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Kidney Stones: Current Diagnosis and Management
Kidney or urinary tract stones (whose presence is referred to as nephrolithiasis) are hard, crystalline mineral concretions that form within the kidney or the urinary tract. They are a common problem, with an estimated annual incidence of 1% and a lifetime risk of 15% to 25%; this constitutes a significant health care burden, particularly for people of working age.1
Nephrolithiasis is currently more prevalent in men than in women (13% vs 7%, respectively), and it is three to four times more likely to present in white than nonwhite patients.2 However, recent epidemiologic data suggest an alarming increase in the number of women and adolescents primarily diagnosed with stone disease.3-6 The pattern of increasing incidence in women can be attributed in part to changes in diet and lifestyle.4,5 Figure 17 represents the prevalence of stone disease, specific to gender and race.2,4
Due to kidney stones’ relatively common occurrence, the diagnosis, management, and prevention of stone disease have become increasingly relevant for the primary care practitioner. In the course of stone disease management, the clinician should be aware of a vital fact: Stones have a tendency to recur.1 Indeed, evidence suggests that following an initial diagnosis of nephrolithiasis, the probability of kidney stone recurrence increases to nearly 50% after five years.8
Even more concerning, evidence from several studies suggests that patients with a history of stone disease have a higher probability of experiencing a significant reduction in renal function (ie, decrease in glomerular filtration rate) and hence end-stage renal disease, when compared with non–stone formers.9-11 This accentuates the importance of early diagnosis, treatment, and initiation of steps to prevent further recurrence of this condition.
PATHOGENESIS
Stones in the urinary tract develop under specific urinary conditions, including supersaturation of the urine with stone-forming ions (ie, calcium, oxalate, uric acid, and phosphate) and deficiency of urinary stone inhibitors (citrate, magnesium, zinc, macromolecules, and pyrophosphate). Stone formation occurs in a mucoprotein matrix that attaches to the renal epithelium. Urine becomes supersaturated as a result of increasing levels of solutes (such as the stone-forming ions) and/or decreasing free water volume. When the concentration of stone-forming ions exceeds solubility in the urine (equilibrium solubility product), these ions can combine to form crystals.12,13
Stones are typed based on the ion composition of their crystals (see Table 12,12).
Once crystals are formed, they can also aggregate with other crystals, developing into a calculus.12 Urinary pH influences ion crystallization: Alkaline urine favors formation of calcium and/or phosphate stones, whereas acidic urine favors uric acid and cystine stone formation.13
Kidney stones can be divided into four broad types: calcium-based, struvite, uric acid, and cystine stones (see Figure 2). Among these, calcium-based stones are by far the most common, with nearly 80% of stones composed of calcium compounds (usually calcium oxalate, and rarely calcium phosphate).4 The etiologies of these four types are vastly different, and prevention of stone formation must be tailored to the stone type. Once stones form, however, the appropriate treatment strategies have many similarities.
RISK FACTORS
Specific risk factors for stone formation vary widely and are unique to the type of stone. A thorough history, including a family or personal history of stone disease and dietary history, must be part of the initial work-up when a patient is being evaluated for stone disease; patients with any of these risk factors should be investigated further.
The risk factors for stone disease can be broadly categorized as either individual risk factors or dietary risk factors.
Individual Risk Factors
A positive family history increases the risk for stone formation by two- to three-fold. Other individual risk factors include congenital anatomic defects, such as medullary sponge kidney, horseshoe kidney, and ureteropelvic junction obstruction (UPJ).14-16 These can cause obstruction that leads to urinary stasis, and subsequently to stone precipitation.
Certain systemic disorders (eg, hyperparathyroidism) and situations have also been associated with stone disease and should be considered risk factors. (See Table 212,17).
In patients who undergo gastrointestinal bypass surgery, the development of hyperoxaluria, hypercalciuria, and decreased urinary volume are associated with an increased risk for stone formation,18,19 and these patients should be watched for this development. Obesity and weight gain are directly proportional to nephrolithiasis risk, especially in women.4,20
Environment plays a very important role in stone formation. Persons who live in a hot, arid climate, for example, and those who work outdoors in hot weather are at increased risk for stone formation due to excessive fluid loss from sweating.2,4,7 (In regions where the risk for kidney stone formation is high, Romero et al7 predict, nephrolithiasis incidence could rise from 40% to 56% by 2050 as a result of the effects of global warming.)
Lastly, an individual’s ability (or inability) to metabolize calcium salts plays a vital role in the pathogenesis of stone disease. Intestinal calcium absorption is a major determinant of hypercalciuria, as nearly 90% of ingested calcium is absorbed in the intestines. People can broadly be divided into high or low calcium absorbers. Hypercalciuria (mean urinary calcium excretion ≥ 300 mg/d in men and ≥ 250 mg/d in women on a 1,000-mg/d calcium diet) is detected in 20% to 40% of those with calcium stones.21-23 Hypocitraturia (mean urinary citrate excretion ≤ 320 mg/d) and hyperoxaluria (mean urinary oxalate excretion > 45 mg/d) can also increase the risk for stone formation.12,24
Dietary Risk Factors
These are primarily related to fluid intake and dietary calcium.7,17,25,26 Drinking less than 1 L of fluids daily is associated with an increased risk for forming stones; this risk is magnified when the urine volume is also decreased.7,17,27 Increased dietary intake of animal protein can elevate the risk for formation of uric acid stones as a result of elevated urinary calcium and uric acid and decreased urinary citrate.17
Low dietary calcium ingestion and high oxalate consumption, resulting in increased oxalate absorption, can also exacerbate the risk for stones.7,27 By contrast, a diet high in calcium (≥ 1,200 mg/d) reduces the risk for calcium oxalate stone recurrence,17 although the effectiveness of supplemental calcium has been questioned.26-28
Patients who are advised to make specific dietary adjustments should later undergo repeat urine chemistries to determine the effectiveness of these changes.17
CLINICAL PRESENTATION
Nephrolithiasis typically presents with colicky flank pain, often accompanied by nausea and vomiting.29 The pain radiates to the ipsilateral groin, and the patient typically has difficulty finding a comfortable position. Nephrolithiasis may also present with chronic, episodic flank pain or may even be asymptomatic.30
Physical examination may reveal signs of severe pain, such as tachycardia and hypertension. Presence of fever indicates associated urinary tract infection and possibly pyelonephritis. Some larger stones can cause urinary tract obstruction; if obstruction occurs along with a preexisting urinary tract infection, it can potentially lead to pyelonephritis, pyonephrosis, and eventually urosepsis—a potentially life-threatening condition that requires immediate surgical drainage.31
Before a diagnosis of renal stones can be confirmed, care should be exercised to rule out the differentials, including abdominal aortic aneurysm, appendicitis, bowel obstruction, cholecystitis, drug-seeking behavior (eg, painkiller addiction), gastritis, mesenteric ischemia, musculoskeletal pain, ovarian abscess, ruptured ovarian cyst, pelvic inflammatory disease, pyelonephritis, and UPJ.2,32,33 All patients with suspected nephrolithiasis should be carefully evaluated using laboratory and radiologic investigations.
LABORATORY EVALUATION
The goals in this two-step process are to confirm the diagnosis of nephrolithiasis, then to identify the composition of the stones formed and the associated risk factors.
Initial Evaluation
Tests include dipstick urine assessment, serum chemistries, and a complete blood count (CBC). Urine dipstick assessment may be positive for blood, protein, or leukocyte esterase, indicating stones or fragments of stones present in the urinary tract. While nearly 10% of patients with stone disease exhibit gross hematuria, nearly 90% of patients have microscopic hematuria.2
Urine osmolality should be reviewed to assess urine concentration. Serum chemistries should be ordered to evaluate kidney function. Elevated creatinine may indicate acute rather than chronic kidney disease. Electrolytes and carbon dioxide should be measured to evaluate the kidneys’ ability to concentrate urine and maintain an acid–base balance. The CBC may reveal mild leukocytosis in nephrolithiasis; presence of significant leukocytosis indicates infection.2
Secondary Evaluation
This step begins with a thorough review of the patient’s medical record and a detailed patient interview to ascertain all risk factors for stone formation (as summarized in Table 1). Specific studies to be considered are mentioned in Table 3.2 This evaluation is critical to prevent formation of future stones and the associated complications. In the patient with a history of stone recurrence or stone formation of identified cause, evaluation is needed for three metabolic abnormalities—hypercalciuria, hyperuricosuria, and hypocitraturia—as these conditions predispose patients to recurrent stone formation.1,25,34
The patient should also be encouraged to collect stones passed for further clinical evaluation. Infrared spectroscopy or quantitative wet analysis is used to identify the specific composition of the stone.32,35
Radiologic Evaluation
Radiologic evaluation of stones is currently performed through plain x-rays, ultrasonography, and noncontrast spiral CT.12,32,33 When a patient presents with acute signs of nephrolithiasis, a plain film x-ray of the kidneys, ureters, and bladder (KUB) is acceptable as the first imaging study, as it is inexpensive and available in most areas.33 Plain film KUB x-rays will identify calcium oxalate, calcium phosphate, struvite, and cystine stones. However, the sensitivity of plain film x-rays has been documented between 24% and 59%, and stones that overlie a bone may be missed.32,36 (See Figure 3.)
