hospital stay.

DISCUSSION
Traumatic injuries often result in bodily deformities, amputations, and death. They represent the leading cause of death among people in the US younger than 45.^1,2

Compartment syndrome develops when increased pressure within a bodily cavity minimizes capillary perfusion, resulting in decreased tissue viability.³ Edema and hemorrhage are also precipitating factors for this condition.³ When it goes unrelieved, compromised circulation can lead to muscle devitalization. Amputation of the affected appendage may be necessary unless circulation is restored.

Surgical fasciotomy can help alleviate pressure within the musculofascial compartment to improve circulation.⁴ Typically, such a procedure leaves large open wounds—a challenge for the clinician who cares for the affected patient. Once the wound is stabilized and the tissue becomes viable with granulation, application of an STSG can be considered.^5,6

STSGs provide effective closure for open wounds. The grafting procedure entails removing, processing, and placing a portion of skin, both epidermal and partial dermal layers, on an open wound. Successful grafting requires adequate circulation, but excess bacteria can impede graft viability.⁷ Graft sites must be kept clean and moist without edema.⁵ Immediate application of negative-pressure therapy directly on an STSG has been shown to result in an outstanding graft “take,” as compared with use of traditional dressings.^5,6,8

Nutritional status must be optimal for a successful graft take, with adequate intake of protein, calories, fluids, vitamins, and minerals.^9,10

Treatment
Since days of old when traumatic wounds were treated with goat dung and honey, an array of methods and products has been developed, including numerous agents for cutaneous injuries alone.⁴ Occlusive, semiocclusive, or bacteriostatic topical ointments, foam, silver, or a combination of products can be used to manage and heal surgical wounds, grafts (including STSGs), and donor sites.^11,12

Currently, negative pressure is also used in STSGs to accelerate healing.^7,11 When applied to a wound, negative-pressure therapy enhances granulation, removes excess exudate, and creates a moist environment for healing.^5,13

Silver-coated absorbent antimicrobial dressings appear to reduce bacteria on the surface of the wound surfaces and postoperative surgical sites without inducing bacterial resistance or adversely affecting healthy tissue.^12,14-16 Silver silicone foam reduces bacterial colonization on wound surfaces and absorbs exudate into the foam dressing.^17,18 Wounds with devitalized tissue and excessive drainage are at risk for infection, inflammation, and chronic duration.¹⁹

Nutrition
It has been reported that about half of all persons admitted to US hospitals are malnourished, with increased risk for morbidity and mortality.²⁰ After experiencing hemorrhage, even well-nourished patients require additional protein and iron for successful recovery.¹⁰ Obese patients appear more susceptible to infection and surgical wound dehiscence than are their thinner counterparts, but further research is needed to study the impact of wound development and healing in this population.¹⁴

Tissue regeneration is known to require the amino acids arginine and glutamine for the construction of protein; additional research is also needed to support the theory that supplemental glutamine promotes wound healing.^9,21 Surgical patients and patients with wounds benefit from protein-enhanced diets; zinc and vitamins A and C can also help improve wound healing and clinical outcomes.²² Monitoring protein and prealbumin levels is helpful in evaluating nutritional status, allowing the clinician to modify the medical nutrition plan and optimize the patient’s health and wellness.²²

Rehabilitation
Surgical amputations of the lower extremities impair balance and mobility, necessitating extensive physical therapy and rehabilitation for affected patients.^23,24 Aggressive rehabilitation typically is exhausting for patients. It is important to initiate a supportive team approach (including physical and occupational therapists) soon after surgery, continuing beyond the acute hospitalization into rehabilitation. Individualized, patient-centered goals are targeted and amended as necessary. Physical and occupational therapy increase in intensity and duration to optimize the patient’s functionality. Prosthetic fitting takes place after edema diminishes and the limb is fully healed.²⁴

Patient Outcome
An obese young woman who sustained traumatic lower-extremity injuries and amputation experienced an optimal clinical outcome after 54 days of management. Exceptional surgical and medical strategies were initiated in the adult regional trauma center’s ICU and concluded at the adjoining rehabilitation center.

Strategic selection of products and interventions—negative pressure, silver silicone foam, silver-coated absorbent antimicrobial dressings, nonadherent contact layers, stretch gauze, and elastic wraps—and constant monitoring, including that of the patient’s nutritional status, resulted in expedient resolution of her traumatic wounds, STSGs, and donor site.

CONCLUSION
Despite revolutionary advances and life-sustaining measures in the surgical, medical, and wound care arena, traumatic events remain potentially debilitating and life-threatening for young adults. Triage of the trauma patient for appropriate medical care and collaborative management involving a team of trauma specialists and clinicians of all disciplines can now provide life-sustaining opportunities for these patients.

While waiting to cross a street, a 30-year-old woman was suddenly struck by an oncoming vehicle, which crushed her legs against a parked automobile. She sustained a life-threatening traumatic injury and nearly exsanguinated at the scene. Nearby pedestrians assisted her, including a man who applied his belt to the woman’s left thigh to prevent complete exsanguination following the crush. She was emergently transported to an adult regional trauma center and admitted to the ICU.

The patient was given multiple transfusions of packed red blood cells, platelets, and frozen plasma in attempts to restore hemostasis. She underwent emergent surgery for a complete washout, debridement, and compartment fasciotomy on the right leg. The left leg required an above-knee amputation. Following surgery, full-thickness and split-thickness wounds were present on both extremities.

Before the accident, the woman had a history of hypertension controlled with a single antihypertensive. She was obese, with a BMI of 31.9. She had no surgical history. She denied excessive alcohol consumption, illicit drug use, or smoking. She was unaware of having any food or drug allergies.

The woman was married and had a 6-month-old baby. Until her accident, she was employed full-time as an investment accountant. She expressed contentment regarding her home, family, work, and busy lifestyle.

Once the patient’s condition was stabilized and hemostasis achieved in the trauma ICU, the bilateral lower-extremity wounds were managed by application of foam dressings via negative-pressure therapy. The dressings were changed on the patient’s lower-extremity wounds three times per week for about three weeks. When the wounds’ depth decreased and granulation was achieved, split-thickness skin grafts (STSGs) harvested from the right anterior thigh were applied to the open wounds (see Figure 1) in the operating room.

Following application of the STSGs and hemostasis of the patient’s donor site, silver silicone foam dressings were applied directly over the right lower-extremity graft and the donor site in the operating room. The dressings remained in place for four days (see Figure 2). A nonadherent, petrolatum-based contact layer was then applied to the left lower-extremity amputation graft site, followed by a negative-pressure foam dressing.

The negative-pressure pump was programmed for 75 mm Hg continuous therapy for four days. The silver silicone foam and negative-pressure foam dressings were removed from the respective graft sites on the fourth postpostoperative day. The grafts were viable and intact (see Figures 3 and 4). The silver silicone foam was reapplied to the lower-extremity STSGs and donor site and changed every four days.

When a few pinpoint dehisced areas were noted on the grafts, a silver-coated absorbent antimicrobial dressing was applied. A nonadherent, petrolatum-based contact layer, followed by wide-mesh stretch gauze, was secured as an exterior dressing over the graft sites. Both lower-extremity dressings were layered with elastic wraps to prevent edema. The dressings were changed daily for two weeks.

On postoperative Day 4, the silver silicone foam was removed from the donor site. A nonadherent contact layer of bismuth tribromophenate petrolatum, followed by the silver silicone foam, was selected for placement over the donor site. Gauze and an elastic wrap were secured as an exterior dressing and removed three days later.

The donor site dressing was reduced to a layer of bismuth tribromophenate petrolatum and left open to air. As the edges of the nonadherent contact layer dried, they were trimmed with scissors (see Figure 5). A moisturizing cocoa butter–based lotion was applied daily to the exposed areas of the donor site.

During the patient’s third postoperative week at the trauma center, as she underwent a continuum of aggressive rehabilitation and wound care, the donor and STSG sites were pronounced healed (see Figures 6, 7, and 8). The donor site was left open to air, with daily use of cocoa butter lotion. Maintenance care of the graft sites included daily application of cocoa butter lotion, stretch gauze, and elastic wraps. The patient was discharged from the rehabilitation unit to home, where she awaited a prosthetic fitting.

Throughout the patient’s hospitalization and rehabilitation, surgical, medical, pain, and nutrition management were monitored on a continuum, as were laboratory values. Her vital signs remained within reasonable limits. The patient remained infection free and experienced neither medical nor surgical complications during the course of her hospital stay.

DISCUSSION
Traumatic injuries often result in bodily deformities, amputations, and death. They represent the leading cause of death among people in the US younger than 45.^1,2

Compartment syndrome develops when increased pressure within a bodily cavity minimizes capillary perfusion, resulting in decreased tissue viability.³ Edema and hemorrhage are also precipitating factors for this condition.³ When it goes unrelieved, compromised circulation can lead to muscle devitalization. Amputation of the affected appendage may be necessary unless circulation is restored.

Surgical fasciotomy can help alleviate pressure within the musculofascial compartment to improve circulation.⁴ Typically, such a procedure leaves large open wounds—a challenge for the clinician who cares for the affected patient. Once the wound is stabilized and the tissue becomes viable with granulation, application of an STSG can be considered.^5,6

STSGs provide effective closure for open wounds. The grafting procedure entails removing, processing, and placing a portion of skin, both epidermal and partial dermal layers, on an open wound. Successful grafting requires adequate circulation, but excess bacteria can impede graft viability.⁷ Graft sites must be kept clean and moist without edema.⁵ Immediate application of negative-pressure therapy directly on an STSG has been shown to result in an outstanding graft “take,” as compared with use of traditional dressings.^5,6,8

Nutritional status must be optimal for a successful graft take, with adequate intake of protein, calories, fluids, vitamins, and minerals.^9,10

Treatment
Since days of old when traumatic wounds were treated with goat dung and honey, an array of methods and products has been developed, including numerous agents for cutaneous injuries alone.⁴ Occlusive, semiocclusive, or bacteriostatic topical ointments, foam, silver, or a combination of products can be used to manage and heal surgical wounds, grafts (including STSGs), and donor sites.^11,12

Currently, negative pressure is also used in STSGs to accelerate healing.^7,11 When applied to a wound, negative-pressure therapy enhances granulation, removes excess exudate, and creates a moist environment for healing.^5,13

Silver-coated absorbent antimicrobial dressings appear to reduce bacteria on the surface of the wound surfaces and postoperative surgical sites without inducing bacterial resistance or adversely affecting healthy tissue.^12,14-16 Silver silicone foam reduces bacterial colonization on wound surfaces and absorbs exudate into the foam dressing.^17,18 Wounds with devitalized tissue and excessive drainage are at risk for infection, inflammation, and chronic duration.¹⁹

Nutrition
It has been reported that about half of all persons admitted to US hospitals are malnourished, with increased risk for morbidity and mortality.²⁰ After experiencing hemorrhage, even well-nourished patients require additional protein and iron for successful recovery.¹⁰ Obese patients appear more susceptible to infection and surgical wound dehiscence than are their thinner counterparts, but further research is needed to study the impact of wound development and healing in this population.¹⁴

Tissue regeneration is known to require the amino acids arginine and glutamine for the construction of protein; additional research is also needed to support the theory that supplemental glutamine promotes wound healing.^9,21 Surgical patients and patients with wounds benefit from protein-enhanced diets; zinc and vitamins A and C can also help improve wound healing and clinical outcomes.²² Monitoring protein and prealbumin levels is helpful in evaluating nutritional status, allowing the clinician to modify the medical nutrition plan and optimize the patient’s health and wellness.²²

Rehabilitation
Surgical amputations of the lower extremities impair balance and mobility, necessitating extensive physical therapy and rehabilitation for affected patients.^23,24 Aggressive rehabilitation typically is exhausting for patients. It is important to initiate a supportive team approach (including physical and occupational therapists) soon after surgery, continuing beyond the acute hospitalization into rehabilitation. Individualized, patient-centered goals are targeted and amended as necessary. Physical and occupational therapy increase in intensity and duration to optimize the patient’s functionality. Prosthetic fitting takes place after edema diminishes and the limb is fully healed.²⁴

Patient Outcome
An obese young woman who sustained traumatic lower-extremity injuries and amputation experienced an optimal clinical outcome after 54 days of management. Exceptional surgical and medical strategies were initiated in the adult regional trauma center’s ICU and concluded at the adjoining rehabilitation center.

Strategic selection of products and interventions—negative pressure, silver silicone foam, silver-coated absorbent antimicrobial dressings, nonadherent contact layers, stretch gauze, and elastic wraps—and constant monitoring, including that of the patient’s nutritional status, resulted in expedient resolution of her traumatic wounds, STSGs, and donor site.

CONCLUSION
Despite revolutionary advances and life-sustaining measures in the surgical, medical, and wound care arena, traumatic events remain potentially debilitating and life-threatening for young adults. Triage of the trauma patient for appropriate medical care and collaborative management involving a team of trauma specialists and clinicians of all disciplines can now provide life-sustaining opportunities for these patients.

While waiting to cross a street, a 30-year-old woman was suddenly struck by an oncoming vehicle, which crushed her legs against a parked automobile. She sustained a life-threatening traumatic injury and nearly exsanguinated at the scene. Nearby pedestrians assisted her, including a man who applied his belt to the woman’s left thigh to prevent complete exsanguination following the crush. She was emergently transported to an adult regional trauma center and admitted to the ICU.

The patient was given multiple transfusions of packed red blood cells, platelets, and frozen plasma in attempts to restore hemostasis. She underwent emergent surgery for a complete washout, debridement, and compartment fasciotomy on the right leg. The left leg required an above-knee amputation. Following surgery, full-thickness and split-thickness wounds were present on both extremities.

Before the accident, the woman had a history of hypertension controlled with a single antihypertensive. She was obese, with a BMI of 31.9. She had no surgical history. She denied excessive alcohol consumption, illicit drug use, or smoking. She was unaware of having any food or drug allergies.

The woman was married and had a 6-month-old baby. Until her accident, she was employed full-time as an investment accountant. She expressed contentment regarding her home, family, work, and busy lifestyle.

Once the patient’s condition was stabilized and hemostasis achieved in the trauma ICU, the bilateral lower-extremity wounds were managed by application of foam dressings via negative-pressure therapy. The dressings were changed on the patient’s lower-extremity wounds three times per week for about three weeks. When the wounds’ depth decreased and granulation was achieved, split-thickness skin grafts (STSGs) harvested from the right anterior thigh were applied to the open wounds (see Figure 1) in the operating room.

