A black man, age 65, with no known history of cardiopulmonary disease presented with acute-onset exertional dyspnea and lower extremity edema. He also reported an episode of syncope, as well as occasional dizziness and abdominal bloating. He said he experienced exertional dyspnea while doing a routine step aerobic exercise. His exercise regimen included distance walking, yoga, and aerobics four to five days per week.

The patient’s medical history was remarkable for a single episode of a bleeding ulcer in previous years, low back pain, shoulder pain, and a septic arthritic hip. His social history was negative for use of tobacco, alcohol, or illegal drugs. He was married and had two biological daughters with fairly unremarkable medical histories. The patient had earned a master’s degree, worked full-time in the insurance business, and was an avid worldwide traveler. He reported diminished quality of life as a result of his acute-onset heart failure symptoms, which reduced his ability to exercise routinely, work full-time, or travel.

The patient’s sudden experience of exertional dyspnea prompted him to visit his primary care provider, who ordered an ECG that demonstrated low voltage patterns and a first-degree atrioventricular (AV) block. Subsequent stress echocardiography showed generalized thickening of the left ventricular myocardium. Posterior wall thickness measured 1.7 cm (normal range, 0.6 to 1.1 cm), septal thickness measured 1.9 cm (normal, 0.6 to 1.1 cm), and ejection fraction was 65%. The stress echocardiogram also showed a speckling pattern (brightly scattered spots) on the myocardium.

Although stress echocardiography results were negative for ischemic disease, the patient did experience dyspnea during the exam. He underwent cardiac catheterization, which indicated normal coronary arteries.

Additional diagnostic studies included cardiac MRI with and without contrast, which showed nulling of the heart muscle and delayed patchy hyperenhancement; this suggested myocardial tissue abnormality as result of amyloid fibril deposition.¹ Both pulmonary and tricuspid aortic valves were normal, with no evidence of stenosis. No regional wall motion abnormalities were noted.

Laboratory findings during the work-up were lipid panel, unremarkable; complete blood count (CBC), mild anemia and leukopenia; and urinalysis, positive for proteinuria. Brain natriuretic peptide (BNP) was measured at 686 pg/mL (normal, 0.0 to 100 pg/mL), indicating moderate heart failure. A peripheral blood smear was negative for monoclonal plasma cells.

The patient’s physical exam was unremarkable except for 2+ pedal edema bilaterally. In consideration of normal coronary arteries on cardiac catheterization, the patient’s heart failure symptoms, and stress echocardiography abnormalities, a heart biopsy was ordered. An endomyocardial biopsy with Congo Red stain demonstrated an apple-green birefringent pattern viewed under high-definition polarized light microscope, which was consistent with amyloid deposition.²

The patient was given a diagnosis of primary amyloidosis by his local cardiologist despite negative findings on the peripheral blood smear for monoclonal plasma cells (which are typically found in primary amyloidosis).³ He presented to an institution well-known for its expertise in amyloidosis, for a second opinion. There, the diagnosis was negated, based on reevaluation of the patient’s previous heart specimen through immunohistochemical studies. These studies were positive for serum amyloid P, which is suggestive of transthyretin (TTR) or familial amyloidosis.⁴ Genetic testing revealed a familial amyloidosis DNA sequence analysis with the Val122Ile variant (ie, isoleucine for valine at position 122⁵). With the correct diagnosis confirmed, the patient was referred to another highly regarded institution to begin a work-up for cardiac transplantation. Meanwhile, he was cautiously treated with the loop diuretic furosemide to manage his shortness of breath and peripheral edema.

Fifteen months later (13 weeks after being listed for transplant), the patient underwent successful cardiac transplantation.

On pathologic review of the patient’s extricated heart, the myocardium was found to be grossly thickened (see figure, above) and weighed 540 g; the average adult heart weighs 300 to 350 g, depending on the patient’s size.⁶ Congo Red staining showed extensive amyloid deposits with infiltration throughout the myocardium.

Ninety percent of the amyloid deposits were interstitial, 5% were in the vessels, and 5% were noted in a nodular pattern. The left ventricular cavity showed dilated and thickened walls. Intramural and extramural blood vessels were infiltrated with amyloid as well.

Six months after transplantation, the patient underwent diagnostic testing to assess the function and structure of his new heart. Cardiac catheterization was negative for coronary artery disease. Thirteen months posttransplantation, endomyocardial biopsy with Congo Red stain was negative for amyloid deposition or organ rejection.

About 24 months posttransplantation, the patient was taking tacrolimus, pravastatin, pantoprazole, dapsone, propanolol, colchicine, and donepezil. Stress echocardiography demonstrated normal right and left ventricular systolic function; no wall-motion abnormalities or left ventricular hypertrophy were detected, and the right atrium was of normal size. There was abnormal structural enlargement of the left atrium at the site of anastamosis—a common finding in cardiac transplant patients. The aortic, tricuspid, and mitral valves were all normal.

At that time, it was decided not to repeat endomyocardial biopsy because of normal results on molecular expression testing (a noninvasive technique called AlloMap^®7-9), which is performed to assess for heart transplant rejection. The patient’s lipid panel remained within normal limits. CBC indicated persistent anemia and leukopenia. Urine protein and BNP test results were not available.

Since undergoing cardiac transplantation, the patient has resumed his normal routine activities, including some type of exercise five days per week. He said his diet is maintained in moderation. He denied shortness of breath, chest pain, dizziness, or edema. He has returned to full-time employment and has vacationed in Croatia, Italy, and Central America.

DISCUSSION
Familial amyloidosis is an autosomal dominant disease characterized by the production of mutated proteins, most commonly ATTR. Presence of the ATTR Val 122Ile allele has been reported in 3.9% of all black Americans, and in one study, 23% of black Americans diagnosed with cardiac amyloidosis at autopsy were heterozygous for this variant allele.^10-12 ATTR Val122Ile usually manifests in the fifth

or sixth decade of life with its characteristic presentation of infiltrative/restrictive cardiomyopathy,¹³ resulting in heart failure and sometimes peripheral neuropathy.^10,11,14

Pathophysiology
In patients with ATTR Val122Ile, cardiomyopathy results from the deposition of mutant protein fibrils in the cardiac muscle, leading to restricted heart wall motion^10,15 and stiffening of the cardiac ventricles, with subsequent disruption of the diastolic filling properties of the cardiac muscle.¹⁶ Fluid overload and heart failure follow.^3,10,17 The atrium of the heart dilates, and the walls of the ventricles become thickened and fibrous.¹⁸ Liepnieks and Benson⁶ reported that the cadaver heart of one Val122Ile patient infiltrated with amyloid protein fibrils weighed 725 g—more than double the weight of an average adult heart.

In patients with cardiac amyloidosis, ECG can detect arrhythmia, and echocardiography shows cardiac enlargement; however, as in the case patient, cardiac catheterization shows normal coronary arteries.^15,16,19,20 Thus, previously healthy patients who present with heart failure and negative results on cardiac catheterization should undergo further work-up for cardiac amyloidosis.¹⁹

Amyloidosis affects all populations globally.¹⁰ In systemic amyloidosis, amyloid releases into the plasma, infiltrating and impairing multiple organs. Poor survival has been reported in patients with heart failure symptoms resulting from amyloid deposition.^20,21

Types of Amyloidosis
Primary amyloidosis, the most common of the three amyloidosis types, can be systemic or localized.²² It occurs when protein fibrils, developed from immunoglobin light chains or monoclonal plasma cells and measuring 7 to 10 nm in diameter, adhere to the heart, kidneys, peripheral nerves, eyes, and other organs.^{5,11,20,23,24} Known for its relation to multiple myeloma,¹⁹ primary amyloidosis is associated with a poor prognosis.^3,10

Secondary amyloidosis results from a chronic inflammatory disorder, such as rheumatoid arthritis or ankylosing spondylitis—conditions that trigger the production of amyloid proteins.^3,10 This type has also been associated with substance abuse and AIDS.²³

Familial or hereditary amyloidosis, according to Benson,¹⁰ is a group of diseases, each resulting from mutation in a specific protein. In the United States, the most common type of familial amyloidosis is ATTR.¹¹ More than 100 mutant types of ATTR proteins have been identified, each involving a specific nationality or group of nationalities.^10,11,23

Mutant ATTR amyloid, when deposited in specific organs, leads to their dysfunction and ultimate failure.⁶ ATTR may affect the cardiac, gastric, renal, ophthalmic, or nervous system. Depending on the ATTR variant, the resulting clinical features are age- and time-dependent, with onset most common between the third and fifth decade of life.¹⁰

Prevalence
The prevalence of ATTR Val 122Ile amyloidosis is reportedly high in West Africa, and in the US African-American population (3.9%).^{4,11,14,25,26} In a study conducted at a county hospital in Indianapolis, 3% of black newborns were found positive for ATTR Val122Ile through DNA sampling of umbilical cord blood.²⁵ These statistics are of concern, as ATTR amyloidosis could be a significant health concern in a patient population that is already medically underserved.

Yamashita et al²⁵ estimate that 1.35 million Americans of African-American descent may be affected by ATTR Val122Ile and vulnerable to restrictive cardiomyopathy–related heart failure and death. At the very least, this disorder can impair quality of life, especially in the presence of other comorbid conditions.

Clinical Presentation
The presence of exertional syncope at presentation is ominous, as it may be a marker of severe restrictive cardiomyopathy, postural hypotension due to excessive diuresis or autonomic neuropathy, ventricular arrhythmias from localized hypoperfusion, and rarely from cardiac tamponade due to pericardial involvement.²⁷ Despite widespread involvement of the conduction system in specimens at autopsy, high-grade IV block is unusual.³

Diagnostic Studies
ECG. Both ECG and Holter monitoring can detect the arrhythmias and conduction disturbances (eg, first-degree AV block, low voltage patterns) associated with cardiac amyloidosis. Patients often experience syncopal and near-syncopal episodes as a result of conduction disturbances.²⁸ Patients with conditions such as cardiac amyloidosis who present with severe heart failure are at high risk for sudden death secondary to conduction disturbances. Many have benefited from implanted defibrillators.²⁹

Echocardiography. In patients with ATTR Val122Ile cardiac amyloidosis, echocardiography reveals thickened ventricular walls (ie, measuring ≥ 15 mm; normal, ≤ 11 mm).¹⁹ Amyloid-restrictive cardiomyopathy is associated with a marked dissociation between short- and long-axis systolic function, in cases in which left ventricular ejection fraction is normal.³⁰

Echocardiography may demonstrate the characteristic specular or granular sparkling appearance that signifies advanced disease.^15,21 Only a minority have this pattern in the myocardium, however, and changes in echocardiographic technology have made this finding less noticeable.³⁰

MRI. Among more recently used diagnostic studies, cardiac magnetic resonance (CMR) has been reported to demonstrate late gadolinium enhancement (LGE) in perhaps 80% of patients with familial amyloidosis and cardiac involvement (as determined through biopsy and Congo Red stain). LGE-CMR shows darkening of the cardiac tissue, a common occurrence in amyloidosis.³¹

LGE is associated with increased thickness of both left and right ventricles, lower ECG voltage patterns, elevated BNP, and elevated troponin T.^31,32 Globally, LGE is associated with the worst prognosis in patients with cardiac amyloidosis. Use of LGE-CMR testing can help facilitate early detection of cardiac amyloidosis in patients who may be vulnerable to cardiac damage.³¹

Cardiac catheterization. In patients with cardiac amyloidosis, cardiac catheterization usually shows normal coronary arteries.³

Diagnosis
Early diagnosis of ATTR cardiac amyloidosis is crucial to the patient’s survival; it should be ruled out in any African-American patient with unexplained heart failure and echocardiography showing increased wall thickness with a nondilated left ventricular cavity. Additional clues include significant proteinuria, hepatomegaly disproportionate to the degree of heart failure, or corresponding neuropathy. Known family history of the disease, along with variant type, allows for a prompt and correct diagnosis.¹⁰

It has been reported that most clinicians who encounter heart failure, particularly in black patients, do not consider amyloidosis in the differential diagnosis, because of the high prevalence of hypertension and congestive heart failure in this population.^10,15,19 As a result, amyloidosis often goes undiagnosed.¹⁹

Findings of enlarged and thickened cardiac walls on echocardiography but normal coronary arteries on cardiac catheterization should alert the treating clinician to further work-up for cardiac amyloidosis.¹⁹ In such a patient, according to Kristen et al,²¹ endomyocardial biopsy with Congo Red staining is the gold standard for diagnosis of amyloidosis.

In ATTR Val122Ile familial amyloidosis, it is unclear whether patients who are homozygous for the disease present with symptoms at earlier onset with more progressive illness or die sooner than those who are heterozygous^.33 Nevertheless, once the diagnosis is confirmed, it is important to determine the patient’s specific variant type by DNA testing so that appropriate treatment can be initiated and the patient’s prognosis evaluated.^5,10,13

Treatment
For familial amyloidosis in general, some researchers advocate liver transplantation to remove the source of mutant amyloid protein and stop all deposition of amyloid fibrils; this procedure can be followed later by transplantation of other affected organs (including the heart).^5,23 Maurer et al³⁴ have reported improved one-year survival rates among patients with ATTR amyloidosis who underwent both cardiac and liver transplantation: 75%, versus 23% in patients who did not receive transplanted organs.

Management of cardiac amyloidosis usually requires a twofold approach: treating associated congestive heart failure, and preventing further deposition of amyloid.²⁴ In the case patient (as in most patients with ATTR amyloidosis), heart transplantation was deemed the only life-sustaining treatment option.^11,19,33

Pharmacotherapeutic options are limited for patients with ATTR Val122Ile familial amyloidosis. Conventional heart failure agents (eg, ACE inhibitors, angiotensin receptor blockers, digoxin, β-blockers, calcium channel blockers) can exacerbate heart failure symptoms, leading to a potentially life-threatening arrhythmia.^{3,11,19,24,35} Amyloid fibrils bind to digitalis, increasing susceptibility to digitalis toxicity; and to nifedipine, causing hemodynamic deterioration. Verapamil should be avoided, as it may induce severe left ventricular dysfunction. ACE inhibitors often provoke profound hypotension in primary amyloidosis.^24,35

Diuretics, too (eg, furosemide, as was prescribed for the case patient), must be used with caution.³ These agents have been used to treat fluid overload and the resulting peripheral edema and shortness of breath found in ATTR Val122Ile patients who experience heart failure.³⁶ According to Dubrey et al,⁵ cautious use of diuretics is necessary for management of heart failure symptoms in these patients.

Because the risk for intracardiac thrombus is high, anticoagulation (using agents other than β-blockers or calcium channel blockers) should be implemented unless compelling risks are involved.^11,24 Amiodarone is relatively well tolerated for ventricular tachydysrhythmias and in atrial fibrillation if the goal is maintaining sinus rhythm.³⁷

Regarding heart transplantation in patients with familial amyloidosis, Jacob et al³³ hypothesize that since mutant amyloid protein is synthesized by the liver, it would take approximately 50 years for a transplanted heart to become affected by amyloid deposition. In a 59-year-old Afro-Caribbean man with familial amyloidosis who underwent cardiac transplantation, Hamour et al¹¹ reported that the donor heart remained amyloid-free three years posttransplantation, as demonstrated by serial cardiac biopsy.

On the Horizon
Clinical trials are now under way to examine pharmacotherapeutic options for patients with ATTR amyloidosis. Now being examined in clinical trials, for example, is Fx-1006A, a drug that stabilizes ATTR and prevents the misfolding of the amyloid protein fibril, in turn preventing it from binding to the target organ.³⁸ Similarly, ALN-TTR, a drug believed to prevent disease manifestation and possibly facilitate disease regression, is being investigated in early human trials.³⁹

Additionally, the use of genetic testing is recommended in at-risk individuals to identify the TTR gene. Affected patients may benefit from prophylactic medical management, which would halt amyloidogenesis of TTR—and possibly treat the condition as well.³⁵ Pharmacotherapeutic agents like diflunisal, an NSAID, antagonize the aggregation of TTR protein and hinder formation of the amyloid fibrils.⁴⁰

CONCLUSION
ATTR Val122Ile familial amyloidosis is a rare disorder that causes abnormal synthesis of amyloid protein in the liver, which then infiltrates the cardiac structure, leading to restrictive cardiomyopathy and progressive heart failure. Patients who present with symptoms of heart failure, cardiac enlargement on echocardiography, and a finding of granular speckling patterns, though not specific on echocardiography, should prompt the health care provider to refer the patient to a cardiologist familiar with cardiac amyloidosis for further work-up.

Diagnosed patients must undergo genetic testing to determine the specific variant type so that prompt treatment can be initiated. In patients with ATTR Val122Ile familial amyloidosis, the treatment of choice is cardiac transplantation. Although the mutant amyloid protein continues to be synthesized in the liver, the donor heart is unlikely to become affected by this substance for many years. Appropriately treated patients can maintain good quality of life, free of heart failure.    

REFERENCES
1. Lim RP, Srichai MB, Lee VS. Non-ischemic causes of delayed myocardial hyperenhancement on MRI. AJR Am J Roentgenol. 2007;188 (6):1675-1681.

2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010;17(3-4):101-104.

3. Kendall H. Cardiac amyloidosis. Crit Care Nurse. 2010;30(2):16-23.

4. Eriksson M, Büttener J, Todorov T, et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with AATR amyloid. Am J Surg Pathol. 2009;33(1):58-65.

5. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84.

6. Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid. 2007;14(4):277-282.

7. XDx Expression Diagnostics. Allomap^®: molecular expression testing (2004). www.allomap.com. Accessed May 14, 2012.

8. Mandras SA, Crespo J, Patel HM. Innovative application of immunologic principles in heart transplantation. Ochsner J. 2010;10(4):231-235.

9. Yamani MH, Taylor DO, Rodriguez R, et al. Transplant vasculopathy is associated with increased AlloMap gene expression score. J Heart Lung Transplant. 2007;26(4):403-406.

10. Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. 2003;17(6):909-927.

11. Hamour IM, Lachmann HJ, Goodman HJ, et al. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am J Transplant. 2008;8(5):1056-1059.

12. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997;336(7):466-473.

13. Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 2010;52(4):347-361.

14. Askanas V, Engel WK, McFerrin J, Vattemi G. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003;61(2):257-260.

15. Hamidi Asl K, Nakamura M, Yamashita T, Benson MD. Cardiac amyloidoses associated with the transthyretin lle122 mutation in a Caucasian family. Amyloid. 2001;8(4):263-269.

16. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24(3): 214-220.

17. Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009;10 (8):iii23-iii33.

18. Bruce J. Getting to the heart of cardiomyopathies. Nursing. 2005;35(8):44-47.

19. Falk RH. The neglected entity of familial cardiac amyloidosis in African Americans. Ethn Dis. 2002;12(1):141-143.

20. Piper C, Butz T, Farr M, et al. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid. 2010;17(1):1-9.

21. Kristen AV, Meyer FJ, Perz JB, et al. Risk stratification in cardiac amyloidosis: novel approaches. Transplantation. 2005;80(1 suppl):S151-S155.

22. Westermark P, Benson MD, Buxbaum JN, et al. A primer of amyloid nomenclature. Amyloid. 2007;14(3):179-183.

23. Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007; 16(3):196-203.

24. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation. 2011;124(9):1079-1085.

25. Yamashita T, Asl KH, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile 122 allele frequency in an African-American population. Amyloid. 2005;12(2):127-130.

26. Benson MD, Yazaki M, Magy N. Laboratory assessment of transthyretin amyloidosis. Clin Chem Lab Med. 2002;40(12):1262-1265.

27. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol. 1997;80(9):1242-1245.

28. Correia MJ, Coutinho CA, Conceiçao I, et al. Role of heart rate variability in the assessment of autonomic dysfunction in type I familial amyloidotic polyneuropathy. Folia Cardiol. 2005;12(suppl C):459-462.

29. Kadish A, Mehra M. Heart failure devices: Implantable cardioverter-defibrillators and biventricular pacing therapy. Circulation. 2005; 111(24):3327-3335.

30. Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415.

31. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3(2):155-164.

32. Fealey ME, Edwards WD, Buadi FK, et al. Echocardiographic features of cardiac amyloidosis presenting as endomyocardial disease in a 54-year-old male. J Cardiol. 2009;54(1):162-166.

33. Jacob EK, Edwards WD, Zucker M, et al. Homozygous transthyretin mutation in an African American male. J Mol Diagn. 2007; 9(1):127-131.

34. Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation. 2007;83(5):539-545.

35. Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African-Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010;159(5):864-870.

36. Rose BD, Colucci WS. Use of diuretics in heart failure (2010). www.uptodate.com/con tents/use-of-diuretics-in-patients-with-heart-failure. Accessed May 14, 2012.

37. Trappe H-J. Treating critical supraventricular and ventricular arrhythmias. J Emerg Trauma Shock. 2010;3(2):143-152.

38. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des. 2008;14(30):3219-3230.

39. Alnylam Pharmaceuticals. TTR Amyloidosis: ALN-TTR (2011). www.alnylam.com/Programs-and-Pipeline/Programs/index.php. Accessed May 14, 2012.

40. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. Diflunisal analogues stabilize the native state of transthyretin: potent inhibition of amyloidogenesis. J Med Chem. 2004;47(2):355-374.

A black man, age 65, with no known history of cardiopulmonary disease presented with acute-onset exertional dyspnea and lower extremity edema. He also reported an episode of syncope, as well as occasional dizziness and abdominal bloating. He said he experienced exertional dyspnea while doing a routine step aerobic exercise. His exercise regimen included distance walking, yoga, and aerobics four to five days per week.

The patient’s medical history was remarkable for a single episode of a bleeding ulcer in previous years, low back pain, shoulder pain, and a septic arthritic hip. His social history was negative for use of tobacco, alcohol, or illegal drugs. He was married and had two biological daughters with fairly unremarkable medical histories. The patient had earned a master’s degree, worked full-time in the insurance business, and was an avid worldwide traveler. He reported diminished quality of life as a result of his acute-onset heart failure symptoms, which reduced his ability to exercise routinely, work full-time, or travel.

The patient’s sudden experience of exertional dyspnea prompted him to visit his primary care provider, who ordered an ECG that demonstrated low voltage patterns and a first-degree atrioventricular (AV) block. Subsequent stress echocardiography showed generalized thickening of the left ventricular myocardium. Posterior wall thickness measured 1.7 cm (normal range, 0.6 to 1.1 cm), septal thickness measured 1.9 cm (normal, 0.6 to 1.1 cm), and ejection fraction was 65%. The stress echocardiogram also showed a speckling pattern (brightly scattered spots) on the myocardium.

Although stress echocardiography results were negative for ischemic disease, the patient did experience dyspnea during the exam. He underwent cardiac catheterization, which indicated normal coronary arteries.

Additional diagnostic studies included cardiac MRI with and without contrast, which showed nulling of the heart muscle and delayed patchy hyperenhancement; this suggested myocardial tissue abnormality as result of amyloid fibril deposition.¹ Both pulmonary and tricuspid aortic valves were normal, with no evidence of stenosis. No regional wall motion abnormalities were noted.

Laboratory findings during the work-up were lipid panel, unremarkable; complete blood count (CBC), mild anemia and leukopenia; and urinalysis, positive for proteinuria. Brain natriuretic peptide (BNP) was measured at 686 pg/mL (normal, 0.0 to 100 pg/mL), indicating moderate heart failure. A peripheral blood smear was negative for monoclonal plasma cells.

The patient’s physical exam was unremarkable except for 2+ pedal edema bilaterally. In consideration of normal coronary arteries on cardiac catheterization, the patient’s heart failure symptoms, and stress echocardiography abnormalities, a heart biopsy was ordered. An endomyocardial biopsy with Congo Red stain demonstrated an apple-green birefringent pattern viewed under high-definition polarized light microscope, which was consistent with amyloid deposition.²

The patient was given a diagnosis of primary amyloidosis by his local cardiologist despite negative findings on the peripheral blood smear for monoclonal plasma cells (which are typically found in primary amyloidosis).³ He presented to an institution well-known for its expertise in amyloidosis, for a second opinion. There, the diagnosis was negated, based on reevaluation of the patient’s previous heart specimen through immunohistochemical studies. These studies were positive for serum amyloid P, which is suggestive of transthyretin (TTR) or familial amyloidosis.⁴ Genetic testing revealed a familial amyloidosis DNA sequence analysis with the Val122Ile variant (ie, isoleucine for valine at position 122⁵). With the correct diagnosis confirmed, the patient was referred to another highly regarded institution to begin a work-up for cardiac transplantation. Meanwhile, he was cautiously treated with the loop diuretic furosemide to manage his shortness of breath and peripheral edema.

Fifteen months later (13 weeks after being listed for transplant), the patient underwent successful cardiac transplantation.

On pathologic review of the patient’s extricated heart, the myocardium was found to be grossly thickened (see figure, above) and weighed 540 g; the average adult heart weighs 300 to 350 g, depending on the patient’s size.⁶ Congo Red staining showed extensive amyloid deposits with infiltration throughout the myocardium.