Hence, because of these limitations and the increasing availability of noncontrast spiral CT, noncontrast spiral CT is now the most commonly used and useful test in the diagnosis of kidney stones (sensitivity, 95% to 100%).32,36 Spiral CT accurately defines the size as well as the location of stones, and may additionally rule out other differential diagnoses (see Figures 4a, 4b, and 4c).
Historically, IV pyelograms and urograms were considered useful in locating urinary tract stones and diagnosing related complications,12 but these modalities carry additional risks related to IV contrast dye and radiation exposure. As a result, they have been almost completely replaced by noncontrast spiral CT because of ease of use and reduced risks.33
Stones may also be seen on renal ultrasound—particularly uric acid stones, which are radiolucent (see Figure 5). Ultrasound is appropriate for evaluation of patients whose exposure to radiation should be limited, such as children or pregnant women. In addition to plain film x-rays, renal ultrasound may also be useful for surveillance of stones.12
TREATMENT
Nephrolithiasis treatment varies between acute and chronic care. Acute care for nephrolithiasis involves management of acute pain and urinary obstruction, as well as patient stabilization. Chronic care includes prevention of recurrence and management of risks.
Acute Management
Patients who present with acute nephrolithiasis most often require fluid administration, aggressive pain management, and treatment for nausea or vomiting.31,32 Most ureteral stones measuring 5.0 mm or less will typically pass spontaneously within a few weeks,1,29 but larger stones usually require intervention—in some cases, surgery.
Patients should be hospitalized if they require IV fluids or pain management. Isotonic IV fluids should be given to increase the urine volume and facilitate passage of stones. Care must be taken to monitor fluids, as patients with kidney stones may have a limited ability to urinate (due to urinary obstruction and/or acute or chronic renal failure). Whenever possible, all urine should be strained to collect any stones for analysis.
One new strategy to assist with stone passage is medical expulsive therapy (MET), using calcium channel blockers (eg, nifedipine) or α-blockers (eg, tamsulosin).1,37 While there is conflicting evidence regarding the efficacy of calcium channel blockers for MET, one meta-analysis revealed a 29% improvement in stone passage with α-blockers.1,38
Pain management can often be accomplished with NSAIDs (eg, ketorolac, diclofenac).29 Since this class of medications can compromise renal function, however, they must be used with caution. Many patients require narcotic medications to control pain adequately.39-41 Antiemetic agents (such as the H1-receptor blocker dimenhydrinate42) should be administered to control nausea and vomiting.
Surgical and interventional management. Surgical intervention may be required if stones are too large to pass spontaneously (typically ≥ 8 mm); if they cause acute renal obstruction; or if they are located at a site with a potential for complications or can lead to persistent symptoms without evidence that they are passing.1,3 Renal obstruction should be treated aggressively to preserve renal function.
The type of intervention chosen depends on the size and location of the stone, as well as the presence or absence of obstruction. Stones that measure less than 20 mm are commonly treated with extracorporeal shockwave lithotripsy (unless they overlie the sacroiliac joint), whereas patients with larger or more complex stones may require percutaneous nephrolithotomy. Nonobstructive or uncomplicated ureteral stones may be managed medically, whereas obstructive or complicated ureteral stones require placement of a stent or a nephrostomy tube until they can be removed by endoscopic surgery.29,43
Obstruction, which may be partial or complete, is more likely when stone size exceeds 10 mm.44 Signs of obstruction include sudden-onset, excruciating flank pain that radiates to the groin, along with nausea and vomiting (renal colic). Larger obstructive stones, such as staghorn calculi (as shown in Figures 3 and 4a), can present with symptoms of a urinary tract infection, mild flank pain, or hematuria.33
Presence of signs of obstruction or infection mandates emergent treatment. Infections of the urinary tract (as serious as pyelonephritis or urosepsis) should be treated with antibiotics: initially with broad coverage, according to the appropriate guidelines for urinary tract infections, then tailored to the results of urine cultures. Obstruction can be relieved directly by nephrostomy tubes (and/or stents) or by interventions in which the stone is removed and normal urinary flow is restored.
Typically, endoscopy is used for direct removal of stones that cause obstruction.44 Nephrostomy tubes and ureteral stents (see Figures 6a and 6b) are placed to relieve obstruction temporarily and provide an alternate route for drainage of urine. The goal is to prevent renal damage until the obstruction can be relieved. Stents can remain in place for several months, but nephrostomy tubes are associated with a higher risk for infection (because they are externalized), and duration of use should be limited to only a few weeks.12,29,38
Stents are also associated with infections, but coated stents are available to reduce infection. As with any catheter material inserted into the urinary tract, ureteral stents are a prime location for development of a persistent bacterial biofilm, thus leading to infection. Recent advances in stent manufacturing have included coating stents with various biomaterials to decrease the development of this bacterial biofilm. In a preliminary study in 10 patients using a diamond-like, carbon-coated ureteral stent, Laube et al45 demonstrated a reduction in formation of this biofilm, hence lowering the probability of stent-induced infection.
Chronic Stone Management
As previously mentioned, one of the seminal characteristics of stone disease is its ability to recur. After incidental detection of kidney stones through routine diagnostic procedures, the risk for recurrence in patients who do not receive chronic medical management is 30% to 40% within five years.17,28 In treated patients, by comparison, this risk falls by approximately 50%.17,26
Patients with a history of stone recurrence must be evaluated for metabolic defects that precipitate stones, since their risk for chronic kidney disease is increased.34 All patients with a history of stone disease should be instructed to increase their fluid intake to maintain a daily urinary output of at least 2.5 L, unless contraindications exist.34
In patients with calcium-based stones who do not benefit from conservative treatment (ie, a low-sodium diet and other dietary modifications), thiazide diuretics may help reduce urinary calcium.1,46
Struvite stones can be prevented through use of long-term antibiotics to reduce the risk for urinary tract infection and by maintaining urinary pH levels below 6.0.17,27,34
For patients with uric acid stones, allopurinol may be prescribed to lower uric acid levels; moreover, the solubility of uric acid is greatly increased at higher pH, so it is beneficial to treat these patients with citrate to maintain their urinary pH above 6.0.47,34
Ensuring a high urine output (≥ 4 L/d34) and alkalinizing urine can help prevent recurrence of cystine stones.17,33 Treatment with potassium citrate has been shown to maintain a urinary pH of 6.5 to 7.0.34
CONCLUSION
The ever-increasing significance of nephrolithiasis has mandated an organized and systematic management approach. Indeed, the diagnosis and initial therapy for kidney stones have undergone considerable evolution in recent years. The basic tenets of nephrolithiasis management include early diagnosis and pertinent treatment as well as adequate prophylaxis to prevent subsequent stone recurrence.
1. Moe OW, Pearle MS, Sakhaee K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int. 2011;79(4):385-392.
2. Schade GR, Faerber GJ. Urinary tract stones. Prim Care. 2010;37(3):565-581, ix.
3. Childs M, Rangel L, Lingeman J, Krambeck A. Contemporary practice patterns in surgical management of stone disease. American Urological Association (AUA) Annual Meeting; May 2011; Washington, DC.
4. Pearle MS, Calhoun E, Curhan GC. Urolithiasis. In: Litwin MS, Saigal CS, eds; National Institute of Diabetes and Digestive and Kidney Diseases. Urologic Diseases in America (2007). 281-320. http://kidney.niddk.nih.gov/statistics/uda/Urologic_Dis eases_in_America.pdf. Accessed January 23, 2012.
5. Scales CD Jr, Curtis LH, Norris RD, et al. Changing gender prevalence of stone disease. J Urol. 2007;177(3):979-982.
6. Lieske JC, Peña de la Vega LS, Slezak JM, et al. Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int. 2006;69(4):760-764.
7. Romero V, Akpinar H, Assimos DG. Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol. 2010;12(2-3):e86-e96.
8. Sutherland JW, Parks JH, Coe FL. Recurrence after a single renal stone in a community practice. Miner Electrolyte Metab. 1985;11(4):267-269.
9. Gillen DL, Worcester EM, Coe FL. Decreased renal function among adults with a history of nephrolithiasis: a study of NHANES III. Kidney Int. 2005;67(2):685-690.
10. Stankus N, Hammes M, Gillen D, Worcester E. African American ESRD patients have a high pre-dialysis prevalence of kidney stones compared to NHANES III. Urol Res. 2007;35(2):83-87.
11. Hassan I, Juncos LA, Milliner DS, et al. Chronic renal failure secondary to oxalate nephropathy: a preventable complication after jejunoileal bypass. Mayo Clin Proc. 2001;76(7):758-760.
12. Johri N, Cooper B, Robertson W, et al. An update and practical guide to renal stone management. Nephron Clin Pract. 2010;116(3): c159-c171.