Following application of the STSGs and hemostasis of the patient’s donor site, silver silicone foam dressings were applied directly over the right lower-extremity graft and the donor site in the operating room. The dressings remained in place for four days (see Figure 2). A nonadherent, petrolatum-based contact layer was then applied to the left lower-extremity amputation graft site, followed by a negative-pressure foam dressing.

The negative-pressure pump was programmed for 75 mm Hg continuous therapy for four days. The silver silicone foam and negative-pressure foam dressings were removed from the respective graft sites on the fourth postpostoperative day. The grafts were viable and intact (see Figures 3 and 4). The silver silicone foam was reapplied to the lower-extremity STSGs and donor site and changed every four days.

When a few pinpoint dehisced areas were noted on the grafts, a silver-coated absorbent antimicrobial dressing was applied. A nonadherent, petrolatum-based contact layer, followed by wide-mesh stretch gauze, was secured as an exterior dressing over the graft sites. Both lower-extremity dressings were layered with elastic wraps to prevent edema. The dressings were changed daily for two weeks.

On postoperative Day 4, the silver silicone foam was removed from the donor site. A nonadherent contact layer of bismuth tribromophenate petrolatum, followed by the silver silicone foam, was selected for placement over the donor site. Gauze and an elastic wrap were secured as an exterior dressing and removed three days later.

The donor site dressing was reduced to a layer of bismuth tribromophenate petrolatum and left open to air. As the edges of the nonadherent contact layer dried, they were trimmed with scissors (see Figure 5). A moisturizing cocoa butter–based lotion was applied daily to the exposed areas of the donor site.

During the patient’s third postoperative week at the trauma center, as she underwent a continuum of aggressive rehabilitation and wound care, the donor and STSG sites were pronounced healed (see Figures 6, 7, and 8). The donor site was left open to air, with daily use of cocoa butter lotion. Maintenance care of the graft sites included daily application of cocoa butter lotion, stretch gauze, and elastic wraps. The patient was discharged from the rehabilitation unit to home, where she awaited a prosthetic fitting.

Throughout the patient’s hospitalization and rehabilitation, surgical, medical, pain, and nutrition management were monitored on a continuum, as were laboratory values. Her vital signs remained within reasonable limits. The patient remained infection free and experienced neither medical nor surgical complications during the course of her hospital stay.

DISCUSSION
Traumatic injuries often result in bodily deformities, amputations, and death. They represent the leading cause of death among people in the US younger than 45.^1,2

Compartment syndrome develops when increased pressure within a bodily cavity minimizes capillary perfusion, resulting in decreased tissue viability.³ Edema and hemorrhage are also precipitating factors for this condition.³ When it goes unrelieved, compromised circulation can lead to muscle devitalization. Amputation of the affected appendage may be necessary unless circulation is restored.

Surgical fasciotomy can help alleviate pressure within the musculofascial compartment to improve circulation.⁴ Typically, such a procedure leaves large open wounds—a challenge for the clinician who cares for the affected patient. Once the wound is stabilized and the tissue becomes viable with granulation, application of an STSG can be considered.^5,6

STSGs provide effective closure for open wounds. The grafting procedure entails removing, processing, and placing a portion of skin, both epidermal and partial dermal layers, on an open wound. Successful grafting requires adequate circulation, but excess bacteria can impede graft viability.⁷ Graft sites must be kept clean and moist without edema.⁵ Immediate application of negative-pressure therapy directly on an STSG has been shown to result in an outstanding graft “take,” as compared with use of traditional dressings.^5,6,8

Nutritional status must be optimal for a successful graft take, with adequate intake of protein, calories, fluids, vitamins, and minerals.^9,10

Treatment
Since days of old when traumatic wounds were treated with goat dung and honey, an array of methods and products has been developed, including numerous agents for cutaneous injuries alone.⁴ Occlusive, semiocclusive, or bacteriostatic topical ointments, foam, silver, or a combination of products can be used to manage and heal surgical wounds, grafts (including STSGs), and donor sites.^11,12

Currently, negative pressure is also used in STSGs to accelerate healing.^7,11 When applied to a wound, negative-pressure therapy enhances granulation, removes excess exudate, and creates a moist environment for healing.^5,13

Silver-coated absorbent antimicrobial dressings appear to reduce bacteria on the surface of the wound surfaces and postoperative surgical sites without inducing bacterial resistance or adversely affecting healthy tissue.^12,14-16 Silver silicone foam reduces bacterial colonization on wound surfaces and absorbs exudate into the foam dressing.^17,18 Wounds with devitalized tissue and excessive drainage are at risk for infection, inflammation, and chronic duration.¹⁹

Nutrition
It has been reported that about half of all persons admitted to US hospitals are malnourished, with increased risk for morbidity and mortality.²⁰ After experiencing hemorrhage, even well-nourished patients require additional protein and iron for successful recovery.¹⁰ Obese patients appear more susceptible to infection and surgical wound dehiscence than are their thinner counterparts, but further research is needed to study the impact of wound development and healing in this population.¹⁴

Tissue regeneration is known to require the amino acids arginine and glutamine for the construction of protein; additional research is also needed to support the theory that supplemental glutamine promotes wound healing.^9,21 Surgical patients and patients with wounds benefit from protein-enhanced diets; zinc and vitamins A and C can also help improve wound healing and clinical outcomes.²² Monitoring protein and prealbumin levels is helpful in evaluating nutritional status, allowing the clinician to modify the medical nutrition plan and optimize the patient’s health and wellness.²²

Rehabilitation
Surgical amputations of the lower extremities impair balance and mobility, necessitating extensive physical therapy and rehabilitation for affected patients.^23,24 Aggressive rehabilitation typically is exhausting for patients. It is important to initiate a supportive team approach (including physical and occupational therapists) soon after surgery, continuing beyond the acute hospitalization into rehabilitation. Individualized, patient-centered goals are targeted and amended as necessary. Physical and occupational therapy increase in intensity and duration to optimize the patient’s functionality. Prosthetic fitting takes place after edema diminishes and the limb is fully healed.²⁴

Patient Outcome
An obese young woman who sustained traumatic lower-extremity injuries and amputation experienced an optimal clinical outcome after 54 days of management. Exceptional surgical and medical strategies were initiated in the adult regional trauma center’s ICU and concluded at the adjoining rehabilitation center.

Strategic selection of products and interventions—negative pressure, silver silicone foam, silver-coated absorbent antimicrobial dressings, nonadherent contact layers, stretch gauze, and elastic wraps—and constant monitoring, including that of the patient’s nutritional status, resulted in expedient resolution of her traumatic wounds, STSGs, and donor site.

CONCLUSION
Despite revolutionary advances and life-sustaining measures in the surgical, medical, and wound care arena, traumatic events remain potentially debilitating and life-threatening for young adults. Triage of the trauma patient for appropriate medical care and collaborative management involving a team of trauma specialists and clinicians of all disciplines can now provide life-sustaining opportunities for these patients.

An 80-year-old Mandarin-speaking Chinese woman was referred to a mental health outpatient clinic for evaluation and treatment. The patient had a history of mild depression, for which she had been treated for many years with sertraline.

Five years earlier at age 75, the patient had been evaluated by a psychiatrist after she began to experience psychotic symptoms, including frequent repetitive auditory hallucinations of people counting, alternating with music from her childhood. At that time, she also had persecutory paranoid thoughts and delusional thinking that she was receiving messages in Mandarin while watching American TV programs. Initially, her only cognitive disturbance was an inability to differentiate among numbers on a calendar or a telephone keypad. No reports of memory problems were noted. Although the patient acknowledged auditory hallucinations, she denied experiencing command auditory hallucinations or hallucinations of other forms. The patient had no history of suicide attempts and denied suicidal or homicidal ideation. She had no history of psychiatric hospitalization.

The psychiatrist made a diagnosis of major depressive disorder with psychotic features, not otherwise specified¹ and prescribed sertraline 50 mg/d. The patient was also started on risperidone 0.25 mg/d for management of her psychotic symptoms, with the dosage gradually increased to 2.0 mg/d over five years. While taking this combination, the patient experienced stable mood and fewer paranoid thoughts, although her auditory hallucinations continued.

Two months before the current visit, the patient moved into a retirement living facility, and she reported having adapted well to the new setting. She was sleeping well and had a good appetite. Her BMI was within normal range.

The patient described herself as a single parent for nearly 40 years, raising one daughter. Formerly high functioning, she had held a full-time clerical job until age 70. She appeared well-groomed, polite but anxious, and oriented to time, person, and place. Her speech was normal, her thought processes were coherent, and her mood was stable. However, her affect was constricted; she acknowledged auditory hallucinations, which impaired her thought content. The patient reported feeling increased anxiety prior to any nonroutine activity, such as a doctor’s appointment; this, she said, would cause insomnia, leaving her to pace in her room.

During the examination, fine tremors on upper and lower extremities were noted. The patient’s Abnormal Involuntary Movement Scale (AIMS) score² was 13, which placed her in the highest risk category for antipsychotic-induced dopamine-blockade extrapyramidal symptoms (EPS). The patient was found to be negative for tardive dyskinesia, with no abnormal facial movements. She was aware of the tremors in her limbs and said she felt bothered by them.

The patient had an unsteady gait and used a four-point walker. Her Mini-Mental State Exam (MMSE) score³ was 28/30, which was normal for her age and education level (high school completed).

Apart from the described symptoms, the patient was healthy for her age and had no other medical diagnosis. Her vital signs were within normal range. The medical work-up to rule out other causes of dementia yielded negative results. Lab values were normal, including electrolyte levels and thyroid tests. The patient’s hearing test showed age-related hearing loss of full range, not limited to high pitch. She was able to engage in a meaningful conversation at a normal volume. Clinically, however, it was concerning to observe the possible signs of EPS and the relatively high risperidone dosage, considering the patient’s advanced age.

After the meeting with the patient, a treatment plan was created to 1) gradually reduce the dosage of antipsychotic medication, and 2) refer her to a neurologist for a complete work-up to rule out underlying neurologic disorders, such as dementia. Risperidone was tapered by increments of 0.25 mg/d every three to four weeks; throughout this process, the patient was closely monitored by the nursing staff at the retirement living facility. Monthly appointments were scheduled at the outpatient mental health clinic for evaluation and medication management.

Two months after the initial mental health clinic visit, the patient’s condition was pronounced stable on the current regimen of sertraline 50 mg/d and risperidone 1.0 mg/d. She was later seen by a neurologist, who made a diagnosis of Parkinson’s disease and placed her on carbidopa-­levodopa (1 1/2 tablets, 25/100 mg, tid). The patient’s auditory hallucinations continued with the same intensity as at baseline, but fewer tremors were noted in her extremities. By six months into the tapering process (with risperidone reduced at that time to 0.25 mg/d and carbidopa-levodopa to 25/100 mg tid), the patient had begun to experience dissipation of the tremors, and her AIMS score² was 0. She was able to replace her four-point walker with a cane.

One year after her initial visit to the mental health clinic, the patient’s neurologist suggested replacing risperidone with quetia­pine (12.5 mg/d) for its improved tolerability and lower adverse effect profile.⁴ She continued to take sertraline and carbidopa-levodopa.

Improvement of symptoms was noted following the switch. After one month on the revised regimen, the patient reported that the number of auditory hallucinations persisted, but that their intensity had decreased dramatically. She had a brighter affect and appeared to feel uplifted and more energetic. She became involved in the social activities offered at the retirement living facility and the mental health clinic. She also maintained a steady gait without her cane. According to the patient’s daughter, her mother was at her best psychological state since the onset of psychotic symptoms six years earlier. The pharmacologic regimen had reached its maximum benefit.

At a mental health appointment at the outpatient clinic 18 months after her initial visit there, it was evident that the patient’s auditory hallucinations persisted as a major stressor. She began to complain about other residents in her facility. She said she disliked the resident with whom she shared meals, and she claimed that other residents often spit on the floor in front of her room. The nursing staff did not confirm these incidents, which they considered a delusion despite the patient’s “evidence” (the tissues she said she had used to clean up).

Additionally, a new theme had emerged in the patient’s auditory hallucinations. She reported hearing a male voice that announced changes in meal times. Although she knew there was no public address system in her room or in the hallway, the “announcement” was so convincing that she would go to the dining room and once there, realize that nothing had changed. She seemed to drift between reality and her hallucinations/delusions. According to her daughter, the patient’s independent and reserved personality forced her to internalize her stressors—in this case, her frustration about the other residents—which fed into her hallucinations and delusions.

In response to her worsening psychotic symptoms, the patient’s provider increased her quetia­pine dosage from 12.5 mg/d to 25 mg/d. Her MMSE score³ at this visit was 25/30.

Two months later, the patient exhibited increasing symptoms of paranoia, delusions, and auditory hallucinations. She continued to respond to the “broadcast” messages about meal times, and she voiced her frustrations to others who spoke Mandarin. She became agitated in response to out-of-the-ordinary events. When her alarm clock battery ran out, for example, she insisted that “a man’s voice” kept reminding her to replace the battery; in response, she placed the alarm clock in the refrigerator, later explaining, “Now I don’t need to worry about it.”

Her cognitive status began to show obvious, progressive deterioration, with an MMSE score³ of 22/30 at this visit—a significant reduction from previous scores. Worsening of her short-term memory became apparent when she had difficulty playing bingo and was unable to remember her appointment or the current date. She became upset when others corrected her.

In a review of the trends in this patient’s clinical presentation, it became increasingly evident to the patient’s mental health care providers that she had Lewy body dementia.

DISCUSSION
Dementia with Lewy bodies (DLB), a progressive disease, is the second most common cause of neurodegenerative dementia after Alzheimer’s disease.^5-7 It is estimated that DLB accounts for 20% of US cases of dementia (ie, about 800,000 patients).^8,9 Although public awareness of DLB is on the rise, the disorder is still underrecognized and underdiagnosed because its clinical manifestations so closely resemble those of Alzheimer’s disease, Parkinson’s disease, and psychosis.^10,11

Clinical symptoms of DLB include progressive cognitive decline, cognitive fluctuation, EPS, and parkinsonism; hallucinations involving all five senses, particularly sight; delusions; REM sleep disturbance, with or without vivid and frightening dreams; changes in mood and behavior; impaired judgment and insight; and autonomic dysfunction, such as orthostatic hypotension and carotid-sinus hypersensitivity.^5,11-15

The symptoms of DLB are caused by the accumulations of Lewy bodies, that is, deposits of alpha-synuclein protein in the nuclei of neurons. Lewy bodies destroy neurons over time, resulting in the destruction of dopaminergic and acetylcholinergic pathways from the brain stem to areas of the cerebral cortex associated with cognition and motor functions.^4,5,16

DLB is a spectrum disorder; it often coexists with Parkinson’s disease or Alzheimer’s disease, as Lewy bodies are also found in patients with these illnesses.⁷ This poses a challenge for formulating a differential diagnosis, particularly in patients with fluctuating cognition,¹⁰ and for attempting to establish disease prevalence.