Ninety percent of the amyloid deposits were interstitial, 5% were in the vessels, and 5% were noted in a nodular pattern. The left ventricular cavity showed dilated and thickened walls. Intramural and extramural blood vessels were infiltrated with amyloid as well.

Six months after transplantation, the patient underwent diagnostic testing to assess the function and structure of his new heart. Cardiac catheterization was negative for coronary artery disease. Thirteen months posttransplantation, endomyocardial biopsy with Congo Red stain was negative for amyloid deposition or organ rejection.

About 24 months posttransplantation, the patient was taking tacrolimus, pravastatin, pantoprazole, dapsone, propanolol, colchicine, and donepezil. Stress echocardiography demonstrated normal right and left ventricular systolic function; no wall-motion abnormalities or left ventricular hypertrophy were detected, and the right atrium was of normal size. There was abnormal structural enlargement of the left atrium at the site of anastamosis—a common finding in cardiac transplant patients. The aortic, tricuspid, and mitral valves were all normal.

At that time, it was decided not to repeat endomyocardial biopsy because of normal results on molecular expression testing (a noninvasive technique called AlloMap^®7-9), which is performed to assess for heart transplant rejection. The patient’s lipid panel remained within normal limits. CBC indicated persistent anemia and leukopenia. Urine protein and BNP test results were not available.

Since undergoing cardiac transplantation, the patient has resumed his normal routine activities, including some type of exercise five days per week. He said his diet is maintained in moderation. He denied shortness of breath, chest pain, dizziness, or edema. He has returned to full-time employment and has vacationed in Croatia, Italy, and Central America.

DISCUSSION
Familial amyloidosis is an autosomal dominant disease characterized by the production of mutated proteins, most commonly ATTR. Presence of the ATTR Val 122Ile allele has been reported in 3.9% of all black Americans, and in one study, 23% of black Americans diagnosed with cardiac amyloidosis at autopsy were heterozygous for this variant allele.^10-12 ATTR Val122Ile usually manifests in the fifth

or sixth decade of life with its characteristic presentation of infiltrative/restrictive cardiomyopathy,¹³ resulting in heart failure and sometimes peripheral neuropathy.^10,11,14

Pathophysiology
In patients with ATTR Val122Ile, cardiomyopathy results from the deposition of mutant protein fibrils in the cardiac muscle, leading to restricted heart wall motion^10,15 and stiffening of the cardiac ventricles, with subsequent disruption of the diastolic filling properties of the cardiac muscle.¹⁶ Fluid overload and heart failure follow.^3,10,17 The atrium of the heart dilates, and the walls of the ventricles become thickened and fibrous.¹⁸ Liepnieks and Benson⁶ reported that the cadaver heart of one Val122Ile patient infiltrated with amyloid protein fibrils weighed 725 g—more than double the weight of an average adult heart.

In patients with cardiac amyloidosis, ECG can detect arrhythmia, and echocardiography shows cardiac enlargement; however, as in the case patient, cardiac catheterization shows normal coronary arteries.^15,16,19,20 Thus, previously healthy patients who present with heart failure and negative results on cardiac catheterization should undergo further work-up for cardiac amyloidosis.¹⁹

Amyloidosis affects all populations globally.¹⁰ In systemic amyloidosis, amyloid releases into the plasma, infiltrating and impairing multiple organs. Poor survival has been reported in patients with heart failure symptoms resulting from amyloid deposition.^20,21

Types of Amyloidosis
Primary amyloidosis, the most common of the three amyloidosis types, can be systemic or localized.²² It occurs when protein fibrils, developed from immunoglobin light chains or monoclonal plasma cells and measuring 7 to 10 nm in diameter, adhere to the heart, kidneys, peripheral nerves, eyes, and other organs.^{5,11,20,23,24} Known for its relation to multiple myeloma,¹⁹ primary amyloidosis is associated with a poor prognosis.^3,10

Secondary amyloidosis results from a chronic inflammatory disorder, such as rheumatoid arthritis or ankylosing spondylitis—conditions that trigger the production of amyloid proteins.^3,10 This type has also been associated with substance abuse and AIDS.²³

Familial or hereditary amyloidosis, according to Benson,¹⁰ is a group of diseases, each resulting from mutation in a specific protein. In the United States, the most common type of familial amyloidosis is ATTR.¹¹ More than 100 mutant types of ATTR proteins have been identified, each involving a specific nationality or group of nationalities.^10,11,23

Mutant ATTR amyloid, when deposited in specific organs, leads to their dysfunction and ultimate failure.⁶ ATTR may affect the cardiac, gastric, renal, ophthalmic, or nervous system. Depending on the ATTR variant, the resulting clinical features are age- and time-dependent, with onset most common between the third and fifth decade of life.¹⁰

Prevalence
The prevalence of ATTR Val 122Ile amyloidosis is reportedly high in West Africa, and in the US African-American population (3.9%).^{4,11,14,25,26} In a study conducted at a county hospital in Indianapolis, 3% of black newborns were found positive for ATTR Val122Ile through DNA sampling of umbilical cord blood.²⁵ These statistics are of concern, as ATTR amyloidosis could be a significant health concern in a patient population that is already medically underserved.

Yamashita et al²⁵ estimate that 1.35 million Americans of African-American descent may be affected by ATTR Val122Ile and vulnerable to restrictive cardiomyopathy–related heart failure and death. At the very least, this disorder can impair quality of life, especially in the presence of other comorbid conditions.

Clinical Presentation
The presence of exertional syncope at presentation is ominous, as it may be a marker of severe restrictive cardiomyopathy, postural hypotension due to excessive diuresis or autonomic neuropathy, ventricular arrhythmias from localized hypoperfusion, and rarely from cardiac tamponade due to pericardial involvement.²⁷ Despite widespread involvement of the conduction system in specimens at autopsy, high-grade IV block is unusual.³

Diagnostic Studies
ECG. Both ECG and Holter monitoring can detect the arrhythmias and conduction disturbances (eg, first-degree AV block, low voltage patterns) associated with cardiac amyloidosis. Patients often experience syncopal and near-syncopal episodes as a result of conduction disturbances.²⁸ Patients with conditions such as cardiac amyloidosis who present with severe heart failure are at high risk for sudden death secondary to conduction disturbances. Many have benefited from implanted defibrillators.²⁹

Echocardiography. In patients with ATTR Val122Ile cardiac amyloidosis, echocardiography reveals thickened ventricular walls (ie, measuring ≥ 15 mm; normal, ≤ 11 mm).¹⁹ Amyloid-restrictive cardiomyopathy is associated with a marked dissociation between short- and long-axis systolic function, in cases in which left ventricular ejection fraction is normal.³⁰

Echocardiography may demonstrate the characteristic specular or granular sparkling appearance that signifies advanced disease.^15,21 Only a minority have this pattern in the myocardium, however, and changes in echocardiographic technology have made this finding less noticeable.³⁰

MRI. Among more recently used diagnostic studies, cardiac magnetic resonance (CMR) has been reported to demonstrate late gadolinium enhancement (LGE) in perhaps 80% of patients with familial amyloidosis and cardiac involvement (as determined through biopsy and Congo Red stain). LGE-CMR shows darkening of the cardiac tissue, a common occurrence in amyloidosis.³¹

LGE is associated with increased thickness of both left and right ventricles, lower ECG voltage patterns, elevated BNP, and elevated troponin T.^31,32 Globally, LGE is associated with the worst prognosis in patients with cardiac amyloidosis. Use of LGE-CMR testing can help facilitate early detection of cardiac amyloidosis in patients who may be vulnerable to cardiac damage.³¹

Cardiac catheterization. In patients with cardiac amyloidosis, cardiac catheterization usually shows normal coronary arteries.³

Diagnosis
Early diagnosis of ATTR cardiac amyloidosis is crucial to the patient’s survival; it should be ruled out in any African-American patient with unexplained heart failure and echocardiography showing increased wall thickness with a nondilated left ventricular cavity. Additional clues include significant proteinuria, hepatomegaly disproportionate to the degree of heart failure, or corresponding neuropathy. Known family history of the disease, along with variant type, allows for a prompt and correct diagnosis.¹⁰

It has been reported that most clinicians who encounter heart failure, particularly in black patients, do not consider amyloidosis in the differential diagnosis, because of the high prevalence of hypertension and congestive heart failure in this population.^10,15,19 As a result, amyloidosis often goes undiagnosed.¹⁹

Findings of enlarged and thickened cardiac walls on echocardiography but normal coronary arteries on cardiac catheterization should alert the treating clinician to further work-up for cardiac amyloidosis.¹⁹ In such a patient, according to Kristen et al,²¹ endomyocardial biopsy with Congo Red staining is the gold standard for diagnosis of amyloidosis.

In ATTR Val122Ile familial amyloidosis, it is unclear whether patients who are homozygous for the disease present with symptoms at earlier onset with more progressive illness or die sooner than those who are heterozygous^.33 Nevertheless, once the diagnosis is confirmed, it is important to determine the patient’s specific variant type by DNA testing so that appropriate treatment can be initiated and the patient’s prognosis evaluated.^5,10,13

Treatment
For familial amyloidosis in general, some researchers advocate liver transplantation to remove the source of mutant amyloid protein and stop all deposition of amyloid fibrils; this procedure can be followed later by transplantation of other affected organs (including the heart).^5,23 Maurer et al³⁴ have reported improved one-year survival rates among patients with ATTR amyloidosis who underwent both cardiac and liver transplantation: 75%, versus 23% in patients who did not receive transplanted organs.

Management of cardiac amyloidosis usually requires a twofold approach: treating associated congestive heart failure, and preventing further deposition of amyloid.²⁴ In the case patient (as in most patients with ATTR amyloidosis), heart transplantation was deemed the only life-sustaining treatment option.^11,19,33

Pharmacotherapeutic options are limited for patients with ATTR Val122Ile familial amyloidosis. Conventional heart failure agents (eg, ACE inhibitors, angiotensin receptor blockers, digoxin, β-blockers, calcium channel blockers) can exacerbate heart failure symptoms, leading to a potentially life-threatening arrhythmia.^{3,11,19,24,35} Amyloid fibrils bind to digitalis, increasing susceptibility to digitalis toxicity; and to nifedipine, causing hemodynamic deterioration. Verapamil should be avoided, as it may induce severe left ventricular dysfunction. ACE inhibitors often provoke profound hypotension in primary amyloidosis.^24,35

Diuretics, too (eg, furosemide, as was prescribed for the case patient), must be used with caution.³ These agents have been used to treat fluid overload and the resulting peripheral edema and shortness of breath found in ATTR Val122Ile patients who experience heart failure.³⁶ According to Dubrey et al,⁵ cautious use of diuretics is necessary for management of heart failure symptoms in these patients.

Because the risk for intracardiac thrombus is high, anticoagulation (using agents other than β-blockers or calcium channel blockers) should be implemented unless compelling risks are involved.^11,24 Amiodarone is relatively well tolerated for ventricular tachydysrhythmias and in atrial fibrillation if the goal is maintaining sinus rhythm.³⁷

Regarding heart transplantation in patients with familial amyloidosis, Jacob et al³³ hypothesize that since mutant amyloid protein is synthesized by the liver, it would take approximately 50 years for a transplanted heart to become affected by amyloid deposition. In a 59-year-old Afro-Caribbean man with familial amyloidosis who underwent cardiac transplantation, Hamour et al¹¹ reported that the donor heart remained amyloid-free three years posttransplantation, as demonstrated by serial cardiac biopsy.

On the Horizon
Clinical trials are now under way to examine pharmacotherapeutic options for patients with ATTR amyloidosis. Now being examined in clinical trials, for example, is Fx-1006A, a drug that stabilizes ATTR and prevents the misfolding of the amyloid protein fibril, in turn preventing it from binding to the target organ.³⁸ Similarly, ALN-TTR, a drug believed to prevent disease manifestation and possibly facilitate disease regression, is being investigated in early human trials.³⁹

Additionally, the use of genetic testing is recommended in at-risk individuals to identify the TTR gene. Affected patients may benefit from prophylactic medical management, which would halt amyloidogenesis of TTR—and possibly treat the condition as well.³⁵ Pharmacotherapeutic agents like diflunisal, an NSAID, antagonize the aggregation of TTR protein and hinder formation of the amyloid fibrils.⁴⁰

CONCLUSION
ATTR Val122Ile familial amyloidosis is a rare disorder that causes abnormal synthesis of amyloid protein in the liver, which then infiltrates the cardiac structure, leading to restrictive cardiomyopathy and progressive heart failure. Patients who present with symptoms of heart failure, cardiac enlargement on echocardiography, and a finding of granular speckling patterns, though not specific on echocardiography, should prompt the health care provider to refer the patient to a cardiologist familiar with cardiac amyloidosis for further work-up.

Diagnosed patients must undergo genetic testing to determine the specific variant type so that prompt treatment can be initiated. In patients with ATTR Val122Ile familial amyloidosis, the treatment of choice is cardiac transplantation. Although the mutant amyloid protein continues to be synthesized in the liver, the donor heart is unlikely to become affected by this substance for many years. Appropriately treated patients can maintain good quality of life, free of heart failure.    

REFERENCES
1. Lim RP, Srichai MB, Lee VS. Non-ischemic causes of delayed myocardial hyperenhancement on MRI. AJR Am J Roentgenol. 2007;188 (6):1675-1681.

2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010;17(3-4):101-104.

3. Kendall H. Cardiac amyloidosis. Crit Care Nurse. 2010;30(2):16-23.

4. Eriksson M, Büttener J, Todorov T, et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with AATR amyloid. Am J Surg Pathol. 2009;33(1):58-65.

5. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84.

6. Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid. 2007;14(4):277-282.

7. XDx Expression Diagnostics. Allomap^®: molecular expression testing (2004). www.allomap.com. Accessed May 14, 2012.

8. Mandras SA, Crespo J, Patel HM. Innovative application of immunologic principles in heart transplantation. Ochsner J. 2010;10(4):231-235.

9. Yamani MH, Taylor DO, Rodriguez R, et al. Transplant vasculopathy is associated with increased AlloMap gene expression score. J Heart Lung Transplant. 2007;26(4):403-406.

10. Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. 2003;17(6):909-927.

11. Hamour IM, Lachmann HJ, Goodman HJ, et al. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am J Transplant. 2008;8(5):1056-1059.

12. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997;336(7):466-473.

13. Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 2010;52(4):347-361.

14. Askanas V, Engel WK, McFerrin J, Vattemi G. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003;61(2):257-260.

15. Hamidi Asl K, Nakamura M, Yamashita T, Benson MD. Cardiac amyloidoses associated with the transthyretin lle122 mutation in a Caucasian family. Amyloid. 2001;8(4):263-269.

16. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24(3): 214-220.

17. Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009;10 (8):iii23-iii33.

18. Bruce J. Getting to the heart of cardiomyopathies. Nursing. 2005;35(8):44-47.

19. Falk RH. The neglected entity of familial cardiac amyloidosis in African Americans. Ethn Dis. 2002;12(1):141-143.

20. Piper C, Butz T, Farr M, et al. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid. 2010;17(1):1-9.

21. Kristen AV, Meyer FJ, Perz JB, et al. Risk stratification in cardiac amyloidosis: novel approaches. Transplantation. 2005;80(1 suppl):S151-S155.

22. Westermark P, Benson MD, Buxbaum JN, et al. A primer of amyloid nomenclature. Amyloid. 2007;14(3):179-183.

23. Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007; 16(3):196-203.

24. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation. 2011;124(9):1079-1085.

25. Yamashita T, Asl KH, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile 122 allele frequency in an African-American population. Amyloid. 2005;12(2):127-130.

26. Benson MD, Yazaki M, Magy N. Laboratory assessment of transthyretin amyloidosis. Clin Chem Lab Med. 2002;40(12):1262-1265.

27. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol. 1997;80(9):1242-1245.

28. Correia MJ, Coutinho CA, Conceiçao I, et al. Role of heart rate variability in the assessment of autonomic dysfunction in type I familial amyloidotic polyneuropathy. Folia Cardiol. 2005;12(suppl C):459-462.

29. Kadish A, Mehra M. Heart failure devices: Implantable cardioverter-defibrillators and biventricular pacing therapy. Circulation. 2005; 111(24):3327-3335.

30. Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415.

31. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3(2):155-164.

32. Fealey ME, Edwards WD, Buadi FK, et al. Echocardiographic features of cardiac amyloidosis presenting as endomyocardial disease in a 54-year-old male. J Cardiol. 2009;54(1):162-166.

33. Jacob EK, Edwards WD, Zucker M, et al. Homozygous transthyretin mutation in an African American male. J Mol Diagn. 2007; 9(1):127-131.

34. Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation. 2007;83(5):539-545.

35. Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African-Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010;159(5):864-870.

36. Rose BD, Colucci WS. Use of diuretics in heart failure (2010). www.uptodate.com/con tents/use-of-diuretics-in-patients-with-heart-failure. Accessed May 14, 2012.

37. Trappe H-J. Treating critical supraventricular and ventricular arrhythmias. J Emerg Trauma Shock. 2010;3(2):143-152.

38. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des. 2008;14(30):3219-3230.

39. Alnylam Pharmaceuticals. TTR Amyloidosis: ALN-TTR (2011). www.alnylam.com/Programs-and-Pipeline/Programs/index.php. Accessed May 14, 2012.

40. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. Diflunisal analogues stabilize the native state of transthyretin: potent inhibition of amyloidogenesis. J Med Chem. 2004;47(2):355-374.

A black man, age 65, with no known history of cardiopulmonary disease presented with acute-onset exertional dyspnea and lower extremity edema. He also reported an episode of syncope, as well as occasional dizziness and abdominal bloating. He said he experienced exertional dyspnea while doing a routine step aerobic exercise. His exercise regimen included distance walking, yoga, and aerobics four to five days per week.

The patient’s medical history was remarkable for a single episode of a bleeding ulcer in previous years, low back pain, shoulder pain, and a septic arthritic hip. His social history was negative for use of tobacco, alcohol, or illegal drugs. He was married and had two biological daughters with fairly unremarkable medical histories. The patient had earned a master’s degree, worked full-time in the insurance business, and was an avid worldwide traveler. He reported diminished quality of life as a result of his acute-onset heart failure symptoms, which reduced his ability to exercise routinely, work full-time, or travel.

The patient’s sudden experience of exertional dyspnea prompted him to visit his primary care provider, who ordered an ECG that demonstrated low voltage patterns and a first-degree atrioventricular (AV) block. Subsequent stress echocardiography showed generalized thickening of the left ventricular myocardium. Posterior wall thickness measured 1.7 cm (normal range, 0.6 to 1.1 cm), septal thickness measured 1.9 cm (normal, 0.6 to 1.1 cm), and ejection fraction was 65%. The stress echocardiogram also showed a speckling pattern (brightly scattered spots) on the myocardium.

Although stress echocardiography results were negative for ischemic disease, the patient did experience dyspnea during the exam. He underwent cardiac catheterization, which indicated normal coronary arteries.

Additional diagnostic studies included cardiac MRI with and without contrast, which showed nulling of the heart muscle and delayed patchy hyperenhancement; this suggested myocardial tissue abnormality as result of amyloid fibril deposition.¹ Both pulmonary and tricuspid aortic valves were normal, with no evidence of stenosis. No regional wall motion abnormalities were noted.

Laboratory findings during the work-up were lipid panel, unremarkable; complete blood count (CBC), mild anemia and leukopenia; and urinalysis, positive for proteinuria. Brain natriuretic peptide (BNP) was measured at 686 pg/mL (normal, 0.0 to 100 pg/mL), indicating moderate heart failure. A peripheral blood smear was negative for monoclonal plasma cells.

The patient’s physical exam was unremarkable except for 2+ pedal edema bilaterally. In consideration of normal coronary arteries on cardiac catheterization, the patient’s heart failure symptoms, and stress echocardiography abnormalities, a heart biopsy was ordered. An endomyocardial biopsy with Congo Red stain demonstrated an apple-green birefringent pattern viewed under high-definition polarized light microscope, which was consistent with amyloid deposition.²

The patient was given a diagnosis of primary amyloidosis by his local cardiologist despite negative findings on the peripheral blood smear for monoclonal plasma cells (which are typically found in primary amyloidosis).³ He presented to an institution well-known for its expertise in amyloidosis, for a second opinion. There, the diagnosis was negated, based on reevaluation of the patient’s previous heart specimen through immunohistochemical studies. These studies were positive for serum amyloid P, which is suggestive of transthyretin (TTR) or familial amyloidosis.⁴ Genetic testing revealed a familial amyloidosis DNA sequence analysis with the Val122Ile variant (ie, isoleucine for valine at position 122⁵). With the correct diagnosis confirmed, the patient was referred to another highly regarded institution to begin a work-up for cardiac transplantation. Meanwhile, he was cautiously treated with the loop diuretic furosemide to manage his shortness of breath and peripheral edema.

Fifteen months later (13 weeks after being listed for transplant), the patient underwent successful cardiac transplantation.

On pathologic review of the patient’s extricated heart, the myocardium was found to be grossly thickened (see figure, above) and weighed 540 g; the average adult heart weighs 300 to 350 g, depending on the patient’s size.⁶ Congo Red staining showed extensive amyloid deposits with infiltration throughout the myocardium.

Ninety percent of the amyloid deposits were interstitial, 5% were in the vessels, and 5% were noted in a nodular pattern. The left ventricular cavity showed dilated and thickened walls. Intramural and extramural blood vessels were infiltrated with amyloid as well.

Six months after transplantation, the patient underwent diagnostic testing to assess the function and structure of his new heart. Cardiac catheterization was negative for coronary artery disease. Thirteen months posttransplantation, endomyocardial biopsy with Congo Red stain was negative for amyloid deposition or organ rejection.

About 24 months posttransplantation, the patient was taking tacrolimus, pravastatin, pantoprazole, dapsone, propanolol, colchicine, and donepezil. Stress echocardiography demonstrated normal right and left ventricular systolic function; no wall-motion abnormalities or left ventricular hypertrophy were detected, and the right atrium was of normal size. There was abnormal structural enlargement of the left atrium at the site of anastamosis—a common finding in cardiac transplant patients. The aortic, tricuspid, and mitral valves were all normal.

At that time, it was decided not to repeat endomyocardial biopsy because of normal results on molecular expression testing (a noninvasive technique called AlloMap^®7-9), which is performed to assess for heart transplant rejection. The patient’s lipid panel remained within normal limits. CBC indicated persistent anemia and leukopenia. Urine protein and BNP test results were not available.

Since undergoing cardiac transplantation, the patient has resumed his normal routine activities, including some type of exercise five days per week. He said his diet is maintained in moderation. He denied shortness of breath, chest pain, dizziness, or edema. He has returned to full-time employment and has vacationed in Croatia, Italy, and Central America.

DISCUSSION
Familial amyloidosis is an autosomal dominant disease characterized by the production of mutated proteins, most commonly ATTR. Presence of the ATTR Val 122Ile allele has been reported in 3.9% of all black Americans, and in one study, 23% of black Americans diagnosed with cardiac amyloidosis at autopsy were heterozygous for this variant allele.^10-12 ATTR Val122Ile usually manifests in the fifth

or sixth decade of life with its characteristic presentation of infiltrative/restrictive cardiomyopathy,¹³ resulting in heart failure and sometimes peripheral neuropathy.^10,11,14

Pathophysiology
In patients with ATTR Val122Ile, cardiomyopathy results from the deposition of mutant protein fibrils in the cardiac muscle, leading to restricted heart wall motion^10,15 and stiffening of the cardiac ventricles, with subsequent disruption of the diastolic filling properties of the cardiac muscle.¹⁶ Fluid overload and heart failure follow.^3,10,17 The atrium of the heart dilates, and the walls of the ventricles become thickened and fibrous.¹⁸ Liepnieks and Benson⁶ reported that the cadaver heart of one Val122Ile patient infiltrated with amyloid protein fibrils weighed 725 g—more than double the weight of an average adult heart.