13. Wagner CA, Mohebbi N. Urinary pH and stone formation. J Nephrol. 2010;23 suppl 16: S165-S169.
14. McPhail EF, Gettman MT, Patterson DE, et al. Nephrolithiasis in medullary sponge kidney: evaluation of clinical and metabolic features. Urology. 2011 Oct 17. [Epub ahead of print]
15. Raj GV, Auge BK, Assimos D, Preminger GM. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys.
J Endourol. 2004;18(2):157-161.
16. Soylu A, Ugras YM, Günes A, Baydinç D. Bilateral kidney stones with ureteropelvic junction obstruction. Nat Clin Pract Urol. 2005;2(7): 351-354.
17. Curhan GC. Diet and the prevention of kidney stones. Nephrology Rounds. 2004(2):4. www
.nephrologyrounds.org/crus/nephUS_0404.pdf. Accessed January 23, 2012.
18. Wu JN, Craig J, Chamie K, et al. Urolithiasis risk factors in the bariatric population undergoing gastric bypass surgery. Surg Obes Relat Dis. 2011 Sep 21. [Epub ahead of print]
19. Patel BN, Passman CM, Fernandez A, et al. Prevalence of hyperoxaluria after bariatric surgery. J Urol. 2009;181(1):161-166.
20. Taylor EN, Stampfer M, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005;293(4):455-462.
21. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J Surg. 1958;46(195):10-18.
22. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int. 2001;59(6):2290-2298.
23. Pak CY. Citrate and renal calculi: an update. Miner Electrolyte Metab. 1994;20(6):371-377.
24. Curhan GC. Epidemiology of stone disease. Urol Clin North Am. 2007;34(3):287-293.
25. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77-84.
26. Curhan G, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126(7):497-504.
27. Grases F, Costa-Bauza A, Prieto RM. Renal lithiasis and nutrition. Nutr J. 2006;5:23.
28. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women. Arch Intern Med. 2004;164(8):885-891.
29. Miller NL, Lingeman JE. Management of kidney stones. BMJ. 2007;334(7591):468-472.
30. Bansal AD, Hui J, Goldfarb DS. Asymptomatic nephrolithiasis detected by ultrasound. Clin J Am Soc Nephrol. 2009;4(3):680-684.
31. Ramakrishnan K, Scheid DC. Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician. 2005;71(5):933-942.
32. Portis AJ, Sundaram CP. Diagnosis and initial management of kidney stones. Am Fam Physician. 2001;63(7):1329-1338.
33. Preminger GM, Assimos DG, Lingeman JE, et al. Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. J Urol. 2005;173(6):1991-2000.
34. Lipkin ME, Preminger GM. Demystifying the medical management of nephrolithiasis. Rev Urol. 2011;13(1):34-38.
35. Kourambas J, Aslan P, Teh CL, et al. Role of stone analysis in metabolic evaluation and medical treatment of nephrolithiasis. J Endourol. 2001;15(2):181-186.
36. Jackman SV, Potter SR, Regan F, Jarrett TW. Plain abdominal x-ray versus computerized tomography screening: sensitivity for stone localization after nonenhanced spiral computerized tomography. J Urol. 2000;164(2):308-310.
37. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006;368 (9542):1171-1179.
38. Preminger GM, Tiselius HG, Assimos DG, et al. 2007 guideline for the management of ureteral calculi. J Urol. 2007;178(6):2418-2434.
39. Huerta C, Castellsague J, Varas-Lorenzo C, García Rodríguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-539.
40. Schneider V, Lévesque LE, Zhang B, et al. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis. Am J Epidemiol. 2006;164(9): 881-889.
41. Davenport K, Timoney AG, Keeley FX. Conventional and alternative methods for providing analgesia in renal colic. BJU Int. 2005;95(3):297-300.
42. Yilmaz E, Batislam E, Deniz T, Yuvanc E. Histamine 1 receptor antagonist in symptomatic treatment of renal colic accompanied by nausea: two birds with one stone? Urology. 2009; 73(1):32-36.
43. Krambeck AE, LeRoy AJ, Patterson DE, Gettman MT. Long-term outcomes of percutaneous nephrolithotomy compared to shock wave lithotripsy and conservative management. J Urol. 2008;179(6):2233-2237.
44. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol. 2002; 178(1):101-103.
45. Laube N, Kleinen L, Bradenahl J, Meissner A. Diamond-like carbon coatings on ureteral stents: a new strategy for decreasing the formation of crystalline bacterial biofilms? J Urol. 2007;177 (5):1923-1927.
46. Khan SR, Glenton PA, Byer KJ. Dietary oxalate and calcium oxalate nephrolithiasis. J Urol. 2007;178(5):2191-2196.
47. Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int. 1986;30(3):422-428.
Kidney or urinary tract stones (whose presence is referred to as nephrolithiasis) are hard, crystalline mineral concretions that form within the kidney or the urinary tract. They are a common problem, with an estimated annual incidence of 1% and a lifetime risk of 15% to 25%; this constitutes a significant health care burden, particularly for people of working age.1
Nephrolithiasis is currently more prevalent in men than in women (13% vs 7%, respectively), and it is three to four times more likely to present in white than nonwhite patients.2 However, recent epidemiologic data suggest an alarming increase in the number of women and adolescents primarily diagnosed with stone disease.3-6 The pattern of increasing incidence in women can be attributed in part to changes in diet and lifestyle.4,5 Figure 17 represents the prevalence of stone disease, specific to gender and race.2,4
Due to kidney stones’ relatively common occurrence, the diagnosis, management, and prevention of stone disease have become increasingly relevant for the primary care practitioner. In the course of stone disease management, the clinician should be aware of a vital fact: Stones have a tendency to recur.1 Indeed, evidence suggests that following an initial diagnosis of nephrolithiasis, the probability of kidney stone recurrence increases to nearly 50% after five years.8
Even more concerning, evidence from several studies suggests that patients with a history of stone disease have a higher probability of experiencing a significant reduction in renal function (ie, decrease in glomerular filtration rate) and hence end-stage renal disease, when compared with non–stone formers.9-11 This accentuates the importance of early diagnosis, treatment, and initiation of steps to prevent further recurrence of this condition.
PATHOGENESIS
Stones in the urinary tract develop under specific urinary conditions, including supersaturation of the urine with stone-forming ions (ie, calcium, oxalate, uric acid, and phosphate) and deficiency of urinary stone inhibitors (citrate, magnesium, zinc, macromolecules, and pyrophosphate). Stone formation occurs in a mucoprotein matrix that attaches to the renal epithelium. Urine becomes supersaturated as a result of increasing levels of solutes (such as the stone-forming ions) and/or decreasing free water volume. When the concentration of stone-forming ions exceeds solubility in the urine (equilibrium solubility product), these ions can combine to form crystals.12,13
Stones are typed based on the ion composition of their crystals (see Table 12,12).
Once crystals are formed, they can also aggregate with other crystals, developing into a calculus.12 Urinary pH influences ion crystallization: Alkaline urine favors formation of calcium and/or phosphate stones, whereas acidic urine favors uric acid and cystine stone formation.13
Kidney stones can be divided into four broad types: calcium-based, struvite, uric acid, and cystine stones (see Figure 2). Among these, calcium-based stones are by far the most common, with nearly 80% of stones composed of calcium compounds (usually calcium oxalate, and rarely calcium phosphate).4 The etiologies of these four types are vastly different, and prevention of stone formation must be tailored to the stone type. Once stones form, however, the appropriate treatment strategies have many similarities.
RISK FACTORS
Specific risk factors for stone formation vary widely and are unique to the type of stone. A thorough history, including a family or personal history of stone disease and dietary history, must be part of the initial work-up when a patient is being evaluated for stone disease; patients with any of these risk factors should be investigated further.
The risk factors for stone disease can be broadly categorized as either individual risk factors or dietary risk factors.
Individual Risk Factors
A positive family history increases the risk for stone formation by two- to three-fold. Other individual risk factors include congenital anatomic defects, such as medullary sponge kidney, horseshoe kidney, and ureteropelvic junction obstruction (UPJ).14-16 These can cause obstruction that leads to urinary stasis, and subsequently to stone precipitation.
Certain systemic disorders (eg, hyperparathyroidism) and situations have also been associated with stone disease and should be considered risk factors. (See Table 212,17).
In patients who undergo gastrointestinal bypass surgery, the development of hyperoxaluria, hypercalciuria, and decreased urinary volume are associated with an increased risk for stone formation,18,19 and these patients should be watched for this development. Obesity and weight gain are directly proportional to nephrolithiasis risk, especially in women.4,20
Environment plays a very important role in stone formation. Persons who live in a hot, arid climate, for example, and those who work outdoors in hot weather are at increased risk for stone formation due to excessive fluid loss from sweating.2,4,7 (In regions where the risk for kidney stone formation is high, Romero et al7 predict, nephrolithiasis incidence could rise from 40% to 56% by 2050 as a result of the effects of global warming.)