Diagnosis
Currently, a conclusive diagnosis of DLB can be confirmed only through postmortem autopsy, although use of medial temporal lobe volume (via structural MRI) and regional blood flow (via single photon emission CT [SPECT] tracers) is being investigated.¹⁷

The diagnosis of DLB is currently based on the presenting clinical symptoms and the exclusion of other medical conditions whose symptoms mimic those of DLB.⁷ The screening assessment may include a neurologic/psychiatric assessment (MMSE, psychiatric evaluation, and interviews with family members or caretakers), neuroimaging such as MRI to rule out other organic causes, and laboratory evaluation to rule out potentially reversible causes of dementia, including electrolyte imbalance, vitamin deficiency (specifically vitamin B12), anemia, thyroid dysfunction, and kidney or liver impairment.¹⁸

The American Psychiatric Assocation¹ categorizes DLB under “Dementia Due to Other General Medical Conditions” (294.1x). The World Health Organization¹⁹ includes it among “Other specified degenerative diseases of the nervous system” (G31.8).

Treatment
Lewy body dementia is an irreversible neurologic degenerative disorder. Treatment for DLB comprises symptom management, primarily through pharmacology; however, the response to medication is highly individualized. Treatment includes management of the following symptoms:

Cognitive impairment. Cholinesterase inhibitors, such as rivastigmine (3 to 12 mg/d), donepezil (10 mg/d), or galantamine (titrated up to 12 mg bid),^20-23 improve attention and behavior and reduce apathy, anxiety, delusions, and hallucinations. As cognitive impairment worsens, memantine (10 mg bid) may be effective.²⁴ The potential for anticholinergic adverse effects requires close monitoring in patients taking these agents.

Parkinsonian symptoms. Medications indicated for Parkinson’s disease and syndrome, such as carbidopa-levodopa (25/100 mg tid), can be effective; dosage may be slowly titrated upward as tolerated and if needed for symptom management.^25,26 The dopaminergic effect of antiparkinson medications may intensify the psychotic symptoms and worsen the REM sleep pattern. In this case, a low-dose atypical antipsychotic is suggested^27,28 (see below).

Psychotic symptoms. An atypical antipsychotic agent, such as quetiapine (12.5 mg), risperidone (0.25 mg), olanzapine (2.5 mg), ziprasidone (20 mg), aripiprazole (2 mg), or paliperidone (1.5 mg), may be used. Because of the DLB-associated risk of neuroleptic sensitivity, atypical antipsychotic agents should be initiated at a low dose with slow upward titration^17,26,29; quetiapine appears less likely than risperidone or olanzapine to cause neuroleptic sensitivity or to trigger EPS.⁴ For Asian patients, who often respond to lower doses of these medications (and are more easily affected by associated adverse effects), Chen et al³⁰ recommend a starting dose of about one-half the recommended dose.

Depression. An SSRI antidepressant with relatively simple pharmacologic properties and moderate half-life may be used to manage symptoms of depression.^26,31,32 Long–half-life SSRIs (eg, fluoxetine) should be avoided in elderly patients; in response to SNRIs (serotonin-norepinephrine reuptake inhibitors), these patients may experience elevated blood pressures and pulses, with subsequent morbidity.³³

REM sleep disturbances. Clo­nazepam (0.25 mg), melatonin (3.0 mg), or quetiapine (12.5 mg) may be administered at bedtime.³⁴

Important Lessons
In general, providers should consider the benefits and risks of any pharmacologic treatment and avoid polypharmacy, if possible. Family and caretakers should be included in the treatment planning, with a focus on prioritizing and managing the most debilitating symptoms or dysfunctions that prompt concerns for safety.

For optimal homeostasis, some DLB patients may require joint pharmacologic modalities that appear counterintuitive—for example, an antiparkinsonism (dopaminergic) agent for parkinsonian symptoms or neuroleptic-induced EPS, versus an antipsychotic (eg, a dopamine antagonist) to treat profound hallucinations.²⁶

As the response to treatment for DLB is highly individualized, it is essential to titrate and augment with care.

CONCLUSION
In DLB, as with other dementing illnesses, the onset of symptoms can be gradual and insidious, posing a great challenge to the clinician who seeks to confirm the diagnosis. In the illness’s early stages, the clinician may have to treat targeted symptoms and adjust the treatment plan once signs of the pathologic origins emerge.

It is critical to understand the mechanisms of psychotropic medications and targeted neurotransmitters when evaluating treatment for DLB. Titrating or augmenting these medications in elderly patients requires the clinician to follow a principle of start low and go slow, making only one change at a time.

It is always helpful to include family members in the patient’s care and to gather information on previous history, personality traits, family history, and cultural components. It is also important to communicate with other specialists to implement collaborative care.

An 80-year-old Mandarin-speaking Chinese woman was referred to a mental health outpatient clinic for evaluation and treatment. The patient had a history of mild depression, for which she had been treated for many years with sertraline.

Five years earlier at age 75, the patient had been evaluated by a psychiatrist after she began to experience psychotic symptoms, including frequent repetitive auditory hallucinations of people counting, alternating with music from her childhood. At that time, she also had persecutory paranoid thoughts and delusional thinking that she was receiving messages in Mandarin while watching American TV programs. Initially, her only cognitive disturbance was an inability to differentiate among numbers on a calendar or a telephone keypad. No reports of memory problems were noted. Although the patient acknowledged auditory hallucinations, she denied experiencing command auditory hallucinations or hallucinations of other forms. The patient had no history of suicide attempts and denied suicidal or homicidal ideation. She had no history of psychiatric hospitalization.

The psychiatrist made a diagnosis of major depressive disorder with psychotic features, not otherwise specified¹ and prescribed sertraline 50 mg/d. The patient was also started on risperidone 0.25 mg/d for management of her psychotic symptoms, with the dosage gradually increased to 2.0 mg/d over five years. While taking this combination, the patient experienced stable mood and fewer paranoid thoughts, although her auditory hallucinations continued.

Two months before the current visit, the patient moved into a retirement living facility, and she reported having adapted well to the new setting. She was sleeping well and had a good appetite. Her BMI was within normal range.

The patient described herself as a single parent for nearly 40 years, raising one daughter. Formerly high functioning, she had held a full-time clerical job until age 70. She appeared well-groomed, polite but anxious, and oriented to time, person, and place. Her speech was normal, her thought processes were coherent, and her mood was stable. However, her affect was constricted; she acknowledged auditory hallucinations, which impaired her thought content. The patient reported feeling increased anxiety prior to any nonroutine activity, such as a doctor’s appointment; this, she said, would cause insomnia, leaving her to pace in her room.

During the examination, fine tremors on upper and lower extremities were noted. The patient’s Abnormal Involuntary Movement Scale (AIMS) score² was 13, which placed her in the highest risk category for antipsychotic-induced dopamine-blockade extrapyramidal symptoms (EPS). The patient was found to be negative for tardive dyskinesia, with no abnormal facial movements. She was aware of the tremors in her limbs and said she felt bothered by them.

The patient had an unsteady gait and used a four-point walker. Her Mini-Mental State Exam (MMSE) score³ was 28/30, which was normal for her age and education level (high school completed).

Apart from the described symptoms, the patient was healthy for her age and had no other medical diagnosis. Her vital signs were within normal range. The medical work-up to rule out other causes of dementia yielded negative results. Lab values were normal, including electrolyte levels and thyroid tests. The patient’s hearing test showed age-related hearing loss of full range, not limited to high pitch. She was able to engage in a meaningful conversation at a normal volume. Clinically, however, it was concerning to observe the possible signs of EPS and the relatively high risperidone dosage, considering the patient’s advanced age.

After the meeting with the patient, a treatment plan was created to 1) gradually reduce the dosage of antipsychotic medication, and 2) refer her to a neurologist for a complete work-up to rule out underlying neurologic disorders, such as dementia. Risperidone was tapered by increments of 0.25 mg/d every three to four weeks; throughout this process, the patient was closely monitored by the nursing staff at the retirement living facility. Monthly appointments were scheduled at the outpatient mental health clinic for evaluation and medication management.

Two months after the initial mental health clinic visit, the patient’s condition was pronounced stable on the current regimen of sertraline 50 mg/d and risperidone 1.0 mg/d. She was later seen by a neurologist, who made a diagnosis of Parkinson’s disease and placed her on carbidopa-­levodopa (1 1/2 tablets, 25/100 mg, tid). The patient’s auditory hallucinations continued with the same intensity as at baseline, but fewer tremors were noted in her extremities. By six months into the tapering process (with risperidone reduced at that time to 0.25 mg/d and carbidopa-levodopa to 25/100 mg tid), the patient had begun to experience dissipation of the tremors, and her AIMS score² was 0. She was able to replace her four-point walker with a cane.

One year after her initial visit to the mental health clinic, the patient’s neurologist suggested replacing risperidone with quetia­pine (12.5 mg/d) for its improved tolerability and lower adverse effect profile.⁴ She continued to take sertraline and carbidopa-levodopa.

Improvement of symptoms was noted following the switch. After one month on the revised regimen, the patient reported that the number of auditory hallucinations persisted, but that their intensity had decreased dramatically. She had a brighter affect and appeared to feel uplifted and more energetic. She became involved in the social activities offered at the retirement living facility and the mental health clinic. She also maintained a steady gait without her cane. According to the patient’s daughter, her mother was at her best psychological state since the onset of psychotic symptoms six years earlier. The pharmacologic regimen had reached its maximum benefit.

At a mental health appointment at the outpatient clinic 18 months after her initial visit there, it was evident that the patient’s auditory hallucinations persisted as a major stressor. She began to complain about other residents in her facility. She said she disliked the resident with whom she shared meals, and she claimed that other residents often spit on the floor in front of her room. The nursing staff did not confirm these incidents, which they considered a delusion despite the patient’s “evidence” (the tissues she said she had used to clean up).

Additionally, a new theme had emerged in the patient’s auditory hallucinations. She reported hearing a male voice that announced changes in meal times. Although she knew there was no public address system in her room or in the hallway, the “announcement” was so convincing that she would go to the dining room and once there, realize that nothing had changed. She seemed to drift between reality and her hallucinations/delusions. According to her daughter, the patient’s independent and reserved personality forced her to internalize her stressors—in this case, her frustration about the other residents—which fed into her hallucinations and delusions.

In response to her worsening psychotic symptoms, the patient’s provider increased her quetia­pine dosage from 12.5 mg/d to 25 mg/d. Her MMSE score³ at this visit was 25/30.

Two months later, the patient exhibited increasing symptoms of paranoia, delusions, and auditory hallucinations. She continued to respond to the “broadcast” messages about meal times, and she voiced her frustrations to others who spoke Mandarin. She became agitated in response to out-of-the-ordinary events. When her alarm clock battery ran out, for example, she insisted that “a man’s voice” kept reminding her to replace the battery; in response, she placed the alarm clock in the refrigerator, later explaining, “Now I don’t need to worry about it.”

Her cognitive status began to show obvious, progressive deterioration, with an MMSE score³ of 22/30 at this visit—a significant reduction from previous scores. Worsening of her short-term memory became apparent when she had difficulty playing bingo and was unable to remember her appointment or the current date. She became upset when others corrected her.

In a review of the trends in this patient’s clinical presentation, it became increasingly evident to the patient’s mental health care providers that she had Lewy body dementia.

DISCUSSION
Dementia with Lewy bodies (DLB), a progressive disease, is the second most common cause of neurodegenerative dementia after Alzheimer’s disease.^5-7 It is estimated that DLB accounts for 20% of US cases of dementia (ie, about 800,000 patients).^8,9 Although public awareness of DLB is on the rise, the disorder is still underrecognized and underdiagnosed because its clinical manifestations so closely resemble those of Alzheimer’s disease, Parkinson’s disease, and psychosis.^10,11

Clinical symptoms of DLB include progressive cognitive decline, cognitive fluctuation, EPS, and parkinsonism; hallucinations involving all five senses, particularly sight; delusions; REM sleep disturbance, with or without vivid and frightening dreams; changes in mood and behavior; impaired judgment and insight; and autonomic dysfunction, such as orthostatic hypotension and carotid-sinus hypersensitivity.^5,11-15

The symptoms of DLB are caused by the accumulations of Lewy bodies, that is, deposits of alpha-synuclein protein in the nuclei of neurons. Lewy bodies destroy neurons over time, resulting in the destruction of dopaminergic and acetylcholinergic pathways from the brain stem to areas of the cerebral cortex associated with cognition and motor functions.^4,5,16

DLB is a spectrum disorder; it often coexists with Parkinson’s disease or Alzheimer’s disease, as Lewy bodies are also found in patients with these illnesses.⁷ This poses a challenge for formulating a differential diagnosis, particularly in patients with fluctuating cognition,¹⁰ and for attempting to establish disease prevalence.

Diagnosis
Currently, a conclusive diagnosis of DLB can be confirmed only through postmortem autopsy, although use of medial temporal lobe volume (via structural MRI) and regional blood flow (via single photon emission CT [SPECT] tracers) is being investigated.¹⁷

The diagnosis of DLB is currently based on the presenting clinical symptoms and the exclusion of other medical conditions whose symptoms mimic those of DLB.⁷ The screening assessment may include a neurologic/psychiatric assessment (MMSE, psychiatric evaluation, and interviews with family members or caretakers), neuroimaging such as MRI to rule out other organic causes, and laboratory evaluation to rule out potentially reversible causes of dementia, including electrolyte imbalance, vitamin deficiency (specifically vitamin B12), anemia, thyroid dysfunction, and kidney or liver impairment.¹⁸

The American Psychiatric Assocation¹ categorizes DLB under “Dementia Due to Other General Medical Conditions” (294.1x). The World Health Organization¹⁹ includes it among “Other specified degenerative diseases of the nervous system” (G31.8).

Treatment
Lewy body dementia is an irreversible neurologic degenerative disorder. Treatment for DLB comprises symptom management, primarily through pharmacology; however, the response to medication is highly individualized. Treatment includes management of the following symptoms:

Cognitive impairment. Cholinesterase inhibitors, such as rivastigmine (3 to 12 mg/d), donepezil (10 mg/d), or galantamine (titrated up to 12 mg bid),^20-23 improve attention and behavior and reduce apathy, anxiety, delusions, and hallucinations. As cognitive impairment worsens, memantine (10 mg bid) may be effective.²⁴ The potential for anticholinergic adverse effects requires close monitoring in patients taking these agents.