In patients with cardiac amyloidosis, ECG can detect arrhythmia, and echocardiography shows cardiac enlargement; however, as in the case patient, cardiac catheterization shows normal coronary arteries.^15,16,19,20 Thus, previously healthy patients who present with heart failure and negative results on cardiac catheterization should undergo further work-up for cardiac amyloidosis.¹⁹

Amyloidosis affects all populations globally.¹⁰ In systemic amyloidosis, amyloid releases into the plasma, infiltrating and impairing multiple organs. Poor survival has been reported in patients with heart failure symptoms resulting from amyloid deposition.^20,21

Types of Amyloidosis
Primary amyloidosis, the most common of the three amyloidosis types, can be systemic or localized.²² It occurs when protein fibrils, developed from immunoglobin light chains or monoclonal plasma cells and measuring 7 to 10 nm in diameter, adhere to the heart, kidneys, peripheral nerves, eyes, and other organs.^{5,11,20,23,24} Known for its relation to multiple myeloma,¹⁹ primary amyloidosis is associated with a poor prognosis.^3,10

Secondary amyloidosis results from a chronic inflammatory disorder, such as rheumatoid arthritis or ankylosing spondylitis—conditions that trigger the production of amyloid proteins.^3,10 This type has also been associated with substance abuse and AIDS.²³

Familial or hereditary amyloidosis, according to Benson,¹⁰ is a group of diseases, each resulting from mutation in a specific protein. In the United States, the most common type of familial amyloidosis is ATTR.¹¹ More than 100 mutant types of ATTR proteins have been identified, each involving a specific nationality or group of nationalities.^10,11,23

Mutant ATTR amyloid, when deposited in specific organs, leads to their dysfunction and ultimate failure.⁶ ATTR may affect the cardiac, gastric, renal, ophthalmic, or nervous system. Depending on the ATTR variant, the resulting clinical features are age- and time-dependent, with onset most common between the third and fifth decade of life.¹⁰

Prevalence
The prevalence of ATTR Val 122Ile amyloidosis is reportedly high in West Africa, and in the US African-American population (3.9%).^{4,11,14,25,26} In a study conducted at a county hospital in Indianapolis, 3% of black newborns were found positive for ATTR Val122Ile through DNA sampling of umbilical cord blood.²⁵ These statistics are of concern, as ATTR amyloidosis could be a significant health concern in a patient population that is already medically underserved.

Yamashita et al²⁵ estimate that 1.35 million Americans of African-American descent may be affected by ATTR Val122Ile and vulnerable to restrictive cardiomyopathy–related heart failure and death. At the very least, this disorder can impair quality of life, especially in the presence of other comorbid conditions.

Clinical Presentation
The presence of exertional syncope at presentation is ominous, as it may be a marker of severe restrictive cardiomyopathy, postural hypotension due to excessive diuresis or autonomic neuropathy, ventricular arrhythmias from localized hypoperfusion, and rarely from cardiac tamponade due to pericardial involvement.²⁷ Despite widespread involvement of the conduction system in specimens at autopsy, high-grade IV block is unusual.³

Diagnostic Studies
ECG. Both ECG and Holter monitoring can detect the arrhythmias and conduction disturbances (eg, first-degree AV block, low voltage patterns) associated with cardiac amyloidosis. Patients often experience syncopal and near-syncopal episodes as a result of conduction disturbances.²⁸ Patients with conditions such as cardiac amyloidosis who present with severe heart failure are at high risk for sudden death secondary to conduction disturbances. Many have benefited from implanted defibrillators.²⁹

Echocardiography. In patients with ATTR Val122Ile cardiac amyloidosis, echocardiography reveals thickened ventricular walls (ie, measuring ≥ 15 mm; normal, ≤ 11 mm).¹⁹ Amyloid-restrictive cardiomyopathy is associated with a marked dissociation between short- and long-axis systolic function, in cases in which left ventricular ejection fraction is normal.³⁰

Echocardiography may demonstrate the characteristic specular or granular sparkling appearance that signifies advanced disease.^15,21 Only a minority have this pattern in the myocardium, however, and changes in echocardiographic technology have made this finding less noticeable.³⁰

MRI. Among more recently used diagnostic studies, cardiac magnetic resonance (CMR) has been reported to demonstrate late gadolinium enhancement (LGE) in perhaps 80% of patients with familial amyloidosis and cardiac involvement (as determined through biopsy and Congo Red stain). LGE-CMR shows darkening of the cardiac tissue, a common occurrence in amyloidosis.³¹

LGE is associated with increased thickness of both left and right ventricles, lower ECG voltage patterns, elevated BNP, and elevated troponin T.^31,32 Globally, LGE is associated with the worst prognosis in patients with cardiac amyloidosis. Use of LGE-CMR testing can help facilitate early detection of cardiac amyloidosis in patients who may be vulnerable to cardiac damage.³¹

Cardiac catheterization. In patients with cardiac amyloidosis, cardiac catheterization usually shows normal coronary arteries.³

Diagnosis
Early diagnosis of ATTR cardiac amyloidosis is crucial to the patient’s survival; it should be ruled out in any African-American patient with unexplained heart failure and echocardiography showing increased wall thickness with a nondilated left ventricular cavity. Additional clues include significant proteinuria, hepatomegaly disproportionate to the degree of heart failure, or corresponding neuropathy. Known family history of the disease, along with variant type, allows for a prompt and correct diagnosis.¹⁰

It has been reported that most clinicians who encounter heart failure, particularly in black patients, do not consider amyloidosis in the differential diagnosis, because of the high prevalence of hypertension and congestive heart failure in this population.^10,15,19 As a result, amyloidosis often goes undiagnosed.¹⁹

Findings of enlarged and thickened cardiac walls on echocardiography but normal coronary arteries on cardiac catheterization should alert the treating clinician to further work-up for cardiac amyloidosis.¹⁹ In such a patient, according to Kristen et al,²¹ endomyocardial biopsy with Congo Red staining is the gold standard for diagnosis of amyloidosis.

In ATTR Val122Ile familial amyloidosis, it is unclear whether patients who are homozygous for the disease present with symptoms at earlier onset with more progressive illness or die sooner than those who are heterozygous^.33 Nevertheless, once the diagnosis is confirmed, it is important to determine the patient’s specific variant type by DNA testing so that appropriate treatment can be initiated and the patient’s prognosis evaluated.^5,10,13

Treatment
For familial amyloidosis in general, some researchers advocate liver transplantation to remove the source of mutant amyloid protein and stop all deposition of amyloid fibrils; this procedure can be followed later by transplantation of other affected organs (including the heart).^5,23 Maurer et al³⁴ have reported improved one-year survival rates among patients with ATTR amyloidosis who underwent both cardiac and liver transplantation: 75%, versus 23% in patients who did not receive transplanted organs.

Management of cardiac amyloidosis usually requires a twofold approach: treating associated congestive heart failure, and preventing further deposition of amyloid.²⁴ In the case patient (as in most patients with ATTR amyloidosis), heart transplantation was deemed the only life-sustaining treatment option.^11,19,33

Pharmacotherapeutic options are limited for patients with ATTR Val122Ile familial amyloidosis. Conventional heart failure agents (eg, ACE inhibitors, angiotensin receptor blockers, digoxin, β-blockers, calcium channel blockers) can exacerbate heart failure symptoms, leading to a potentially life-threatening arrhythmia.^{3,11,19,24,35} Amyloid fibrils bind to digitalis, increasing susceptibility to digitalis toxicity; and to nifedipine, causing hemodynamic deterioration. Verapamil should be avoided, as it may induce severe left ventricular dysfunction. ACE inhibitors often provoke profound hypotension in primary amyloidosis.^24,35

Diuretics, too (eg, furosemide, as was prescribed for the case patient), must be used with caution.³ These agents have been used to treat fluid overload and the resulting peripheral edema and shortness of breath found in ATTR Val122Ile patients who experience heart failure.³⁶ According to Dubrey et al,⁵ cautious use of diuretics is necessary for management of heart failure symptoms in these patients.

Because the risk for intracardiac thrombus is high, anticoagulation (using agents other than β-blockers or calcium channel blockers) should be implemented unless compelling risks are involved.^11,24 Amiodarone is relatively well tolerated for ventricular tachydysrhythmias and in atrial fibrillation if the goal is maintaining sinus rhythm.³⁷

Regarding heart transplantation in patients with familial amyloidosis, Jacob et al³³ hypothesize that since mutant amyloid protein is synthesized by the liver, it would take approximately 50 years for a transplanted heart to become affected by amyloid deposition. In a 59-year-old Afro-Caribbean man with familial amyloidosis who underwent cardiac transplantation, Hamour et al¹¹ reported that the donor heart remained amyloid-free three years posttransplantation, as demonstrated by serial cardiac biopsy.

On the Horizon
Clinical trials are now under way to examine pharmacotherapeutic options for patients with ATTR amyloidosis. Now being examined in clinical trials, for example, is Fx-1006A, a drug that stabilizes ATTR and prevents the misfolding of the amyloid protein fibril, in turn preventing it from binding to the target organ.³⁸ Similarly, ALN-TTR, a drug believed to prevent disease manifestation and possibly facilitate disease regression, is being investigated in early human trials.³⁹

Additionally, the use of genetic testing is recommended in at-risk individuals to identify the TTR gene. Affected patients may benefit from prophylactic medical management, which would halt amyloidogenesis of TTR—and possibly treat the condition as well.³⁵ Pharmacotherapeutic agents like diflunisal, an NSAID, antagonize the aggregation of TTR protein and hinder formation of the amyloid fibrils.⁴⁰

CONCLUSION
ATTR Val122Ile familial amyloidosis is a rare disorder that causes abnormal synthesis of amyloid protein in the liver, which then infiltrates the cardiac structure, leading to restrictive cardiomyopathy and progressive heart failure. Patients who present with symptoms of heart failure, cardiac enlargement on echocardiography, and a finding of granular speckling patterns, though not specific on echocardiography, should prompt the health care provider to refer the patient to a cardiologist familiar with cardiac amyloidosis for further work-up.

Diagnosed patients must undergo genetic testing to determine the specific variant type so that prompt treatment can be initiated. In patients with ATTR Val122Ile familial amyloidosis, the treatment of choice is cardiac transplantation. Although the mutant amyloid protein continues to be synthesized in the liver, the donor heart is unlikely to become affected by this substance for many years. Appropriately treated patients can maintain good quality of life, free of heart failure.    

REFERENCES
1. Lim RP, Srichai MB, Lee VS. Non-ischemic causes of delayed myocardial hyperenhancement on MRI. AJR Am J Roentgenol. 2007;188 (6):1675-1681.

2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010;17(3-4):101-104.

3. Kendall H. Cardiac amyloidosis. Crit Care Nurse. 2010;30(2):16-23.

4. Eriksson M, Büttener J, Todorov T, et al. Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with AATR amyloid. Am J Surg Pathol. 2009;33(1):58-65.

5. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84.

6. Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid. 2007;14(4):277-282.

7. XDx Expression Diagnostics. Allomap^®: molecular expression testing (2004). www.allomap.com. Accessed May 14, 2012.

8. Mandras SA, Crespo J, Patel HM. Innovative application of immunologic principles in heart transplantation. Ochsner J. 2010;10(4):231-235.

9. Yamani MH, Taylor DO, Rodriguez R, et al. Transplant vasculopathy is associated with increased AlloMap gene expression score. J Heart Lung Transplant. 2007;26(4):403-406.

10. Benson MD. The hereditary amyloidoses. Best Pract Res Clin Rheumatol. 2003;17(6):909-927.

11. Hamour IM, Lachmann HJ, Goodman HJ, et al. Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am J Transplant. 2008;8(5):1056-1059.

12. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997;336(7):466-473.

13. Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 2010;52(4):347-361.

14. Askanas V, Engel WK, McFerrin J, Vattemi G. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003;61(2):257-260.

15. Hamidi Asl K, Nakamura M, Yamashita T, Benson MD. Cardiac amyloidoses associated with the transthyretin lle122 mutation in a Caucasian family. Amyloid. 2001;8(4):263-269.

16. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24(3): 214-220.

17. Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009;10 (8):iii23-iii33.

18. Bruce J. Getting to the heart of cardiomyopathies. Nursing. 2005;35(8):44-47.

19. Falk RH. The neglected entity of familial cardiac amyloidosis in African Americans. Ethn Dis. 2002;12(1):141-143.

20. Piper C, Butz T, Farr M, et al. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid. 2010;17(1):1-9.

21. Kristen AV, Meyer FJ, Perz JB, et al. Risk stratification in cardiac amyloidosis: novel approaches. Transplantation. 2005;80(1 suppl):S151-S155.

22. Westermark P, Benson MD, Buxbaum JN, et al. A primer of amyloid nomenclature. Amyloid. 2007;14(3):179-183.

23. Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007; 16(3):196-203.

24. Falk RH. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation. 2011;124(9):1079-1085.

25. Yamashita T, Asl KH, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile 122 allele frequency in an African-American population. Amyloid. 2005;12(2):127-130.

26. Benson MD, Yazaki M, Magy N. Laboratory assessment of transthyretin amyloidosis. Clin Chem Lab Med. 2002;40(12):1262-1265.

27. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol. 1997;80(9):1242-1245.

28. Correia MJ, Coutinho CA, Conceiçao I, et al. Role of heart rate variability in the assessment of autonomic dysfunction in type I familial amyloidotic polyneuropathy. Folia Cardiol. 2005;12(suppl C):459-462.

29. Kadish A, Mehra M. Heart failure devices: Implantable cardioverter-defibrillators and biventricular pacing therapy. Circulation. 2005; 111(24):3327-3335.

30. Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415.

31. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3(2):155-164.

32. Fealey ME, Edwards WD, Buadi FK, et al. Echocardiographic features of cardiac amyloidosis presenting as endomyocardial disease in a 54-year-old male. J Cardiol. 2009;54(1):162-166.

33. Jacob EK, Edwards WD, Zucker M, et al. Homozygous transthyretin mutation in an African American male. J Mol Diagn. 2007; 9(1):127-131.

34. Maurer MS, Raina A, Hesdorffer C, et al. Cardiac transplantation using extended-donor criteria organs for systemic amyloidosis complicated by heart failure. Transplantation. 2007;83(5):539-545.

35. Buxbaum J, Alexander A, Koziol J, et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African-Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010;159(5):864-870.

36. Rose BD, Colucci WS. Use of diuretics in heart failure (2010). www.uptodate.com/con tents/use-of-diuretics-in-patients-with-heart-failure. Accessed May 14, 2012.

37. Trappe H-J. Treating critical supraventricular and ventricular arrhythmias. J Emerg Trauma Shock. 2010;3(2):143-152.

38. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des. 2008;14(30):3219-3230.

39. Alnylam Pharmaceuticals. TTR Amyloidosis: ALN-TTR (2011). www.alnylam.com/Programs-and-Pipeline/Programs/index.php. Accessed May 14, 2012.

40. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW. Diflunisal analogues stabilize the native state of transthyretin: potent inhibition of amyloidogenesis. J Med Chem. 2004;47(2):355-374.

CASE: Medication sensitivity

Mrs. C, age 48, is admitted to a tertiary care inpatient mood disorder unit for evaluation of severe depression characterized by depressed mood, anhedonia, and insomnia. Her initial Hamilton Rating Scale for Depression 17-Item (HRSD-17) score is 30, indicating severe depression. Her medications are fluoxetine, 10 mg/d, and diazepam, 0.5 mg/d.

Mrs. C describes a 10-month history of depression and extreme anxiety in the context of several psychosocial stressors. Her father recently died and she is having difficulty with the demands of administering her father’s estate. She is intensely obsessive and focused on nihilistic themes, her diagnosis, somatic themes, and medications side effects. Her husband confirms our observations. No history or current symptoms of typical compulsions (eg, washing hands or checking doors) are elicited. She has limited insight into her obsessive tendencies.

Mrs. C had no psychiatric history before her depressive and obsessive symptoms developed 10 months ago. However, in the past 10 months, she has been hospitalized in a psychiatric facility twice. She also received a series of 8 electroconvulsive therapy treatments, but reported minimal improvement of her depressive symptoms. Mrs. C had a few cognitive-behavioral therapy (CBT) sessions with a psychotherapist, but she said they didn’t help much.

Mrs. C has substantial difficulty adhering to medications, even at subtherapeutic doses. She states she is “extremely sensitive” to all medications. Mrs. C says she develops dizziness, increased anxiety, insomnia, nausea, and other vague reactions whenever she attempts to increase her psychotropics to therapeutic doses. She took sertraline, 10 mg/d, for 4 days, but discontinued it because of unspecified side effects. She then received escitalopram, 2.5 mg/d, for 10 days, but again stopped it because of vague side effects. She was taking paroxetine, 10 mg/d, for 2 days, but experienced vomiting and discontinued the drug. She tried venlafaxine at a low dose and also discontinued it because of vomiting. Mrs. C stayed on mirtazapine, 22.5 mg/d, for 3 months, but stopped it because of lack of efficacy and she was unwilling to increase the dose. Other unsuccessful trials include citalopram and doxepin. Mrs. C is hesitant to try another medication or increase to therapeutic doses any of the previous medications.

The authors’ observations

Before initiating another treatment, the treatment team considered Mrs. C’s pervasive medication intolerance. Her enzymatic activity may be genetically compromised, which could lead to high blood levels of medications and significant side effects when she takes very low doses. Individual variations in response to psychotropics are influenced by genetic factors.¹ Variants in the cytochrome P450 (CYP450) genes produce enzymes with increased activity, normal activity, reduced activity, or no activity, creating phenotypes of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. These genetic variations can affect blood levels of medications that employ these enzymes in their metabolic pathways.² Mrs. C could be a poor metabolizer of common CYP450 variant enzymes, which led to her exquisite sensitivity to psychotropics. We felt this was a reasonable hypothesis given her tumultuous 10-month course of psychiatric treatment and multiple failed medication trials.

An alternative hypothesis is that Mrs. C’s somatic obsessions about drug side effects were the primary clinical issue that led to her severe medication intolerance. Mrs. C spends hours questioning the inpatient staff about her diagnosis (eg, “Are you sure I don’t have bipolar disorder?”), medications (eg, “Are you sure this medication won’t make me sick?”), somatic themes (eg, “Are you sure I don’t have Meniere’s disease with all my dizziness?”), and nihilistic themes (eg, “What if I never get better?”). Mrs. C’s husband attested that she has spent hours researching her new medications on the Internet and reading the medication handouts from the pharmacy. She admits to mentally cycling through the DSM-IV-TR criteria for hours at a time to “figure out” if she has bipolar disorder (BD).

We initiated pharmacogenomic testing to help distinguish between these hypotheses. Mrs. C’s results are presented in Table 1. Genotype results were applied using an interpretive algorithm (Figure) in which 26 psychiatric medications were placed in categories of “use as directed” (green column), “use with caution” (yellow column), and “use with caution or more frequent monitoring” (red column). The algorithm incorporates the genetic information with the known pharmacologic profile for each of the medications in the panel. Highlights of Mrs. C’s interpretive report are shown in Table 2.

Table 1

Mrs. C’s genotype results

Figure

Genotype-phenotype integration into Mrs. C’s interpretive report

  Table 2

Mrs. C’s pharmacogenomic-based interpretive report

The authors’ observations

Mrs. C’s genotype might explain some sensitivity to medications metabolized by CYP2D6 (eg, venlafaxine, paroxetine, fluoxetine), but does not explain her acute sensitivity to all of the medications she has taken. For example, she is an extensive metabolizer for CYP2C19, which metabolizes escitalopram; therefore, it is unlikely escitalopram, 2.5 mg/d, would result in high blood levels and side effects.³ Regardless of the next step in treatment, we deemed her somatic obsessions to be the most important clinical issue. It seems unlikely that Mrs. C would adhere to any medication regimen until this underlying problem was addressed.

The focus of treatment shifted to Mrs. C’s obsessions about her medications and their side effects. Mrs. C was fixated on the content of her obsessions (eg, medications, side effects) rather than the process of her obsessional thinking. The goal was to help Mrs. C identify, label, and ultimately create distance from her obsessive thoughts associated with side effects. The treatment team employed an acceptance and commitment therapy (ACT) model of observing and defusing thoughts in the inpatient setting (Table 3).⁴ ACT is based on mindfulness and committed, values-based action.⁵ When patients are “fused” with their thoughts, they believe these thoughts are important and representative of reality. In Mrs. C’s case, she fused with the concept that her medications were making her sick and the idea that she may have BD. The treatment team thought these fused thoughts were the major problem that resulted in 10 months of protracted illness.

Conversely, in a “defused” state, patients can separate from their thoughts and observe them as disparate sounds, words, stories, or bits of language. The goal is to observe and allow the patient’s thoughts to simply be thoughts rather than trying to determine if they are “true.” Mrs. C was fused with the idea that her medications were making her ill, so this belief became the story underlying her obsessional thinking. Helping her disengage from this story became the focus of her treatment.

Table 3

6 core principles of acceptance and commitment therapy

Results guide pharmacotherapy

In addition to helping change the focus of Mrs. C’s psychotherapy, we used the pharmacogenomic results to guide medication treatment. We initially prescribed fluvoxamine, 50 mg/d, because her partially compromised CYP2D6 pathway probably would play only a minor role in metabolizing the drug.¹ Smoking induces CYP1A2, which is fluvoxamine’s primary metabolic pathway; however, Mrs. C does not smoke.⁶ When we saw Mrs. C in January 2009, the author (JGW) was unaware of any available genetic testing for CYP1A2, although now such testing is clinically available.

Mirtazapine is in the “use as directed” category for Mrs. C’s genotype (Table 2) and was the only medication she had adhered to at a therapeutic dose for more than a few days. However, she indicated that she would not adhere to this medication if we prescribed it again. Duloxetine also is in the “use as directed” category; however, given the entire clinical picture, we chose fluvoxamine because of Mrs. C’s obsessive symptomatology and because she had never reached a therapeutic dose of a selective serotonin reuptake inhibitor.

OUTCOME: Obsessions abate

Given Mrs. C’s lack of insight, we initiate a family approach to help broach the topic of obsessions as the focus of treatment. With her husband’s help, she participates in defusion techniques as an inpatient and follows up with an acceptance-based psychotherapist after discharge. After we share the pharmacogenomic information with Mrs. C, she agrees to try fluvoxamine, which is titrated to 100 mg/d. She maintains this dose at her 4-week follow-up visit. Notably, this was only the second time Mrs. C adhered to a medication trial since illness onset. Upon admission, Mrs. C had an HRSD-17 score of 30, indicating severe depression; at 4 weeks, her HRSD-17 score is 8, indicating mild depression.

The authors’ observations

In a complementary case, the author (JGW) consulted on a patient who was taking paroxetine and experiencing anorgasmia, weight gain, and loss of libido. Pharmacogenomic testing revealed that the patient was a poor metabolizer of CYP2D6. Paroxetine is substantially metabolized by CYP2D6; therefore, it was likely that high blood levels were contributing to the side effects.^3,7 The key clinical distinction is that although this patient was bothered by intrusive side effects, he was not fixated on them like Mrs. C. His pharmacogenomic test results were used to identify a metabolic issue that was causing the side effects. This is in contrast with Mrs. C, for whom the pharmacogenomic information ruled out a metabolic issue as the primary problem and helped guide the next step in treatment.

Mrs. C’s case illustrates how pharmacogenomics and ACT complemented each other to create a desirable outcome. Pharmacogenomic testing originally was developed as a safety mechanism for medication choice and dosing, but clinical applications have grown as astute clinicians utilize it to help care for their patients.⁸ ACT can be a powerful tool for patients who have difficulties creating distance from their thoughts. Both pharmacogenomic testing and ACT are noninvasive interventions that can be implemented as part of a multi-faceted treatment approach.

Related Resources

• Hayes SC, Strosahl KD, Wilson KG. Acceptance and commitment therapy: The process and practice of mindful change. 2nd ed. New York, NY: The Guilford Press; 2011.
• Mrazek DA. Psychiatric pharmacogenomics. New York, NY: Oxford University Press; 2010.

Drug Brand Names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Diazepam • Valium
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

The authors are employed by AssureRx Health, Inc., the provider of the pharmacogenomic testing used in this article.

CASE: Medication sensitivity

Mrs. C, age 48, is admitted to a tertiary care inpatient mood disorder unit for evaluation of severe depression characterized by depressed mood, anhedonia, and insomnia. Her initial Hamilton Rating Scale for Depression 17-Item (HRSD-17) score is 30, indicating severe depression. Her medications are fluoxetine, 10 mg/d, and diazepam, 0.5 mg/d.

Mrs. C describes a 10-month history of depression and extreme anxiety in the context of several psychosocial stressors. Her father recently died and she is having difficulty with the demands of administering her father’s estate. She is intensely obsessive and focused on nihilistic themes, her diagnosis, somatic themes, and medications side effects. Her husband confirms our observations. No history or current symptoms of typical compulsions (eg, washing hands or checking doors) are elicited. She has limited insight into her obsessive tendencies.

Mrs. C had no psychiatric history before her depressive and obsessive symptoms developed 10 months ago. However, in the past 10 months, she has been hospitalized in a psychiatric facility twice. She also received a series of 8 electroconvulsive therapy treatments, but reported minimal improvement of her depressive symptoms. Mrs. C had a few cognitive-behavioral therapy (CBT) sessions with a psychotherapist, but she said they didn’t help much.

Mrs. C has substantial difficulty adhering to medications, even at subtherapeutic doses. She states she is “extremely sensitive” to all medications. Mrs. C says she develops dizziness, increased anxiety, insomnia, nausea, and other vague reactions whenever she attempts to increase her psychotropics to therapeutic doses. She took sertraline, 10 mg/d, for 4 days, but discontinued it because of unspecified side effects. She then received escitalopram, 2.5 mg/d, for 10 days, but again stopped it because of vague side effects. She was taking paroxetine, 10 mg/d, for 2 days, but experienced vomiting and discontinued the drug. She tried venlafaxine at a low dose and also discontinued it because of vomiting. Mrs. C stayed on mirtazapine, 22.5 mg/d, for 3 months, but stopped it because of lack of efficacy and she was unwilling to increase the dose. Other unsuccessful trials include citalopram and doxepin. Mrs. C is hesitant to try another medication or increase to therapeutic doses any of the previous medications.