Lastly, an individual’s ability (or inability) to metabolize calcium salts plays a vital role in the pathogenesis of stone disease. Intestinal calcium absorption is a major determinant of hypercalciuria, as nearly 90% of ingested calcium is absorbed in the intestines. People can broadly be divided into high or low calcium absorbers. Hypercalciuria (mean urinary calcium excretion ≥ 300 mg/d in men and ≥ 250 mg/d in women on a 1,000-mg/d calcium diet) is detected in 20% to 40% of those with calcium stones.21-23 Hypocitraturia (mean urinary citrate excretion ≤ 320 mg/d) and hyperoxaluria (mean urinary oxalate excretion > 45 mg/d) can also increase the risk for stone formation.12,24
Dietary Risk Factors
These are primarily related to fluid intake and dietary calcium.7,17,25,26 Drinking less than 1 L of fluids daily is associated with an increased risk for forming stones; this risk is magnified when the urine volume is also decreased.7,17,27 Increased dietary intake of animal protein can elevate the risk for formation of uric acid stones as a result of elevated urinary calcium and uric acid and decreased urinary citrate.17
Low dietary calcium ingestion and high oxalate consumption, resulting in increased oxalate absorption, can also exacerbate the risk for stones.7,27 By contrast, a diet high in calcium (≥ 1,200 mg/d) reduces the risk for calcium oxalate stone recurrence,17 although the effectiveness of supplemental calcium has been questioned.26-28
Patients who are advised to make specific dietary adjustments should later undergo repeat urine chemistries to determine the effectiveness of these changes.17
CLINICAL PRESENTATION
Nephrolithiasis typically presents with colicky flank pain, often accompanied by nausea and vomiting.29 The pain radiates to the ipsilateral groin, and the patient typically has difficulty finding a comfortable position. Nephrolithiasis may also present with chronic, episodic flank pain or may even be asymptomatic.30
Physical examination may reveal signs of severe pain, such as tachycardia and hypertension. Presence of fever indicates associated urinary tract infection and possibly pyelonephritis. Some larger stones can cause urinary tract obstruction; if obstruction occurs along with a preexisting urinary tract infection, it can potentially lead to pyelonephritis, pyonephrosis, and eventually urosepsis—a potentially life-threatening condition that requires immediate surgical drainage.31
Before a diagnosis of renal stones can be confirmed, care should be exercised to rule out the differentials, including abdominal aortic aneurysm, appendicitis, bowel obstruction, cholecystitis, drug-seeking behavior (eg, painkiller addiction), gastritis, mesenteric ischemia, musculoskeletal pain, ovarian abscess, ruptured ovarian cyst, pelvic inflammatory disease, pyelonephritis, and UPJ.2,32,33 All patients with suspected nephrolithiasis should be carefully evaluated using laboratory and radiologic investigations.
LABORATORY EVALUATION
The goals in this two-step process are to confirm the diagnosis of nephrolithiasis, then to identify the composition of the stones formed and the associated risk factors.
Initial Evaluation
Tests include dipstick urine assessment, serum chemistries, and a complete blood count (CBC). Urine dipstick assessment may be positive for blood, protein, or leukocyte esterase, indicating stones or fragments of stones present in the urinary tract. While nearly 10% of patients with stone disease exhibit gross hematuria, nearly 90% of patients have microscopic hematuria.2
Urine osmolality should be reviewed to assess urine concentration. Serum chemistries should be ordered to evaluate kidney function. Elevated creatinine may indicate acute rather than chronic kidney disease. Electrolytes and carbon dioxide should be measured to evaluate the kidneys’ ability to concentrate urine and maintain an acid–base balance. The CBC may reveal mild leukocytosis in nephrolithiasis; presence of significant leukocytosis indicates infection.2
Secondary Evaluation
This step begins with a thorough review of the patient’s medical record and a detailed patient interview to ascertain all risk factors for stone formation (as summarized in Table 1). Specific studies to be considered are mentioned in Table 3.2 This evaluation is critical to prevent formation of future stones and the associated complications. In the patient with a history of stone recurrence or stone formation of identified cause, evaluation is needed for three metabolic abnormalities—hypercalciuria, hyperuricosuria, and hypocitraturia—as these conditions predispose patients to recurrent stone formation.1,25,34
The patient should also be encouraged to collect stones passed for further clinical evaluation. Infrared spectroscopy or quantitative wet analysis is used to identify the specific composition of the stone.32,35
Radiologic Evaluation
Radiologic evaluation of stones is currently performed through plain x-rays, ultrasonography, and noncontrast spiral CT.12,32,33 When a patient presents with acute signs of nephrolithiasis, a plain film x-ray of the kidneys, ureters, and bladder (KUB) is acceptable as the first imaging study, as it is inexpensive and available in most areas.33 Plain film KUB x-rays will identify calcium oxalate, calcium phosphate, struvite, and cystine stones. However, the sensitivity of plain film x-rays has been documented between 24% and 59%, and stones that overlie a bone may be missed.32,36 (See Figure 3.)
Hence, because of these limitations and the increasing availability of noncontrast spiral CT, noncontrast spiral CT is now the most commonly used and useful test in the diagnosis of kidney stones (sensitivity, 95% to 100%).32,36 Spiral CT accurately defines the size as well as the location of stones, and may additionally rule out other differential diagnoses (see Figures 4a, 4b, and 4c).
Historically, IV pyelograms and urograms were considered useful in locating urinary tract stones and diagnosing related complications,12 but these modalities carry additional risks related to IV contrast dye and radiation exposure. As a result, they have been almost completely replaced by noncontrast spiral CT because of ease of use and reduced risks.33
Stones may also be seen on renal ultrasound—particularly uric acid stones, which are radiolucent (see Figure 5). Ultrasound is appropriate for evaluation of patients whose exposure to radiation should be limited, such as children or pregnant women. In addition to plain film x-rays, renal ultrasound may also be useful for surveillance of stones.12
TREATMENT
Nephrolithiasis treatment varies between acute and chronic care. Acute care for nephrolithiasis involves management of acute pain and urinary obstruction, as well as patient stabilization. Chronic care includes prevention of recurrence and management of risks.
Acute Management
Patients who present with acute nephrolithiasis most often require fluid administration, aggressive pain management, and treatment for nausea or vomiting.31,32 Most ureteral stones measuring 5.0 mm or less will typically pass spontaneously within a few weeks,1,29 but larger stones usually require intervention—in some cases, surgery.
Patients should be hospitalized if they require IV fluids or pain management. Isotonic IV fluids should be given to increase the urine volume and facilitate passage of stones. Care must be taken to monitor fluids, as patients with kidney stones may have a limited ability to urinate (due to urinary obstruction and/or acute or chronic renal failure). Whenever possible, all urine should be strained to collect any stones for analysis.
One new strategy to assist with stone passage is medical expulsive therapy (MET), using calcium channel blockers (eg, nifedipine) or α-blockers (eg, tamsulosin).1,37 While there is conflicting evidence regarding the efficacy of calcium channel blockers for MET, one meta-analysis revealed a 29% improvement in stone passage with α-blockers.1,38
Pain management can often be accomplished with NSAIDs (eg, ketorolac, diclofenac).29 Since this class of medications can compromise renal function, however, they must be used with caution. Many patients require narcotic medications to control pain adequately.39-41 Antiemetic agents (such as the H1-receptor blocker dimenhydrinate42) should be administered to control nausea and vomiting.
Surgical and interventional management. Surgical intervention may be required if stones are too large to pass spontaneously (typically ≥ 8 mm); if they cause acute renal obstruction; or if they are located at a site with a potential for complications or can lead to persistent symptoms without evidence that they are passing.1,3 Renal obstruction should be treated aggressively to preserve renal function.
The type of intervention chosen depends on the size and location of the stone, as well as the presence or absence of obstruction. Stones that measure less than 20 mm are commonly treated with extracorporeal shockwave lithotripsy (unless they overlie the sacroiliac joint), whereas patients with larger or more complex stones may require percutaneous nephrolithotomy. Nonobstructive or uncomplicated ureteral stones may be managed medically, whereas obstructive or complicated ureteral stones require placement of a stent or a nephrostomy tube until they can be removed by endoscopic surgery.29,43
Obstruction, which may be partial or complete, is more likely when stone size exceeds 10 mm.44 Signs of obstruction include sudden-onset, excruciating flank pain that radiates to the groin, along with nausea and vomiting (renal colic). Larger obstructive stones, such as staghorn calculi (as shown in Figures 3 and 4a), can present with symptoms of a urinary tract infection, mild flank pain, or hematuria.33
Presence of signs of obstruction or infection mandates emergent treatment. Infections of the urinary tract (as serious as pyelonephritis or urosepsis) should be treated with antibiotics: initially with broad coverage, according to the appropriate guidelines for urinary tract infections, then tailored to the results of urine cultures. Obstruction can be relieved directly by nephrostomy tubes (and/or stents) or by interventions in which the stone is removed and normal urinary flow is restored.