Parkinsonian symptoms. Medications indicated for Parkinson’s disease and syndrome, such as carbidopa-levodopa (25/100 mg tid), can be effective; dosage may be slowly titrated upward as tolerated and if needed for symptom management.^25,26 The dopaminergic effect of antiparkinson medications may intensify the psychotic symptoms and worsen the REM sleep pattern. In this case, a low-dose atypical antipsychotic is suggested^27,28 (see below).

Psychotic symptoms. An atypical antipsychotic agent, such as quetiapine (12.5 mg), risperidone (0.25 mg), olanzapine (2.5 mg), ziprasidone (20 mg), aripiprazole (2 mg), or paliperidone (1.5 mg), may be used. Because of the DLB-associated risk of neuroleptic sensitivity, atypical antipsychotic agents should be initiated at a low dose with slow upward titration^17,26,29; quetiapine appears less likely than risperidone or olanzapine to cause neuroleptic sensitivity or to trigger EPS.⁴ For Asian patients, who often respond to lower doses of these medications (and are more easily affected by associated adverse effects), Chen et al³⁰ recommend a starting dose of about one-half the recommended dose.

Depression. An SSRI antidepressant with relatively simple pharmacologic properties and moderate half-life may be used to manage symptoms of depression.^26,31,32 Long–half-life SSRIs (eg, fluoxetine) should be avoided in elderly patients; in response to SNRIs (serotonin-norepinephrine reuptake inhibitors), these patients may experience elevated blood pressures and pulses, with subsequent morbidity.³³

REM sleep disturbances. Clo­nazepam (0.25 mg), melatonin (3.0 mg), or quetiapine (12.5 mg) may be administered at bedtime.³⁴

Important Lessons
In general, providers should consider the benefits and risks of any pharmacologic treatment and avoid polypharmacy, if possible. Family and caretakers should be included in the treatment planning, with a focus on prioritizing and managing the most debilitating symptoms or dysfunctions that prompt concerns for safety.

For optimal homeostasis, some DLB patients may require joint pharmacologic modalities that appear counterintuitive—for example, an antiparkinsonism (dopaminergic) agent for parkinsonian symptoms or neuroleptic-induced EPS, versus an antipsychotic (eg, a dopamine antagonist) to treat profound hallucinations.²⁶

As the response to treatment for DLB is highly individualized, it is essential to titrate and augment with care.

CONCLUSION
In DLB, as with other dementing illnesses, the onset of symptoms can be gradual and insidious, posing a great challenge to the clinician who seeks to confirm the diagnosis. In the illness’s early stages, the clinician may have to treat targeted symptoms and adjust the treatment plan once signs of the pathologic origins emerge.

It is critical to understand the mechanisms of psychotropic medications and targeted neurotransmitters when evaluating treatment for DLB. Titrating or augmenting these medications in elderly patients requires the clinician to follow a principle of start low and go slow, making only one change at a time.

It is always helpful to include family members in the patient’s care and to gather information on previous history, personality traits, family history, and cultural components. It is also important to communicate with other specialists to implement collaborative care.

An 80-year-old Mandarin-speaking Chinese woman was referred to a mental health outpatient clinic for evaluation and treatment. The patient had a history of mild depression, for which she had been treated for many years with sertraline.

Five years earlier at age 75, the patient had been evaluated by a psychiatrist after she began to experience psychotic symptoms, including frequent repetitive auditory hallucinations of people counting, alternating with music from her childhood. At that time, she also had persecutory paranoid thoughts and delusional thinking that she was receiving messages in Mandarin while watching American TV programs. Initially, her only cognitive disturbance was an inability to differentiate among numbers on a calendar or a telephone keypad. No reports of memory problems were noted. Although the patient acknowledged auditory hallucinations, she denied experiencing command auditory hallucinations or hallucinations of other forms. The patient had no history of suicide attempts and denied suicidal or homicidal ideation. She had no history of psychiatric hospitalization.

The psychiatrist made a diagnosis of major depressive disorder with psychotic features, not otherwise specified¹ and prescribed sertraline 50 mg/d. The patient was also started on risperidone 0.25 mg/d for management of her psychotic symptoms, with the dosage gradually increased to 2.0 mg/d over five years. While taking this combination, the patient experienced stable mood and fewer paranoid thoughts, although her auditory hallucinations continued.

Two months before the current visit, the patient moved into a retirement living facility, and she reported having adapted well to the new setting. She was sleeping well and had a good appetite. Her BMI was within normal range.

The patient described herself as a single parent for nearly 40 years, raising one daughter. Formerly high functioning, she had held a full-time clerical job until age 70. She appeared well-groomed, polite but anxious, and oriented to time, person, and place. Her speech was normal, her thought processes were coherent, and her mood was stable. However, her affect was constricted; she acknowledged auditory hallucinations, which impaired her thought content. The patient reported feeling increased anxiety prior to any nonroutine activity, such as a doctor’s appointment; this, she said, would cause insomnia, leaving her to pace in her room.

During the examination, fine tremors on upper and lower extremities were noted. The patient’s Abnormal Involuntary Movement Scale (AIMS) score² was 13, which placed her in the highest risk category for antipsychotic-induced dopamine-blockade extrapyramidal symptoms (EPS). The patient was found to be negative for tardive dyskinesia, with no abnormal facial movements. She was aware of the tremors in her limbs and said she felt bothered by them.

The patient had an unsteady gait and used a four-point walker. Her Mini-Mental State Exam (MMSE) score³ was 28/30, which was normal for her age and education level (high school completed).

Apart from the described symptoms, the patient was healthy for her age and had no other medical diagnosis. Her vital signs were within normal range. The medical work-up to rule out other causes of dementia yielded negative results. Lab values were normal, including electrolyte levels and thyroid tests. The patient’s hearing test showed age-related hearing loss of full range, not limited to high pitch. She was able to engage in a meaningful conversation at a normal volume. Clinically, however, it was concerning to observe the possible signs of EPS and the relatively high risperidone dosage, considering the patient’s advanced age.

After the meeting with the patient, a treatment plan was created to 1) gradually reduce the dosage of antipsychotic medication, and 2) refer her to a neurologist for a complete work-up to rule out underlying neurologic disorders, such as dementia. Risperidone was tapered by increments of 0.25 mg/d every three to four weeks; throughout this process, the patient was closely monitored by the nursing staff at the retirement living facility. Monthly appointments were scheduled at the outpatient mental health clinic for evaluation and medication management.

Two months after the initial mental health clinic visit, the patient’s condition was pronounced stable on the current regimen of sertraline 50 mg/d and risperidone 1.0 mg/d. She was later seen by a neurologist, who made a diagnosis of Parkinson’s disease and placed her on carbidopa-­levodopa (1 1/2 tablets, 25/100 mg, tid). The patient’s auditory hallucinations continued with the same intensity as at baseline, but fewer tremors were noted in her extremities. By six months into the tapering process (with risperidone reduced at that time to 0.25 mg/d and carbidopa-levodopa to 25/100 mg tid), the patient had begun to experience dissipation of the tremors, and her AIMS score² was 0. She was able to replace her four-point walker with a cane.

One year after her initial visit to the mental health clinic, the patient’s neurologist suggested replacing risperidone with quetia­pine (12.5 mg/d) for its improved tolerability and lower adverse effect profile.⁴ She continued to take sertraline and carbidopa-levodopa.

Improvement of symptoms was noted following the switch. After one month on the revised regimen, the patient reported that the number of auditory hallucinations persisted, but that their intensity had decreased dramatically. She had a brighter affect and appeared to feel uplifted and more energetic. She became involved in the social activities offered at the retirement living facility and the mental health clinic. She also maintained a steady gait without her cane. According to the patient’s daughter, her mother was at her best psychological state since the onset of psychotic symptoms six years earlier. The pharmacologic regimen had reached its maximum benefit.

At a mental health appointment at the outpatient clinic 18 months after her initial visit there, it was evident that the patient’s auditory hallucinations persisted as a major stressor. She began to complain about other residents in her facility. She said she disliked the resident with whom she shared meals, and she claimed that other residents often spit on the floor in front of her room. The nursing staff did not confirm these incidents, which they considered a delusion despite the patient’s “evidence” (the tissues she said she had used to clean up).

Additionally, a new theme had emerged in the patient’s auditory hallucinations. She reported hearing a male voice that announced changes in meal times. Although she knew there was no public address system in her room or in the hallway, the “announcement” was so convincing that she would go to the dining room and once there, realize that nothing had changed. She seemed to drift between reality and her hallucinations/delusions. According to her daughter, the patient’s independent and reserved personality forced her to internalize her stressors—in this case, her frustration about the other residents—which fed into her hallucinations and delusions.

In response to her worsening psychotic symptoms, the patient’s provider increased her quetia­pine dosage from 12.5 mg/d to 25 mg/d. Her MMSE score³ at this visit was 25/30.

Two months later, the patient exhibited increasing symptoms of paranoia, delusions, and auditory hallucinations. She continued to respond to the “broadcast” messages about meal times, and she voiced her frustrations to others who spoke Mandarin. She became agitated in response to out-of-the-ordinary events. When her alarm clock battery ran out, for example, she insisted that “a man’s voice” kept reminding her to replace the battery; in response, she placed the alarm clock in the refrigerator, later explaining, “Now I don’t need to worry about it.”

Her cognitive status began to show obvious, progressive deterioration, with an MMSE score³ of 22/30 at this visit—a significant reduction from previous scores. Worsening of her short-term memory became apparent when she had difficulty playing bingo and was unable to remember her appointment or the current date. She became upset when others corrected her.

In a review of the trends in this patient’s clinical presentation, it became increasingly evident to the patient’s mental health care providers that she had Lewy body dementia.

DISCUSSION
Dementia with Lewy bodies (DLB), a progressive disease, is the second most common cause of neurodegenerative dementia after Alzheimer’s disease.^5-7 It is estimated that DLB accounts for 20% of US cases of dementia (ie, about 800,000 patients).^8,9 Although public awareness of DLB is on the rise, the disorder is still underrecognized and underdiagnosed because its clinical manifestations so closely resemble those of Alzheimer’s disease, Parkinson’s disease, and psychosis.^10,11

Clinical symptoms of DLB include progressive cognitive decline, cognitive fluctuation, EPS, and parkinsonism; hallucinations involving all five senses, particularly sight; delusions; REM sleep disturbance, with or without vivid and frightening dreams; changes in mood and behavior; impaired judgment and insight; and autonomic dysfunction, such as orthostatic hypotension and carotid-sinus hypersensitivity.^5,11-15

The symptoms of DLB are caused by the accumulations of Lewy bodies, that is, deposits of alpha-synuclein protein in the nuclei of neurons. Lewy bodies destroy neurons over time, resulting in the destruction of dopaminergic and acetylcholinergic pathways from the brain stem to areas of the cerebral cortex associated with cognition and motor functions.^4,5,16

DLB is a spectrum disorder; it often coexists with Parkinson’s disease or Alzheimer’s disease, as Lewy bodies are also found in patients with these illnesses.⁷ This poses a challenge for formulating a differential diagnosis, particularly in patients with fluctuating cognition,¹⁰ and for attempting to establish disease prevalence.

Diagnosis
Currently, a conclusive diagnosis of DLB can be confirmed only through postmortem autopsy, although use of medial temporal lobe volume (via structural MRI) and regional blood flow (via single photon emission CT [SPECT] tracers) is being investigated.¹⁷

The diagnosis of DLB is currently based on the presenting clinical symptoms and the exclusion of other medical conditions whose symptoms mimic those of DLB.⁷ The screening assessment may include a neurologic/psychiatric assessment (MMSE, psychiatric evaluation, and interviews with family members or caretakers), neuroimaging such as MRI to rule out other organic causes, and laboratory evaluation to rule out potentially reversible causes of dementia, including electrolyte imbalance, vitamin deficiency (specifically vitamin B12), anemia, thyroid dysfunction, and kidney or liver impairment.¹⁸

The American Psychiatric Assocation¹ categorizes DLB under “Dementia Due to Other General Medical Conditions” (294.1x). The World Health Organization¹⁹ includes it among “Other specified degenerative diseases of the nervous system” (G31.8).

Treatment
Lewy body dementia is an irreversible neurologic degenerative disorder. Treatment for DLB comprises symptom management, primarily through pharmacology; however, the response to medication is highly individualized. Treatment includes management of the following symptoms:

Cognitive impairment. Cholinesterase inhibitors, such as rivastigmine (3 to 12 mg/d), donepezil (10 mg/d), or galantamine (titrated up to 12 mg bid),^20-23 improve attention and behavior and reduce apathy, anxiety, delusions, and hallucinations. As cognitive impairment worsens, memantine (10 mg bid) may be effective.²⁴ The potential for anticholinergic adverse effects requires close monitoring in patients taking these agents.

Parkinsonian symptoms. Medications indicated for Parkinson’s disease and syndrome, such as carbidopa-levodopa (25/100 mg tid), can be effective; dosage may be slowly titrated upward as tolerated and if needed for symptom management.^25,26 The dopaminergic effect of antiparkinson medications may intensify the psychotic symptoms and worsen the REM sleep pattern. In this case, a low-dose atypical antipsychotic is suggested^27,28 (see below).

Psychotic symptoms. An atypical antipsychotic agent, such as quetiapine (12.5 mg), risperidone (0.25 mg), olanzapine (2.5 mg), ziprasidone (20 mg), aripiprazole (2 mg), or paliperidone (1.5 mg), may be used. Because of the DLB-associated risk of neuroleptic sensitivity, atypical antipsychotic agents should be initiated at a low dose with slow upward titration^17,26,29; quetiapine appears less likely than risperidone or olanzapine to cause neuroleptic sensitivity or to trigger EPS.⁴ For Asian patients, who often respond to lower doses of these medications (and are more easily affected by associated adverse effects), Chen et al³⁰ recommend a starting dose of about one-half the recommended dose.

Depression. An SSRI antidepressant with relatively simple pharmacologic properties and moderate half-life may be used to manage symptoms of depression.^26,31,32 Long–half-life SSRIs (eg, fluoxetine) should be avoided in elderly patients; in response to SNRIs (serotonin-norepinephrine reuptake inhibitors), these patients may experience elevated blood pressures and pulses, with subsequent morbidity.³³

REM sleep disturbances. Clo­nazepam (0.25 mg), melatonin (3.0 mg), or quetiapine (12.5 mg) may be administered at bedtime.³⁴

Important Lessons
In general, providers should consider the benefits and risks of any pharmacologic treatment and avoid polypharmacy, if possible. Family and caretakers should be included in the treatment planning, with a focus on prioritizing and managing the most debilitating symptoms or dysfunctions that prompt concerns for safety.

For optimal homeostasis, some DLB patients may require joint pharmacologic modalities that appear counterintuitive—for example, an antiparkinsonism (dopaminergic) agent for parkinsonian symptoms or neuroleptic-induced EPS, versus an antipsychotic (eg, a dopamine antagonist) to treat profound hallucinations.²⁶

As the response to treatment for DLB is highly individualized, it is essential to titrate and augment with care.

CONCLUSION
In DLB, as with other dementing illnesses, the onset of symptoms can be gradual and insidious, posing a great challenge to the clinician who seeks to confirm the diagnosis. In the illness’s early stages, the clinician may have to treat targeted symptoms and adjust the treatment plan once signs of the pathologic origins emerge.

It is critical to understand the mechanisms of psychotropic medications and targeted neurotransmitters when evaluating treatment for DLB. Titrating or augmenting these medications in elderly patients requires the clinician to follow a principle of start low and go slow, making only one change at a time.

It is always helpful to include family members in the patient’s care and to gather information on previous history, personality traits, family history, and cultural components. It is also important to communicate with other specialists to implement collaborative care.

A 65-year-old man presented to the emergency department (ED) with a two-week history of progressively severe pain in his right hand and difficulty moving his fingers. He reported that approximately two weeks earlier, while shoveling snow, he slipped and fell, landing on his right hand. Initially, he had no problems with his hand. He finished his shoveling and continued his normal daily activities.

Within two to three days he started to experience pain in his right hand, which grew progressively worse.

Because he did not have a primary care provider, the patient had a limited medical history. He reported having a mildly elevated prostate-specific antigen test years earlier. He underwent an appendectomy at age 15. He denied any other medical problems.

The patient was taking no medications and reported no known allergies to medications. He denied the use of tobacco, said he had one or two beers on an average day, and denied IV drug use. He was an artist and was married with one adult child. His family history was unremarkable with the exception of an alcoholic sister who died of cirrhosis at age 70.

During triage, vital signs were essentially normal: blood pressure, 142/74 mm Hg; heart rate, 78 beats/min; and respiratory rate, 20 breaths/min. The patient was afebrile at 37.2°C (98.9°F). Physical examination was remarkable for some edema and warmth of the right hand without any notable erythema. There was no evidence of any wound. Fingers all had good sensation; however, flexion of the index and long fingers elicited a significant increase in pain.

The remainder of the exam was unremarkable. The patient’s head was normocephalic and atraumatic. Pupils were equal, round, and reactive to light. Eyes were anicteric, and no rhinorrhea was evident. The neck was supple without palpable lymphadenopathy. Lungs were clear to auscultation bilaterally. No wheezes, rales, or rhonchi were appreciated. The heart had a regular rate and rhythm; no murmurs, rubs, or gallups were noted. The abdomen was soft and non-tender. The extremities, except as previously stated, were normal, with good pulses, sensation, and strength.

Initially, only radiographs of the right hand were ordered (see Figures 1 and 2). These demonstrated soft tissue swelling on the dorsum of the hand, and an area of hypodensity between the first and second metacarpals. There were no fractures, dislocations, or other bone or joint abnormalities.

After a review of the radiographs, it was clear that the patient’s diagnosis was not a simple answer of hand contusion or fracture; thus, the evaluation was expanded. Vital signs were repeated three hours after triage: blood pressure, 128/74 mm Hg; heart rate, 76 beats/min; and respiration, 20 breaths/min. The patient was now febrile at 37.6°C (99.7°F). Because of his fever and the anomaly on the patient’s hand radiograph, expansion of the evaluation continued.

Laboratory studies included a complete blood count: white blood cells (WBCs), 30,700/mcL (reference range,¹ 4,500 to 11,000/mcL); hemoglobin, 13.3 g/dL (13.8 to 17.2 g/dL for men); hematocrit, 40.0% (41% to 50% for men); platelets, 217,000/mcL (130 to 400 x 10³/mcL). Initial chemistry panel results were normal except for serum glucose, 143 mg/dL (70 to 125 mg/dL).

Liver function test results were normal except for aspartate aminotransferase, 33 U/L (reference range,¹ 10 to 30 U/L) and albumin, 2.5 g/dL (3.5 to 5.0 g/dL). Once WBCs were found to exceed 30,000/mcL, the search for a cause was widened once more.

The continued studies included a chest radiograph with normal results, unremarkable CT of the abdomen and pelvis with IV contrast, blood cultures, and urinalysis. The urinalysis showed: blood, moderate; protein, trace; nitrites, positive; leukocytes, large; WBCs > 50/high-power field (reference range,¹ 5/high-power field or less); and numerous bacteria.

The final study performed in the ED evaluation of the patient was a CT of the right hand with IV contrast (see Figure 3). It demonstrated diffuse edema and a 9.0-mm area of low attenuation with some rim enhancement. The differential for these findings includes an abscess or a foreign body; the latter was deemed unlikely in light of the patient’s physical exam. In consideration of his elevated WBC count, the high number of WBCs in his urine, the fever, and the CT results, the patient was diagnosed with an abscess in his right hand that had been seeded, it was surmised, by an occult urosepsis after his fall.

Before the patient’s admission, a hand surgeon was consulted. The surgeon agreed with the diagnosis, and the patient was taken to the operating room (OR). He had been given piperacillin/tazobactam in the ED.

In the OR, the surgeon made a 3.0-cm incision, conducted an exploration, and identified a cavity that contained a small amount of purulence. He determined the lesion to be a resolving abscess. The wound was washed out, and the area was closed with a Penrose drain.

The patient was continued on the piperacillin/tazobactam. His blood culture was positive for gram-positive rods, and a low-grade fever persisted. An infectious disease specialist was consulted, and levofloxacin was added to the patient’s regimen.

After 24 hours of treatment, findings on urinalysis improved: blood, small; protein, trace; nitrites, negative; leukocytes, small; WBCs, 15 to 20/high-power field; and no bacteria. Over the next three days, the patient’s condition continued to improve. His hand drain was removed, and the pain and swelling subsided. He became afebrile, and his WBC count fell to 24,700/mcL. He was discharged to home with prescriptions for cephalexin and levofloxacin. Follow-up for postoperative care was arranged with the hand surgeon.

Discussion
Pyomyositis is defined as abscess formation deep within large striated muscles.¹ Although this condition is uncommon, it is believed that an occult bacteremia can seed an area of damaged muscle (compared with healthy muscle, which ordinarily resists infection), allowing an abscess to form.^1,2

Epidemiology
In a 2002 review involving 676 patients with primary pyomyositis, Bickels et al³ reported the condition in ages ranging from two months to 82 years (mean, 28.1 years). In a majority of cases, only a single muscle was involved; 112 patients (16.6%) were identified with multiple-site involvement. Only seven cases (0.1%) involved the hand.

In 452 cases (66.9%), a bacterial agent was identified. Among these, 350 (77%) had a positive culture for Staphylococcus aureus. Other isolates included Streptococcus pyogenes, Escherichia coli, Salmonella enteritidus, and Mycobacterium tuberculosis.^1,3 It should be noted that community-­acquired methicillin-resistant S aureus (CA-MRSA) is being implicated with increasing frequency in cases of pyomyositis.^4-6

Because pyomyositis is not a reportable disease and has not been studied in large clinical trials, its incidence is uncertain, and proposed risk factors have not all been confirmed² (see Table^2,7).

Pathophysiology
While the etiology of primary pyomyositis is unclear, it is believed to be caused by a combination of bacteremia (chronic or transient) and damaged muscle. In a 1960 study published in the Lancet, Smith and Vickers⁸ performed autopsies on 327 patients who had died of culture-positive septicemia. Only two patients were found to have a muscle abscess. At that time, the investigators concluded that both muscle injury and bacteremia would need to be present in order for an abscess to form. In animal studies, bacteremia (eg, S aureus) does not appear to lead to pyomyositis except in cases of muscle abnormality or trauma (eg, electric shock, pinching injury).^9,10

When a history of trauma can be identified in patients with pyomyositis, the condition typically develops near the affected muscle, and the infection appears within days to weeks.3 In cases in which an antecedent infection is identified and hematogenous spread of the bacteria to the skeletal muscle occurs, this is termed secondary pyomyositis.¹¹

Disease Progression
Pyomyositis generally progresses in three stages, beginning with inflammation and advancing to a focal abscess, then to a septic state.³ The first stage develops between seven and 21 days after the initial incident, is typically subacute, involves mild pain and swelling with a “woody” texture, and is occasionally associated with fevers.²

Diagnosis of pyomyositis is usually made during the second stage, 10 to 21 days after the initial incident; by that time, the pain has increased, and the fever is more pronounced. Third-stage infection usually involves fluctuance and sepsis.²

Although MRI is considered most useful in the diagnosis of pyomyositis, CT and ultrasound allow for percutaneous needle aspiration and drainage.³

Treatment
The correct treatment for pyomyositis depends upon the stage at which the disease is identified. During the first stage (before formation of an abscess), antibiotic treatment alone may be sufficient.¹ Once an abscess has formed, an incision and drainage will be required, in conjunction with or followed by appropriate antibiotic therapy.

When pyomyositis is properly treated during the first or second stage, a full recovery is likely.^2,3 By the third stage, surgical debridement is required. Additionally, osteomyelitis may develop in the adjacent bones, followed by muscle scarring, residual weakness, and functional impairment.^2,3 Reported pyomyositis-associated mortality ranges between less than 1% and 4%.^2,12

The Case Patient

The case presented here was of particular interest for two reasons. First, the patient had a traumatic injury that initially caused him no concern but worsened progressively over 14 days. Although this is not the typical presentation of a traumatic injury, the ED staff could very easily have performed a radiograph, made a diagnosis of traumatic hand injury, and discharged the patient.

Second, men in their 60s do not commonly have urinary tract infections.¹³ The patient was questioned frequently by several providers about sexual behaviors, medical problems, and urinary symptoms. Repeatedly, he denied all of these issues. While a urinalysis may be omitted in the evaluation of an otherwise healthy, asymptomatic patient, its results in this case were a key piece of data.

It should be noted that the patient thought it inappropriate to be asked for urine samples. He repeatedly said, “It’s my hand!”

Conclusion
Even in patients presenting with the most routine complaint, a careful evaluation can reveal unexpected, serious problems. This patient complained of pain in his hand some time after a fall and ultimately was treated for an occult urosepsis and hand abscess—pyomyositis, which rarely occurs in small muscles, such as those of the hand. Either condition, left untreated, could have led to serious morbidity or even mortality.

A 65-year-old man presented to the emergency department (ED) with a two-week history of progressively severe pain in his right hand and difficulty moving his fingers. He reported that approximately two weeks earlier, while shoveling snow, he slipped and fell, landing on his right hand. Initially, he had no problems with his hand. He finished his shoveling and continued his normal daily activities.

Within two to three days he started to experience pain in his right hand, which grew progressively worse.

Because he did not have a primary care provider, the patient had a limited medical history. He reported having a mildly elevated prostate-specific antigen test years earlier. He underwent an appendectomy at age 15. He denied any other medical problems.

The patient was taking no medications and reported no known allergies to medications. He denied the use of tobacco, said he had one or two beers on an average day, and denied IV drug use. He was an artist and was married with one adult child. His family history was unremarkable with the exception of an alcoholic sister who died of cirrhosis at age 70.

During triage, vital signs were essentially normal: blood pressure, 142/74 mm Hg; heart rate, 78 beats/min; and respiratory rate, 20 breaths/min. The patient was afebrile at 37.2°C (98.9°F). Physical examination was remarkable for some edema and warmth of the right hand without any notable erythema. There was no evidence of any wound. Fingers all had good sensation; however, flexion of the index and long fingers elicited a significant increase in pain.

The remainder of the exam was unremarkable. The patient’s head was normocephalic and atraumatic. Pupils were equal, round, and reactive to light. Eyes were anicteric, and no rhinorrhea was evident. The neck was supple without palpable lymphadenopathy. Lungs were clear to auscultation bilaterally. No wheezes, rales, or rhonchi were appreciated. The heart had a regular rate and rhythm; no murmurs, rubs, or gallups were noted. The abdomen was soft and non-tender. The extremities, except as previously stated, were normal, with good pulses, sensation, and strength.

Initially, only radiographs of the right hand were ordered (see Figures 1 and 2). These demonstrated soft tissue swelling on the dorsum of the hand, and an area of hypodensity between the first and second metacarpals. There were no fractures, dislocations, or other bone or joint abnormalities.

After a review of the radiographs, it was clear that the patient’s diagnosis was not a simple answer of hand contusion or fracture; thus, the evaluation was expanded. Vital signs were repeated three hours after triage: blood pressure, 128/74 mm Hg; heart rate, 76 beats/min; and respiration, 20 breaths/min. The patient was now febrile at 37.6°C (99.7°F). Because of his fever and the anomaly on the patient’s hand radiograph, expansion of the evaluation continued.

Laboratory studies included a complete blood count: white blood cells (WBCs), 30,700/mcL (reference range,¹ 4,500 to 11,000/mcL); hemoglobin, 13.3 g/dL (13.8 to 17.2 g/dL for men); hematocrit, 40.0% (41% to 50% for men); platelets, 217,000/mcL (130 to 400 x 10³/mcL). Initial chemistry panel results were normal except for serum glucose, 143 mg/dL (70 to 125 mg/dL).

Liver function test results were normal except for aspartate aminotransferase, 33 U/L (reference range,¹ 10 to 30 U/L) and albumin, 2.5 g/dL (3.5 to 5.0 g/dL). Once WBCs were found to exceed 30,000/mcL, the search for a cause was widened once more.

The continued studies included a chest radiograph with normal results, unremarkable CT of the abdomen and pelvis with IV contrast, blood cultures, and urinalysis. The urinalysis showed: blood, moderate; protein, trace; nitrites, positive; leukocytes, large; WBCs > 50/high-power field (reference range,¹ 5/high-power field or less); and numerous bacteria.

The final study performed in the ED evaluation of the patient was a CT of the right hand with IV contrast (see Figure 3). It demonstrated diffuse edema and a 9.0-mm area of low attenuation with some rim enhancement. The differential for these findings includes an abscess or a foreign body; the latter was deemed unlikely in light of the patient’s physical exam. In consideration of his elevated WBC count, the high number of WBCs in his urine, the fever, and the CT results, the patient was diagnosed with an abscess in his right hand that had been seeded, it was surmised, by an occult urosepsis after his fall.

Before the patient’s admission, a hand surgeon was consulted. The surgeon agreed with the diagnosis, and the patient was taken to the operating room (OR). He had been given piperacillin/tazobactam in the ED.

In the OR, the surgeon made a 3.0-cm incision, conducted an exploration, and identified a cavity that contained a small amount of purulence. He determined the lesion to be a resolving abscess. The wound was washed out, and the area was closed with a Penrose drain.

The patient was continued on the piperacillin/tazobactam. His blood culture was positive for gram-positive rods, and a low-grade fever persisted. An infectious disease specialist was consulted, and levofloxacin was added to the patient’s regimen.

After 24 hours of treatment, findings on urinalysis improved: blood, small; protein, trace; nitrites, negative; leukocytes, small; WBCs, 15 to 20/high-power field; and no bacteria. Over the next three days, the patient’s condition continued to improve. His hand drain was removed, and the pain and swelling subsided. He became afebrile, and his WBC count fell to 24,700/mcL. He was discharged to home with prescriptions for cephalexin and levofloxacin. Follow-up for postoperative care was arranged with the hand surgeon.

Discussion
Pyomyositis is defined as abscess formation deep within large striated muscles.¹ Although this condition is uncommon, it is believed that an occult bacteremia can seed an area of damaged muscle (compared with healthy muscle, which ordinarily resists infection), allowing an abscess to form.^1,2

Epidemiology
In a 2002 review involving 676 patients with primary pyomyositis, Bickels et al³ reported the condition in ages ranging from two months to 82 years (mean, 28.1 years). In a majority of cases, only a single muscle was involved; 112 patients (16.6%) were identified with multiple-site involvement. Only seven cases (0.1%) involved the hand.

In 452 cases (66.9%), a bacterial agent was identified. Among these, 350 (77%) had a positive culture for Staphylococcus aureus. Other isolates included Streptococcus pyogenes, Escherichia coli, Salmonella enteritidus, and Mycobacterium tuberculosis.^1,3 It should be noted that community-­acquired methicillin-resistant S aureus (CA-MRSA) is being implicated with increasing frequency in cases of pyomyositis.^4-6

Because pyomyositis is not a reportable disease and has not been studied in large clinical trials, its incidence is uncertain, and proposed risk factors have not all been confirmed² (see Table^2,7).

Pathophysiology
While the etiology of primary pyomyositis is unclear, it is believed to be caused by a combination of bacteremia (chronic or transient) and damaged muscle. In a 1960 study published in the Lancet, Smith and Vickers⁸ performed autopsies on 327 patients who had died of culture-positive septicemia. Only two patients were found to have a muscle abscess. At that time, the investigators concluded that both muscle injury and bacteremia would need to be present in order for an abscess to form. In animal studies, bacteremia (eg, S aureus) does not appear to lead to pyomyositis except in cases of muscle abnormality or trauma (eg, electric shock, pinching injury).^9,10

When a history of trauma can be identified in patients with pyomyositis, the condition typically develops near the affected muscle, and the infection appears within days to weeks.3 In cases in which an antecedent infection is identified and hematogenous spread of the bacteria to the skeletal muscle occurs, this is termed secondary pyomyositis.¹¹

Disease Progression
Pyomyositis generally progresses in three stages, beginning with inflammation and advancing to a focal abscess, then to a septic state.³ The first stage develops between seven and 21 days after the initial incident, is typically subacute, involves mild pain and swelling with a “woody” texture, and is occasionally associated with fevers.²

Diagnosis of pyomyositis is usually made during the second stage, 10 to 21 days after the initial incident; by that time, the pain has increased, and the fever is more pronounced. Third-stage infection usually involves fluctuance and sepsis.²

Although MRI is considered most useful in the diagnosis of pyomyositis, CT and ultrasound allow for percutaneous needle aspiration and drainage.³

Treatment
The correct treatment for pyomyositis depends upon the stage at which the disease is identified. During the first stage (before formation of an abscess), antibiotic treatment alone may be sufficient.¹ Once an abscess has formed, an incision and drainage will be required, in conjunction with or followed by appropriate antibiotic therapy.

When pyomyositis is properly treated during the first or second stage, a full recovery is likely.^2,3 By the third stage, surgical debridement is required. Additionally, osteomyelitis may develop in the adjacent bones, followed by muscle scarring, residual weakness, and functional impairment.^2,3 Reported pyomyositis-associated mortality ranges between less than 1% and 4%.^2,12

The Case Patient

The case presented here was of particular interest for two reasons. First, the patient had a traumatic injury that initially caused him no concern but worsened progressively over 14 days. Although this is not the typical presentation of a traumatic injury, the ED staff could very easily have performed a radiograph, made a diagnosis of traumatic hand injury, and discharged the patient.

Second, men in their 60s do not commonly have urinary tract infections.¹³ The patient was questioned frequently by several providers about sexual behaviors, medical problems, and urinary symptoms. Repeatedly, he denied all of these issues. While a urinalysis may be omitted in the evaluation of an otherwise healthy, asymptomatic patient, its results in this case were a key piece of data.

It should be noted that the patient thought it inappropriate to be asked for urine samples. He repeatedly said, “It’s my hand!”

Conclusion
Even in patients presenting with the most routine complaint, a careful evaluation can reveal unexpected, serious problems. This patient complained of pain in his hand some time after a fall and ultimately was treated for an occult urosepsis and hand abscess—pyomyositis, which rarely occurs in small muscles, such as those of the hand. Either condition, left untreated, could have led to serious morbidity or even mortality.

A 65-year-old man presented to the emergency department (ED) with a two-week history of progressively severe pain in his right hand and difficulty moving his fingers. He reported that approximately two weeks earlier, while shoveling snow, he slipped and fell, landing on his right hand. Initially, he had no problems with his hand. He finished his shoveling and continued his normal daily activities.

Within two to three days he started to experience pain in his right hand, which grew progressively worse.

Because he did not have a primary care provider, the patient had a limited medical history. He reported having a mildly elevated prostate-specific antigen test years earlier. He underwent an appendectomy at age 15. He denied any other medical problems.

The patient was taking no medications and reported no known allergies to medications. He denied the use of tobacco, said he had one or two beers on an average day, and denied IV drug use. He was an artist and was married with one adult child. His family history was unremarkable with the exception of an alcoholic sister who died of cirrhosis at age 70.

During triage, vital signs were essentially normal: blood pressure, 142/74 mm Hg; heart rate, 78 beats/min; and respiratory rate, 20 breaths/min. The patient was afebrile at 37.2°C (98.9°F). Physical examination was remarkable for some edema and warmth of the right hand without any notable erythema. There was no evidence of any wound. Fingers all had good sensation; however, flexion of the index and long fingers elicited a significant increase in pain.

The remainder of the exam was unremarkable. The patient’s head was normocephalic and atraumatic. Pupils were equal, round, and reactive to light. Eyes were anicteric, and no rhinorrhea was evident. The neck was supple without palpable lymphadenopathy. Lungs were clear to auscultation bilaterally. No wheezes, rales, or rhonchi were appreciated. The heart had a regular rate and rhythm; no murmurs, rubs, or gallups were noted. The abdomen was soft and non-tender. The extremities, except as previously stated, were normal, with good pulses, sensation, and strength.

Initially, only radiographs of the right hand were ordered (see Figures 1 and 2). These demonstrated soft tissue swelling on the dorsum of the hand, and an area of hypodensity between the first and second metacarpals. There were no fractures, dislocations, or other bone or joint abnormalities.

After a review of the radiographs, it was clear that the patient’s diagnosis was not a simple answer of hand contusion or fracture; thus, the evaluation was expanded. Vital signs were repeated three hours after triage: blood pressure, 128/74 mm Hg; heart rate, 76 beats/min; and respiration, 20 breaths/min. The patient was now febrile at 37.6°C (99.7°F). Because of his fever and the anomaly on the patient’s hand radiograph, expansion of the evaluation continued.

Laboratory studies included a complete blood count: white blood cells (WBCs), 30,700/mcL (reference range,¹ 4,500 to 11,000/mcL); hemoglobin, 13.3 g/dL (13.8 to 17.2 g/dL for men); hematocrit, 40.0% (41% to 50% for men); platelets, 217,000/mcL (130 to 400 x 10³/mcL). Initial chemistry panel results were normal except for serum glucose, 143 mg/dL (70 to 125 mg/dL).

Liver function test results were normal except for aspartate aminotransferase, 33 U/L (reference range,¹ 10 to 30 U/L) and albumin, 2.5 g/dL (3.5 to 5.0 g/dL). Once WBCs were found to exceed 30,000/mcL, the search for a cause was widened once more.

The continued studies included a chest radiograph with normal results, unremarkable CT of the abdomen and pelvis with IV contrast, blood cultures, and urinalysis. The urinalysis showed: blood, moderate; protein, trace; nitrites, positive; leukocytes, large; WBCs > 50/high-power field (reference range,¹ 5/high-power field or less); and numerous bacteria.

The final study performed in the ED evaluation of the patient was a CT of the right hand with IV contrast (see Figure 3). It demonstrated diffuse edema and a 9.0-mm area of low attenuation with some rim enhancement. The differential for these findings includes an abscess or a foreign body; the latter was deemed unlikely in light of the patient’s physical exam. In consideration of his elevated WBC count, the high number of WBCs in his urine, the fever, and the CT results, the patient was diagnosed with an abscess in his right hand that had been seeded, it was surmised, by an occult urosepsis after his fall.

Before the patient’s admission, a hand surgeon was consulted. The surgeon agreed with the diagnosis, and the patient was taken to the operating room (OR). He had been given piperacillin/tazobactam in the ED.

In the OR, the surgeon made a 3.0-cm incision, conducted an exploration, and identified a cavity that contained a small amount of purulence. He determined the lesion to be a resolving abscess. The wound was washed out, and the area was closed with a Penrose drain.

The patient was continued on the piperacillin/tazobactam. His blood culture was positive for gram-positive rods, and a low-grade fever persisted. An infectious disease specialist was consulted, and levofloxacin was added to the patient’s regimen.

After 24 hours of treatment, findings on urinalysis improved: blood, small; protein, trace; nitrites, negative; leukocytes, small; WBCs, 15 to 20/high-power field; and no bacteria. Over the next three days, the patient’s condition continued to improve. His hand drain was removed, and the pain and swelling subsided. He became afebrile, and his WBC count fell to 24,700/mcL. He was discharged to home with prescriptions for cephalexin and levofloxacin. Follow-up for postoperative care was arranged with the hand surgeon.

Discussion
Pyomyositis is defined as abscess formation deep within large striated muscles.¹ Although this condition is uncommon, it is believed that an occult bacteremia can seed an area of damaged muscle (compared with healthy muscle, which ordinarily resists infection), allowing an abscess to form.^1,2

Epidemiology
In a 2002 review involving 676 patients with primary pyomyositis, Bickels et al³ reported the condition in ages ranging from two months to 82 years (mean, 28.1 years). In a majority of cases, only a single muscle was involved; 112 patients (16.6%) were identified with multiple-site involvement. Only seven cases (0.1%) involved the hand.

In 452 cases (66.9%), a bacterial agent was identified. Among these, 350 (77%) had a positive culture for Staphylococcus aureus. Other isolates included Streptococcus pyogenes, Escherichia coli, Salmonella enteritidus, and Mycobacterium tuberculosis.^1,3 It should be noted that community-­acquired methicillin-resistant S aureus (CA-MRSA) is being implicated with increasing frequency in cases of pyomyositis.^4-6

Because pyomyositis is not a reportable disease and has not been studied in large clinical trials, its incidence is uncertain, and proposed risk factors have not all been confirmed² (see Table^2,7).

Pathophysiology
While the etiology of primary pyomyositis is unclear, it is believed to be caused by a combination of bacteremia (chronic or transient) and damaged muscle. In a 1960 study published in the Lancet, Smith and Vickers⁸ performed autopsies on 327 patients who had died of culture-positive septicemia. Only two patients were found to have a muscle abscess. At that time, the investigators concluded that both muscle injury and bacteremia would need to be present in order for an abscess to form. In animal studies, bacteremia (eg, S aureus) does not appear to lead to pyomyositis except in cases of muscle abnormality or trauma (eg, electric shock, pinching injury).^9,10

When a history of trauma can be identified in patients with pyomyositis, the condition typically develops near the affected muscle, and the infection appears within days to weeks.3 In cases in which an antecedent infection is identified and hematogenous spread of the bacteria to the skeletal muscle occurs, this is termed secondary pyomyositis.¹¹

Disease Progression
Pyomyositis generally progresses in three stages, beginning with inflammation and advancing to a focal abscess, then to a septic state.³ The first stage develops between seven and 21 days after the initial incident, is typically subacute, involves mild pain and swelling with a “woody” texture, and is occasionally associated with fevers.²

Diagnosis of pyomyositis is usually made during the second stage, 10 to 21 days after the initial incident; by that time, the pain has increased, and the fever is more pronounced. Third-stage infection usually involves fluctuance and sepsis.²

Although MRI is considered most useful in the diagnosis of pyomyositis, CT and ultrasound allow for percutaneous needle aspiration and drainage.³

Treatment
The correct treatment for pyomyositis depends upon the stage at which the disease is identified. During the first stage (before formation of an abscess), antibiotic treatment alone may be sufficient.¹ Once an abscess has formed, an incision and drainage will be required, in conjunction with or followed by appropriate antibiotic therapy.

When pyomyositis is properly treated during the first or second stage, a full recovery is likely.^2,3 By the third stage, surgical debridement is required. Additionally, osteomyelitis may develop in the adjacent bones, followed by muscle scarring, residual weakness, and functional impairment.^2,3 Reported pyomyositis-associated mortality ranges between less than 1% and 4%.^2,12

The Case Patient

The case presented here was of particular interest for two reasons. First, the patient had a traumatic injury that initially caused him no concern but worsened progressively over 14 days. Although this is not the typical presentation of a traumatic injury, the ED staff could very easily have performed a radiograph, made a diagnosis of traumatic hand injury, and discharged the patient.

Second, men in their 60s do not commonly have urinary tract infections.¹³ The patient was questioned frequently by several providers about sexual behaviors, medical problems, and urinary symptoms. Repeatedly, he denied all of these issues. While a urinalysis may be omitted in the evaluation of an otherwise healthy, asymptomatic patient, its results in this case were a key piece of data.

It should be noted that the patient thought it inappropriate to be asked for urine samples. He repeatedly said, “It’s my hand!”

Conclusion
Even in patients presenting with the most routine complaint, a careful evaluation can reveal unexpected, serious problems. This patient complained of pain in his hand some time after a fall and ultimately was treated for an occult urosepsis and hand abscess—pyomyositis, which rarely occurs in small muscles, such as those of the hand. Either condition, left untreated, could have led to serious morbidity or even mortality.

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 39-year-old woman presented to the emergency department (ED) with a chief complaint of muscle aches and pain. She stated that three days earlier, she had begun exercising in a 45-minute “spinning” class (ie, riding a stationary bicycle with a weighted front wheel). The patient had not engaged in any aerobic exercise for at least six months before the spinning class. She mentioned that much older participants in the class were outperforming her, but she did not feel the need to keep up with them.

After dismounting, the woman said, she experienced weakness in her legs and had great difficulty ambulating. She went home, took 400 mg of ibuprofen, and went to bed. She awoke with pain and swelling in both thighs and continued to take ibuprofen, in addition to applying a topical mentholated preparation to her thighs. She took an Epsom salts bath two days later.

On the morning of the third day after the spinning class, she voided black urine and presented to the ED.

The patient had no significant medical history. Surgical history was limited to removal of a ganglion cyst on her wrist. She denied any history of seizure disorder, thyroid disease, hepatitis, heart disease, or hyperlipidemia.

The patient had been taking ibuprofen as needed since the spinning class. She was taking no other medications. She denied any allergies to drugs or food.

The patient admitted to smoking one pack of cigarettes per week and to occasional alcohol consumption but denied use of illicit drugs. She was employed as an executive officer for a large business association.

On physical examination, the patient’s vital signs were blood pressure, 134/73 mm/Hg; pulse, 86 beats/min; and respirations, 16 breaths/min. She was afebrile, alert, and oriented. Her sclera were nonicteric. Her neck was supple with no anterior cervical lymphadenopathy. There was no thyroid enlargement, her lungs were clear to auscultation, and her heart sounds were regular. There was no peripheral edema, and dorsalis pedis pulses were present bilaterally. Her thighs appeared swollen but were not tender to palpation.

The patient’s history, combined with an extremely high level of serum creatine phosphokinase (CPK; ie, 123,800 U/L [reference range, 45 to 260 U/L¹]), confirmed a diagnosis of rhabdomyolysis. She was admitted for close observation. The patient’s urinalysis revealed 2 to 5 red blood cells and 6 to 10 white blood cells per high-power field. Moderate occult blood was detected, with no casts or protein noted. A urine myoglobin test was not performed.

The patient underwent IV hydration with dextrose 5% in water and three ampules of sodium bicarbonate after being given a 2.0-L saline bolus. Ibuprofen was discontinued. IV hydration with bicarbonate solution was continued until the patient’s CPK level declined significantly. She underwent daily laboratory testing (see Table 1). Her renal function remained stable, and she was discharged on hospital day 7.

DISCUSSION
Rhabdomyolysis is a clinical condition defined as muscle necrosis resulting from the release of intracellular skeletal muscle components (including myoglobin, CPK, potassium, phosphorus, and aldolase) into the extracellular compartment.^1-3 The condition was first described during the bombing of London in World War II, with high incidence of crush injuries, shock, and associated kidney damage.⁴ The preponderance of such injuries during a 1988 earthquake in Armenia led the International Society of Nephrology to form its Renal Disaster Relief Task Force, which has provided support at numerous other disaster scenes since then.⁵

Rhabdomyolysis has been identified with a variety of pathologic events: those that cause muscle trauma, those associated with muscle use or overuse, and other etiologies involving genetic, metabolic, infectious, or pharmaceutical factors.¹ Many of the reported causes of rhabdomyolysis are listed in Table 2.^1,2

For patients with muscle trauma, the etiology of rhabdomyolysis is clear, but for those with other disease states, diagnosis may be more elusive. Patients who present with rhabdomyolysis after excessive exercise, for example, may have underlying metabolic disorders that predispose them to exertional rhabdomyolysis, such as chronic hypokalemia resulting from primary hyperaldosteronism.¹ Others may have a muscle enzyme deficiency, as in McArdle’s syndrome or carnitine deficiency.⁶

Alterations in blood chemistries can also contribute to development of rhabdomyolysis, even when more obvious etiologies for muscle necrosis are evident. Hypokalemia interferes with the vasodilation that normally occurs during exercise to increase muscle blood flow.^1,7,8 Continued exercise can lead to muscle necrosis, raising a concern for athletes who take diuretics.¹ Hypophosphatemia leads to a state of muscle necrosis; this is of particular concern for alcoholic patients who receive hyperalimentation without repletion of phosphates.⁹

Diagnosis
Patients with rhabdomyolysis usually present with myalgias, darkened urine (red, brown, or black), and a clinical scenario that corroborates the diagnosis (ie, history of trauma, excessive exercise, use of an offending medication).¹ Some patients may have minimal to absent symptoms or symptoms that occur only after exercise.³

A careful history is key. While traumatic causes are obvious, it is important to ask a patient with rhabdomyolysis after exertion about previous history of excessive weakness during or immediately after exercise, excessive cramping, or discoloration of urine after exercise. The family history may point to a genetic abnormality. A thorough understanding of the patient’s use of medications, including OTC agents, is also important. Rhabdomyolysis has been reported in patients who use herbal remedies, including those taken to facilitate weight loss or to improve lipid profiles.^10,11

For patients suspected of having rhabdomyolysis, a serum CPK level should be obtained; results exceeding normal values by five times confirm the diagnosis.³ Measurements for potassium, phosphorus, and calcium are also important to determine, as is renal function. A high level of serum aldolase (an enzyme that breaks down glucose in muscle tissue) can also support a diagnosis of rhabdomyolysis.^1,12 Urinalysis and urine myoglobin testing are also warranted, although a negative urine myoglobin test result does not rule out rhabdomyolysis in the presence of an elevated CPK level. Myoglobin is cleared rapidly by the kidneys, whereas serum CPK levels change slowly.¹

Any patient who presents with acute rhabdomyolysis and low to normal values for potassium or phosphate should be evaluated further for hypokalemia and hypophosphatemia as contributing or etiologic factors. Hypocalcemia may occur in the early course of rhabdomyolysis as calcium salt is deposited in muscle tissue. Patients recovering from rhabdomyolysis may experience rebound hypercalcemia as the damaged muscle releases the deposited calcium.^7,13

In most cases of rhabdomyolysis, only laboratory values are needed to make the diagnosis and follow the course of the episode.¹ However, when the etiology appears to involve metabolic deficiencies or genetic etiologies, it may become necessary to order additional diagnostic tests. These may include tests for thyroid function, a carnitine level to screen for glycogen storage diseases, and toxin screening (eg, for illicit drugs, such as cocaine).^2,6

Treatment and Management
Effective treatment of rhabdomyolysis relies on recognizing the underlying disorder.¹ For patients with muscle trauma (eg, crush injury) or muscle overuse, the mainstay of treatment is aggressive fluid resuscitation and prevention of acute injury to the kidneys.¹³ As for patients with an injury induced by a pharmaceutical agent or a toxin, removal of the offending agent is required, followed by hydration and prevention of renal damage. Supportive care during an infectious illness is also essential.¹⁴

Additionally, treatment must address the complications inherent with rhabdomyolysis.¹ In addition to CPK, potassium, phosphorus, and myoglobin are also released from skeletal muscle tissue. Hyperkalemia can be fatal, and potassium levels must be monitored closely to avert this condition.^7,8,13 During an episode of rhabdomyolysis, normal levels of both potassium and phosphorus should raise the clinician’s suspicion for underlying hypokalemia and hypophosphatemia—conditions that may have contributed to the episode of rhabdomyolysis. Hypocalcemia may also develop.¹³

Released myoglobin may cause acute kidney injury, as is the case in 33% to 50% of patients with rhabdomyolysis.³ In early studies, it was determined that alkalinizing the urine with IV isotonic bicarbonate might thwart onset of acute kidney injury.^1,2,15 Time is critical, and even on the battlefield or at the scene of a recent disaster, most attempts at resuscitation are begun immediately. IV access may be problematic, but administration of oral bicarbonate solutions has also proven effective.¹⁵ Close follow-up of the serum urea and creatinine levels and measurement of the urine pH during alkalinization is warranted throughout the course of the episode.

Unfortunately, some patients respond poorly to these conservative measures, and the released myoglobin can cause renal tubular blockage and necrosis, resulting in acute kidney injury.¹ Renal replacement therapy may be required.¹⁶ However, most episodes of dialysis-dependent acute renal injury do subside with time.

For patients with less elusive causes of rhabdomyolysis, treatment will hinge on a workup of the possible etiologies and follow-up treatment to target the apparent cause. For example, carnitine may be administered to patients with carnitine deficiency, and hypokalemic patients may be given potassium.^1,6,7 These patients will also need counseling before they consider engaging in an exercise program.

Patient’s Outcome
The case patient presented with exertional rhabdomyolysis; improper hydration, severe deconditioning, and a relatively low serum potassium level may all have contributed to the muscle necrosis she experienced. She was given IV alkaline solutions and did not develop acute kidney injury. She was discharged from the hospital and at the time of this writing was awaiting outpatient follow-up.

It should be interesting to see whether the case patient experiences any further episodes of severe weakness after engaging in exercise. Her low-normal potassium level (reference range, 3.5 to 5.3 mmol/L¹⁷) warrants further follow-up, as does her mildly elevated thyroid-stimulating hormone level (reference range, 0.5 to 4.7 mcIU/mL¹⁷).

CONCLUSION
Patients with rhabdomyolysis may present with muscle aches, darkened urine, and/or weakness; an elevated CPK level confirms the diagnosis. Management is mainly conservative, with IV hydration accompanied by alkalinizing the urine and correcting any metabolic abnormalities, such as potassium deficiencies. For the few patients who experience severe acute kidney injury, renal replacement therapy may be necessary.

While most causes of rhabdomyolysis have obvious clinical scenarios, such as a crush injury, a search for muscle enzyme deficiencies, disorders of potassium homeostasis, and thyroid abnormalities is also warranted in patients who present with exertional rhabdomyolysis.

A 39-year-old woman presented to the emergency department (ED) with a chief complaint of muscle aches and pain. She stated that three days earlier, she had begun exercising in a 45-minute “spinning” class (ie, riding a stationary bicycle with a weighted front wheel). The patient had not engaged in any aerobic exercise for at least six months before the spinning class. She mentioned that much older participants in the class were outperforming her, but she did not feel the need to keep up with them.

After dismounting, the woman said, she experienced weakness in her legs and had great difficulty ambulating. She went home, took 400 mg of ibuprofen, and went to bed. She awoke with pain and swelling in both thighs and continued to take ibuprofen, in addition to applying a topical mentholated preparation to her thighs. She took an Epsom salts bath two days later.

On the morning of the third day after the spinning class, she voided black urine and presented to the ED.

The patient had no significant medical history. Surgical history was limited to removal of a ganglion cyst on her wrist. She denied any history of seizure disorder, thyroid disease, hepatitis, heart disease, or hyperlipidemia.

The patient had been taking ibuprofen as needed since the spinning class. She was taking no other medications. She denied any allergies to drugs or food.

The patient admitted to smoking one pack of cigarettes per week and to occasional alcohol consumption but denied use of illicit drugs. She was employed as an executive officer for a large business association.

On physical examination, the patient’s vital signs were blood pressure, 134/73 mm/Hg; pulse, 86 beats/min; and respirations, 16 breaths/min. She was afebrile, alert, and oriented. Her sclera were nonicteric. Her neck was supple with no anterior cervical lymphadenopathy. There was no thyroid enlargement, her lungs were clear to auscultation, and her heart sounds were regular. There was no peripheral edema, and dorsalis pedis pulses were present bilaterally. Her thighs appeared swollen but were not tender to palpation.

The patient’s history, combined with an extremely high level of serum creatine phosphokinase (CPK; ie, 123,800 U/L [reference range, 45 to 260 U/L¹]), confirmed a diagnosis of rhabdomyolysis. She was admitted for close observation. The patient’s urinalysis revealed 2 to 5 red blood cells and 6 to 10 white blood cells per high-power field. Moderate occult blood was detected, with no casts or protein noted. A urine myoglobin test was not performed.

The patient underwent IV hydration with dextrose 5% in water and three ampules of sodium bicarbonate after being given a 2.0-L saline bolus. Ibuprofen was discontinued. IV hydration with bicarbonate solution was continued until the patient’s CPK level declined significantly. She underwent daily laboratory testing (see Table 1). Her renal function remained stable, and she was discharged on hospital day 7.

DISCUSSION
Rhabdomyolysis is a clinical condition defined as muscle necrosis resulting from the release of intracellular skeletal muscle components (including myoglobin, CPK, potassium, phosphorus, and aldolase) into the extracellular compartment.^1-3 The condition was first described during the bombing of London in World War II, with high incidence of crush injuries, shock, and associated kidney damage.⁴ The preponderance of such injuries during a 1988 earthquake in Armenia led the International Society of Nephrology to form its Renal Disaster Relief Task Force, which has provided support at numerous other disaster scenes since then.⁵

Rhabdomyolysis has been identified with a variety of pathologic events: those that cause muscle trauma, those associated with muscle use or overuse, and other etiologies involving genetic, metabolic, infectious, or pharmaceutical factors.¹ Many of the reported causes of rhabdomyolysis are listed in Table 2.^1,2

For patients with muscle trauma, the etiology of rhabdomyolysis is clear, but for those with other disease states, diagnosis may be more elusive. Patients who present with rhabdomyolysis after excessive exercise, for example, may have underlying metabolic disorders that predispose them to exertional rhabdomyolysis, such as chronic hypokalemia resulting from primary hyperaldosteronism.¹ Others may have a muscle enzyme deficiency, as in McArdle’s syndrome or carnitine deficiency.⁶

Alterations in blood chemistries can also contribute to development of rhabdomyolysis, even when more obvious etiologies for muscle necrosis are evident. Hypokalemia interferes with the vasodilation that normally occurs during exercise to increase muscle blood flow.^1,7,8 Continued exercise can lead to muscle necrosis, raising a concern for athletes who take diuretics.¹ Hypophosphatemia leads to a state of muscle necrosis; this is of particular concern for alcoholic patients who receive hyperalimentation without repletion of phosphates.⁹

Diagnosis
Patients with rhabdomyolysis usually present with myalgias, darkened urine (red, brown, or black), and a clinical scenario that corroborates the diagnosis (ie, history of trauma, excessive exercise, use of an offending medication).¹ Some patients may have minimal to absent symptoms or symptoms that occur only after exercise.³

A careful history is key. While traumatic causes are obvious, it is important to ask a patient with rhabdomyolysis after exertion about previous history of excessive weakness during or immediately after exercise, excessive cramping, or discoloration of urine after exercise. The family history may point to a genetic abnormality. A thorough understanding of the patient’s use of medications, including OTC agents, is also important. Rhabdomyolysis has been reported in patients who use herbal remedies, including those taken to facilitate weight loss or to improve lipid profiles.^10,11

For patients suspected of having rhabdomyolysis, a serum CPK level should be obtained; results exceeding normal values by five times confirm the diagnosis.³ Measurements for potassium, phosphorus, and calcium are also important to determine, as is renal function. A high level of serum aldolase (an enzyme that breaks down glucose in muscle tissue) can also support a diagnosis of rhabdomyolysis.^1,12 Urinalysis and urine myoglobin testing are also warranted, although a negative urine myoglobin test result does not rule out rhabdomyolysis in the presence of an elevated CPK level. Myoglobin is cleared rapidly by the kidneys, whereas serum CPK levels change slowly.¹

Any patient who presents with acute rhabdomyolysis and low to normal values for potassium or phosphate should be evaluated further for hypokalemia and hypophosphatemia as contributing or etiologic factors. Hypocalcemia may occur in the early course of rhabdomyolysis as calcium salt is deposited in muscle tissue. Patients recovering from rhabdomyolysis may experience rebound hypercalcemia as the damaged muscle releases the deposited calcium.^7,13

In most cases of rhabdomyolysis, only laboratory values are needed to make the diagnosis and follow the course of the episode.¹ However, when the etiology appears to involve metabolic deficiencies or genetic etiologies, it may become necessary to order additional diagnostic tests. These may include tests for thyroid function, a carnitine level to screen for glycogen storage diseases, and toxin screening (eg, for illicit drugs, such as cocaine).^2,6

Treatment and Management
Effective treatment of rhabdomyolysis relies on recognizing the underlying disorder.¹ For patients with muscle trauma (eg, crush injury) or muscle overuse, the mainstay of treatment is aggressive fluid resuscitation and prevention of acute injury to the kidneys.¹³ As for patients with an injury induced by a pharmaceutical agent or a toxin, removal of the offending agent is required, followed by hydration and prevention of renal damage. Supportive care during an infectious illness is also essential.¹⁴

Additionally, treatment must address the complications inherent with rhabdomyolysis.¹ In addition to CPK, potassium, phosphorus, and myoglobin are also released from skeletal muscle tissue. Hyperkalemia can be fatal, and potassium levels must be monitored closely to avert this condition.^7,8,13 During an episode of rhabdomyolysis, normal levels of both potassium and phosphorus should raise the clinician’s suspicion for underlying hypokalemia and hypophosphatemia—conditions that may have contributed to the episode of rhabdomyolysis. Hypocalcemia may also develop.¹³

Released myoglobin may cause acute kidney injury, as is the case in 33% to 50% of patients with rhabdomyolysis.³ In early studies, it was determined that alkalinizing the urine with IV isotonic bicarbonate might thwart onset of acute kidney injury.^1,2,15 Time is critical, and even on the battlefield or at the scene of a recent disaster, most attempts at resuscitation are begun immediately. IV access may be problematic, but administration of oral bicarbonate solutions has also proven effective.¹⁵ Close follow-up of the serum urea and creatinine levels and measurement of the urine pH during alkalinization is warranted throughout the course of the episode.

Unfortunately, some patients respond poorly to these conservative measures, and the released myoglobin can cause renal tubular blockage and necrosis, resulting in acute kidney injury.¹ Renal replacement therapy may be required.¹⁶ However, most episodes of dialysis-dependent acute renal injury do subside with time.

For patients with less elusive causes of rhabdomyolysis, treatment will hinge on a workup of the possible etiologies and follow-up treatment to target the apparent cause. For example, carnitine may be administered to patients with carnitine deficiency, and hypokalemic patients may be given potassium.^1,6,7 These patients will also need counseling before they consider engaging in an exercise program.

Patient’s Outcome
The case patient presented with exertional rhabdomyolysis; improper hydration, severe deconditioning, and a relatively low serum potassium level may all have contributed to the muscle necrosis she experienced. She was given IV alkaline solutions and did not develop acute kidney injury. She was discharged from the hospital and at the time of this writing was awaiting outpatient follow-up.

It should be interesting to see whether the case patient experiences any further episodes of severe weakness after engaging in exercise. Her low-normal potassium level (reference range, 3.5 to 5.3 mmol/L¹⁷) warrants further follow-up, as does her mildly elevated thyroid-stimulating hormone level (reference range, 0.5 to 4.7 mcIU/mL¹⁷).

CONCLUSION
Patients with rhabdomyolysis may present with muscle aches, darkened urine, and/or weakness; an elevated CPK level confirms the diagnosis. Management is mainly conservative, with IV hydration accompanied by alkalinizing the urine and correcting any metabolic abnormalities, such as potassium deficiencies. For the few patients who experience severe acute kidney injury, renal replacement therapy may be necessary.

While most causes of rhabdomyolysis have obvious clinical scenarios, such as a crush injury, a search for muscle enzyme deficiencies, disorders of potassium homeostasis, and thyroid abnormalities is also warranted in patients who present with exertional rhabdomyolysis.

A 39-year-old woman presented to the emergency department (ED) with a chief complaint of muscle aches and pain. She stated that three days earlier, she had begun exercising in a 45-minute “spinning” class (ie, riding a stationary bicycle with a weighted front wheel). The patient had not engaged in any aerobic exercise for at least six months before the spinning class. She mentioned that much older participants in the class were outperforming her, but she did not feel the need to keep up with them.

After dismounting, the woman said, she experienced weakness in her legs and had great difficulty ambulating. She went home, took 400 mg of ibuprofen, and went to bed. She awoke with pain and swelling in both thighs and continued to take ibuprofen, in addition to applying a topical mentholated preparation to her thighs. She took an Epsom salts bath two days later.

On the morning of the third day after the spinning class, she voided black urine and presented to the ED.

The patient had no significant medical history. Surgical history was limited to removal of a ganglion cyst on her wrist. She denied any history of seizure disorder, thyroid disease, hepatitis, heart disease, or hyperlipidemia.

The patient had been taking ibuprofen as needed since the spinning class. She was taking no other medications. She denied any allergies to drugs or food.

The patient admitted to smoking one pack of cigarettes per week and to occasional alcohol consumption but denied use of illicit drugs. She was employed as an executive officer for a large business association.

On physical examination, the patient’s vital signs were blood pressure, 134/73 mm/Hg; pulse, 86 beats/min; and respirations, 16 breaths/min. She was afebrile, alert, and oriented. Her sclera were nonicteric. Her neck was supple with no anterior cervical lymphadenopathy. There was no thyroid enlargement, her lungs were clear to auscultation, and her heart sounds were regular. There was no peripheral edema, and dorsalis pedis pulses were present bilaterally. Her thighs appeared swollen but were not tender to palpation.

The patient’s history, combined with an extremely high level of serum creatine phosphokinase (CPK; ie, 123,800 U/L [reference range, 45 to 260 U/L¹]), confirmed a diagnosis of rhabdomyolysis. She was admitted for close observation. The patient’s urinalysis revealed 2 to 5 red blood cells and 6 to 10 white blood cells per high-power field. Moderate occult blood was detected, with no casts or protein noted. A urine myoglobin test was not performed.

The patient underwent IV hydration with dextrose 5% in water and three ampules of sodium bicarbonate after being given a 2.0-L saline bolus. Ibuprofen was discontinued. IV hydration with bicarbonate solution was continued until the patient’s CPK level declined significantly. She underwent daily laboratory testing (see Table 1). Her renal function remained stable, and she was discharged on hospital day 7.

DISCUSSION
Rhabdomyolysis is a clinical condition defined as muscle necrosis resulting from the release of intracellular skeletal muscle components (including myoglobin, CPK, potassium, phosphorus, and aldolase) into the extracellular compartment.^1-3 The condition was first described during the bombing of London in World War II, with high incidence of crush injuries, shock, and associated kidney damage.⁴ The preponderance of such injuries during a 1988 earthquake in Armenia led the International Society of Nephrology to form its Renal Disaster Relief Task Force, which has provided support at numerous other disaster scenes since then.⁵

Rhabdomyolysis has been identified with a variety of pathologic events: those that cause muscle trauma, those associated with muscle use or overuse, and other etiologies involving genetic, metabolic, infectious, or pharmaceutical factors.¹ Many of the reported causes of rhabdomyolysis are listed in Table 2.^1,2

For patients with muscle trauma, the etiology of rhabdomyolysis is clear, but for those with other disease states, diagnosis may be more elusive. Patients who present with rhabdomyolysis after excessive exercise, for example, may have underlying metabolic disorders that predispose them to exertional rhabdomyolysis, such as chronic hypokalemia resulting from primary hyperaldosteronism.¹ Others may have a muscle enzyme deficiency, as in McArdle’s syndrome or carnitine deficiency.⁶

Alterations in blood chemistries can also contribute to development of rhabdomyolysis, even when more obvious etiologies for muscle necrosis are evident. Hypokalemia interferes with the vasodilation that normally occurs during exercise to increase muscle blood flow.^1,7,8 Continued exercise can lead to muscle necrosis, raising a concern for athletes who take diuretics.¹ Hypophosphatemia leads to a state of muscle necrosis; this is of particular concern for alcoholic patients who receive hyperalimentation without repletion of phosphates.⁹

Diagnosis
Patients with rhabdomyolysis usually present with myalgias, darkened urine (red, brown, or black), and a clinical scenario that corroborates the diagnosis (ie, history of trauma, excessive exercise, use of an offending medication).¹ Some patients may have minimal to absent symptoms or symptoms that occur only after exercise.³

A careful history is key. While traumatic causes are obvious, it is important to ask a patient with rhabdomyolysis after exertion about previous history of excessive weakness during or immediately after exercise, excessive cramping, or discoloration of urine after exercise. The family history may point to a genetic abnormality. A thorough understanding of the patient’s use of medications, including OTC agents, is also important. Rhabdomyolysis has been reported in patients who use herbal remedies, including those taken to facilitate weight loss or to improve lipid profiles.^10,11

For patients suspected of having rhabdomyolysis, a serum CPK level should be obtained; results exceeding normal values by five times confirm the diagnosis.³ Measurements for potassium, phosphorus, and calcium are also important to determine, as is renal function. A high level of serum aldolase (an enzyme that breaks down glucose in muscle tissue) can also support a diagnosis of rhabdomyolysis.^1,12 Urinalysis and urine myoglobin testing are also warranted, although a negative urine myoglobin test result does not rule out rhabdomyolysis in the presence of an elevated CPK level. Myoglobin is cleared rapidly by the kidneys, whereas serum CPK levels change slowly.¹

Any patient who presents with acute rhabdomyolysis and low to normal values for potassium or phosphate should be evaluated further for hypokalemia and hypophosphatemia as contributing or etiologic factors. Hypocalcemia may occur in the early course of rhabdomyolysis as calcium salt is deposited in muscle tissue. Patients recovering from rhabdomyolysis may experience rebound hypercalcemia as the damaged muscle releases the deposited calcium.^7,13

In most cases of rhabdomyolysis, only laboratory values are needed to make the diagnosis and follow the course of the episode.¹ However, when the etiology appears to involve metabolic deficiencies or genetic etiologies, it may become necessary to order additional diagnostic tests. These may include tests for thyroid function, a carnitine level to screen for glycogen storage diseases, and toxin screening (eg, for illicit drugs, such as cocaine).^2,6

Treatment and Management
Effective treatment of rhabdomyolysis relies on recognizing the underlying disorder.¹ For patients with muscle trauma (eg, crush injury) or muscle overuse, the mainstay of treatment is aggressive fluid resuscitation and prevention of acute injury to the kidneys.¹³ As for patients with an injury induced by a pharmaceutical agent or a toxin, removal of the offending agent is required, followed by hydration and prevention of renal damage. Supportive care during an infectious illness is also essential.¹⁴

Additionally, treatment must address the complications inherent with rhabdomyolysis.¹ In addition to CPK, potassium, phosphorus, and myoglobin are also released from skeletal muscle tissue. Hyperkalemia can be fatal, and potassium levels must be monitored closely to avert this condition.^7,8,13 During an episode of rhabdomyolysis, normal levels of both potassium and phosphorus should raise the clinician’s suspicion for underlying hypokalemia and hypophosphatemia—conditions that may have contributed to the episode of rhabdomyolysis. Hypocalcemia may also develop.¹³

Released myoglobin may cause acute kidney injury, as is the case in 33% to 50% of patients with rhabdomyolysis.³ In early studies, it was determined that alkalinizing the urine with IV isotonic bicarbonate might thwart onset of acute kidney injury.^1,2,15 Time is critical, and even on the battlefield or at the scene of a recent disaster, most attempts at resuscitation are begun immediately. IV access may be problematic, but administration of oral bicarbonate solutions has also proven effective.¹⁵ Close follow-up of the serum urea and creatinine levels and measurement of the urine pH during alkalinization is warranted throughout the course of the episode.

Unfortunately, some patients respond poorly to these conservative measures, and the released myoglobin can cause renal tubular blockage and necrosis, resulting in acute kidney injury.¹ Renal replacement therapy may be required.¹⁶ However, most episodes of dialysis-dependent acute renal injury do subside with time.

For patients with less elusive causes of rhabdomyolysis, treatment will hinge on a workup of the possible etiologies and follow-up treatment to target the apparent cause. For example, carnitine may be administered to patients with carnitine deficiency, and hypokalemic patients may be given potassium.^1,6,7 These patients will also need counseling before they consider engaging in an exercise program.

Patient’s Outcome
The case patient presented with exertional rhabdomyolysis; improper hydration, severe deconditioning, and a relatively low serum potassium level may all have contributed to the muscle necrosis she experienced. She was given IV alkaline solutions and did not develop acute kidney injury. She was discharged from the hospital and at the time of this writing was awaiting outpatient follow-up.

It should be interesting to see whether the case patient experiences any further episodes of severe weakness after engaging in exercise. Her low-normal potassium level (reference range, 3.5 to 5.3 mmol/L¹⁷) warrants further follow-up, as does her mildly elevated thyroid-stimulating hormone level (reference range, 0.5 to 4.7 mcIU/mL¹⁷).

CONCLUSION
Patients with rhabdomyolysis may present with muscle aches, darkened urine, and/or weakness; an elevated CPK level confirms the diagnosis. Management is mainly conservative, with IV hydration accompanied by alkalinizing the urine and correcting any metabolic abnormalities, such as potassium deficiencies. For the few patients who experience severe acute kidney injury, renal replacement therapy may be necessary.

While most causes of rhabdomyolysis have obvious clinical scenarios, such as a crush injury, a search for muscle enzyme deficiencies, disorders of potassium homeostasis, and thyroid abnormalities is also warranted in patients who present with exertional rhabdomyolysis.

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.         

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.         

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.