The authors’ observations

Before initiating another treatment, the treatment team considered Mrs. C’s pervasive medication intolerance. Her enzymatic activity may be genetically compromised, which could lead to high blood levels of medications and significant side effects when she takes very low doses. Individual variations in response to psychotropics are influenced by genetic factors.¹ Variants in the cytochrome P450 (CYP450) genes produce enzymes with increased activity, normal activity, reduced activity, or no activity, creating phenotypes of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. These genetic variations can affect blood levels of medications that employ these enzymes in their metabolic pathways.² Mrs. C could be a poor metabolizer of common CYP450 variant enzymes, which led to her exquisite sensitivity to psychotropics. We felt this was a reasonable hypothesis given her tumultuous 10-month course of psychiatric treatment and multiple failed medication trials.

An alternative hypothesis is that Mrs. C’s somatic obsessions about drug side effects were the primary clinical issue that led to her severe medication intolerance. Mrs. C spends hours questioning the inpatient staff about her diagnosis (eg, “Are you sure I don’t have bipolar disorder?”), medications (eg, “Are you sure this medication won’t make me sick?”), somatic themes (eg, “Are you sure I don’t have Meniere’s disease with all my dizziness?”), and nihilistic themes (eg, “What if I never get better?”). Mrs. C’s husband attested that she has spent hours researching her new medications on the Internet and reading the medication handouts from the pharmacy. She admits to mentally cycling through the DSM-IV-TR criteria for hours at a time to “figure out” if she has bipolar disorder (BD).

We initiated pharmacogenomic testing to help distinguish between these hypotheses. Mrs. C’s results are presented in Table 1. Genotype results were applied using an interpretive algorithm (Figure) in which 26 psychiatric medications were placed in categories of “use as directed” (green column), “use with caution” (yellow column), and “use with caution or more frequent monitoring” (red column). The algorithm incorporates the genetic information with the known pharmacologic profile for each of the medications in the panel. Highlights of Mrs. C’s interpretive report are shown in Table 2.

Table 1

Mrs. C’s genotype results

Figure

Genotype-phenotype integration into Mrs. C’s interpretive report

  Table 2

Mrs. C’s pharmacogenomic-based interpretive report

The authors’ observations

Mrs. C’s genotype might explain some sensitivity to medications metabolized by CYP2D6 (eg, venlafaxine, paroxetine, fluoxetine), but does not explain her acute sensitivity to all of the medications she has taken. For example, she is an extensive metabolizer for CYP2C19, which metabolizes escitalopram; therefore, it is unlikely escitalopram, 2.5 mg/d, would result in high blood levels and side effects.³ Regardless of the next step in treatment, we deemed her somatic obsessions to be the most important clinical issue. It seems unlikely that Mrs. C would adhere to any medication regimen until this underlying problem was addressed.

The focus of treatment shifted to Mrs. C’s obsessions about her medications and their side effects. Mrs. C was fixated on the content of her obsessions (eg, medications, side effects) rather than the process of her obsessional thinking. The goal was to help Mrs. C identify, label, and ultimately create distance from her obsessive thoughts associated with side effects. The treatment team employed an acceptance and commitment therapy (ACT) model of observing and defusing thoughts in the inpatient setting (Table 3).⁴ ACT is based on mindfulness and committed, values-based action.⁵ When patients are “fused” with their thoughts, they believe these thoughts are important and representative of reality. In Mrs. C’s case, she fused with the concept that her medications were making her sick and the idea that she may have BD. The treatment team thought these fused thoughts were the major problem that resulted in 10 months of protracted illness.

Conversely, in a “defused” state, patients can separate from their thoughts and observe them as disparate sounds, words, stories, or bits of language. The goal is to observe and allow the patient’s thoughts to simply be thoughts rather than trying to determine if they are “true.” Mrs. C was fused with the idea that her medications were making her ill, so this belief became the story underlying her obsessional thinking. Helping her disengage from this story became the focus of her treatment.

Table 3

6 core principles of acceptance and commitment therapy

Results guide pharmacotherapy

In addition to helping change the focus of Mrs. C’s psychotherapy, we used the pharmacogenomic results to guide medication treatment. We initially prescribed fluvoxamine, 50 mg/d, because her partially compromised CYP2D6 pathway probably would play only a minor role in metabolizing the drug.¹ Smoking induces CYP1A2, which is fluvoxamine’s primary metabolic pathway; however, Mrs. C does not smoke.⁶ When we saw Mrs. C in January 2009, the author (JGW) was unaware of any available genetic testing for CYP1A2, although now such testing is clinically available.

Mirtazapine is in the “use as directed” category for Mrs. C’s genotype (Table 2) and was the only medication she had adhered to at a therapeutic dose for more than a few days. However, she indicated that she would not adhere to this medication if we prescribed it again. Duloxetine also is in the “use as directed” category; however, given the entire clinical picture, we chose fluvoxamine because of Mrs. C’s obsessive symptomatology and because she had never reached a therapeutic dose of a selective serotonin reuptake inhibitor.

OUTCOME: Obsessions abate

Given Mrs. C’s lack of insight, we initiate a family approach to help broach the topic of obsessions as the focus of treatment. With her husband’s help, she participates in defusion techniques as an inpatient and follows up with an acceptance-based psychotherapist after discharge. After we share the pharmacogenomic information with Mrs. C, she agrees to try fluvoxamine, which is titrated to 100 mg/d. She maintains this dose at her 4-week follow-up visit. Notably, this was only the second time Mrs. C adhered to a medication trial since illness onset. Upon admission, Mrs. C had an HRSD-17 score of 30, indicating severe depression; at 4 weeks, her HRSD-17 score is 8, indicating mild depression.

The authors’ observations

In a complementary case, the author (JGW) consulted on a patient who was taking paroxetine and experiencing anorgasmia, weight gain, and loss of libido. Pharmacogenomic testing revealed that the patient was a poor metabolizer of CYP2D6. Paroxetine is substantially metabolized by CYP2D6; therefore, it was likely that high blood levels were contributing to the side effects.^3,7 The key clinical distinction is that although this patient was bothered by intrusive side effects, he was not fixated on them like Mrs. C. His pharmacogenomic test results were used to identify a metabolic issue that was causing the side effects. This is in contrast with Mrs. C, for whom the pharmacogenomic information ruled out a metabolic issue as the primary problem and helped guide the next step in treatment.

Mrs. C’s case illustrates how pharmacogenomics and ACT complemented each other to create a desirable outcome. Pharmacogenomic testing originally was developed as a safety mechanism for medication choice and dosing, but clinical applications have grown as astute clinicians utilize it to help care for their patients.⁸ ACT can be a powerful tool for patients who have difficulties creating distance from their thoughts. Both pharmacogenomic testing and ACT are noninvasive interventions that can be implemented as part of a multi-faceted treatment approach.

Related Resources

• Hayes SC, Strosahl KD, Wilson KG. Acceptance and commitment therapy: The process and practice of mindful change. 2nd ed. New York, NY: The Guilford Press; 2011.
• Mrazek DA. Psychiatric pharmacogenomics. New York, NY: Oxford University Press; 2010.

Drug Brand Names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Diazepam • Valium
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

The authors are employed by AssureRx Health, Inc., the provider of the pharmacogenomic testing used in this article.

CASE: Medication sensitivity

Mrs. C, age 48, is admitted to a tertiary care inpatient mood disorder unit for evaluation of severe depression characterized by depressed mood, anhedonia, and insomnia. Her initial Hamilton Rating Scale for Depression 17-Item (HRSD-17) score is 30, indicating severe depression. Her medications are fluoxetine, 10 mg/d, and diazepam, 0.5 mg/d.

Mrs. C describes a 10-month history of depression and extreme anxiety in the context of several psychosocial stressors. Her father recently died and she is having difficulty with the demands of administering her father’s estate. She is intensely obsessive and focused on nihilistic themes, her diagnosis, somatic themes, and medications side effects. Her husband confirms our observations. No history or current symptoms of typical compulsions (eg, washing hands or checking doors) are elicited. She has limited insight into her obsessive tendencies.

Mrs. C had no psychiatric history before her depressive and obsessive symptoms developed 10 months ago. However, in the past 10 months, she has been hospitalized in a psychiatric facility twice. She also received a series of 8 electroconvulsive therapy treatments, but reported minimal improvement of her depressive symptoms. Mrs. C had a few cognitive-behavioral therapy (CBT) sessions with a psychotherapist, but she said they didn’t help much.

Mrs. C has substantial difficulty adhering to medications, even at subtherapeutic doses. She states she is “extremely sensitive” to all medications. Mrs. C says she develops dizziness, increased anxiety, insomnia, nausea, and other vague reactions whenever she attempts to increase her psychotropics to therapeutic doses. She took sertraline, 10 mg/d, for 4 days, but discontinued it because of unspecified side effects. She then received escitalopram, 2.5 mg/d, for 10 days, but again stopped it because of vague side effects. She was taking paroxetine, 10 mg/d, for 2 days, but experienced vomiting and discontinued the drug. She tried venlafaxine at a low dose and also discontinued it because of vomiting. Mrs. C stayed on mirtazapine, 22.5 mg/d, for 3 months, but stopped it because of lack of efficacy and she was unwilling to increase the dose. Other unsuccessful trials include citalopram and doxepin. Mrs. C is hesitant to try another medication or increase to therapeutic doses any of the previous medications.

The authors’ observations

Before initiating another treatment, the treatment team considered Mrs. C’s pervasive medication intolerance. Her enzymatic activity may be genetically compromised, which could lead to high blood levels of medications and significant side effects when she takes very low doses. Individual variations in response to psychotropics are influenced by genetic factors.¹ Variants in the cytochrome P450 (CYP450) genes produce enzymes with increased activity, normal activity, reduced activity, or no activity, creating phenotypes of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. These genetic variations can affect blood levels of medications that employ these enzymes in their metabolic pathways.² Mrs. C could be a poor metabolizer of common CYP450 variant enzymes, which led to her exquisite sensitivity to psychotropics. We felt this was a reasonable hypothesis given her tumultuous 10-month course of psychiatric treatment and multiple failed medication trials.

An alternative hypothesis is that Mrs. C’s somatic obsessions about drug side effects were the primary clinical issue that led to her severe medication intolerance. Mrs. C spends hours questioning the inpatient staff about her diagnosis (eg, “Are you sure I don’t have bipolar disorder?”), medications (eg, “Are you sure this medication won’t make me sick?”), somatic themes (eg, “Are you sure I don’t have Meniere’s disease with all my dizziness?”), and nihilistic themes (eg, “What if I never get better?”). Mrs. C’s husband attested that she has spent hours researching her new medications on the Internet and reading the medication handouts from the pharmacy. She admits to mentally cycling through the DSM-IV-TR criteria for hours at a time to “figure out” if she has bipolar disorder (BD).

We initiated pharmacogenomic testing to help distinguish between these hypotheses. Mrs. C’s results are presented in Table 1. Genotype results were applied using an interpretive algorithm (Figure) in which 26 psychiatric medications were placed in categories of “use as directed” (green column), “use with caution” (yellow column), and “use with caution or more frequent monitoring” (red column). The algorithm incorporates the genetic information with the known pharmacologic profile for each of the medications in the panel. Highlights of Mrs. C’s interpretive report are shown in Table 2.

Table 1

Mrs. C’s genotype results

Figure

Genotype-phenotype integration into Mrs. C’s interpretive report

  Table 2

Mrs. C’s pharmacogenomic-based interpretive report

The authors’ observations

Mrs. C’s genotype might explain some sensitivity to medications metabolized by CYP2D6 (eg, venlafaxine, paroxetine, fluoxetine), but does not explain her acute sensitivity to all of the medications she has taken. For example, she is an extensive metabolizer for CYP2C19, which metabolizes escitalopram; therefore, it is unlikely escitalopram, 2.5 mg/d, would result in high blood levels and side effects.³ Regardless of the next step in treatment, we deemed her somatic obsessions to be the most important clinical issue. It seems unlikely that Mrs. C would adhere to any medication regimen until this underlying problem was addressed.

The focus of treatment shifted to Mrs. C’s obsessions about her medications and their side effects. Mrs. C was fixated on the content of her obsessions (eg, medications, side effects) rather than the process of her obsessional thinking. The goal was to help Mrs. C identify, label, and ultimately create distance from her obsessive thoughts associated with side effects. The treatment team employed an acceptance and commitment therapy (ACT) model of observing and defusing thoughts in the inpatient setting (Table 3).⁴ ACT is based on mindfulness and committed, values-based action.⁵ When patients are “fused” with their thoughts, they believe these thoughts are important and representative of reality. In Mrs. C’s case, she fused with the concept that her medications were making her sick and the idea that she may have BD. The treatment team thought these fused thoughts were the major problem that resulted in 10 months of protracted illness.

Conversely, in a “defused” state, patients can separate from their thoughts and observe them as disparate sounds, words, stories, or bits of language. The goal is to observe and allow the patient’s thoughts to simply be thoughts rather than trying to determine if they are “true.” Mrs. C was fused with the idea that her medications were making her ill, so this belief became the story underlying her obsessional thinking. Helping her disengage from this story became the focus of her treatment.

Table 3

6 core principles of acceptance and commitment therapy

Results guide pharmacotherapy

In addition to helping change the focus of Mrs. C’s psychotherapy, we used the pharmacogenomic results to guide medication treatment. We initially prescribed fluvoxamine, 50 mg/d, because her partially compromised CYP2D6 pathway probably would play only a minor role in metabolizing the drug.¹ Smoking induces CYP1A2, which is fluvoxamine’s primary metabolic pathway; however, Mrs. C does not smoke.⁶ When we saw Mrs. C in January 2009, the author (JGW) was unaware of any available genetic testing for CYP1A2, although now such testing is clinically available.

Mirtazapine is in the “use as directed” category for Mrs. C’s genotype (Table 2) and was the only medication she had adhered to at a therapeutic dose for more than a few days. However, she indicated that she would not adhere to this medication if we prescribed it again. Duloxetine also is in the “use as directed” category; however, given the entire clinical picture, we chose fluvoxamine because of Mrs. C’s obsessive symptomatology and because she had never reached a therapeutic dose of a selective serotonin reuptake inhibitor.

OUTCOME: Obsessions abate

Given Mrs. C’s lack of insight, we initiate a family approach to help broach the topic of obsessions as the focus of treatment. With her husband’s help, she participates in defusion techniques as an inpatient and follows up with an acceptance-based psychotherapist after discharge. After we share the pharmacogenomic information with Mrs. C, she agrees to try fluvoxamine, which is titrated to 100 mg/d. She maintains this dose at her 4-week follow-up visit. Notably, this was only the second time Mrs. C adhered to a medication trial since illness onset. Upon admission, Mrs. C had an HRSD-17 score of 30, indicating severe depression; at 4 weeks, her HRSD-17 score is 8, indicating mild depression.

The authors’ observations

In a complementary case, the author (JGW) consulted on a patient who was taking paroxetine and experiencing anorgasmia, weight gain, and loss of libido. Pharmacogenomic testing revealed that the patient was a poor metabolizer of CYP2D6. Paroxetine is substantially metabolized by CYP2D6; therefore, it was likely that high blood levels were contributing to the side effects.^3,7 The key clinical distinction is that although this patient was bothered by intrusive side effects, he was not fixated on them like Mrs. C. His pharmacogenomic test results were used to identify a metabolic issue that was causing the side effects. This is in contrast with Mrs. C, for whom the pharmacogenomic information ruled out a metabolic issue as the primary problem and helped guide the next step in treatment.

Mrs. C’s case illustrates how pharmacogenomics and ACT complemented each other to create a desirable outcome. Pharmacogenomic testing originally was developed as a safety mechanism for medication choice and dosing, but clinical applications have grown as astute clinicians utilize it to help care for their patients.⁸ ACT can be a powerful tool for patients who have difficulties creating distance from their thoughts. Both pharmacogenomic testing and ACT are noninvasive interventions that can be implemented as part of a multi-faceted treatment approach.

Related Resources

• Hayes SC, Strosahl KD, Wilson KG. Acceptance and commitment therapy: The process and practice of mindful change. 2nd ed. New York, NY: The Guilford Press; 2011.
• Mrazek DA. Psychiatric pharmacogenomics. New York, NY: Oxford University Press; 2010.

Drug Brand Names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Diazepam • Valium
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel, Oleptro
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

The authors are employed by AssureRx Health, Inc., the provider of the pharmacogenomic testing used in this article.

A 64-year-old woman came into our emergency department (ED) complaining of constipation and worsening rectal pain. In an attempt to promote her overall health, the patient had recently begun experimenting with healthy alternatives to her regular diet. Three days before her visit, she had ceased having stools and was experiencing intermittent abdominal cramping. She self-administered 2 bisacodyl suppositories, 2 sodium biphosphate enemas, one 10-ounce bottle of magnesium citrate, and 15 senna-containing laxative tablets without improvement.

She sought care at an urgent care clinic where she received 2 additional enemas and a trial of manual disimpaction—without results. She was sent home to rest and asked to return the next morning for another trial of disimpaction. When the patient’s efforts to manually disimpact herself at home were unsuccessful, she contacted her primary care physician, who arranged a house call. When his own protracted disimpaction procedure was unsuccessful, he referred her to our ED.

On presentation, the patient had lower abdominal and rectal discomfort. Her vital signs were normal except for a temperature of 38.8° C. Her abdomen was soft and nontender. Inspection of her perianal area revealed erythema and excoriations. On digital rectal exam (which was poorly tolerated because of pain), we noted a moderate amount of soft, clay-like feces in the rectal vault, with overflow liquid stool expulsion.

Computed tomography (CT) imaging of the abdomen was obtained to rule out rectal injury or colonic perforation (FIGURE 1).

FIGURE 1
CT scan reveals a speckled intraluminal mass

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Fecal impaction caused by a proctophytobezoar

CT imaging revealed a proctophytobezoar. On follow-up questioning, the patient recalled consuming approximately 10 ounces of cooked quinoa, a nutritious, gluten-free, high-protein seed, just prior to the onset of her constipation.

Constipation disproportionately affects the elderly and the young.¹ Fecal impaction is a sequelae of constipation. Most commonly defined as hard, compacted feces in the rectum, fecal impaction can also include more proximal impactions due to fecal loading or retention.²

Causes of constipation and fecal impaction are similar and include low intake of dietary fiber, dehydration, immobility, alcohol ingestion, laxative abuse, medication adverse effects, depression, dementia, spinal cord dysfunction, diabetes, metabolic imbalances, and hypothyroidism.^2,3 Insufficient hydration with consumption of a high-fiber food, as in this case, or with a bulk-forming laxative such as psyllium seed can result in fecal impaction.³

The many causes of a bezoar
A bezoar is a mass of poorly digested material that forms within the gastrointestinal tract—usually in the stomach—and less commonly in the small or large intestine.⁴ Trichobezoars (hair), lactobezoars (milk curd), phytobezoars (plant fiber), medication bezoars, and lithobezoars (small stones, pebbles, or gravel) are named after their contents. In keeping with this naming tradition, a gummi bear bezoar⁵ has also been described. Fecal impaction due to phytobezoars primarily composed of seeds has been associated with prickly pears, watermelons, sunflowers, pumpkins, pomegranates,^6,7 and sesame seeds.⁴ Our patient’s experience adds quinoa seeds to this list.

Patients will complain of nausea and rectal urgency
Patients with fecal impaction may complain of nausea, rectal urgency, and rectalgia. A ball-valve effect of the fecal mass may allow paradoxical fecal incontinence and diarrhea.³ Digital rectal exam may demonstrate stool of any consistency, from rock hard pellets to soft clay-like stool.³ Absence of stool in the rectal vault does not rule out fecal impaction, and more proximal impactions may be revealed on plain abdominal radiography as bubbly, speckled masses of stool with associated signs of obstruction, such as colonic dilatation.

Fever, increased leukocyte count, and abdominal tenderness may indicate colonic perforation or ulceration. Signs of generalized peritonitis and free air on abdominal radiography warrant an immediate surgical consult.³

Complications from fecal impaction include bowel obstruction, sigmoid volvulus, and rectal prolapse.² Stercoral ulceration and perforation due to pressure necrosis from a hard, inspissated fecal mass is an uncommon but life-threatening complication requiring resection of the affected colonic segment.⁸

What to look for on the CT. When the diagnosis is unclear or signs of complications are present, an abdominal CT is indicated. Concerning CT findings include ulceration, bowel wall enhancement and thickening (FIGURE 2), discontinuity of the bowel wall, presence of fecal material either protruding through the colonic wall or lying free within the intra-abdominal cavity, and extraluminal air.⁸

FIGURE 2
CT scan shows bowel wall thickening

Treatment begins with a pharmacologic approach

By the time a patient with a fecal impaction gets to your office, it’s likely that he or she will have already tried over-the-counter laxatives, stool softeners, and perhaps an enema.

When such pharmacologic management has failed, you’ll need to perform a manual fragmentation and extraction of the fecal mass. Apply topical 2% lidocaine jelly for analgesia and lubrication, and then gently and progressively dilate the anal sphincter with one and then 2 fingers. A scissoring action will fragment the impaction.³

Once fragmentation and partial expulsion has been achieved, you may want to try a lubricating mineral oil enema, bisacodyl suppository, or rectal lavage. If the impaction extends beyond the reach of the fingers, sigmoidoscopic visualization and lavage are indicated.

Adding water-soluble contrast material (Gastrografin) in 20% to 50% solutions directed by fluoroscopy draws water into the lumen, thus lubricating the fecal mass^3,9 and helping it to pass spontaneously.

Our patient’s case resolved with a trip to the OR
Since conservative and comprehensive management to improve our patient’s condition failed, she was taken to the operating room for a proctosigmoidoscopic disimpaction. A beveled metal proctoscope was used to disimpact the distal-most 10 cm and then a rigid sigmoidoscope was used to clear the colon of quinoa-laden fecal material to a total distance of 18 cm. Bowel walls were ecchymotic, yet viable and without laceration. She made an uneventful recovery and was discharged on hospital Day 3.

CORRESPONDENCE George L. Higgins, III, MD, Maine Medical Center, Department of Emergency Medicine, 47 Bramhall Street, Portland, ME 04102; [email protected]

A 64-year-old woman came into our emergency department (ED) complaining of constipation and worsening rectal pain. In an attempt to promote her overall health, the patient had recently begun experimenting with healthy alternatives to her regular diet. Three days before her visit, she had ceased having stools and was experiencing intermittent abdominal cramping. She self-administered 2 bisacodyl suppositories, 2 sodium biphosphate enemas, one 10-ounce bottle of magnesium citrate, and 15 senna-containing laxative tablets without improvement.

She sought care at an urgent care clinic where she received 2 additional enemas and a trial of manual disimpaction—without results. She was sent home to rest and asked to return the next morning for another trial of disimpaction. When the patient’s efforts to manually disimpact herself at home were unsuccessful, she contacted her primary care physician, who arranged a house call. When his own protracted disimpaction procedure was unsuccessful, he referred her to our ED.

On presentation, the patient had lower abdominal and rectal discomfort. Her vital signs were normal except for a temperature of 38.8° C. Her abdomen was soft and nontender. Inspection of her perianal area revealed erythema and excoriations. On digital rectal exam (which was poorly tolerated because of pain), we noted a moderate amount of soft, clay-like feces in the rectal vault, with overflow liquid stool expulsion.

Computed tomography (CT) imaging of the abdomen was obtained to rule out rectal injury or colonic perforation (FIGURE 1).

FIGURE 1
CT scan reveals a speckled intraluminal mass

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Fecal impaction caused by a proctophytobezoar

CT imaging revealed a proctophytobezoar. On follow-up questioning, the patient recalled consuming approximately 10 ounces of cooked quinoa, a nutritious, gluten-free, high-protein seed, just prior to the onset of her constipation.

Constipation disproportionately affects the elderly and the young.¹ Fecal impaction is a sequelae of constipation. Most commonly defined as hard, compacted feces in the rectum, fecal impaction can also include more proximal impactions due to fecal loading or retention.²

Causes of constipation and fecal impaction are similar and include low intake of dietary fiber, dehydration, immobility, alcohol ingestion, laxative abuse, medication adverse effects, depression, dementia, spinal cord dysfunction, diabetes, metabolic imbalances, and hypothyroidism.^2,3 Insufficient hydration with consumption of a high-fiber food, as in this case, or with a bulk-forming laxative such as psyllium seed can result in fecal impaction.³

The many causes of a bezoar
A bezoar is a mass of poorly digested material that forms within the gastrointestinal tract—usually in the stomach—and less commonly in the small or large intestine.⁴ Trichobezoars (hair), lactobezoars (milk curd), phytobezoars (plant fiber), medication bezoars, and lithobezoars (small stones, pebbles, or gravel) are named after their contents. In keeping with this naming tradition, a gummi bear bezoar⁵ has also been described. Fecal impaction due to phytobezoars primarily composed of seeds has been associated with prickly pears, watermelons, sunflowers, pumpkins, pomegranates,^6,7 and sesame seeds.⁴ Our patient’s experience adds quinoa seeds to this list.