Typically, endoscopy is used for direct removal of stones that cause obstruction.44 Nephrostomy tubes and ureteral stents (see Figures 6a and 6b) are placed to relieve obstruction temporarily and provide an alternate route for drainage of urine. The goal is to prevent renal damage until the obstruction can be relieved. Stents can remain in place for several months, but nephrostomy tubes are associated with a higher risk for infection (because they are externalized), and duration of use should be limited to only a few weeks.12,29,38
Stents are also associated with infections, but coated stents are available to reduce infection. As with any catheter material inserted into the urinary tract, ureteral stents are a prime location for development of a persistent bacterial biofilm, thus leading to infection. Recent advances in stent manufacturing have included coating stents with various biomaterials to decrease the development of this bacterial biofilm. In a preliminary study in 10 patients using a diamond-like, carbon-coated ureteral stent, Laube et al45 demonstrated a reduction in formation of this biofilm, hence lowering the probability of stent-induced infection.
Chronic Stone Management
As previously mentioned, one of the seminal characteristics of stone disease is its ability to recur. After incidental detection of kidney stones through routine diagnostic procedures, the risk for recurrence in patients who do not receive chronic medical management is 30% to 40% within five years.17,28 In treated patients, by comparison, this risk falls by approximately 50%.17,26
Patients with a history of stone recurrence must be evaluated for metabolic defects that precipitate stones, since their risk for chronic kidney disease is increased.34 All patients with a history of stone disease should be instructed to increase their fluid intake to maintain a daily urinary output of at least 2.5 L, unless contraindications exist.34
In patients with calcium-based stones who do not benefit from conservative treatment (ie, a low-sodium diet and other dietary modifications), thiazide diuretics may help reduce urinary calcium.1,46
Struvite stones can be prevented through use of long-term antibiotics to reduce the risk for urinary tract infection and by maintaining urinary pH levels below 6.0.17,27,34
For patients with uric acid stones, allopurinol may be prescribed to lower uric acid levels; moreover, the solubility of uric acid is greatly increased at higher pH, so it is beneficial to treat these patients with citrate to maintain their urinary pH above 6.0.47,34
Ensuring a high urine output (≥ 4 L/d34) and alkalinizing urine can help prevent recurrence of cystine stones.17,33 Treatment with potassium citrate has been shown to maintain a urinary pH of 6.5 to 7.0.34
CONCLUSION
The ever-increasing significance of nephrolithiasis has mandated an organized and systematic management approach. Indeed, the diagnosis and initial therapy for kidney stones have undergone considerable evolution in recent years. The basic tenets of nephrolithiasis management include early diagnosis and pertinent treatment as well as adequate prophylaxis to prevent subsequent stone recurrence.
Kidney or urinary tract stones (whose presence is referred to as nephrolithiasis) are hard, crystalline mineral concretions that form within the kidney or the urinary tract. They are a common problem, with an estimated annual incidence of 1% and a lifetime risk of 15% to 25%; this constitutes a significant health care burden, particularly for people of working age.1
Nephrolithiasis is currently more prevalent in men than in women (13% vs 7%, respectively), and it is three to four times more likely to present in white than nonwhite patients.2 However, recent epidemiologic data suggest an alarming increase in the number of women and adolescents primarily diagnosed with stone disease.3-6 The pattern of increasing incidence in women can be attributed in part to changes in diet and lifestyle.4,5 Figure 17 represents the prevalence of stone disease, specific to gender and race.2,4
Due to kidney stones’ relatively common occurrence, the diagnosis, management, and prevention of stone disease have become increasingly relevant for the primary care practitioner. In the course of stone disease management, the clinician should be aware of a vital fact: Stones have a tendency to recur.1 Indeed, evidence suggests that following an initial diagnosis of nephrolithiasis, the probability of kidney stone recurrence increases to nearly 50% after five years.8
Even more concerning, evidence from several studies suggests that patients with a history of stone disease have a higher probability of experiencing a significant reduction in renal function (ie, decrease in glomerular filtration rate) and hence end-stage renal disease, when compared with non–stone formers.9-11 This accentuates the importance of early diagnosis, treatment, and initiation of steps to prevent further recurrence of this condition.
PATHOGENESIS
Stones in the urinary tract develop under specific urinary conditions, including supersaturation of the urine with stone-forming ions (ie, calcium, oxalate, uric acid, and phosphate) and deficiency of urinary stone inhibitors (citrate, magnesium, zinc, macromolecules, and pyrophosphate). Stone formation occurs in a mucoprotein matrix that attaches to the renal epithelium. Urine becomes supersaturated as a result of increasing levels of solutes (such as the stone-forming ions) and/or decreasing free water volume. When the concentration of stone-forming ions exceeds solubility in the urine (equilibrium solubility product), these ions can combine to form crystals.12,13
Stones are typed based on the ion composition of their crystals (see Table 12,12).
Once crystals are formed, they can also aggregate with other crystals, developing into a calculus.12 Urinary pH influences ion crystallization: Alkaline urine favors formation of calcium and/or phosphate stones, whereas acidic urine favors uric acid and cystine stone formation.13
Kidney stones can be divided into four broad types: calcium-based, struvite, uric acid, and cystine stones (see Figure 2). Among these, calcium-based stones are by far the most common, with nearly 80% of stones composed of calcium compounds (usually calcium oxalate, and rarely calcium phosphate).4 The etiologies of these four types are vastly different, and prevention of stone formation must be tailored to the stone type. Once stones form, however, the appropriate treatment strategies have many similarities.
RISK FACTORS
Specific risk factors for stone formation vary widely and are unique to the type of stone. A thorough history, including a family or personal history of stone disease and dietary history, must be part of the initial work-up when a patient is being evaluated for stone disease; patients with any of these risk factors should be investigated further.
The risk factors for stone disease can be broadly categorized as either individual risk factors or dietary risk factors.
Individual Risk Factors
A positive family history increases the risk for stone formation by two- to three-fold. Other individual risk factors include congenital anatomic defects, such as medullary sponge kidney, horseshoe kidney, and ureteropelvic junction obstruction (UPJ).14-16 These can cause obstruction that leads to urinary stasis, and subsequently to stone precipitation.
Certain systemic disorders (eg, hyperparathyroidism) and situations have also been associated with stone disease and should be considered risk factors. (See Table 212,17).
In patients who undergo gastrointestinal bypass surgery, the development of hyperoxaluria, hypercalciuria, and decreased urinary volume are associated with an increased risk for stone formation,18,19 and these patients should be watched for this development. Obesity and weight gain are directly proportional to nephrolithiasis risk, especially in women.4,20
Environment plays a very important role in stone formation. Persons who live in a hot, arid climate, for example, and those who work outdoors in hot weather are at increased risk for stone formation due to excessive fluid loss from sweating.2,4,7 (In regions where the risk for kidney stone formation is high, Romero et al7 predict, nephrolithiasis incidence could rise from 40% to 56% by 2050 as a result of the effects of global warming.)
Lastly, an individual’s ability (or inability) to metabolize calcium salts plays a vital role in the pathogenesis of stone disease. Intestinal calcium absorption is a major determinant of hypercalciuria, as nearly 90% of ingested calcium is absorbed in the intestines. People can broadly be divided into high or low calcium absorbers. Hypercalciuria (mean urinary calcium excretion ≥ 300 mg/d in men and ≥ 250 mg/d in women on a 1,000-mg/d calcium diet) is detected in 20% to 40% of those with calcium stones.21-23 Hypocitraturia (mean urinary citrate excretion ≤ 320 mg/d) and hyperoxaluria (mean urinary oxalate excretion > 45 mg/d) can also increase the risk for stone formation.12,24
Dietary Risk Factors
These are primarily related to fluid intake and dietary calcium.7,17,25,26 Drinking less than 1 L of fluids daily is associated with an increased risk for forming stones; this risk is magnified when the urine volume is also decreased.7,17,27 Increased dietary intake of animal protein can elevate the risk for formation of uric acid stones as a result of elevated urinary calcium and uric acid and decreased urinary citrate.17
Low dietary calcium ingestion and high oxalate consumption, resulting in increased oxalate absorption, can also exacerbate the risk for stones.7,27 By contrast, a diet high in calcium (≥ 1,200 mg/d) reduces the risk for calcium oxalate stone recurrence,17 although the effectiveness of supplemental calcium has been questioned.26-28
Patients who are advised to make specific dietary adjustments should later undergo repeat urine chemistries to determine the effectiveness of these changes.17
CLINICAL PRESENTATION
Nephrolithiasis typically presents with colicky flank pain, often accompanied by nausea and vomiting.29 The pain radiates to the ipsilateral groin, and the patient typically has difficulty finding a comfortable position. Nephrolithiasis may also present with chronic, episodic flank pain or may even be asymptomatic.30
Physical examination may reveal signs of severe pain, such as tachycardia and hypertension. Presence of fever indicates associated urinary tract infection and possibly pyelonephritis. Some larger stones can cause urinary tract obstruction; if obstruction occurs along with a preexisting urinary tract infection, it can potentially lead to pyelonephritis, pyonephrosis, and eventually urosepsis—a potentially life-threatening condition that requires immediate surgical drainage.31
Before a diagnosis of renal stones can be confirmed, care should be exercised to rule out the differentials, including abdominal aortic aneurysm, appendicitis, bowel obstruction, cholecystitis, drug-seeking behavior (eg, painkiller addiction), gastritis, mesenteric ischemia, musculoskeletal pain, ovarian abscess, ruptured ovarian cyst, pelvic inflammatory disease, pyelonephritis, and UPJ.2,32,33 All patients with suspected nephrolithiasis should be carefully evaluated using laboratory and radiologic investigations.
LABORATORY EVALUATION
The goals in this two-step process are to confirm the diagnosis of nephrolithiasis, then to identify the composition of the stones formed and the associated risk factors.
Initial Evaluation
Tests include dipstick urine assessment, serum chemistries, and a complete blood count (CBC). Urine dipstick assessment may be positive for blood, protein, or leukocyte esterase, indicating stones or fragments of stones present in the urinary tract. While nearly 10% of patients with stone disease exhibit gross hematuria, nearly 90% of patients have microscopic hematuria.2
Urine osmolality should be reviewed to assess urine concentration. Serum chemistries should be ordered to evaluate kidney function. Elevated creatinine may indicate acute rather than chronic kidney disease. Electrolytes and carbon dioxide should be measured to evaluate the kidneys’ ability to concentrate urine and maintain an acid–base balance. The CBC may reveal mild leukocytosis in nephrolithiasis; presence of significant leukocytosis indicates infection.2
Secondary Evaluation
This step begins with a thorough review of the patient’s medical record and a detailed patient interview to ascertain all risk factors for stone formation (as summarized in Table 1). Specific studies to be considered are mentioned in Table 3.2 This evaluation is critical to prevent formation of future stones and the associated complications. In the patient with a history of stone recurrence or stone formation of identified cause, evaluation is needed for three metabolic abnormalities—hypercalciuria, hyperuricosuria, and hypocitraturia—as these conditions predispose patients to recurrent stone formation.1,25,34
The patient should also be encouraged to collect stones passed for further clinical evaluation. Infrared spectroscopy or quantitative wet analysis is used to identify the specific composition of the stone.32,35
Radiologic Evaluation
Radiologic evaluation of stones is currently performed through plain x-rays, ultrasonography, and noncontrast spiral CT.12,32,33 When a patient presents with acute signs of nephrolithiasis, a plain film x-ray of the kidneys, ureters, and bladder (KUB) is acceptable as the first imaging study, as it is inexpensive and available in most areas.33 Plain film KUB x-rays will identify calcium oxalate, calcium phosphate, struvite, and cystine stones. However, the sensitivity of plain film x-rays has been documented between 24% and 59%, and stones that overlie a bone may be missed.32,36 (See Figure 3.)
Hence, because of these limitations and the increasing availability of noncontrast spiral CT, noncontrast spiral CT is now the most commonly used and useful test in the diagnosis of kidney stones (sensitivity, 95% to 100%).32,36 Spiral CT accurately defines the size as well as the location of stones, and may additionally rule out other differential diagnoses (see Figures 4a, 4b, and 4c).
Historically, IV pyelograms and urograms were considered useful in locating urinary tract stones and diagnosing related complications,12 but these modalities carry additional risks related to IV contrast dye and radiation exposure. As a result, they have been almost completely replaced by noncontrast spiral CT because of ease of use and reduced risks.33
Stones may also be seen on renal ultrasound—particularly uric acid stones, which are radiolucent (see Figure 5). Ultrasound is appropriate for evaluation of patients whose exposure to radiation should be limited, such as children or pregnant women. In addition to plain film x-rays, renal ultrasound may also be useful for surveillance of stones.12
TREATMENT
Nephrolithiasis treatment varies between acute and chronic care. Acute care for nephrolithiasis involves management of acute pain and urinary obstruction, as well as patient stabilization. Chronic care includes prevention of recurrence and management of risks.
Acute Management
Patients who present with acute nephrolithiasis most often require fluid administration, aggressive pain management, and treatment for nausea or vomiting.31,32 Most ureteral stones measuring 5.0 mm or less will typically pass spontaneously within a few weeks,1,29 but larger stones usually require intervention—in some cases, surgery.
Patients should be hospitalized if they require IV fluids or pain management. Isotonic IV fluids should be given to increase the urine volume and facilitate passage of stones. Care must be taken to monitor fluids, as patients with kidney stones may have a limited ability to urinate (due to urinary obstruction and/or acute or chronic renal failure). Whenever possible, all urine should be strained to collect any stones for analysis.
One new strategy to assist with stone passage is medical expulsive therapy (MET), using calcium channel blockers (eg, nifedipine) or α-blockers (eg, tamsulosin).1,37 While there is conflicting evidence regarding the efficacy of calcium channel blockers for MET, one meta-analysis revealed a 29% improvement in stone passage with α-blockers.1,38
Pain management can often be accomplished with NSAIDs (eg, ketorolac, diclofenac).29 Since this class of medications can compromise renal function, however, they must be used with caution. Many patients require narcotic medications to control pain adequately.39-41 Antiemetic agents (such as the H1-receptor blocker dimenhydrinate42) should be administered to control nausea and vomiting.
Surgical and interventional management. Surgical intervention may be required if stones are too large to pass spontaneously (typically ≥ 8 mm); if they cause acute renal obstruction; or if they are located at a site with a potential for complications or can lead to persistent symptoms without evidence that they are passing.1,3 Renal obstruction should be treated aggressively to preserve renal function.
The type of intervention chosen depends on the size and location of the stone, as well as the presence or absence of obstruction. Stones that measure less than 20 mm are commonly treated with extracorporeal shockwave lithotripsy (unless they overlie the sacroiliac joint), whereas patients with larger or more complex stones may require percutaneous nephrolithotomy. Nonobstructive or uncomplicated ureteral stones may be managed medically, whereas obstructive or complicated ureteral stones require placement of a stent or a nephrostomy tube until they can be removed by endoscopic surgery.29,43
Obstruction, which may be partial or complete, is more likely when stone size exceeds 10 mm.44 Signs of obstruction include sudden-onset, excruciating flank pain that radiates to the groin, along with nausea and vomiting (renal colic). Larger obstructive stones, such as staghorn calculi (as shown in Figures 3 and 4a), can present with symptoms of a urinary tract infection, mild flank pain, or hematuria.33
Presence of signs of obstruction or infection mandates emergent treatment. Infections of the urinary tract (as serious as pyelonephritis or urosepsis) should be treated with antibiotics: initially with broad coverage, according to the appropriate guidelines for urinary tract infections, then tailored to the results of urine cultures. Obstruction can be relieved directly by nephrostomy tubes (and/or stents) or by interventions in which the stone is removed and normal urinary flow is restored.
Typically, endoscopy is used for direct removal of stones that cause obstruction.44 Nephrostomy tubes and ureteral stents (see Figures 6a and 6b) are placed to relieve obstruction temporarily and provide an alternate route for drainage of urine. The goal is to prevent renal damage until the obstruction can be relieved. Stents can remain in place for several months, but nephrostomy tubes are associated with a higher risk for infection (because they are externalized), and duration of use should be limited to only a few weeks.12,29,38
Stents are also associated with infections, but coated stents are available to reduce infection. As with any catheter material inserted into the urinary tract, ureteral stents are a prime location for development of a persistent bacterial biofilm, thus leading to infection. Recent advances in stent manufacturing have included coating stents with various biomaterials to decrease the development of this bacterial biofilm. In a preliminary study in 10 patients using a diamond-like, carbon-coated ureteral stent, Laube et al45 demonstrated a reduction in formation of this biofilm, hence lowering the probability of stent-induced infection.
Chronic Stone Management
As previously mentioned, one of the seminal characteristics of stone disease is its ability to recur. After incidental detection of kidney stones through routine diagnostic procedures, the risk for recurrence in patients who do not receive chronic medical management is 30% to 40% within five years.17,28 In treated patients, by comparison, this risk falls by approximately 50%.17,26
Patients with a history of stone recurrence must be evaluated for metabolic defects that precipitate stones, since their risk for chronic kidney disease is increased.34 All patients with a history of stone disease should be instructed to increase their fluid intake to maintain a daily urinary output of at least 2.5 L, unless contraindications exist.34
In patients with calcium-based stones who do not benefit from conservative treatment (ie, a low-sodium diet and other dietary modifications), thiazide diuretics may help reduce urinary calcium.1,46
Struvite stones can be prevented through use of long-term antibiotics to reduce the risk for urinary tract infection and by maintaining urinary pH levels below 6.0.17,27,34
For patients with uric acid stones, allopurinol may be prescribed to lower uric acid levels; moreover, the solubility of uric acid is greatly increased at higher pH, so it is beneficial to treat these patients with citrate to maintain their urinary pH above 6.0.47,34
Ensuring a high urine output (≥ 4 L/d34) and alkalinizing urine can help prevent recurrence of cystine stones.17,33 Treatment with potassium citrate has been shown to maintain a urinary pH of 6.5 to 7.0.34
CONCLUSION
The ever-increasing significance of nephrolithiasis has mandated an organized and systematic management approach. Indeed, the diagnosis and initial therapy for kidney stones have undergone considerable evolution in recent years. The basic tenets of nephrolithiasis management include early diagnosis and pertinent treatment as well as adequate prophylaxis to prevent subsequent stone recurrence.