Patients will complain of nausea and rectal urgency
Patients with fecal impaction may complain of nausea, rectal urgency, and rectalgia. A ball-valve effect of the fecal mass may allow paradoxical fecal incontinence and diarrhea.³ Digital rectal exam may demonstrate stool of any consistency, from rock hard pellets to soft clay-like stool.³ Absence of stool in the rectal vault does not rule out fecal impaction, and more proximal impactions may be revealed on plain abdominal radiography as bubbly, speckled masses of stool with associated signs of obstruction, such as colonic dilatation.

Fever, increased leukocyte count, and abdominal tenderness may indicate colonic perforation or ulceration. Signs of generalized peritonitis and free air on abdominal radiography warrant an immediate surgical consult.³

Complications from fecal impaction include bowel obstruction, sigmoid volvulus, and rectal prolapse.² Stercoral ulceration and perforation due to pressure necrosis from a hard, inspissated fecal mass is an uncommon but life-threatening complication requiring resection of the affected colonic segment.⁸

What to look for on the CT. When the diagnosis is unclear or signs of complications are present, an abdominal CT is indicated. Concerning CT findings include ulceration, bowel wall enhancement and thickening (FIGURE 2), discontinuity of the bowel wall, presence of fecal material either protruding through the colonic wall or lying free within the intra-abdominal cavity, and extraluminal air.⁸

FIGURE 2
CT scan shows bowel wall thickening

Treatment begins with a pharmacologic approach

By the time a patient with a fecal impaction gets to your office, it’s likely that he or she will have already tried over-the-counter laxatives, stool softeners, and perhaps an enema.

When such pharmacologic management has failed, you’ll need to perform a manual fragmentation and extraction of the fecal mass. Apply topical 2% lidocaine jelly for analgesia and lubrication, and then gently and progressively dilate the anal sphincter with one and then 2 fingers. A scissoring action will fragment the impaction.³

Once fragmentation and partial expulsion has been achieved, you may want to try a lubricating mineral oil enema, bisacodyl suppository, or rectal lavage. If the impaction extends beyond the reach of the fingers, sigmoidoscopic visualization and lavage are indicated.

Adding water-soluble contrast material (Gastrografin) in 20% to 50% solutions directed by fluoroscopy draws water into the lumen, thus lubricating the fecal mass^3,9 and helping it to pass spontaneously.

Our patient’s case resolved with a trip to the OR
Since conservative and comprehensive management to improve our patient’s condition failed, she was taken to the operating room for a proctosigmoidoscopic disimpaction. A beveled metal proctoscope was used to disimpact the distal-most 10 cm and then a rigid sigmoidoscope was used to clear the colon of quinoa-laden fecal material to a total distance of 18 cm. Bowel walls were ecchymotic, yet viable and without laceration. She made an uneventful recovery and was discharged on hospital Day 3.

CORRESPONDENCE George L. Higgins, III, MD, Maine Medical Center, Department of Emergency Medicine, 47 Bramhall Street, Portland, ME 04102; [email protected]

A 64-year-old woman came into our emergency department (ED) complaining of constipation and worsening rectal pain. In an attempt to promote her overall health, the patient had recently begun experimenting with healthy alternatives to her regular diet. Three days before her visit, she had ceased having stools and was experiencing intermittent abdominal cramping. She self-administered 2 bisacodyl suppositories, 2 sodium biphosphate enemas, one 10-ounce bottle of magnesium citrate, and 15 senna-containing laxative tablets without improvement.

She sought care at an urgent care clinic where she received 2 additional enemas and a trial of manual disimpaction—without results. She was sent home to rest and asked to return the next morning for another trial of disimpaction. When the patient’s efforts to manually disimpact herself at home were unsuccessful, she contacted her primary care physician, who arranged a house call. When his own protracted disimpaction procedure was unsuccessful, he referred her to our ED.

On presentation, the patient had lower abdominal and rectal discomfort. Her vital signs were normal except for a temperature of 38.8° C. Her abdomen was soft and nontender. Inspection of her perianal area revealed erythema and excoriations. On digital rectal exam (which was poorly tolerated because of pain), we noted a moderate amount of soft, clay-like feces in the rectal vault, with overflow liquid stool expulsion.

Computed tomography (CT) imaging of the abdomen was obtained to rule out rectal injury or colonic perforation (FIGURE 1).

FIGURE 1
CT scan reveals a speckled intraluminal mass

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Fecal impaction caused by a proctophytobezoar

CT imaging revealed a proctophytobezoar. On follow-up questioning, the patient recalled consuming approximately 10 ounces of cooked quinoa, a nutritious, gluten-free, high-protein seed, just prior to the onset of her constipation.

Constipation disproportionately affects the elderly and the young.¹ Fecal impaction is a sequelae of constipation. Most commonly defined as hard, compacted feces in the rectum, fecal impaction can also include more proximal impactions due to fecal loading or retention.²

Causes of constipation and fecal impaction are similar and include low intake of dietary fiber, dehydration, immobility, alcohol ingestion, laxative abuse, medication adverse effects, depression, dementia, spinal cord dysfunction, diabetes, metabolic imbalances, and hypothyroidism.^2,3 Insufficient hydration with consumption of a high-fiber food, as in this case, or with a bulk-forming laxative such as psyllium seed can result in fecal impaction.³

The many causes of a bezoar
A bezoar is a mass of poorly digested material that forms within the gastrointestinal tract—usually in the stomach—and less commonly in the small or large intestine.⁴ Trichobezoars (hair), lactobezoars (milk curd), phytobezoars (plant fiber), medication bezoars, and lithobezoars (small stones, pebbles, or gravel) are named after their contents. In keeping with this naming tradition, a gummi bear bezoar⁵ has also been described. Fecal impaction due to phytobezoars primarily composed of seeds has been associated with prickly pears, watermelons, sunflowers, pumpkins, pomegranates,^6,7 and sesame seeds.⁴ Our patient’s experience adds quinoa seeds to this list.

Patients will complain of nausea and rectal urgency
Patients with fecal impaction may complain of nausea, rectal urgency, and rectalgia. A ball-valve effect of the fecal mass may allow paradoxical fecal incontinence and diarrhea.³ Digital rectal exam may demonstrate stool of any consistency, from rock hard pellets to soft clay-like stool.³ Absence of stool in the rectal vault does not rule out fecal impaction, and more proximal impactions may be revealed on plain abdominal radiography as bubbly, speckled masses of stool with associated signs of obstruction, such as colonic dilatation.

Fever, increased leukocyte count, and abdominal tenderness may indicate colonic perforation or ulceration. Signs of generalized peritonitis and free air on abdominal radiography warrant an immediate surgical consult.³

Complications from fecal impaction include bowel obstruction, sigmoid volvulus, and rectal prolapse.² Stercoral ulceration and perforation due to pressure necrosis from a hard, inspissated fecal mass is an uncommon but life-threatening complication requiring resection of the affected colonic segment.⁸

What to look for on the CT. When the diagnosis is unclear or signs of complications are present, an abdominal CT is indicated. Concerning CT findings include ulceration, bowel wall enhancement and thickening (FIGURE 2), discontinuity of the bowel wall, presence of fecal material either protruding through the colonic wall or lying free within the intra-abdominal cavity, and extraluminal air.⁸

FIGURE 2
CT scan shows bowel wall thickening

Treatment begins with a pharmacologic approach

By the time a patient with a fecal impaction gets to your office, it’s likely that he or she will have already tried over-the-counter laxatives, stool softeners, and perhaps an enema.

When such pharmacologic management has failed, you’ll need to perform a manual fragmentation and extraction of the fecal mass. Apply topical 2% lidocaine jelly for analgesia and lubrication, and then gently and progressively dilate the anal sphincter with one and then 2 fingers. A scissoring action will fragment the impaction.³

Once fragmentation and partial expulsion has been achieved, you may want to try a lubricating mineral oil enema, bisacodyl suppository, or rectal lavage. If the impaction extends beyond the reach of the fingers, sigmoidoscopic visualization and lavage are indicated.

Adding water-soluble contrast material (Gastrografin) in 20% to 50% solutions directed by fluoroscopy draws water into the lumen, thus lubricating the fecal mass^3,9 and helping it to pass spontaneously.

Our patient’s case resolved with a trip to the OR
Since conservative and comprehensive management to improve our patient’s condition failed, she was taken to the operating room for a proctosigmoidoscopic disimpaction. A beveled metal proctoscope was used to disimpact the distal-most 10 cm and then a rigid sigmoidoscope was used to clear the colon of quinoa-laden fecal material to a total distance of 18 cm. Bowel walls were ecchymotic, yet viable and without laceration. She made an uneventful recovery and was discharged on hospital Day 3.

CORRESPONDENCE George L. Higgins, III, MD, Maine Medical Center, Department of Emergency Medicine, 47 Bramhall Street, Portland, ME 04102; [email protected]

Most acute respiratory tract infections (ARTIs) are caused by viruses, do not require antibiotics, and resolve spontaneously.^1,2 And yet, unnecessary prescribing of antibiotics for ARTIs continues—accounting for approximately half of all such prescriptions²—despite its well-known contribution to antimicrobial resistance, a public health threat as declared by the Institute of Medicine, the Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO).^3-5

Even though the CDC has widely disseminated clinical guidelines for ARTI^6-10 and annually publicizes recommendations for ARTI management during “Get Smart About Antibiotics Week,”¹¹ it appears that providers have difficulty implementing the guidelines.^12-14 Granted, antibiotic prescription rates in general have declined somewhat, but the use of broad-spectrum antibiotics (macrolides and fluoroquinolones) and antibiotics for older Americans has increased.¹²

There are several plausible reasons for overprescribing. Patients have expectations for treatment based on prior experience or on a false assumption that their illness is bacterial in origin.¹⁴ Providers may be concerned that certain individuals are at risk of complications if not treated. Patient race, health maintenance organization membership, and insurance status have all been implicated as factors related to antimicrobial overutilization.^12-16 It can be perceived as time consuming to educate patients about the likely viral nature of their illness and the lack of utility and increased risks in taking unneeded antibiotics.¹⁷ Furthermore, attempts at patient and physician education (eg, physician performance feedback) do not always reduce antibiotic overuse.^18-20

We wanted to know the state of ARTI antibiotic use in our practice and whether we could identify goals for improvement through quality interventions. We sought to determine the distribution of ARTI final diagnoses in our practice, the frequency and types of antibiotics prescribed, and factors associated with antibiotic prescribing.

Methods

Setting and subjects
Subjects were adult patients seen at Mayo Clinic Family Medicine offices in Arizona between December 14, 2009, and March 4, 2010. We created a convenience sample from visits scheduled for patients with ARTI symptoms. We encouraged, but did not require, clinic staff to use a standardized data collection form to document symptoms, physical examination findings, diagnostic impressions, and prescription decisions that were then entered into an Excel spreadsheet. At one of our 2 sites, clinicians (attending physicians, nurse practitioners, and resident physicians) used the form at the point of care to enroll a portion of the sample population. A retrospective chart audit (with or without use of the form) was the means of selecting the remainder of the sample at this site and the entire sample at our second site. We obtained informed consent from all patients enrolled with the data collection form. The Mayo Foundation Institutional Review Board approved the project.

We defined an ARTI as a new illness occurring within the previous 3 weeks, associated with cough, sinus pain, nasal congestion or rhinorrhea, sore throat, or fever. We excluded patients who had a longer duration of symptoms, a previous evaluation, or a noninfectious diagnosis. We included ARTI patients with concomitant asthma or chronic obstructive pulmonary disease (COPD).

We enrolled 438 patients. Two hundred thirty-one (53%) consented prospectively to data collection with our standardized form; 207 (47%) were reviewed by retrospective chart audit. The mean age of subjects was 54 years (range 18-94, intraquartile range 45-69). Cough was the most frequent chief complaint (58%).

Statistical analysis
We calculated the frequency of each ARTI final diagnosis and its associated antibiotic prescription rate. We also tested for associations between clinical features and the provision of antibiotics. We hypothesized that our providers would be more likely to prescribe antibiotics for patients of advanced age and in the presence of other risk factors for complications.

Results

We determined patient risks for ARTI complication in the prospective data collection group only. Of the 231 patients, 147 (64%) had at least one risk for complication, the most common being age ≥65 (37%). Other risks were employment as a health care worker (12%), asthma (11%), atherosclerotic heart disease (8%), COPD (7%), and tobacco use (5%).

Final diagnoses for all patients appear in TABLE 1. We allowed clinicians to report more than one diagnosis, resulting in 501 final diagnoses reported for 438 patients (63 received 2 final diagnoses). Sinusitis was diagnosed most frequently (32%). Other common diagnoses were viral upper respiratory infection (URI) and acute bronchitis (29% and 24%, respectively).

Antibiotics most often prescribed. Three hundred four ARTI patients (69%) received antibiotic prescriptions. Macrolides were most commonly prescribed (167/304 [55%]). Two hundred eight ARTI patients (68%) received broad-spectrum antibiotics (macrolides or fluoroquinolones); 96 (32%) received narrow-spectrum agents (penicillin, cephalosporin, sulfa, or tetracycline derivatives). TABLE 2 lists the frequency of antibiotic prescription and the antibiotic class most frequently prescribed for each ARTI diagnosis.

Factors associated with increased prescribing included specific history and physical exam findings (TABLE 3). A major determinant of treatment was duration of illness. Those who received antibiotics had a mean duration of illness of 8.3 days, compared with 7.0 days for those not receiving antibiotic therapy (P = .03).

The rate of antibiotic prescribing varied by provider type (TABLE 4). Four resident physicians (all of whom were investigators) prescribed least often, followed by attending physicians, then nurse practitioners. Investigators were significantly less likely to prescribe antimicrobials than noninvestigators (P<.001). We assessed whether use of our standardized data collection form affected prescribing rates. When we excluded patients whose data were entered with this form, no difference in rates was seen.

We also noted wide ranges of prescribing rates between individual providers. While all providers enrolled patients, numbers ranged from one to 51, with a mean of 18. For those who enrolled ≥10 subjects, prescribing rates ranged from a low of 29% (8/28) for a resident physician investigator to 93% (63/68) for 4 noninvestigator attending physicians.

Factors not associated with increased prescribing. We had hypothesized that specific patient characteristics (age and medical complication) would be associated with provision of antimicrobials. However, there was no correlation between patient age and rate of prescribing. The 304 patients who received an antibiotic had a mean age of 54 years (standard deviation [SD]=18), as did the 134 who did not receive one (mean age, 54; SD=20; P=.95). There was a nonsignificant trend for a reduced rate of prescribing for patients younger than age 30. For patients 18 to 29 years old, the rate was 60% (31/52); for those ≥30 years, it was 71% (273/386; odds ratio [OR]=1.64; 95% confidence interval, 0.90-2.97).

Similarly, presence of medical complication did not significantly affect antibiotic prescribing rates. Patients with any risk factor for complication (age >65, diabetes, atherosclerotic heart disease, heart failure, COPD, asthma, tobacco smoking, or active cancer treatment) had a 62% prescription rate (91/147), which was the same as that of patients without such risks (52/84 [62%]; P=1.0).

TABLE 1
Final diagnoses for 438 patients with ARTI

TABLE 2
Antibiotic use and type prescribed for ARTI varied by diagnosis

TABLE 3
Historical features, exam findings associated with antibiotic prescribing

TABLE 4
Antibiotic prescription rates for ARTI varied by provider type, investigator status

Discussion

Providers in our practice had surprisingly high rates of antibiotic prescribing for ARTIs (69% overall). By comparison, the overall antibiotic use rate for ARTIs in the most recent National Ambulatory Medical Care Survey (NAMCS) analysis (1995-2006) was 58%.¹² The prescribing rate for office settings alone was just 52%. Steinman’s analysis of NAMCS data from 1997-1999 revealed an overall rate of 63%.¹³

Data analyzed from >4200 Medicare enrollees seen for ARTI visits revealed great variation in prescribing rates by office site: 21% to 88%, with a median rate of 54%.²⁰ The rate varied by final diagnoses: sinusitis, 69%; bronchitis, 59%; pharyngitis, 50%; and URI, 26%. A rate of 77% was recently reported in a Veterans Administration office setting.²¹ Those with sinusitis and bronchitis similarly received more prescriptions than those with acute pharyngitis and URI.

In addition to our high overall rate, we also diagnosed patients with sinusitis and bronchitis frequently (32% and 24% of all patients, respectively), perhaps as false justification for prescribing antibiotics (provided for 99% and 91%, respectively). Also noteworthy is that more than one-third of URI patients in our practice received antibiotics.

We had expected, but did not see, differences in prescribing rates between older and younger patients, as well as those with and without risk factors for complications. Our expectations were based on NAMCS data, which have demonstrated increasing use of antibiotics in older patients.²

Treatment for those with bronchitis was surprisingly frequent; 91% received antibiotics. A Cochrane systematic review attributes slight symptom benefit to antibiotic use (improvement in cough by about one day).²² This benefit, however, is rarely seen in patients who have been ill for <1 week. The magnitude of this benefit must be weighed against the cost and adverse effects of antibiotics and the potential for promoting antimicrobial resistance. Most patients’ symptoms are mild and self-limited, and risks may exceed benefits.

Guidelines state, “The widespread use of antibiotics for the treatment of acute bronchitis is not justified and vigorous efforts to curtail their use should be encouraged.”²³ The CDC agrees, noting that “routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough.”¹⁰

As observed in another study,¹⁴ a clinical factor associated with prescribing decisions at our practice was the duration of illness. Patients in our practice had been ill, on average, 8 days before presenting to the office. Over time, our encounters with regular patients may have taught them to wait until their symptoms are prolonged or progressive before seeking evaluation.

We saw large differences in prescribing rates between providers, and hope this means there is room for improvement by addressing reasons for variability. Education about individual prescribing behaviors may motivate those with the highest rates of use to improve.

We noted high rates of broad-spectrum antibiotic use. This is consistent with other research findings of a shift away from narrow-spectrum agents.¹² We did not determine the frequency of allergies to narrow-spectrum agents. Anecdotally, the opinion of some patients was that narrow-spectrum medicines “just don’t work,” given their experience of persistent cold symptoms when using such agents.

Quality-improvement processes such as DMAIC (Define, Measure, Analyze, Improve, Control) or PDSA (Plan, Do, Study, Act) require collection of baseline data so that interventions can be tailored to meet the root causes identified.²⁴ This project determined preintervention practice behaviors and allowed us to create quality metrics that could define our future success.

Study limitations. One obvious reason for the prescribing variability noted above is that those who helped plan and implement the project knew their practice behaviors were being reviewed and had studied the relevant practice guidelines. Whether non-investigator providers were up to date with recommendations and could carefully select appropriate treatment candidates is unclear.

This study was of our practice alone, and findings may not be generalizable to other practices. We encourage physicians to similarly examine their own prescribing habits in order to set practice-improvement goals.

CORRESPONDENCE Michael L. Grover, DO, Department of Family Medicine, Mayo Clinic, 13737 N 92nd Street, Scottsdale, AZ 85260; [email protected]

Most acute respiratory tract infections (ARTIs) are caused by viruses, do not require antibiotics, and resolve spontaneously.^1,2 And yet, unnecessary prescribing of antibiotics for ARTIs continues—accounting for approximately half of all such prescriptions²—despite its well-known contribution to antimicrobial resistance, a public health threat as declared by the Institute of Medicine, the Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO).^3-5

Even though the CDC has widely disseminated clinical guidelines for ARTI^6-10 and annually publicizes recommendations for ARTI management during “Get Smart About Antibiotics Week,”¹¹ it appears that providers have difficulty implementing the guidelines.^12-14 Granted, antibiotic prescription rates in general have declined somewhat, but the use of broad-spectrum antibiotics (macrolides and fluoroquinolones) and antibiotics for older Americans has increased.¹²

There are several plausible reasons for overprescribing. Patients have expectations for treatment based on prior experience or on a false assumption that their illness is bacterial in origin.¹⁴ Providers may be concerned that certain individuals are at risk of complications if not treated. Patient race, health maintenance organization membership, and insurance status have all been implicated as factors related to antimicrobial overutilization.^12-16 It can be perceived as time consuming to educate patients about the likely viral nature of their illness and the lack of utility and increased risks in taking unneeded antibiotics.¹⁷ Furthermore, attempts at patient and physician education (eg, physician performance feedback) do not always reduce antibiotic overuse.^18-20

We wanted to know the state of ARTI antibiotic use in our practice and whether we could identify goals for improvement through quality interventions. We sought to determine the distribution of ARTI final diagnoses in our practice, the frequency and types of antibiotics prescribed, and factors associated with antibiotic prescribing.

Methods

Setting and subjects
Subjects were adult patients seen at Mayo Clinic Family Medicine offices in Arizona between December 14, 2009, and March 4, 2010. We created a convenience sample from visits scheduled for patients with ARTI symptoms. We encouraged, but did not require, clinic staff to use a standardized data collection form to document symptoms, physical examination findings, diagnostic impressions, and prescription decisions that were then entered into an Excel spreadsheet. At one of our 2 sites, clinicians (attending physicians, nurse practitioners, and resident physicians) used the form at the point of care to enroll a portion of the sample population. A retrospective chart audit (with or without use of the form) was the means of selecting the remainder of the sample at this site and the entire sample at our second site. We obtained informed consent from all patients enrolled with the data collection form. The Mayo Foundation Institutional Review Board approved the project.

We defined an ARTI as a new illness occurring within the previous 3 weeks, associated with cough, sinus pain, nasal congestion or rhinorrhea, sore throat, or fever. We excluded patients who had a longer duration of symptoms, a previous evaluation, or a noninfectious diagnosis. We included ARTI patients with concomitant asthma or chronic obstructive pulmonary disease (COPD).

We enrolled 438 patients. Two hundred thirty-one (53%) consented prospectively to data collection with our standardized form; 207 (47%) were reviewed by retrospective chart audit. The mean age of subjects was 54 years (range 18-94, intraquartile range 45-69). Cough was the most frequent chief complaint (58%).

Statistical analysis
We calculated the frequency of each ARTI final diagnosis and its associated antibiotic prescription rate. We also tested for associations between clinical features and the provision of antibiotics. We hypothesized that our providers would be more likely to prescribe antibiotics for patients of advanced age and in the presence of other risk factors for complications.

Results

We determined patient risks for ARTI complication in the prospective data collection group only. Of the 231 patients, 147 (64%) had at least one risk for complication, the most common being age ≥65 (37%). Other risks were employment as a health care worker (12%), asthma (11%), atherosclerotic heart disease (8%), COPD (7%), and tobacco use (5%).

Final diagnoses for all patients appear in TABLE 1. We allowed clinicians to report more than one diagnosis, resulting in 501 final diagnoses reported for 438 patients (63 received 2 final diagnoses). Sinusitis was diagnosed most frequently (32%). Other common diagnoses were viral upper respiratory infection (URI) and acute bronchitis (29% and 24%, respectively).

Antibiotics most often prescribed. Three hundred four ARTI patients (69%) received antibiotic prescriptions. Macrolides were most commonly prescribed (167/304 [55%]). Two hundred eight ARTI patients (68%) received broad-spectrum antibiotics (macrolides or fluoroquinolones); 96 (32%) received narrow-spectrum agents (penicillin, cephalosporin, sulfa, or tetracycline derivatives). TABLE 2 lists the frequency of antibiotic prescription and the antibiotic class most frequently prescribed for each ARTI diagnosis.

Factors associated with increased prescribing included specific history and physical exam findings (TABLE 3). A major determinant of treatment was duration of illness. Those who received antibiotics had a mean duration of illness of 8.3 days, compared with 7.0 days for those not receiving antibiotic therapy (P = .03).

The rate of antibiotic prescribing varied by provider type (TABLE 4). Four resident physicians (all of whom were investigators) prescribed least often, followed by attending physicians, then nurse practitioners. Investigators were significantly less likely to prescribe antimicrobials than noninvestigators (P<.001). We assessed whether use of our standardized data collection form affected prescribing rates. When we excluded patients whose data were entered with this form, no difference in rates was seen.

We also noted wide ranges of prescribing rates between individual providers. While all providers enrolled patients, numbers ranged from one to 51, with a mean of 18. For those who enrolled ≥10 subjects, prescribing rates ranged from a low of 29% (8/28) for a resident physician investigator to 93% (63/68) for 4 noninvestigator attending physicians.

Factors not associated with increased prescribing. We had hypothesized that specific patient characteristics (age and medical complication) would be associated with provision of antimicrobials. However, there was no correlation between patient age and rate of prescribing. The 304 patients who received an antibiotic had a mean age of 54 years (standard deviation [SD]=18), as did the 134 who did not receive one (mean age, 54; SD=20; P=.95). There was a nonsignificant trend for a reduced rate of prescribing for patients younger than age 30. For patients 18 to 29 years old, the rate was 60% (31/52); for those ≥30 years, it was 71% (273/386; odds ratio [OR]=1.64; 95% confidence interval, 0.90-2.97).

Similarly, presence of medical complication did not significantly affect antibiotic prescribing rates. Patients with any risk factor for complication (age >65, diabetes, atherosclerotic heart disease, heart failure, COPD, asthma, tobacco smoking, or active cancer treatment) had a 62% prescription rate (91/147), which was the same as that of patients without such risks (52/84 [62%]; P=1.0).

TABLE 1
Final diagnoses for 438 patients with ARTI

TABLE 2
Antibiotic use and type prescribed for ARTI varied by diagnosis

TABLE 3
Historical features, exam findings associated with antibiotic prescribing

TABLE 4
Antibiotic prescription rates for ARTI varied by provider type, investigator status

Discussion

Providers in our practice had surprisingly high rates of antibiotic prescribing for ARTIs (69% overall). By comparison, the overall antibiotic use rate for ARTIs in the most recent National Ambulatory Medical Care Survey (NAMCS) analysis (1995-2006) was 58%.¹² The prescribing rate for office settings alone was just 52%. Steinman’s analysis of NAMCS data from 1997-1999 revealed an overall rate of 63%.¹³

Data analyzed from >4200 Medicare enrollees seen for ARTI visits revealed great variation in prescribing rates by office site: 21% to 88%, with a median rate of 54%.²⁰ The rate varied by final diagnoses: sinusitis, 69%; bronchitis, 59%; pharyngitis, 50%; and URI, 26%. A rate of 77% was recently reported in a Veterans Administration office setting.²¹ Those with sinusitis and bronchitis similarly received more prescriptions than those with acute pharyngitis and URI.

In addition to our high overall rate, we also diagnosed patients with sinusitis and bronchitis frequently (32% and 24% of all patients, respectively), perhaps as false justification for prescribing antibiotics (provided for 99% and 91%, respectively). Also noteworthy is that more than one-third of URI patients in our practice received antibiotics.

We had expected, but did not see, differences in prescribing rates between older and younger patients, as well as those with and without risk factors for complications. Our expectations were based on NAMCS data, which have demonstrated increasing use of antibiotics in older patients.²

Treatment for those with bronchitis was surprisingly frequent; 91% received antibiotics. A Cochrane systematic review attributes slight symptom benefit to antibiotic use (improvement in cough by about one day).²² This benefit, however, is rarely seen in patients who have been ill for <1 week. The magnitude of this benefit must be weighed against the cost and adverse effects of antibiotics and the potential for promoting antimicrobial resistance. Most patients’ symptoms are mild and self-limited, and risks may exceed benefits.

Guidelines state, “The widespread use of antibiotics for the treatment of acute bronchitis is not justified and vigorous efforts to curtail their use should be encouraged.”²³ The CDC agrees, noting that “routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough.”¹⁰

As observed in another study,¹⁴ a clinical factor associated with prescribing decisions at our practice was the duration of illness. Patients in our practice had been ill, on average, 8 days before presenting to the office. Over time, our encounters with regular patients may have taught them to wait until their symptoms are prolonged or progressive before seeking evaluation.

We saw large differences in prescribing rates between providers, and hope this means there is room for improvement by addressing reasons for variability. Education about individual prescribing behaviors may motivate those with the highest rates of use to improve.

We noted high rates of broad-spectrum antibiotic use. This is consistent with other research findings of a shift away from narrow-spectrum agents.¹² We did not determine the frequency of allergies to narrow-spectrum agents. Anecdotally, the opinion of some patients was that narrow-spectrum medicines “just don’t work,” given their experience of persistent cold symptoms when using such agents.

Quality-improvement processes such as DMAIC (Define, Measure, Analyze, Improve, Control) or PDSA (Plan, Do, Study, Act) require collection of baseline data so that interventions can be tailored to meet the root causes identified.²⁴ This project determined preintervention practice behaviors and allowed us to create quality metrics that could define our future success.

Study limitations. One obvious reason for the prescribing variability noted above is that those who helped plan and implement the project knew their practice behaviors were being reviewed and had studied the relevant practice guidelines. Whether non-investigator providers were up to date with recommendations and could carefully select appropriate treatment candidates is unclear.

This study was of our practice alone, and findings may not be generalizable to other practices. We encourage physicians to similarly examine their own prescribing habits in order to set practice-improvement goals.

CORRESPONDENCE Michael L. Grover, DO, Department of Family Medicine, Mayo Clinic, 13737 N 92nd Street, Scottsdale, AZ 85260; [email protected]

Most acute respiratory tract infections (ARTIs) are caused by viruses, do not require antibiotics, and resolve spontaneously.^1,2 And yet, unnecessary prescribing of antibiotics for ARTIs continues—accounting for approximately half of all such prescriptions²—despite its well-known contribution to antimicrobial resistance, a public health threat as declared by the Institute of Medicine, the Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO).^3-5

Even though the CDC has widely disseminated clinical guidelines for ARTI^6-10 and annually publicizes recommendations for ARTI management during “Get Smart About Antibiotics Week,”¹¹ it appears that providers have difficulty implementing the guidelines.^12-14 Granted, antibiotic prescription rates in general have declined somewhat, but the use of broad-spectrum antibiotics (macrolides and fluoroquinolones) and antibiotics for older Americans has increased.¹²

There are several plausible reasons for overprescribing. Patients have expectations for treatment based on prior experience or on a false assumption that their illness is bacterial in origin.¹⁴ Providers may be concerned that certain individuals are at risk of complications if not treated. Patient race, health maintenance organization membership, and insurance status have all been implicated as factors related to antimicrobial overutilization.^12-16 It can be perceived as time consuming to educate patients about the likely viral nature of their illness and the lack of utility and increased risks in taking unneeded antibiotics.¹⁷ Furthermore, attempts at patient and physician education (eg, physician performance feedback) do not always reduce antibiotic overuse.^18-20

We wanted to know the state of ARTI antibiotic use in our practice and whether we could identify goals for improvement through quality interventions. We sought to determine the distribution of ARTI final diagnoses in our practice, the frequency and types of antibiotics prescribed, and factors associated with antibiotic prescribing.

Methods

Setting and subjects
Subjects were adult patients seen at Mayo Clinic Family Medicine offices in Arizona between December 14, 2009, and March 4, 2010. We created a convenience sample from visits scheduled for patients with ARTI symptoms. We encouraged, but did not require, clinic staff to use a standardized data collection form to document symptoms, physical examination findings, diagnostic impressions, and prescription decisions that were then entered into an Excel spreadsheet. At one of our 2 sites, clinicians (attending physicians, nurse practitioners, and resident physicians) used the form at the point of care to enroll a portion of the sample population. A retrospective chart audit (with or without use of the form) was the means of selecting the remainder of the sample at this site and the entire sample at our second site. We obtained informed consent from all patients enrolled with the data collection form. The Mayo Foundation Institutional Review Board approved the project.

We defined an ARTI as a new illness occurring within the previous 3 weeks, associated with cough, sinus pain, nasal congestion or rhinorrhea, sore throat, or fever. We excluded patients who had a longer duration of symptoms, a previous evaluation, or a noninfectious diagnosis. We included ARTI patients with concomitant asthma or chronic obstructive pulmonary disease (COPD).

We enrolled 438 patients. Two hundred thirty-one (53%) consented prospectively to data collection with our standardized form; 207 (47%) were reviewed by retrospective chart audit. The mean age of subjects was 54 years (range 18-94, intraquartile range 45-69). Cough was the most frequent chief complaint (58%).

Statistical analysis
We calculated the frequency of each ARTI final diagnosis and its associated antibiotic prescription rate. We also tested for associations between clinical features and the provision of antibiotics. We hypothesized that our providers would be more likely to prescribe antibiotics for patients of advanced age and in the presence of other risk factors for complications.

Results

We determined patient risks for ARTI complication in the prospective data collection group only. Of the 231 patients, 147 (64%) had at least one risk for complication, the most common being age ≥65 (37%). Other risks were employment as a health care worker (12%), asthma (11%), atherosclerotic heart disease (8%), COPD (7%), and tobacco use (5%).

Final diagnoses for all patients appear in TABLE 1. We allowed clinicians to report more than one diagnosis, resulting in 501 final diagnoses reported for 438 patients (63 received 2 final diagnoses). Sinusitis was diagnosed most frequently (32%). Other common diagnoses were viral upper respiratory infection (URI) and acute bronchitis (29% and 24%, respectively).

Antibiotics most often prescribed. Three hundred four ARTI patients (69%) received antibiotic prescriptions. Macrolides were most commonly prescribed (167/304 [55%]). Two hundred eight ARTI patients (68%) received broad-spectrum antibiotics (macrolides or fluoroquinolones); 96 (32%) received narrow-spectrum agents (penicillin, cephalosporin, sulfa, or tetracycline derivatives). TABLE 2 lists the frequency of antibiotic prescription and the antibiotic class most frequently prescribed for each ARTI diagnosis.

Factors associated with increased prescribing included specific history and physical exam findings (TABLE 3). A major determinant of treatment was duration of illness. Those who received antibiotics had a mean duration of illness of 8.3 days, compared with 7.0 days for those not receiving antibiotic therapy (P = .03).

The rate of antibiotic prescribing varied by provider type (TABLE 4). Four resident physicians (all of whom were investigators) prescribed least often, followed by attending physicians, then nurse practitioners. Investigators were significantly less likely to prescribe antimicrobials than noninvestigators (P<.001). We assessed whether use of our standardized data collection form affected prescribing rates. When we excluded patients whose data were entered with this form, no difference in rates was seen.

We also noted wide ranges of prescribing rates between individual providers. While all providers enrolled patients, numbers ranged from one to 51, with a mean of 18. For those who enrolled ≥10 subjects, prescribing rates ranged from a low of 29% (8/28) for a resident physician investigator to 93% (63/68) for 4 noninvestigator attending physicians.

Factors not associated with increased prescribing. We had hypothesized that specific patient characteristics (age and medical complication) would be associated with provision of antimicrobials. However, there was no correlation between patient age and rate of prescribing. The 304 patients who received an antibiotic had a mean age of 54 years (standard deviation [SD]=18), as did the 134 who did not receive one (mean age, 54; SD=20; P=.95). There was a nonsignificant trend for a reduced rate of prescribing for patients younger than age 30. For patients 18 to 29 years old, the rate was 60% (31/52); for those ≥30 years, it was 71% (273/386; odds ratio [OR]=1.64; 95% confidence interval, 0.90-2.97).

Similarly, presence of medical complication did not significantly affect antibiotic prescribing rates. Patients with any risk factor for complication (age >65, diabetes, atherosclerotic heart disease, heart failure, COPD, asthma, tobacco smoking, or active cancer treatment) had a 62% prescription rate (91/147), which was the same as that of patients without such risks (52/84 [62%]; P=1.0).

TABLE 1
Final diagnoses for 438 patients with ARTI

TABLE 2
Antibiotic use and type prescribed for ARTI varied by diagnosis

TABLE 3
Historical features, exam findings associated with antibiotic prescribing

TABLE 4
Antibiotic prescription rates for ARTI varied by provider type, investigator status

Discussion

Providers in our practice had surprisingly high rates of antibiotic prescribing for ARTIs (69% overall). By comparison, the overall antibiotic use rate for ARTIs in the most recent National Ambulatory Medical Care Survey (NAMCS) analysis (1995-2006) was 58%.¹² The prescribing rate for office settings alone was just 52%. Steinman’s analysis of NAMCS data from 1997-1999 revealed an overall rate of 63%.¹³

Data analyzed from >4200 Medicare enrollees seen for ARTI visits revealed great variation in prescribing rates by office site: 21% to 88%, with a median rate of 54%.²⁰ The rate varied by final diagnoses: sinusitis, 69%; bronchitis, 59%; pharyngitis, 50%; and URI, 26%. A rate of 77% was recently reported in a Veterans Administration office setting.²¹ Those with sinusitis and bronchitis similarly received more prescriptions than those with acute pharyngitis and URI.

In addition to our high overall rate, we also diagnosed patients with sinusitis and bronchitis frequently (32% and 24% of all patients, respectively), perhaps as false justification for prescribing antibiotics (provided for 99% and 91%, respectively). Also noteworthy is that more than one-third of URI patients in our practice received antibiotics.

We had expected, but did not see, differences in prescribing rates between older and younger patients, as well as those with and without risk factors for complications. Our expectations were based on NAMCS data, which have demonstrated increasing use of antibiotics in older patients.²

Treatment for those with bronchitis was surprisingly frequent; 91% received antibiotics. A Cochrane systematic review attributes slight symptom benefit to antibiotic use (improvement in cough by about one day).²² This benefit, however, is rarely seen in patients who have been ill for <1 week. The magnitude of this benefit must be weighed against the cost and adverse effects of antibiotics and the potential for promoting antimicrobial resistance. Most patients’ symptoms are mild and self-limited, and risks may exceed benefits.

Guidelines state, “The widespread use of antibiotics for the treatment of acute bronchitis is not justified and vigorous efforts to curtail their use should be encouraged.”²³ The CDC agrees, noting that “routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough.”¹⁰

As observed in another study,¹⁴ a clinical factor associated with prescribing decisions at our practice was the duration of illness. Patients in our practice had been ill, on average, 8 days before presenting to the office. Over time, our encounters with regular patients may have taught them to wait until their symptoms are prolonged or progressive before seeking evaluation.

We saw large differences in prescribing rates between providers, and hope this means there is room for improvement by addressing reasons for variability. Education about individual prescribing behaviors may motivate those with the highest rates of use to improve.

We noted high rates of broad-spectrum antibiotic use. This is consistent with other research findings of a shift away from narrow-spectrum agents.¹² We did not determine the frequency of allergies to narrow-spectrum agents. Anecdotally, the opinion of some patients was that narrow-spectrum medicines “just don’t work,” given their experience of persistent cold symptoms when using such agents.

Quality-improvement processes such as DMAIC (Define, Measure, Analyze, Improve, Control) or PDSA (Plan, Do, Study, Act) require collection of baseline data so that interventions can be tailored to meet the root causes identified.²⁴ This project determined preintervention practice behaviors and allowed us to create quality metrics that could define our future success.

Study limitations. One obvious reason for the prescribing variability noted above is that those who helped plan and implement the project knew their practice behaviors were being reviewed and had studied the relevant practice guidelines. Whether non-investigator providers were up to date with recommendations and could carefully select appropriate treatment candidates is unclear.

This study was of our practice alone, and findings may not be generalizable to other practices. We encourage physicians to similarly examine their own prescribing habits in order to set practice-improvement goals.

CORRESPONDENCE Michael L. Grover, DO, Department of Family Medicine, Mayo Clinic, 13737 N 92nd Street, Scottsdale, AZ 85260; [email protected]

Undiluted acid used for vulvar surgery

WIDE LOCAL EXCISION was performed on a 42-year-old woman with vulvar intraepithelial neoplasm, VIN II, with moderate dysplasia. Her ObGyn performed the surgery.

Instead of applying a diluted solution of acetic acid wash to delineate the borders of the dysplastic area, a highly concentrated acetic acid or trichloroacetic acid was used. The patient suffered severe chemical burns of the vulva that took several months to heal. She has permanent scarring of the vulvar area, severe tenderness, discoloration, and atrophy of the vaginal opening, with a band of thick scar tissue at the posterior fourchette. The perineum, extending to the anal area, is scarred, including a 2-mm plaque layer.

PATIENT’S CLAIM Sexual intercourse is extremely painful, and therefore impossible. She suffers discomfort at all times. Additional surgery has been recommended to alleviate her condition.

DEFENDANTS’ DEFENSE The case was settled before trial.

VERDICT A $600,000 Ohio settlement was reached.

Large baby with cervical spine injury

A WOMAN WAS IN LABOR with her third child. Her first baby was born by cesarean delivery. During the vaginal birth of her second child, shoulder dystocia was encountered; this child weighed 8 lb 4 oz at birth.

Using ultrasonography, the ObGyn determined vaginal birth was appropriate. Shoulder dystocia was encountered and the infant suffered injuries to the cervical spine and right arm. The newborn weighed 9 lb 13 oz.

PATIENT’S CLAIM The baby’s weight was grossly underestimated prior to delivery; ultrasonography was not properly performed or evaluated. The mother’s history, large fundal height, estimated fetal weight, and the mother’s request for a cesarean delivery should have resulted in the performance of a cesarean delivery.

PHYSICIAN’S DEFENSE Shoulder dystocia was not reasonably foreseeable. Injuries to the baby were due to the forces of labor.

VERDICT A confidential Texas settlement was reached.

Suture causes nerve damage

PELVIC PROLAPSE RECONSTRUCTION was performed; surgery included a pubovaginal sling procedure with graft, and repairs of Grade 2 cystocele and Grade 3 rectocele. The gynecologist used transvaginal sutures to attach the mesh to the sacrospinous ligament.

The patient immediately reported pain, tingling, and weakness in her buttocks and legs. The gynecologist diagnosed a hematoma and continued conservative treatment while waiting for the hematoma to resorb.

After 10 days, the patient terminated the gynecologist’s services and left the hospital. She saw a neurologist, who diagnosed proximal sciatic nerve irritation secondary to suturing. When a suture was removed from the sacral spinous ligament plexus, many of the patient’s neurologic symptoms immediately resolved. She still has pain and walks with a noticeable limp using a cane.

PATIENT’S CLAIM The gynecologist failed to determine that a suture was causing nerve damage. Removal of the suture within the first 3 days would have avoided neurologic injury.

PHYSICIAN’S DEFENSE Postsurgical care was proper. A neurologist was consulted, and a sonogram had ruled out deep vein thrombosis.

VERDICT A $1.58 million Illinois verdict was returned.

Colon damage after embolization

UTERINE FIBROID EMBOLIZATION was performed on a 51-year-old woman. The next day, she reported severe abdominal pain and was readmitted. A uterine infection was suspected, and she underwent a hysterectomy. Necrosis of the colon was found; a surgeon removed one-third of the colon and performed a colostomy. She underwent several operations, including rectal-vaginal fistula repair, before the colostomy was corrected.

PATIENT’S CLAIM Misdirected embolization injured an artery supplying the colon. She continues to suffer ongoing fecal urgency and frequency.

PHYSICIAN’S DEFENSE An anomalous connection between the patient’s uterine artery and mesenteric artery was impossible for the physician to have known prior to the embolization procedure.

VERDICT A California defense verdict was returned.

$1.18 M verdict set aside because of Facebook   postings

SEVERAL HOURS AFTER A WOMAN’S LABOR BEGAN, fetal bradycardia developed precipitously. The on-call ObGyn arrived after 10 minutes and ordered an immediate cesarean delivery, which occurred 22 minutes later. The child suffered a catastrophic, irreversible brain injury. He lived for 39 days before life support was removed and he died.

ESTATE’S CLAIM The nurses did not report decelerations to the ObGyn, and they were slow to notify him of the fetal bradycardia. The child would not have been injured if the nursing staff had reacted appropriately.

DEFENDANTS’ DEFENSE Isolated heart-rate decelerations during labor are not troubling. A cord accident occurred, which could not be predicted nor avoided. The ObGyn was called promptly; the emergency cesarean delivery was performed quickly. However, the injury already had occurred and was irreparable.

VERDICT A $1.18 million Kentucky verdict was returned. The hospital sought a mistrial because Facebook postings by a juror proved the case had been discussed and prejudged. The court found in favor of the hospital on its post-trial motion.

Bilateral mastectomy: nipples not spared

A 46-YEAR-OLD WOMAN UNDERWENT prophylactic bilateral mastectomy. A plastic surgeon drew presurgical markings on the day of surgery; the breast surgeon removed the nipples.

PATIENT’S CLAIM All parties had agreed the nipples would be spared. The plastic surgeon drew improper markings and failed to remind the breast surgeon prior to surgery that the nipples would be preserved.

PHYSICIAN’S DEFENSE The breast surgeon was at fault for misinterpreting the markings.

VERDICT The patient reached a pretrial settlement with the breast surgeon. The case proceeded against the plastic surgeon. A Maryland defense verdict was returned for the plastic surgeon.

Signs of intrauterine growth restriction; stillborn child

AT 24 WEEKS’ GESTATION, a 17-year-old woman who smoked reported spotting. An ultrasound demonstrated significant fetal growth restriction. The mother was hospitalized to assess the spotting; no testing was ordered to assess fetal growth. When blood was not found in the birth canal, she was discharged. During the next month, she saw the ObGyn three times; testing indicated that the fetus was at least 3 weeks behind the stage of pregnancy. The ObGyn did not order additional testing nor consult a specialist. At 31 weeks’ gestation, ultrasonography found no fetal heart tones. The stillborn was delivered by cesarean section.

ESTATE’S CLAIM A wrongful death suit was filed by the parents, who also claimed lack of informed consent concerning the risk of stillbirth in the presence of intrauterine growth restriction.

PHYSICIANS’ DEFENSE The mother’s smoking was mentioned at trial as a possible explanation of why fetal development was delayed. The ObGyn denied negligence.

VERDICT A $800,000 Maryland verdict was awarded to the parents.

Three BrCa patients share $72.6 M

THREE MENOPAUSAL WOMEN took Premarin (conjugated estrogens) plus Provera (medroxyprogesterone), and/or Prempro (conjugated estrogens/medroxyprogesterone acetate). Each discontinued hormone therapy after being diagnosed with hormone-positive breast cancer.

PATIENTS’ CLAIM The only source of hormonal stimulation for their cancer was the use of estrogen plus progestin.

DEFENDANTS’ DEFENSE Science is currently unable to determine precisely what causes breast cancer. Each plaintiff had risk factors.

VERDICT The three cases were consolidated to a reverse-bifurcated trial, with causation and damages assessed first. The Pennsylvania jury found the Wyeth Pharmaceutical products to be factual causes of the patients’ cancer, and awarded a total of $72.6 million in compensatory damages. The parties settled for confidential amounts before the liability phase began.

Undiluted acid used for vulvar surgery

WIDE LOCAL EXCISION was performed on a 42-year-old woman with vulvar intraepithelial neoplasm, VIN II, with moderate dysplasia. Her ObGyn performed the surgery.

Instead of applying a diluted solution of acetic acid wash to delineate the borders of the dysplastic area, a highly concentrated acetic acid or trichloroacetic acid was used. The patient suffered severe chemical burns of the vulva that took several months to heal. She has permanent scarring of the vulvar area, severe tenderness, discoloration, and atrophy of the vaginal opening, with a band of thick scar tissue at the posterior fourchette. The perineum, extending to the anal area, is scarred, including a 2-mm plaque layer.

PATIENT’S CLAIM Sexual intercourse is extremely painful, and therefore impossible. She suffers discomfort at all times. Additional surgery has been recommended to alleviate her condition.

DEFENDANTS’ DEFENSE The case was settled before trial.

VERDICT A $600,000 Ohio settlement was reached.

Large baby with cervical spine injury

A WOMAN WAS IN LABOR with her third child. Her first baby was born by cesarean delivery. During the vaginal birth of her second child, shoulder dystocia was encountered; this child weighed 8 lb 4 oz at birth.

Using ultrasonography, the ObGyn determined vaginal birth was appropriate. Shoulder dystocia was encountered and the infant suffered injuries to the cervical spine and right arm. The newborn weighed 9 lb 13 oz.

PATIENT’S CLAIM The baby’s weight was grossly underestimated prior to delivery; ultrasonography was not properly performed or evaluated. The mother’s history, large fundal height, estimated fetal weight, and the mother’s request for a cesarean delivery should have resulted in the performance of a cesarean delivery.

PHYSICIAN’S DEFENSE Shoulder dystocia was not reasonably foreseeable. Injuries to the baby were due to the forces of labor.

VERDICT A confidential Texas settlement was reached.

Suture causes nerve damage

PELVIC PROLAPSE RECONSTRUCTION was performed; surgery included a pubovaginal sling procedure with graft, and repairs of Grade 2 cystocele and Grade 3 rectocele. The gynecologist used transvaginal sutures to attach the mesh to the sacrospinous ligament.

The patient immediately reported pain, tingling, and weakness in her buttocks and legs. The gynecologist diagnosed a hematoma and continued conservative treatment while waiting for the hematoma to resorb.

After 10 days, the patient terminated the gynecologist’s services and left the hospital. She saw a neurologist, who diagnosed proximal sciatic nerve irritation secondary to suturing. When a suture was removed from the sacral spinous ligament plexus, many of the patient’s neurologic symptoms immediately resolved. She still has pain and walks with a noticeable limp using a cane.

PATIENT’S CLAIM The gynecologist failed to determine that a suture was causing nerve damage. Removal of the suture within the first 3 days would have avoided neurologic injury.

PHYSICIAN’S DEFENSE Postsurgical care was proper. A neurologist was consulted, and a sonogram had ruled out deep vein thrombosis.