1. Moe OW, Pearle MS, Sakhaee K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int. 2011;79(4):385-392.
2. Schade GR, Faerber GJ. Urinary tract stones. Prim Care. 2010;37(3):565-581, ix.
3. Childs M, Rangel L, Lingeman J, Krambeck A. Contemporary practice patterns in surgical management of stone disease. American Urological Association (AUA) Annual Meeting; May 2011; Washington, DC.
4. Pearle MS, Calhoun E, Curhan GC. Urolithiasis. In: Litwin MS, Saigal CS, eds; National Institute of Diabetes and Digestive and Kidney Diseases. Urologic Diseases in America (2007). 281-320. http://kidney.niddk.nih.gov/statistics/uda/Urologic_Dis eases_in_America.pdf. Accessed January 23, 2012.
5. Scales CD Jr, Curtis LH, Norris RD, et al. Changing gender prevalence of stone disease. J Urol. 2007;177(3):979-982.
6. Lieske JC, Peña de la Vega LS, Slezak JM, et al. Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int. 2006;69(4):760-764.
7. Romero V, Akpinar H, Assimos DG. Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol. 2010;12(2-3):e86-e96.
8. Sutherland JW, Parks JH, Coe FL. Recurrence after a single renal stone in a community practice. Miner Electrolyte Metab. 1985;11(4):267-269.
9. Gillen DL, Worcester EM, Coe FL. Decreased renal function among adults with a history of nephrolithiasis: a study of NHANES III. Kidney Int. 2005;67(2):685-690.
10. Stankus N, Hammes M, Gillen D, Worcester E. African American ESRD patients have a high pre-dialysis prevalence of kidney stones compared to NHANES III. Urol Res. 2007;35(2):83-87.
11. Hassan I, Juncos LA, Milliner DS, et al. Chronic renal failure secondary to oxalate nephropathy: a preventable complication after jejunoileal bypass. Mayo Clin Proc. 2001;76(7):758-760.
12. Johri N, Cooper B, Robertson W, et al. An update and practical guide to renal stone management. Nephron Clin Pract. 2010;116(3): c159-c171.
13. Wagner CA, Mohebbi N. Urinary pH and stone formation. J Nephrol. 2010;23 suppl 16: S165-S169.
14. McPhail EF, Gettman MT, Patterson DE, et al. Nephrolithiasis in medullary sponge kidney: evaluation of clinical and metabolic features. Urology. 2011 Oct 17. [Epub ahead of print]
15. Raj GV, Auge BK, Assimos D, Preminger GM. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys.
J Endourol. 2004;18(2):157-161.
16. Soylu A, Ugras YM, Günes A, Baydinç D. Bilateral kidney stones with ureteropelvic junction obstruction. Nat Clin Pract Urol. 2005;2(7): 351-354.
17. Curhan GC. Diet and the prevention of kidney stones. Nephrology Rounds. 2004(2):4. www
.nephrologyrounds.org/crus/nephUS_0404.pdf. Accessed January 23, 2012.
18. Wu JN, Craig J, Chamie K, et al. Urolithiasis risk factors in the bariatric population undergoing gastric bypass surgery. Surg Obes Relat Dis. 2011 Sep 21. [Epub ahead of print]
19. Patel BN, Passman CM, Fernandez A, et al. Prevalence of hyperoxaluria after bariatric surgery. J Urol. 2009;181(1):161-166.
20. Taylor EN, Stampfer M, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005;293(4):455-462.
21. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J Surg. 1958;46(195):10-18.
22. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int. 2001;59(6):2290-2298.
23. Pak CY. Citrate and renal calculi: an update. Miner Electrolyte Metab. 1994;20(6):371-377.
24. Curhan GC. Epidemiology of stone disease. Urol Clin North Am. 2007;34(3):287-293.
25. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77-84.
26. Curhan G, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126(7):497-504.
27. Grases F, Costa-Bauza A, Prieto RM. Renal lithiasis and nutrition. Nutr J. 2006;5:23.
28. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women. Arch Intern Med. 2004;164(8):885-891.
29. Miller NL, Lingeman JE. Management of kidney stones. BMJ. 2007;334(7591):468-472.
30. Bansal AD, Hui J, Goldfarb DS. Asymptomatic nephrolithiasis detected by ultrasound. Clin J Am Soc Nephrol. 2009;4(3):680-684.
31. Ramakrishnan K, Scheid DC. Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician. 2005;71(5):933-942.
32. Portis AJ, Sundaram CP. Diagnosis and initial management of kidney stones. Am Fam Physician. 2001;63(7):1329-1338.
33. Preminger GM, Assimos DG, Lingeman JE, et al. Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. J Urol. 2005;173(6):1991-2000.
34. Lipkin ME, Preminger GM. Demystifying the medical management of nephrolithiasis. Rev Urol. 2011;13(1):34-38.
35. Kourambas J, Aslan P, Teh CL, et al. Role of stone analysis in metabolic evaluation and medical treatment of nephrolithiasis. J Endourol. 2001;15(2):181-186.
36. Jackman SV, Potter SR, Regan F, Jarrett TW. Plain abdominal x-ray versus computerized tomography screening: sensitivity for stone localization after nonenhanced spiral computerized tomography. J Urol. 2000;164(2):308-310.
37. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006;368 (9542):1171-1179.
38. Preminger GM, Tiselius HG, Assimos DG, et al. 2007 guideline for the management of ureteral calculi. J Urol. 2007;178(6):2418-2434.
39. Huerta C, Castellsague J, Varas-Lorenzo C, García Rodríguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-539.
40. Schneider V, Lévesque LE, Zhang B, et al. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis. Am J Epidemiol. 2006;164(9): 881-889.
41. Davenport K, Timoney AG, Keeley FX. Conventional and alternative methods for providing analgesia in renal colic. BJU Int. 2005;95(3):297-300.
42. Yilmaz E, Batislam E, Deniz T, Yuvanc E. Histamine 1 receptor antagonist in symptomatic treatment of renal colic accompanied by nausea: two birds with one stone? Urology. 2009; 73(1):32-36.
43. Krambeck AE, LeRoy AJ, Patterson DE, Gettman MT. Long-term outcomes of percutaneous nephrolithotomy compared to shock wave lithotripsy and conservative management. J Urol. 2008;179(6):2233-2237.
44. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol. 2002; 178(1):101-103.
45. Laube N, Kleinen L, Bradenahl J, Meissner A. Diamond-like carbon coatings on ureteral stents: a new strategy for decreasing the formation of crystalline bacterial biofilms? J Urol. 2007;177 (5):1923-1927.
46. Khan SR, Glenton PA, Byer KJ. Dietary oxalate and calcium oxalate nephrolithiasis. J Urol. 2007;178(5):2191-2196.
47. Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int. 1986;30(3):422-428.
1. Moe OW, Pearle MS, Sakhaee K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int. 2011;79(4):385-392.
2. Schade GR, Faerber GJ. Urinary tract stones. Prim Care. 2010;37(3):565-581, ix.
3. Childs M, Rangel L, Lingeman J, Krambeck A. Contemporary practice patterns in surgical management of stone disease. American Urological Association (AUA) Annual Meeting; May 2011; Washington, DC.
4. Pearle MS, Calhoun E, Curhan GC. Urolithiasis. In: Litwin MS, Saigal CS, eds; National Institute of Diabetes and Digestive and Kidney Diseases. Urologic Diseases in America (2007). 281-320. http://kidney.niddk.nih.gov/statistics/uda/Urologic_Dis eases_in_America.pdf. Accessed January 23, 2012.
5. Scales CD Jr, Curtis LH, Norris RD, et al. Changing gender prevalence of stone disease. J Urol. 2007;177(3):979-982.
6. Lieske JC, Peña de la Vega LS, Slezak JM, et al. Renal stone epidemiology in Rochester, Minnesota: an update. Kidney Int. 2006;69(4):760-764.
7. Romero V, Akpinar H, Assimos DG. Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol. 2010;12(2-3):e86-e96.
8. Sutherland JW, Parks JH, Coe FL. Recurrence after a single renal stone in a community practice. Miner Electrolyte Metab. 1985;11(4):267-269.
9. Gillen DL, Worcester EM, Coe FL. Decreased renal function among adults with a history of nephrolithiasis: a study of NHANES III. Kidney Int. 2005;67(2):685-690.
10. Stankus N, Hammes M, Gillen D, Worcester E. African American ESRD patients have a high pre-dialysis prevalence of kidney stones compared to NHANES III. Urol Res. 2007;35(2):83-87.
11. Hassan I, Juncos LA, Milliner DS, et al. Chronic renal failure secondary to oxalate nephropathy: a preventable complication after jejunoileal bypass. Mayo Clin Proc. 2001;76(7):758-760.
12. Johri N, Cooper B, Robertson W, et al. An update and practical guide to renal stone management. Nephron Clin Pract. 2010;116(3): c159-c171.
13. Wagner CA, Mohebbi N. Urinary pH and stone formation. J Nephrol. 2010;23 suppl 16: S165-S169.
14. McPhail EF, Gettman MT, Patterson DE, et al. Nephrolithiasis in medullary sponge kidney: evaluation of clinical and metabolic features. Urology. 2011 Oct 17. [Epub ahead of print]
15. Raj GV, Auge BK, Assimos D, Preminger GM. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys.
J Endourol. 2004;18(2):157-161.
16. Soylu A, Ugras YM, Günes A, Baydinç D. Bilateral kidney stones with ureteropelvic junction obstruction. Nat Clin Pract Urol. 2005;2(7): 351-354.
17. Curhan GC. Diet and the prevention of kidney stones. Nephrology Rounds. 2004(2):4. www
.nephrologyrounds.org/crus/nephUS_0404.pdf. Accessed January 23, 2012.
18. Wu JN, Craig J, Chamie K, et al. Urolithiasis risk factors in the bariatric population undergoing gastric bypass surgery. Surg Obes Relat Dis. 2011 Sep 21. [Epub ahead of print]
19. Patel BN, Passman CM, Fernandez A, et al. Prevalence of hyperoxaluria after bariatric surgery. J Urol. 2009;181(1):161-166.
20. Taylor EN, Stampfer M, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005;293(4):455-462.
21. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J Surg. 1958;46(195):10-18.
22. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int. 2001;59(6):2290-2298.
23. Pak CY. Citrate and renal calculi: an update. Miner Electrolyte Metab. 1994;20(6):371-377.
24. Curhan GC. Epidemiology of stone disease. Urol Clin North Am. 2007;34(3):287-293.
25. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77-84.
26. Curhan G, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126(7):497-504.
27. Grases F, Costa-Bauza A, Prieto RM. Renal lithiasis and nutrition. Nutr J. 2006;5:23.
28. Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women. Arch Intern Med. 2004;164(8):885-891.
29. Miller NL, Lingeman JE. Management of kidney stones. BMJ. 2007;334(7591):468-472.
30. Bansal AD, Hui J, Goldfarb DS. Asymptomatic nephrolithiasis detected by ultrasound. Clin J Am Soc Nephrol. 2009;4(3):680-684.
31. Ramakrishnan K, Scheid DC. Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician. 2005;71(5):933-942.
32. Portis AJ, Sundaram CP. Diagnosis and initial management of kidney stones. Am Fam Physician. 2001;63(7):1329-1338.
33. Preminger GM, Assimos DG, Lingeman JE, et al. Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. J Urol. 2005;173(6):1991-2000.
34. Lipkin ME, Preminger GM. Demystifying the medical management of nephrolithiasis. Rev Urol. 2011;13(1):34-38.
35. Kourambas J, Aslan P, Teh CL, et al. Role of stone analysis in metabolic evaluation and medical treatment of nephrolithiasis. J Endourol. 2001;15(2):181-186.
36. Jackman SV, Potter SR, Regan F, Jarrett TW. Plain abdominal x-ray versus computerized tomography screening: sensitivity for stone localization after nonenhanced spiral computerized tomography. J Urol. 2000;164(2):308-310.
37. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006;368 (9542):1171-1179.
38. Preminger GM, Tiselius HG, Assimos DG, et al. 2007 guideline for the management of ureteral calculi. J Urol. 2007;178(6):2418-2434.
39. Huerta C, Castellsague J, Varas-Lorenzo C, García Rodríguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-539.
40. Schneider V, Lévesque LE, Zhang B, et al. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis. Am J Epidemiol. 2006;164(9): 881-889.
41. Davenport K, Timoney AG, Keeley FX. Conventional and alternative methods for providing analgesia in renal colic. BJU Int. 2005;95(3):297-300.
42. Yilmaz E, Batislam E, Deniz T, Yuvanc E. Histamine 1 receptor antagonist in symptomatic treatment of renal colic accompanied by nausea: two birds with one stone? Urology. 2009; 73(1):32-36.
43. Krambeck AE, LeRoy AJ, Patterson DE, Gettman MT. Long-term outcomes of percutaneous nephrolithotomy compared to shock wave lithotripsy and conservative management. J Urol. 2008;179(6):2233-2237.
44. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol. 2002; 178(1):101-103.
45. Laube N, Kleinen L, Bradenahl J, Meissner A. Diamond-like carbon coatings on ureteral stents: a new strategy for decreasing the formation of crystalline bacterial biofilms? J Urol. 2007;177 (5):1923-1927.
46. Khan SR, Glenton PA, Byer KJ. Dietary oxalate and calcium oxalate nephrolithiasis. J Urol. 2007;178(5):2191-2196.
47. Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int. 1986;30(3):422-428.
Transfusion Medicine
Transfusion therapy is an essential part of hematology practice, allowing for curative therapy of diseases such as leukemia, aplastic anemia, and aggressive lymphomas. Nonetheless, transfusions are associated with significant risks, including transfusion-transmitted infections and transfusion-related reactions, and controversy remains about key issues in transfusion therapy, such as triggers for red cell transfusions. This article reviews the available blood products and indications for transfusion along with the associated risks and also discusses specific clinical situations, such as massive transfusion.
To read the full article in PDF:
Transfusion therapy is an essential part of hematology practice, allowing for curative therapy of diseases such as leukemia, aplastic anemia, and aggressive lymphomas. Nonetheless, transfusions are associated with significant risks, including transfusion-transmitted infections and transfusion-related reactions, and controversy remains about key issues in transfusion therapy, such as triggers for red cell transfusions. This article reviews the available blood products and indications for transfusion along with the associated risks and also discusses specific clinical situations, such as massive transfusion.
To read the full article in PDF:
Transfusion therapy is an essential part of hematology practice, allowing for curative therapy of diseases such as leukemia, aplastic anemia, and aggressive lymphomas. Nonetheless, transfusions are associated with significant risks, including transfusion-transmitted infections and transfusion-related reactions, and controversy remains about key issues in transfusion therapy, such as triggers for red cell transfusions. This article reviews the available blood products and indications for transfusion along with the associated risks and also discusses specific clinical situations, such as massive transfusion.
To read the full article in PDF:
The Effects of Sleep Deprivation on the Performance of Surgery
Diagnosis, Treatment, and Monitoring of the Patient With REM Sleep Behavior Disorder
Dopamine Antagonist Prescribing Practices in Patients With Parkinson Disease
Posterior Reversible Encephalopathy Syndrome as a Complication of Chemotherapy
Grand Rounds: Woman, 29, With Persistent Migraine
A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.
The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.
The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.
The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.
On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.
Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)1 diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.
She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire2 (see Tables 1 and 22) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.
The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.
Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,1 demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).
Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.
The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.
DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”3 Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.
Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period1) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.4 Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period5; this is defined as two days before to three days after the start of menstruation.
It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).6 Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.7
History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.7 In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).1 Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.8 Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.9
In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.1
In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.10 This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.
Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.1 An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.11 Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.
Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.12
Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.13 Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.4
Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.4 Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.14
Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.15 Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.15
Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.4 A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.14
Preventive therapy should be considered when responsiveness to acute treatment is inadequate.4 Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.16 Longer-acting triptans, such as frovatriptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.17,18
The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.3 However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.16 Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.19
The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.4 Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.19 Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.19
Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.14
CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.
REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.
2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.
3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.
4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.
5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.
6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.
7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.
8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.
9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.
10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.
11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.
12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.
13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.
14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.
15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.
16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.
17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.
18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.
19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.
A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.
The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.
The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.
The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.
On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.
Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)1 diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.
She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire2 (see Tables 1 and 22) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.
The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.
Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,1 demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).
Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.
The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.
DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”3 Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.
Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period1) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.4 Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period5; this is defined as two days before to three days after the start of menstruation.
It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).6 Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.7
History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.7 In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).1 Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.8 Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.9
In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.1
In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.10 This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.
Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.1 An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.11 Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.
Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.12
Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.13 Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.4
Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.4 Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.14
Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.15 Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.15
Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.4 A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.14
Preventive therapy should be considered when responsiveness to acute treatment is inadequate.4 Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.16 Longer-acting triptans, such as frovatriptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.17,18
The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.3 However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.16 Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.19
The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.4 Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.19 Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.19
Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.14
CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.
REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.
2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.
3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.
4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.
5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.
6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.
7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.
8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.
9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.
10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.
11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.
12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.
13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.
14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.
15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.
16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.
17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.
18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.
19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.
A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.
The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.
The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.
The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.
On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.
Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)1 diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.
She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire2 (see Tables 1 and 22) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.
The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.
Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,1 demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).
Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.
The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.
DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”3 Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.
Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period1) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.4 Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period5; this is defined as two days before to three days after the start of menstruation.
It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).6 Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.7
History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.7 In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).1 Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.8 Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.9
In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.1
In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.10 This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.
Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.1 An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.11 Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.
Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.12
Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.13 Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.4
Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.4 Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.14
Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.15 Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.15
Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.4 A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.14
Preventive therapy should be considered when responsiveness to acute treatment is inadequate.4 Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.16 Longer-acting triptans, such as frovatriptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.17,18
The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.3 However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.16 Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.19
The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.4 Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.19 Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.19
Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.14
CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.
REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.
2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.
3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.
4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.
5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.
6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.
7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.
8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.
9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.
10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.
11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.
12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.
13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.
14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.
15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.
16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.
17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.
18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.
19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.