VERDICT A $1.58 million Illinois verdict was returned.

Colon damage after embolization

UTERINE FIBROID EMBOLIZATION was performed on a 51-year-old woman. The next day, she reported severe abdominal pain and was readmitted. A uterine infection was suspected, and she underwent a hysterectomy. Necrosis of the colon was found; a surgeon removed one-third of the colon and performed a colostomy. She underwent several operations, including rectal-vaginal fistula repair, before the colostomy was corrected.

PATIENT’S CLAIM Misdirected embolization injured an artery supplying the colon. She continues to suffer ongoing fecal urgency and frequency.

PHYSICIAN’S DEFENSE An anomalous connection between the patient’s uterine artery and mesenteric artery was impossible for the physician to have known prior to the embolization procedure.

VERDICT A California defense verdict was returned.

$1.18 M verdict set aside because of Facebook   postings

SEVERAL HOURS AFTER A WOMAN’S LABOR BEGAN, fetal bradycardia developed precipitously. The on-call ObGyn arrived after 10 minutes and ordered an immediate cesarean delivery, which occurred 22 minutes later. The child suffered a catastrophic, irreversible brain injury. He lived for 39 days before life support was removed and he died.

ESTATE’S CLAIM The nurses did not report decelerations to the ObGyn, and they were slow to notify him of the fetal bradycardia. The child would not have been injured if the nursing staff had reacted appropriately.

DEFENDANTS’ DEFENSE Isolated heart-rate decelerations during labor are not troubling. A cord accident occurred, which could not be predicted nor avoided. The ObGyn was called promptly; the emergency cesarean delivery was performed quickly. However, the injury already had occurred and was irreparable.

VERDICT A $1.18 million Kentucky verdict was returned. The hospital sought a mistrial because Facebook postings by a juror proved the case had been discussed and prejudged. The court found in favor of the hospital on its post-trial motion.

Bilateral mastectomy: nipples not spared

A 46-YEAR-OLD WOMAN UNDERWENT prophylactic bilateral mastectomy. A plastic surgeon drew presurgical markings on the day of surgery; the breast surgeon removed the nipples.

PATIENT’S CLAIM All parties had agreed the nipples would be spared. The plastic surgeon drew improper markings and failed to remind the breast surgeon prior to surgery that the nipples would be preserved.

PHYSICIAN’S DEFENSE The breast surgeon was at fault for misinterpreting the markings.

VERDICT The patient reached a pretrial settlement with the breast surgeon. The case proceeded against the plastic surgeon. A Maryland defense verdict was returned for the plastic surgeon.

Signs of intrauterine growth restriction; stillborn child

AT 24 WEEKS’ GESTATION, a 17-year-old woman who smoked reported spotting. An ultrasound demonstrated significant fetal growth restriction. The mother was hospitalized to assess the spotting; no testing was ordered to assess fetal growth. When blood was not found in the birth canal, she was discharged. During the next month, she saw the ObGyn three times; testing indicated that the fetus was at least 3 weeks behind the stage of pregnancy. The ObGyn did not order additional testing nor consult a specialist. At 31 weeks’ gestation, ultrasonography found no fetal heart tones. The stillborn was delivered by cesarean section.

ESTATE’S CLAIM A wrongful death suit was filed by the parents, who also claimed lack of informed consent concerning the risk of stillbirth in the presence of intrauterine growth restriction.

PHYSICIANS’ DEFENSE The mother’s smoking was mentioned at trial as a possible explanation of why fetal development was delayed. The ObGyn denied negligence.

VERDICT A $800,000 Maryland verdict was awarded to the parents.

Three BrCa patients share $72.6 M

THREE MENOPAUSAL WOMEN took Premarin (conjugated estrogens) plus Provera (medroxyprogesterone), and/or Prempro (conjugated estrogens/medroxyprogesterone acetate). Each discontinued hormone therapy after being diagnosed with hormone-positive breast cancer.

PATIENTS’ CLAIM The only source of hormonal stimulation for their cancer was the use of estrogen plus progestin.

DEFENDANTS’ DEFENSE Science is currently unable to determine precisely what causes breast cancer. Each plaintiff had risk factors.

VERDICT The three cases were consolidated to a reverse-bifurcated trial, with causation and damages assessed first. The Pennsylvania jury found the Wyeth Pharmaceutical products to be factual causes of the patients’ cancer, and awarded a total of $72.6 million in compensatory damages. The parties settled for confidential amounts before the liability phase began.

Undiluted acid used for vulvar surgery

WIDE LOCAL EXCISION was performed on a 42-year-old woman with vulvar intraepithelial neoplasm, VIN II, with moderate dysplasia. Her ObGyn performed the surgery.

Instead of applying a diluted solution of acetic acid wash to delineate the borders of the dysplastic area, a highly concentrated acetic acid or trichloroacetic acid was used. The patient suffered severe chemical burns of the vulva that took several months to heal. She has permanent scarring of the vulvar area, severe tenderness, discoloration, and atrophy of the vaginal opening, with a band of thick scar tissue at the posterior fourchette. The perineum, extending to the anal area, is scarred, including a 2-mm plaque layer.

PATIENT’S CLAIM Sexual intercourse is extremely painful, and therefore impossible. She suffers discomfort at all times. Additional surgery has been recommended to alleviate her condition.

DEFENDANTS’ DEFENSE The case was settled before trial.

VERDICT A $600,000 Ohio settlement was reached.

Large baby with cervical spine injury

A WOMAN WAS IN LABOR with her third child. Her first baby was born by cesarean delivery. During the vaginal birth of her second child, shoulder dystocia was encountered; this child weighed 8 lb 4 oz at birth.

Using ultrasonography, the ObGyn determined vaginal birth was appropriate. Shoulder dystocia was encountered and the infant suffered injuries to the cervical spine and right arm. The newborn weighed 9 lb 13 oz.

PATIENT’S CLAIM The baby’s weight was grossly underestimated prior to delivery; ultrasonography was not properly performed or evaluated. The mother’s history, large fundal height, estimated fetal weight, and the mother’s request for a cesarean delivery should have resulted in the performance of a cesarean delivery.

PHYSICIAN’S DEFENSE Shoulder dystocia was not reasonably foreseeable. Injuries to the baby were due to the forces of labor.

VERDICT A confidential Texas settlement was reached.

Suture causes nerve damage

PELVIC PROLAPSE RECONSTRUCTION was performed; surgery included a pubovaginal sling procedure with graft, and repairs of Grade 2 cystocele and Grade 3 rectocele. The gynecologist used transvaginal sutures to attach the mesh to the sacrospinous ligament.

The patient immediately reported pain, tingling, and weakness in her buttocks and legs. The gynecologist diagnosed a hematoma and continued conservative treatment while waiting for the hematoma to resorb.

After 10 days, the patient terminated the gynecologist’s services and left the hospital. She saw a neurologist, who diagnosed proximal sciatic nerve irritation secondary to suturing. When a suture was removed from the sacral spinous ligament plexus, many of the patient’s neurologic symptoms immediately resolved. She still has pain and walks with a noticeable limp using a cane.

PATIENT’S CLAIM The gynecologist failed to determine that a suture was causing nerve damage. Removal of the suture within the first 3 days would have avoided neurologic injury.

PHYSICIAN’S DEFENSE Postsurgical care was proper. A neurologist was consulted, and a sonogram had ruled out deep vein thrombosis.

VERDICT A $1.58 million Illinois verdict was returned.

Colon damage after embolization

UTERINE FIBROID EMBOLIZATION was performed on a 51-year-old woman. The next day, she reported severe abdominal pain and was readmitted. A uterine infection was suspected, and she underwent a hysterectomy. Necrosis of the colon was found; a surgeon removed one-third of the colon and performed a colostomy. She underwent several operations, including rectal-vaginal fistula repair, before the colostomy was corrected.

PATIENT’S CLAIM Misdirected embolization injured an artery supplying the colon. She continues to suffer ongoing fecal urgency and frequency.

PHYSICIAN’S DEFENSE An anomalous connection between the patient’s uterine artery and mesenteric artery was impossible for the physician to have known prior to the embolization procedure.

VERDICT A California defense verdict was returned.

$1.18 M verdict set aside because of Facebook   postings

SEVERAL HOURS AFTER A WOMAN’S LABOR BEGAN, fetal bradycardia developed precipitously. The on-call ObGyn arrived after 10 minutes and ordered an immediate cesarean delivery, which occurred 22 minutes later. The child suffered a catastrophic, irreversible brain injury. He lived for 39 days before life support was removed and he died.

ESTATE’S CLAIM The nurses did not report decelerations to the ObGyn, and they were slow to notify him of the fetal bradycardia. The child would not have been injured if the nursing staff had reacted appropriately.

DEFENDANTS’ DEFENSE Isolated heart-rate decelerations during labor are not troubling. A cord accident occurred, which could not be predicted nor avoided. The ObGyn was called promptly; the emergency cesarean delivery was performed quickly. However, the injury already had occurred and was irreparable.

VERDICT A $1.18 million Kentucky verdict was returned. The hospital sought a mistrial because Facebook postings by a juror proved the case had been discussed and prejudged. The court found in favor of the hospital on its post-trial motion.

Bilateral mastectomy: nipples not spared

A 46-YEAR-OLD WOMAN UNDERWENT prophylactic bilateral mastectomy. A plastic surgeon drew presurgical markings on the day of surgery; the breast surgeon removed the nipples.

PATIENT’S CLAIM All parties had agreed the nipples would be spared. The plastic surgeon drew improper markings and failed to remind the breast surgeon prior to surgery that the nipples would be preserved.

PHYSICIAN’S DEFENSE The breast surgeon was at fault for misinterpreting the markings.

VERDICT The patient reached a pretrial settlement with the breast surgeon. The case proceeded against the plastic surgeon. A Maryland defense verdict was returned for the plastic surgeon.

Signs of intrauterine growth restriction; stillborn child

AT 24 WEEKS’ GESTATION, a 17-year-old woman who smoked reported spotting. An ultrasound demonstrated significant fetal growth restriction. The mother was hospitalized to assess the spotting; no testing was ordered to assess fetal growth. When blood was not found in the birth canal, she was discharged. During the next month, she saw the ObGyn three times; testing indicated that the fetus was at least 3 weeks behind the stage of pregnancy. The ObGyn did not order additional testing nor consult a specialist. At 31 weeks’ gestation, ultrasonography found no fetal heart tones. The stillborn was delivered by cesarean section.

ESTATE’S CLAIM A wrongful death suit was filed by the parents, who also claimed lack of informed consent concerning the risk of stillbirth in the presence of intrauterine growth restriction.

PHYSICIANS’ DEFENSE The mother’s smoking was mentioned at trial as a possible explanation of why fetal development was delayed. The ObGyn denied negligence.

VERDICT A $800,000 Maryland verdict was awarded to the parents.

Three BrCa patients share $72.6 M

THREE MENOPAUSAL WOMEN took Premarin (conjugated estrogens) plus Provera (medroxyprogesterone), and/or Prempro (conjugated estrogens/medroxyprogesterone acetate). Each discontinued hormone therapy after being diagnosed with hormone-positive breast cancer.

PATIENTS’ CLAIM The only source of hormonal stimulation for their cancer was the use of estrogen plus progestin.

DEFENDANTS’ DEFENSE Science is currently unable to determine precisely what causes breast cancer. Each plaintiff had risk factors.

VERDICT The three cases were consolidated to a reverse-bifurcated trial, with causation and damages assessed first. The Pennsylvania jury found the Wyeth Pharmaceutical products to be factual causes of the patients’ cancer, and awarded a total of $72.6 million in compensatory damages. The parties settled for confidential amounts before the liability phase began.

Placement of a suture around an incompetent cervix to prevent premature pregnancy loss was first described more than 50 years ago^1,2—but the few randomized studies that have been published (all of them in the past decade) devote very little attention to technique.^3-7

Are we to assume, then, that over more than 50 years, no modifications to technique have been devised?

Are we to assume as well that in the two largest randomized studies to date, which involved 266 cerclages inserted in 27 different medical centers over more than 4 years,^5,7 all cerclages were inserted in an identical manner using the same technique originated more than half a century ago?

In this article, we lay out five principles to achieve effective cerclage and describe a stepwise approach to technique. This technique is based on our experience with approximately 2,000 cerclages performed in a single medical center. We emphasize anatomic landmarks and surgical principles that are based on the published literature as well as our personal experience.

Five principles of effective cerclage

Place the cerclage as high as possible

In the original paper on cerclage, McDonald emphasized the need to place the suture as high as possible to be as close as possible to the level of the internal cervical os.²

Zilianti and colleagues elegantly described how—in the absence of cerclage—cervical tissue begins to change at the level of the internal os, forming a funnel that advances downward in the shape of the letters “Y,” “V,” and “U.”⁸ If we accept this notion, then the only way to prevent further shortening from the top down is by placing a high cerclage.

Studies have demonstrated improved pregnancy outcomes after placement of a high cervico-isthmic cerclage following failure of a “conventional” low cerclage.^9,10

Place the cerclage adjacent to the cervical stroma

Macroscopic and microscopic visualization of the cervix reveals the following main layers:

• epithelium/mucosa, which covers the deeper connective tissue known as cervical stroma
• cervical stroma, which may be divided into two zones: 1) a superficial, subepithelial zone that appears histologically as loose stromal bands and 2) a deeper, dense collagen layer.

It is the dense collagen layer of the cervical stroma that affords most of the resistance to forces of deformation, whereas the loose stromal layer and the epithelium above it slide easily over the deeper stroma. Including too great a proportion of these “slippery” components within the cerclage could increase the risk of displacement and failure.^11,12

Shirodkar was the first to suggest that the mucosa and submucosa be excluded from cerclage,¹ and a detailed submucosal cerclage insertion was described by Fahmy more than 30 years ago.¹³ We support his recommendation that cerclage placement be as close to the inner cervical stroma as possible and that it include as little as possible of the surrounding tissue.

Take three encircling cervical “bites”

In his original publication, McDonald described “five or six bites with the needle” to encircle the cervix.² Later authors usually described four encircling steps, but no reliable study has challenged the original dogma.

Although we lack science to favor one approach over another, common sense suggests that three bites (versus four or five) offer the following advantages. They:

• produce less penetrating injury
• require less manipulation of the cervix
• are simpler and quicker to perform
• offer less opportunity for the cerclage tape to get twisted (a flat tape provides for better distribution of the load)
• permit a small gap between the two final exit points of the tape (at 5 o’clock and 7 o’clock), which allows for easier cinching and tightening of the cerclage (FIGURE 1).

FIGURE 1 A small gap between the ends of the cerclage tape, which exit at 5 o’clock and 7 o’clock, allows for easier cinching and tightening.

Place the knot at 6 o’clock

Both Shirodkar¹ and McDonald² described placement of the knot (or approximation of the “ends”) at 12 o’clock, anteriorly. However, this approach can complicate removal if strong pressure is applied to the cerclage or if it is covered by tissue. Attempts to remove the cerclage can result in bladder injury.

For these reasons, we prefer the approach described by Caspi and colleagues, who placed the knot in the back of the cervix at 6 o’clock.¹⁴ In that location, the surgeon can reach as high as desired, and there is no risk of organ injury during removal.

That said, it should be noted that removal of a cerclage with a knot at 6 o’clock is more difficult than removal of one with a knot at 12 o’clock—but the convenience of the operator should be secondary to safety and efficacy of the cerclage.

Place a figure of 8 around the cerclage knot

Because of the proximity of the bladder anteriorly, there is a limit to how high one can place the cerclage anteriorly. However, in the back of the cervix, one can place the cerclage much higher without risk of injury. This approach sometimes will result in downward forces on the posterior part (where the knot is) and occasionally may cover the knot with tissue from the posterior vaginal fornix.

For these reasons, we propose securing the knot of the cerclage tape to the posterior surface of the cervical “core” by placing a figure of 8 using bright blue Prolene #1 (Ethicon) to prevent slippage and help call attention to the knot when the time for removal comes.

Stepwise surgical technique

1. Use a weighted speculum to retract the posterior-inferior vaginal wall. Have an assistant hold one or two right-angle retractors to retract the other aspects of the vaginal wall, including the bladder anteriorly, as needed.

2. Clamp the anterior and posterior lips of the cervix and tug them lightly—at all times—in an outward direction (FIGURE 2).

FIGURE 2 Clamping of the cervix
Clamp the anterior and posterior lips of the cervix and tug them lightly and steadily in an outward direction.

3. Retract and release the bladder several times using a right-angle retractor for more accurate identification of the cervico-vesical fold (FIGURE 3 and FIGURE 4). Note the distance from the external os to the cervico-vesical fold; it should be 2 cm or farther. (If it is less than 2 cm, another type of cerclage may be preferable.)

FIGURE 3 Anatomic landmarks
Cerclage is facilitated by orientation to the following landmarks; A. cervico-vesical fold; B. posterior fornix; C. cervical stroma; D. cervical mucosa.

FIGURE 4 Cervico-vesical fold
The black line indicates the location of the fold.

4. Identify the roof of the posterior fornix (FIGURE 3 and FIGURE 5).

FIGURE 5 Roof of the posterior fornix
This landmark is delineated in black.

5. Using Allis clamps bilaterally, clamp the soft tissue covering the cervical core (stroma), between the cervico-vesical junction anteriorly and the superior point of the posterior fornix posteriorly. This is a cardinal step because it separates the core from the mucosal/ submucosal elements (FIGURE 6). (Helpful hint: To achieve optimal placement of the lateral Allis clamps, place the open clamp ever so slightly to one side of the middle of the cervix. As you close the instrument, let the clamp slide off the cervical core until it is locked adjacent to it. This takes the soft tissue and supporting blood vessels out of the operative field.)

FIGURE 6 Anterolateral view
The pericervical mucosa (black arrow) after application of an Allis clamp.

6. Take three bites, 1 mm in depth, through the cervical core using a 5-mm Mersilene tape and a blunt-tipped needle (RS21; Ethicon). One bite should encompass 12:30 to 11:30 anteriorly. Another bite should go in at 3 o’clock and out at 5 o’clock, and another bite should go in at 9 o’clock and out at 7 o’clock (FIGURE 1). (Helpful hint: Ensure that the direction of the pull always is a direct extension of the passage through tissue in small steps and not an outward direction toward the operator. An instrument such as a curved Mayo clamp should be placed at the point of the needle’s exit to reduce the risk of injury. At the conclusion of the three bites, the Mersilene tape should be the same length on each side, exiting at 5 o’clock and 7 o’clock, as stated earlier [FIGURE 7].)

FIGURE 7 Ensure equal distribution of the tape
After taking three bites of tissue, ensure that the ends of the Mersilene tape are of equal length on each side.

7. Once the tape is of equal length on both sides, closely encircling three sides of the cervical core, empty the bladder with a catheter to ensure the presence of clear urine. Bloody urine could be an indication for cystoscopy to rule out bladder injury.

8. Cut the needles off of the tape and tie the cerclage in three ties, the first one being a surgical tie. After tying the first tie, ensure proper tension by pressing gently with the index finger up and down on the knot; if it is properly tensioned, it will not be displaced by this movement. (Helpful hint: There is no clear indication of how tight a cerclage should be tied. We suggest making the first tie as close as possible to the cervical core to create a visible, and palpable, depression in the soft tissue at the area of the knot [FIGURE 8]).

FIGURE 8 Tying the cerclage
Make the first tie as close as possible to the cervical core so that it creates a visible, and palpable, depression in the soft tissue at the area of the knot. Inset: Cerclage tie secured by a figure of 8.

9. Trim the ends of the tape to 3 cm to facilitate easy identification and manipulation at the time of removal. Place a figure of 8, using bright blue Prolene #1 (Ethicon), around the knot, securing it to the posterior surface of the cervical core (FIGURE 9). The tape should encircle the firm part of the cervix near the internal os, as shown by transvaginal ultrasonography in FIGURE 10. (Helpful hint: Place surgical gauze under pressure around the cervix to support hemostasis after removal of the clamps. Remove the gauze approximately 30 minutes after the procedure.)

FIGURE 9 Mark the cerclage
Place a figure of 8, using bright blue Prolene #1, around the knot of the cerclage, securing it to the posterior surface of the cervical core.

FIGURE 10 Final placement
The cerclage tape should encircle the firm part of the cervix near the internal os, as shown by transvaginal ultrasonography.

Technique is applicable to most cerclage procedures

One potential limitation of this technique is the fact that it is based on surgical experience in a single center, although it includes more than 2,000 operations performed at that center. Therefore, we lack data on the ease of teaching and reproducing this technique. Nevertheless, our approach incorporates various elements that previously were proposed to enhance the effectiveness of cerclage. It likely will be applicable to most cerclage procedures, with the exception of a few unique cases. These unique cases—most of them involving the failure of conventional cerclage—may require more elaborate technique.

As for data on the location of biomechanical stresses on cervical tissue during pregnancy, the literature indicates that the forces of maximum deformation begin internally at the level of the cervico-uterine junction.¹² If not successfully resisted, these forces will proceed down along the cervical canal and could lead to premature pregnancy loss.

Although the superiority of a high cerclage has not yet been proven clinically, it appears to be more effective than low placement because it is more likely to provide support at the right location.

As pregnancy progresses, the challenge to the cervix increases—not only because of increasing uterine volume but also because of greater uterine activity. Both raise the risk of cerclage slippage and displacement.¹⁵ To address these issues, several investigators proposed an approach that excludes the slippery mucosal layer.^1,13,14

The original Shirodkar cerclage and its modifications—but not the McDonald cerclage and its subsequent modifications—included an “anchor” suture attaching the cerclage band to the firm cervical stromal layer as a means to prevent downward slippage and displacement.¹ It remains to be seen whether this addition of a figure of 8 using nonabsorbable suture, as proposed here, is indeed effective.

We believe that, if a standardized way to perform effective cerclage can be agreed upon, we also might devise a better way to compare results based on proper patient selection.

We want to hear from you! Tell us what you think.

Placement of a suture around an incompetent cervix to prevent premature pregnancy loss was first described more than 50 years ago^1,2—but the few randomized studies that have been published (all of them in the past decade) devote very little attention to technique.^3-7

Are we to assume, then, that over more than 50 years, no modifications to technique have been devised?

Are we to assume as well that in the two largest randomized studies to date, which involved 266 cerclages inserted in 27 different medical centers over more than 4 years,^5,7 all cerclages were inserted in an identical manner using the same technique originated more than half a century ago?

In this article, we lay out five principles to achieve effective cerclage and describe a stepwise approach to technique. This technique is based on our experience with approximately 2,000 cerclages performed in a single medical center. We emphasize anatomic landmarks and surgical principles that are based on the published literature as well as our personal experience.

Five principles of effective cerclage

Place the cerclage as high as possible

In the original paper on cerclage, McDonald emphasized the need to place the suture as high as possible to be as close as possible to the level of the internal cervical os.²

Zilianti and colleagues elegantly described how—in the absence of cerclage—cervical tissue begins to change at the level of the internal os, forming a funnel that advances downward in the shape of the letters “Y,” “V,” and “U.”⁸ If we accept this notion, then the only way to prevent further shortening from the top down is by placing a high cerclage.

Studies have demonstrated improved pregnancy outcomes after placement of a high cervico-isthmic cerclage following failure of a “conventional” low cerclage.^9,10

Place the cerclage adjacent to the cervical stroma

Macroscopic and microscopic visualization of the cervix reveals the following main layers:

• epithelium/mucosa, which covers the deeper connective tissue known as cervical stroma
• cervical stroma, which may be divided into two zones: 1) a superficial, subepithelial zone that appears histologically as loose stromal bands and 2) a deeper, dense collagen layer.

It is the dense collagen layer of the cervical stroma that affords most of the resistance to forces of deformation, whereas the loose stromal layer and the epithelium above it slide easily over the deeper stroma. Including too great a proportion of these “slippery” components within the cerclage could increase the risk of displacement and failure.^11,12

Shirodkar was the first to suggest that the mucosa and submucosa be excluded from cerclage,¹ and a detailed submucosal cerclage insertion was described by Fahmy more than 30 years ago.¹³ We support his recommendation that cerclage placement be as close to the inner cervical stroma as possible and that it include as little as possible of the surrounding tissue.

Take three encircling cervical “bites”

In his original publication, McDonald described “five or six bites with the needle” to encircle the cervix.² Later authors usually described four encircling steps, but no reliable study has challenged the original dogma.

Although we lack science to favor one approach over another, common sense suggests that three bites (versus four or five) offer the following advantages. They:

• produce less penetrating injury
• require less manipulation of the cervix
• are simpler and quicker to perform
• offer less opportunity for the cerclage tape to get twisted (a flat tape provides for better distribution of the load)
• permit a small gap between the two final exit points of the tape (at 5 o’clock and 7 o’clock), which allows for easier cinching and tightening of the cerclage (FIGURE 1).

FIGURE 1 A small gap between the ends of the cerclage tape, which exit at 5 o’clock and 7 o’clock, allows for easier cinching and tightening.

Place the knot at 6 o’clock

Both Shirodkar¹ and McDonald² described placement of the knot (or approximation of the “ends”) at 12 o’clock, anteriorly. However, this approach can complicate removal if strong pressure is applied to the cerclage or if it is covered by tissue. Attempts to remove the cerclage can result in bladder injury.

For these reasons, we prefer the approach described by Caspi and colleagues, who placed the knot in the back of the cervix at 6 o’clock.¹⁴ In that location, the surgeon can reach as high as desired, and there is no risk of organ injury during removal.

That said, it should be noted that removal of a cerclage with a knot at 6 o’clock is more difficult than removal of one with a knot at 12 o’clock—but the convenience of the operator should be secondary to safety and efficacy of the cerclage.

Place a figure of 8 around the cerclage knot

Because of the proximity of the bladder anteriorly, there is a limit to how high one can place the cerclage anteriorly. However, in the back of the cervix, one can place the cerclage much higher without risk of injury. This approach sometimes will result in downward forces on the posterior part (where the knot is) and occasionally may cover the knot with tissue from the posterior vaginal fornix.

For these reasons, we propose securing the knot of the cerclage tape to the posterior surface of the cervical “core” by placing a figure of 8 using bright blue Prolene #1 (Ethicon) to prevent slippage and help call attention to the knot when the time for removal comes.

Stepwise surgical technique

1. Use a weighted speculum to retract the posterior-inferior vaginal wall. Have an assistant hold one or two right-angle retractors to retract the other aspects of the vaginal wall, including the bladder anteriorly, as needed.

2. Clamp the anterior and posterior lips of the cervix and tug them lightly—at all times—in an outward direction (FIGURE 2).

FIGURE 2 Clamping of the cervix
Clamp the anterior and posterior lips of the cervix and tug them lightly and steadily in an outward direction.

3. Retract and release the bladder several times using a right-angle retractor for more accurate identification of the cervico-vesical fold (FIGURE 3 and FIGURE 4). Note the distance from the external os to the cervico-vesical fold; it should be 2 cm or farther. (If it is less than 2 cm, another type of cerclage may be preferable.)

FIGURE 3 Anatomic landmarks
Cerclage is facilitated by orientation to the following landmarks; A. cervico-vesical fold; B. posterior fornix; C. cervical stroma; D. cervical mucosa.

FIGURE 4 Cervico-vesical fold
The black line indicates the location of the fold.

4. Identify the roof of the posterior fornix (FIGURE 3 and FIGURE 5).

FIGURE 5 Roof of the posterior fornix
This landmark is delineated in black.

5. Using Allis clamps bilaterally, clamp the soft tissue covering the cervical core (stroma), between the cervico-vesical junction anteriorly and the superior point of the posterior fornix posteriorly. This is a cardinal step because it separates the core from the mucosal/ submucosal elements (FIGURE 6). (Helpful hint: To achieve optimal placement of the lateral Allis clamps, place the open clamp ever so slightly to one side of the middle of the cervix. As you close the instrument, let the clamp slide off the cervical core until it is locked adjacent to it. This takes the soft tissue and supporting blood vessels out of the operative field.)

FIGURE 6 Anterolateral view
The pericervical mucosa (black arrow) after application of an Allis clamp.

6. Take three bites, 1 mm in depth, through the cervical core using a 5-mm Mersilene tape and a blunt-tipped needle (RS21; Ethicon). One bite should encompass 12:30 to 11:30 anteriorly. Another bite should go in at 3 o’clock and out at 5 o’clock, and another bite should go in at 9 o’clock and out at 7 o’clock (FIGURE 1). (Helpful hint: Ensure that the direction of the pull always is a direct extension of the passage through tissue in small steps and not an outward direction toward the operator. An instrument such as a curved Mayo clamp should be placed at the point of the needle’s exit to reduce the risk of injury. At the conclusion of the three bites, the Mersilene tape should be the same length on each side, exiting at 5 o’clock and 7 o’clock, as stated earlier [FIGURE 7].)

FIGURE 7 Ensure equal distribution of the tape
After taking three bites of tissue, ensure that the ends of the Mersilene tape are of equal length on each side.

7. Once the tape is of equal length on both sides, closely encircling three sides of the cervical core, empty the bladder with a catheter to ensure the presence of clear urine. Bloody urine could be an indication for cystoscopy to rule out bladder injury.

8. Cut the needles off of the tape and tie the cerclage in three ties, the first one being a surgical tie. After tying the first tie, ensure proper tension by pressing gently with the index finger up and down on the knot; if it is properly tensioned, it will not be displaced by this movement. (Helpful hint: There is no clear indication of how tight a cerclage should be tied. We suggest making the first tie as close as possible to the cervical core to create a visible, and palpable, depression in the soft tissue at the area of the knot [FIGURE 8]).

FIGURE 8 Tying the cerclage
Make the first tie as close as possible to the cervical core so that it creates a visible, and palpable, depression in the soft tissue at the area of the knot. Inset: Cerclage tie secured by a figure of 8.

9. Trim the ends of the tape to 3 cm to facilitate easy identification and manipulation at the time of removal. Place a figure of 8, using bright blue Prolene #1 (Ethicon), around the knot, securing it to the posterior surface of the cervical core (FIGURE 9). The tape should encircle the firm part of the cervix near the internal os, as shown by transvaginal ultrasonography in FIGURE 10. (Helpful hint: Place surgical gauze under pressure around the cervix to support hemostasis after removal of the clamps. Remove the gauze approximately 30 minutes after the procedure.)

FIGURE 9 Mark the cerclage
Place a figure of 8, using bright blue Prolene #1, around the knot of the cerclage, securing it to the posterior surface of the cervical core.

FIGURE 10 Final placement
The cerclage tape should encircle the firm part of the cervix near the internal os, as shown by transvaginal ultrasonography.

Technique is applicable to most cerclage procedures

One potential limitation of this technique is the fact that it is based on surgical experience in a single center, although it includes more than 2,000 operations performed at that center. Therefore, we lack data on the ease of teaching and reproducing this technique. Nevertheless, our approach incorporates various elements that previously were proposed to enhance the effectiveness of cerclage. It likely will be applicable to most cerclage procedures, with the exception of a few unique cases. These unique cases—most of them involving the failure of conventional cerclage—may require more elaborate technique.

As for data on the location of biomechanical stresses on cervical tissue during pregnancy, the literature indicates that the forces of maximum deformation begin internally at the level of the cervico-uterine junction.¹² If not successfully resisted, these forces will proceed down along the cervical canal and could lead to premature pregnancy loss.

Although the superiority of a high cerclage has not yet been proven clinically, it appears to be more effective than low placement because it is more likely to provide support at the right location.

As pregnancy progresses, the challenge to the cervix increases—not only because of increasing uterine volume but also because of greater uterine activity. Both raise the risk of cerclage slippage and displacement.¹⁵ To address these issues, several investigators proposed an approach that excludes the slippery mucosal layer.^1,13,14

The original Shirodkar cerclage and its modifications—but not the McDonald cerclage and its subsequent modifications—included an “anchor” suture attaching the cerclage band to the firm cervical stromal layer as a means to prevent downward slippage and displacement.¹ It remains to be seen whether this addition of a figure of 8 using nonabsorbable suture, as proposed here, is indeed effective.

We believe that, if a standardized way to perform effective cerclage can be agreed upon, we also might devise a better way to compare results based on proper patient selection.

We want to hear from you! Tell us what you think.

Placement of a suture around an incompetent cervix to prevent premature pregnancy loss was first described more than 50 years ago^1,2—but the few randomized studies that have been published (all of them in the past decade) devote very little attention to technique.^3-7

Are we to assume, then, that over more than 50 years, no modifications to technique have been devised?

Are we to assume as well that in the two largest randomized studies to date, which involved 266 cerclages inserted in 27 different medical centers over more than 4 years,^5,7 all cerclages were inserted in an identical manner using the same technique originated more than half a century ago?

In this article, we lay out five principles to achieve effective cerclage and describe a stepwise approach to technique. This technique is based on our experience with approximately 2,000 cerclages performed in a single medical center. We emphasize anatomic landmarks and surgical principles that are based on the published literature as well as our personal experience.

Five principles of effective cerclage

Place the cerclage as high as possible

In the original paper on cerclage, McDonald emphasized the need to place the suture as high as possible to be as close as possible to the level of the internal cervical os.²

Zilianti and colleagues elegantly described how—in the absence of cerclage—cervical tissue begins to change at the level of the internal os, forming a funnel that advances downward in the shape of the letters “Y,” “V,” and “U.”⁸ If we accept this notion, then the only way to prevent further shortening from the top down is by placing a high cerclage.

Studies have demonstrated improved pregnancy outcomes after placement of a high cervico-isthmic cerclage following failure of a “conventional” low cerclage.^9,10

Place the cerclage adjacent to the cervical stroma

Macroscopic and microscopic visualization of the cervix reveals the following main layers:

• epithelium/mucosa, which covers the deeper connective tissue known as cervical stroma
• cervical stroma, which may be divided into two zones: 1) a superficial, subepithelial zone that appears histologically as loose stromal bands and 2) a deeper, dense collagen layer.

It is the dense collagen layer of the cervical stroma that affords most of the resistance to forces of deformation, whereas the loose stromal layer and the epithelium above it slide easily over the deeper stroma. Including too great a proportion of these “slippery” components within the cerclage could increase the risk of displacement and failure.^11,12

Shirodkar was the first to suggest that the mucosa and submucosa be excluded from cerclage,¹ and a detailed submucosal cerclage insertion was described by Fahmy more than 30 years ago.¹³ We support his recommendation that cerclage placement be as close to the inner cervical stroma as possible and that it include as little as possible of the surrounding tissue.

Take three encircling cervical “bites”

In his original publication, McDonald described “five or six bites with the needle” to encircle the cervix.² Later authors usually described four encircling steps, but no reliable study has challenged the original dogma.

Although we lack science to favor one approach over another, common sense suggests that three bites (versus four or five) offer the following advantages. They:

• produce less penetrating injury
• require less manipulation of the cervix
• are simpler and quicker to perform
• offer less opportunity for the cerclage tape to get twisted (a flat tape provides for better distribution of the load)
• permit a small gap between the two final exit points of the tape (at 5 o’clock and 7 o’clock), which allows for easier cinching and tightening of the cerclage (FIGURE 1).

FIGURE 1 A small gap between the ends of the cerclage tape, which exit at 5 o’clock and 7 o’clock, allows for easier cinching and tightening.

Place the knot at 6 o’clock

Both Shirodkar¹ and McDonald² described placement of the knot (or approximation of the “ends”) at 12 o’clock, anteriorly. However, this approach can complicate removal if strong pressure is applied to the cerclage or if it is covered by tissue. Attempts to remove the cerclage can result in bladder injury.

For these reasons, we prefer the approach described by Caspi and colleagues, who placed the knot in the back of the cervix at 6 o’clock.¹⁴ In that location, the surgeon can reach as high as desired, and there is no risk of organ injury during removal.

That said, it should be noted that removal of a cerclage with a knot at 6 o’clock is more difficult than removal of one with a knot at 12 o’clock—but the convenience of the operator should be secondary to safety and efficacy of the cerclage.

Place a figure of 8 around the cerclage knot

Because of the proximity of the bladder anteriorly, there is a limit to how high one can place the cerclage anteriorly. However, in the back of the cervix, one can place the cerclage much higher without risk of injury. This approach sometimes will result in downward forces on the posterior part (where the knot is) and occasionally may cover the knot with tissue from the posterior vaginal fornix.

For these reasons, we propose securing the knot of the cerclage tape to the posterior surface of the cervical “core” by placing a figure of 8 using bright blue Prolene #1 (Ethicon) to prevent slippage and help call attention to the knot when the time for removal comes.

Stepwise surgical technique

1. Use a weighted speculum to retract the posterior-inferior vaginal wall. Have an assistant hold one or two right-angle retractors to retract the other aspects of the vaginal wall, including the bladder anteriorly, as needed.

2. Clamp the anterior and posterior lips of the cervix and tug them lightly—at all times—in an outward direction (FIGURE 2).

FIGURE 2 Clamping of the cervix
Clamp the anterior and posterior lips of the cervix and tug them lightly and steadily in an outward direction.

3. Retract and release the bladder several times using a right-angle retractor for more accurate identification of the cervico-vesical fold (FIGURE 3 and FIGURE 4). Note the distance from the external os to the cervico-vesical fold; it should be 2 cm or farther. (If it is less than 2 cm, another type of cerclage may be preferable.)

FIGURE 3 Anatomic landmarks
Cerclage is facilitated by orientation to the following landmarks; A. cervico-vesical fold; B. posterior fornix; C. cervical stroma; D. cervical mucosa.

FIGURE 4 Cervico-vesical fold
The black line indicates the location of the fold.

4. Identify the roof of the posterior fornix (FIGURE 3 and FIGURE 5).

FIGURE 5 Roof of the posterior fornix
This landmark is delineated in black.

5. Using Allis clamps bilaterally, clamp the soft tissue covering the cervical core (stroma), between the cervico-vesical junction anteriorly and the superior point of the posterior fornix posteriorly. This is a cardinal step because it separates the core from the mucosal/ submucosal elements (FIGURE 6). (Helpful hint: To achieve optimal placement of the lateral Allis clamps, place the open clamp ever so slightly to one side of the middle of the cervix. As you close the instrument, let the clamp slide off the cervical core until it is locked adjacent to it. This takes the soft tissue and supporting blood vessels out of the operative field.)

FIGURE 6 Anterolateral view
The pericervical mucosa (black arrow) after application of an Allis clamp.

6. Take three bites, 1 mm in depth, through the cervical core using a 5-mm Mersilene tape and a blunt-tipped needle (RS21; Ethicon). One bite should encompass 12:30 to 11:30 anteriorly. Another bite should go in at 3 o’clock and out at 5 o’clock, and another bite should go in at 9 o’clock and out at 7 o’clock (FIGURE 1). (Helpful hint: Ensure that the direction of the pull always is a direct extension of the passage through tissue in small steps and not an outward direction toward the operator. An instrument such as a curved Mayo clamp should be placed at the point of the needle’s exit to reduce the risk of injury. At the conclusion of the three bites, the Mersilene tape should be the same length on each side, exiting at 5 o’clock and 7 o’clock, as stated earlier [FIGURE 7].)

FIGURE 7 Ensure equal distribution of the tape
After taking three bites of tissue, ensure that the ends of the Mersilene tape are of equal length on each side.

7. Once the tape is of equal length on both sides, closely encircling three sides of the cervical core, empty the bladder with a catheter to ensure the presence of clear urine. Bloody urine could be an indication for cystoscopy to rule out bladder injury.

8. Cut the needles off of the tape and tie the cerclage in three ties, the first one being a surgical tie. After tying the first tie, ensure proper tension by pressing gently with the index finger up and down on the knot; if it is properly tensioned, it will not be displaced by this movement. (Helpful hint: There is no clear indication of how tight a cerclage should be tied. We suggest making the first tie as close as possible to the cervical core to create a visible, and palpable, depression in the soft tissue at the area of the knot [FIGURE 8]).

FIGURE 8 Tying the cerclage
Make the first tie as close as possible to the cervical core so that it creates a visible, and palpable, depression in the soft tissue at the area of the knot. Inset: Cerclage tie secured by a figure of 8.

9. Trim the ends of the tape to 3 cm to facilitate easy identification and manipulation at the time of removal. Place a figure of 8, using bright blue Prolene #1 (Ethicon), around the knot, securing it to the posterior surface of the cervical core (FIGURE 9). The tape should encircle the firm part of the cervix near the internal os, as shown by transvaginal ultrasonography in FIGURE 10. (Helpful hint: Place surgical gauze under pressure around the cervix to support hemostasis after removal of the clamps. Remove the gauze approximately 30 minutes after the procedure.)

FIGURE 9 Mark the cerclage
Place a figure of 8, using bright blue Prolene #1, around the knot of the cerclage, securing it to the posterior surface of the cervical core.

FIGURE 10 Final placement
The cerclage tape should encircle the firm part of the cervix near the internal os, as shown by transvaginal ultrasonography.

Technique is applicable to most cerclage procedures

One potential limitation of this technique is the fact that it is based on surgical experience in a single center, although it includes more than 2,000 operations performed at that center. Therefore, we lack data on the ease of teaching and reproducing this technique. Nevertheless, our approach incorporates various elements that previously were proposed to enhance the effectiveness of cerclage. It likely will be applicable to most cerclage procedures, with the exception of a few unique cases. These unique cases—most of them involving the failure of conventional cerclage—may require more elaborate technique.

As for data on the location of biomechanical stresses on cervical tissue during pregnancy, the literature indicates that the forces of maximum deformation begin internally at the level of the cervico-uterine junction.¹² If not successfully resisted, these forces will proceed down along the cervical canal and could lead to premature pregnancy loss.

Although the superiority of a high cerclage has not yet been proven clinically, it appears to be more effective than low placement because it is more likely to provide support at the right location.

As pregnancy progresses, the challenge to the cervix increases—not only because of increasing uterine volume but also because of greater uterine activity. Both raise the risk of cerclage slippage and displacement.¹⁵ To address these issues, several investigators proposed an approach that excludes the slippery mucosal layer.^1,13,14

The original Shirodkar cerclage and its modifications—but not the McDonald cerclage and its subsequent modifications—included an “anchor” suture attaching the cerclage band to the firm cervical stromal layer as a means to prevent downward slippage and displacement.¹ It remains to be seen whether this addition of a figure of 8 using nonabsorbable suture, as proposed here, is indeed effective.

We believe that, if a standardized way to perform effective cerclage can be agreed upon, we also might devise a better way to compare results based on proper patient selection.

We want to hear from you! Tell us what you think.

RELATED ARTICLE WITH VIDEOS

• Which sling for which SUI patient?
  Mark D. Walters, MD, and Anne M. Weber, MD (Surgical Techniques, May 2012)

3 video clips illustrating midurethral sling procedures

These videos were selected by Dr. Walters and presented courtesy of the International Academy of Pelvic Surgery (IAPS)

When ISD is present, the urethra cannot coaptate and loses its ability to maintain a watertight seal. Women who have this condition often are severely incontinent, leaking urine at low volumes and pressures and with minimal exertion.

In this randomized trial, Schierlitz and colleagues hypothesized that TOT would produce higher objective and subjective failure rates than the TVT. This was confirmed by 6-month data published in 2008.

Details of the trial

Women who had SUI were included in the trial if they had ISD based on urodynamic findings (i.e., maximum urethral closure pressure ≤20 cm H₂O or Valsalva leak-point pressure ≤60 cm H₂O, or both) and were randomly assigned to TVT or TOT. The primary endpoint was symptomatic SUI (confirmed by repeat urodynamic testing) that required a second procedure upon patient request.

Participants were followed for 3 years. If a patient reported symptoms, urodynamic testing was repeated. In addition, the patient was offered another surgery, usually involving placement of a TVT sling.

Schierlitz and colleagues concluded that, if TVT were used in all patients, repeat surgery would be avoided in one in every six patients. The risk of repeat surgery was 15 times greater for TOT, compared with the TVT sling. The median time to failure was 15.6 months for the TOT sling, compared with 43.7 months for the TVT.

Of the 16 patients who underwent repeat surgery, 56% were cured, 25% reported minimal leakage, and 19% remained unchanged.

Quality-of-life scores were similar between groups at the 6-month follow-up.

Why did the TVT outperform the TOT in this population?

Investigators theorized that there is a difference in sling axis, with the TVT placed at a more acute angle than the TOT sling. In addition, the location of the TOT sling is more distal than that of the TVT, based on ultrasonographic imaging. As a result, more effective urethral kinking and support are likely with the TVT sling, improving continence rates.

Strengths and limitations of the trial

The randomization of participants and long-term follow-up bolster the trial’s credibility.

Weaknesses include unblinded participation and postoperative surgical assessment.

Although the sample size was underpowered, there was a significant difference in the primary outcome between the two groups.

We want to hear from you! Tell us what you think.

RELATED ARTICLE WITH VIDEOS

• Which sling for which SUI patient?
  Mark D. Walters, MD, and Anne M. Weber, MD (Surgical Techniques, May 2012)

3 video clips illustrating midurethral sling procedures

These videos were selected by Dr. Walters and presented courtesy of the International Academy of Pelvic Surgery (IAPS)

When ISD is present, the urethra cannot coaptate and loses its ability to maintain a watertight seal. Women who have this condition often are severely incontinent, leaking urine at low volumes and pressures and with minimal exertion.

In this randomized trial, Schierlitz and colleagues hypothesized that TOT would produce higher objective and subjective failure rates than the TVT. This was confirmed by 6-month data published in 2008.

Details of the trial

Women who had SUI were included in the trial if they had ISD based on urodynamic findings (i.e., maximum urethral closure pressure ≤20 cm H₂O or Valsalva leak-point pressure ≤60 cm H₂O, or both) and were randomly assigned to TVT or TOT. The primary endpoint was symptomatic SUI (confirmed by repeat urodynamic testing) that required a second procedure upon patient request.

Participants were followed for 3 years. If a patient reported symptoms, urodynamic testing was repeated. In addition, the patient was offered another surgery, usually involving placement of a TVT sling.

Schierlitz and colleagues concluded that, if TVT were used in all patients, repeat surgery would be avoided in one in every six patients. The risk of repeat surgery was 15 times greater for TOT, compared with the TVT sling. The median time to failure was 15.6 months for the TOT sling, compared with 43.7 months for the TVT.

Of the 16 patients who underwent repeat surgery, 56% were cured, 25% reported minimal leakage, and 19% remained unchanged.

Quality-of-life scores were similar between groups at the 6-month follow-up.

Why did the TVT outperform the TOT in this population?

Investigators theorized that there is a difference in sling axis, with the TVT placed at a more acute angle than the TOT sling. In addition, the location of the TOT sling is more distal than that of the TVT, based on ultrasonographic imaging. As a result, more effective urethral kinking and support are likely with the TVT sling, improving continence rates.

Strengths and limitations of the trial

The randomization of participants and long-term follow-up bolster the trial’s credibility.

Weaknesses include unblinded participation and postoperative surgical assessment.

Although the sample size was underpowered, there was a significant difference in the primary outcome between the two groups.

We want to hear from you! Tell us what you think.

RELATED ARTICLE WITH VIDEOS

• Which sling for which SUI patient?
  Mark D. Walters, MD, and Anne M. Weber, MD (Surgical Techniques, May 2012)

3 video clips illustrating midurethral sling procedures

These videos were selected by Dr. Walters and presented courtesy of the International Academy of Pelvic Surgery (IAPS)

When ISD is present, the urethra cannot coaptate and loses its ability to maintain a watertight seal. Women who have this condition often are severely incontinent, leaking urine at low volumes and pressures and with minimal exertion.

In this randomized trial, Schierlitz and colleagues hypothesized that TOT would produce higher objective and subjective failure rates than the TVT. This was confirmed by 6-month data published in 2008.

Details of the trial

Women who had SUI were included in the trial if they had ISD based on urodynamic findings (i.e., maximum urethral closure pressure ≤20 cm H₂O or Valsalva leak-point pressure ≤60 cm H₂O, or both) and were randomly assigned to TVT or TOT. The primary endpoint was symptomatic SUI (confirmed by repeat urodynamic testing) that required a second procedure upon patient request.

Participants were followed for 3 years. If a patient reported symptoms, urodynamic testing was repeated. In addition, the patient was offered another surgery, usually involving placement of a TVT sling.

Schierlitz and colleagues concluded that, if TVT were used in all patients, repeat surgery would be avoided in one in every six patients. The risk of repeat surgery was 15 times greater for TOT, compared with the TVT sling. The median time to failure was 15.6 months for the TOT sling, compared with 43.7 months for the TVT.

Of the 16 patients who underwent repeat surgery, 56% were cured, 25% reported minimal leakage, and 19% remained unchanged.

Quality-of-life scores were similar between groups at the 6-month follow-up.

Why did the TVT outperform the TOT in this population?

Investigators theorized that there is a difference in sling axis, with the TVT placed at a more acute angle than the TOT sling. In addition, the location of the TOT sling is more distal than that of the TVT, based on ultrasonographic imaging. As a result, more effective urethral kinking and support are likely with the TVT sling, improving continence rates.

Strengths and limitations of the trial

The randomization of participants and long-term follow-up bolster the trial’s credibility.

Weaknesses include unblinded participation and postoperative surgical assessment.

Although the sample size was underpowered, there was a significant difference in the primary outcome between the two groups.

We want to hear from you! Tell us what you think.

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans¹ and 14% of service members returning from Iraq and Afghanistan.² PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.³ Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.⁴ Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery^4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).⁸

Table 2

Psychosocial consequences of sleep disruption in PTSD

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.^9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.¹¹ See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.

Prazosin

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.^12,13 In open-label trials,^14-18 a chart review,¹⁹ and placebo-controlled trials,^20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.¹¹

Table 4

RCTs of prazosin for trauma-related nightmares

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.¹¹ Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics