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Current Trends in the Practice of Medicine Vol. 27, No. 1, 2011

INSIDE THIS ISSUE

2Perspectives onthe ContinuingEvolution of Therapy

for Atrial Fibrillation

4Advances in SeizurePrevention and Prediction

6Childhood Fractures:When to Worry

A

The Challenge

Most thyroid nodulesabout 95%are entirelybenign. However, identifying the occasionalthyroid cancer requires careful evaluation of every

nodule found, using a combination of clinicalassessment, neck palpation, ultrasound imaging(Figure 1), and, in many cases, analysis of a biopsyspecimen (Figure 2, see page 2).

Sometimes, thyroid nodules are noticed bythe patient or a family member or are discoveredduring a routine physical examination. They rarelycause symptoms, unless they are large enoughto interfere with swallowing. Thyroid cancer caninvade and damage the recurrent laryngeal nerve,causing hoarseness. Such invasion and damage areinfrequent, however. Most nodules are incidental

discoveries, and now many more such nodules arediscovered because of the increased use of imagingperformed for other reasons, including carotidultrasonography, neck or chest computed tomog-raphy, magnetic resonance imaging, and evenpositron emission tomography. Early and prompt diagnosis improves the

likelihood that a cancer can be discovered whilestill contained within the thyroid gland andamenable to surgery. Once soft tissue invasion hasoccurred or lymph nodes are extensively involved,the chance of surgical cure drops substantiallyand there is a much higher incidence of meta-static spread of these late-stage cancers. Prompt

diagnosis is also important for the patient becausethe finding of a nodule often raises fears aboutcancer and a delay in diagnosis fuels the concernand anxiety.

The most recent set of guidelines from theAmerican Thyroid Association specifies that theevaluation of a thyroid nodule should includeclinical assessment to determine the number, size,and location of all nodules within the gland; mea-surement of serum thyrotropin (TSH) to excludehyperthyroidism; ultrasonography to assess thenodule for features of malignancy; and fine-needle

The Thyroid Nodule Clinic

Figure 1.Ultrasound-guided fine-needle aspirationof a thyroid nodule.

Points to Remember

Thyroid nodules are common, with

palpable nodules found in 4% to 7% ofthe adult US population and solitary ormultiple nodules found at much higherrates during ultrasonographic screening.

Early diagnosis improves the likelihoodthat a cancer can be discovered while stillcontained within the thyroid gland andamenable to surgery.

Mayo Clinic endocrinologists opened theThyroid Nodule Clinic in 2009, providing

coordinated care, a thorough assessment,and a definitive diagnosis completed at asingle visit.

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Scope of the Problem

Atrial fibrillation (AF) remains the leadingarrhythmia in North America, both in num-bers of patients affected and the frequencyof accompanying sequelae. The prevalence

continues to increase, despite progress in thetreatment of contributing factors. Although1% of individuals in their 60s may have AF, theprevalence increases to 10% to 12% in individ-uals older than 80 years. Currently 2.5 millionAmericans have AF, but with the aging popula-tion and improved cardiovascular survival, thisnumber may increase to 5 million or 6 millionby the year 2050.

In most patients, AF is initially paroxysmal;other patients, particularly those with underly-

ing heart disease, may have more persistent oreven chronic AF. Nevertheless, the previouslyheld belief that most paroxysmal AF ultimatelyprogresses to a chronic form has been ques-tioned. Recent studies have suggested that pro-

gression occurs in only 20% to 40% of patientsover the course of 3 to 5 years, although longer-term data are lacking.

Drug Therapy for AF

Because of stroke risk, most patients requiresome form of antithrombotic therapy in theform of aspirin, warfarin, or dabigatran. Thosepatients with no risk factors may completelyforgo antithrombotic therapy, while recentlypublished guidelines suggest that therapy with

aspiration (FNA) of nodules that meet the appro-priate size and ultrasound criteria. However, notevery nodule needs to be biopsied, so the clinicalscenario and ultrasound features are important inselecting the appropriate nodule for biopsy.

Mayo Clinic endocrinologists opened theThyroid Nodule Clinic in 2009 to streamline thisevaluation and provide a coordinated approachthat meets the needs of patients with thyroid nod-

ules. The Thyroid Nodule Clinic provides a 1-stopthyroid nodule evaluation that includes a focusedclinical assessment, ultrasound evaluation, andFNAall typically performed within a 60-minuteappointment at a single visit. The ultrasoundallows Mayo staff to select both palpable andimpalpable nodules for biopsy and target the mostsuspicious nodule, which is not always the largestnodule. Using ultrasound guidance for thosebiopsies, Mayo Clinic endocrinologists typicallyperform more than 600 biopsies per year andexpect a clear diagnosis in more that 95% of casesat the first attempt.

Because of the coordinated assessmentprovided through the Thyroid Nodule Clinic, FNAresults are typically available within 2 hours, so thepatient usually receives a definitive result of theentire assessment within 4 hours. Patients with abenign nodule can be reassured, and those witha malignant or suspicious nodule can be offeredan appropriate surgical referral, often within 24hours. Mayo Clinic endocrinologists believe thatthe Thyroid Nodule Clinic improves the care they

provide for these patients, while lowering costs,improving efficiency, and providing a better serviceto referring physicians.

2 MAYO CLINIC|ClinicalUpdate

Figure 2.Thyroid cytology of a specimen of papil-lary thyroid carcinoma showing papillary archi-tecture and nuclear enlargement with crowding ofclassic papillary thyroid cancer (Papanicolaou stain,original magnification 100).

Perspectives on the Continuing

Evolution of Therapy for Atrial Fibrillation

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aspirin alone is adequate in patients at lowrisk with a CHADS score less than 1. Patientswith several risk factors (age >75 years, hyper-tension, diabetes, prior stroke or transientischemic attack, left ventricular dysfunction)are at higher risk, necessitating anticoagulationtherapy with warfarin.

While relatively rare in the absence of otherheart disease, the possibility of an AF contribu-

tion to ventricular dysfunction should be con-sidered in patients who have a rapid ventricularresponse rate and reduced ejection fraction.Establishing appropriate rate control, however,requires some assessment of rate during restand exertion. While most guidelines recommendthat resting rates during AF be less than 90 to100 bpm, a recent large clinical trial has shownthat a resting rate less than 110 bpm is adequatefor rate control. During exercise, the heart rateshould be maintained at less than 120 bpm.

Restoration of normal sinus rhythm maybe the most effective means of rate control.

A number of studies have shown the useful-ness of membrane-active, antiarrhythmic drugtherapy for maintaining sinus rhythm. Approxi-mately 30% to 40% of patients treated withantiarrhythmic therapy achieve control over thecourse of 1 year of follow-up. These data havebeen validated by larger comparative clinicaltrials. Similar results have been reported instudies designed to compare rate and rhythmcontrol therapy. Although an increase in mor-

tality may accompany AF, comparative studiesexamining the utility of rate vs rhythm controltherapy have had disappointing results.

Nonpharmacologic Therapy for AF

A number of observational studies have shownthat AF ablation is of benefit in eliminating AF,reducing its frequency, and improving patientsquality of life (Figure). In most studies, 75%to 85% of patients with paroxysmal AF have

been rendered free ofthis arrhythmia over

the course of 1 year ofobservation. Even inpatients with persis-tent or chronic AF afterablation, the incidenceof the arrhythmia issignificantly decreasedin 10% to 20%.

When Mayoresearchers reviewedoutcomes of ablationperformed at MayoClinic, they found

(over 2 years of follow-up) that the responseto ablation was excel-lent in more than 75%of patients with par-oxysmal AF. Patientswith persistent andchronic AF likewisehave shown enhancedbenefit, althougha more aggressive

MAYO CLINIC|ClinicalUpdate

Points to Remember

Atrial fibrillation (AF) is an increasingburden on the global health care systembecause of the numbers of patientsaffected, the impact of stroke, and thecost of both inpatient and outpatienttherapy.

Because of stroke risk, most patientswith AF require some form of anti-thrombotic therapy in the form ofaspirin, warfarin, or the newer directantithrombin agents such as dabigatran.

A number of observational studies haveshown that ablation is of benefit ineliminating AF, reducing its frequency,and improving patients quality of life.

Figure.Computer-generated map of left atrial activation. Red dots indicateablation sites.

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Clarification of Optimal Anticoagulation Through Genetics (COAG) Trial

A randomized, multicenter, double-blind clinical trial to evaluate the efficacy of clinical plus genetic

information to guide the initiation of warfarin therapy and to improve anticoagulation control for patients.

The protocol includes

Warfarin therapy for at least 3 months

Target INR 2-3

Study enrollment before receiving the first dose

Follow-up visits at the Gonda 4 Thrombophilia Clinic

For information, contact Nancy Lexvold, RN, at 507-255-7013 or Robert D. McBane, MD, at 507-266-3964

Anatomy vs Physiology-Guided Ablation for Atrial Fibrillation

A study to establish the differential success rate for complete elimination of atrial fibrillation (AF) with

combined wide-area circumferential ablation and linear ablation vs combined wide-area circumferential

ablation and complex fractionated atrial electrogram (CFAE) ablation. Inclusion criteria are

History of symptomatic persistent/permanent AF

Patient recommended for catheter-based, wide-area pulmonary vein isolation

Available for 13 months of follow-up after ablation

For information, contact Celeste Koestler, RN, or Yong-Mei Cha, MD, at 507-255-2200

Clinical Trials

4 MAYO CLINIC|ClinicalUpdate

The earlier seizure activity is detected, the betterthe chance of preventing it. For several years,Mayo Clinic neurologists and their neurosurgi-cal colleagues have been working to pinpointthe exact moment and the precise location ofseizure generation.

Isolating the Where and When of MicroseizuresThree years ago, using microelectrodes 40microns in diameter, or thinner than a humanhair, Mayo Clinic researchers began recordingelectroencephalographic (EEG) activity frombrain regions the size of cortical columns atfrequencies beyond the limits of standard EEGrecordings. Cortical columns, the smallest func-tional unit in the cortex, are approximately 300microns across and contain from 1,000 to 7,500neurons. In perspective, a typical EEG electrode

captures the activity of millions of neurons andhundreds of cortical columns (Figure).

This research revealed that isolated brainregions the size of cortical columns do, indeed,show evidence of seizure activity (microsei-zures) in humans. The investigators found thatmicroseizures occurred most often in patients

with epilepsy but also occurred, althoughrarely, in control patients without epilepsy. Thislatter finding demonstrates that pathologicoscillations can occur even in people who donot have epilepsy.

How do microseizures transition to clinicalseizures in patients with epilepsy? Mayo Clinicresearch findings support the hypothesis that inpatients with epilepsy, individual microdomainsthe size of cortical columns generate frequenthypersynchronous discharges, which recruit

Advances in Seizure Prevention and Prediction

ablative approach has been required. In thosewith paroxysmal AF, ablation for the isola-tion of pulmonary veins may be sufficient,while wider-area circumferential ablation withadditional linear ablation or energy deliverydirected at the underlying substrate has beenrequired. Additional review demonstrated

notable benefit in patients with underlyingdilated cardiomyopathies. In many patients,not only was AF eliminated, but a substantialimprovement in ejection fraction was observed,particularly in those with nonischemic leftventricular dysfunction.

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other columns of neurons. Similar, noncolumnargroupings of neurons have been identified in

the rat hippocampus by researchers at UCLAand are known as pathologically interconnectedneuron (PIN) clusters. These PIN clusters canbe considered microdomains of epileptogenesisor seizure initiation. When a critical volume ofmicrodomain activity is reached, a large-scaleseizure is generated. This explanation can bereferred to as the sick column hypothesis.

Clinical EEG recordings do not probe thespatial and temporal scales of microdomainactivity, which makes early detection difficult.This hypothesis may explain why some patientsdo not respond to first-generation responsive

stimulation devices designed to detect and abortseizures.

Update on Implanted Devices to

Detect and Abort Epileptic Seizures

Two new implantable epilepsy devices that useelectrical stimulation are undergoing multi-center trials for treatment of medically refractoryepilepsy. One device uses electrical stimula-tion of the anterior nucleus of the thalamusto modulate the brain activity and prevent

seizures. Another device under investigation isthe responsive neurostimulator system. Initial

Points to Remember

Mayo Clinic neurologists and neurosur-geons have been working to pinpoint theexact moment and the precise location ofseizure generation.

The recent discovery that seizurelikeevents can occur in pathologic micro-domains (ie, microseizures) in humansadds to a growing body of evidencethat seizures may begin before they areevident on clinical recording systems andwell before patients have symptoms.

Initial results from 2 pivotal multicentertrials have demonstrated the efficacy andsafety of implantable epilepsy devicesthat use electrical stimulation for reduc-ing seizure frequency in patients withmedically intractable partial epilepsy.

Figure. Top, The large volume sampled by the millimeter-scale clinical electrode (about 1 million neurons) vs a0.04-mm microwire. The cortex is organized into columns of neuronal clusters about 0.03 to 0.6 mm in diam-eter (cortical columns, about 7,500 neurons). Bottom, The frequency range of neuronal network oscillations.

Clinical contact Microwire

10-3

DC Ultraslow Berger bands MultiunitactivityFast

ripple

Ripple

Gamm

a

10-2 10-1 100 101 102 103 104

40m

150m

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Childhood bone fractures are common and oftencause concern for patients, parents, and clinicians.Understanding the typical timing and types offractures is helpful when deciding who needsfurther evaluation for potential underlying disease.The rate of fractures increases substantially duringpuberty for both boys and girls, but to a greaterdegree for boys. The peak incidence of fracturesin girls occurs around 10 to 12 years of age and inboys around 13 to 15 years of age. Forearm frac-tures are by far the most common type of fracture

during childhood (Figure 1). However, vertebralcompression fractures are distinctly uncommon inchildren and should always be a cause for concernand additional evaluation (Figure 2).

Children with 1 or 2 traumatic fractures are

unlikely to have an identifiable disorder and donot routinely require further evaluation. Obtain-ing a detailed history about the circumstancessurrounding a fracture is important in determining

the level of concern. Multiple fractures, atypicalfractures (such as vertebral compression frac-tures), low-trauma fractures, and a family historyof metabolic bone disease are all red flags thatshould prompt further investigation. Childrenwith inflammatory bowel disease, celiac disease,chronic glucocorticoid exposure, neuromusculardisorders, and others (Box) warrant special atten-tion to optimize bone health, since they are atincreased risk for low bone density. A family his-tory of frequent fractures should prompt consider-

6 MAYO CLINIC|ClinicalUpdate

Figure 1.Trauma-related fracture of the distal radius. A, Radius shortly afterinjury. B and C, Subsequent normal bone healing.

Points to Remember

Approximately one-third of childrenwill sustain a fracture by the age of 18years. Most of these children do nothave an underlying metabolic bonedisorder that requires evaluation andtreatment.

Multiple fractures, unexplained frac-

tures (especially in infants), atypicalfractures (such as vertebral compres-sion fractures), low-trauma fractures,and a family history of metabolic bonedisease are all red flags that shouldprompt further investigation.

Childhood Fractures: When to Worry

results from these 2 pivotal multicenter trialshave demonstrated the efficacy and safety ofthese devices.

Predicting Seizures: Devices on the Horizon

Not knowing when a seizure will occur is one ofthe most debilitating aspects of epilepsy. Patientsmay have only 4 or 5 seizures a month, eachlasting a few minutes. But those few minutes

mean they cant drive, and they may be afraidto go out in public for fear of having a seizure,which can lead to social isolation.

The recent discovery that seizurelike eventscan occur in pathologic microdomains (ie,microseizures) in humans adds to a growing

body of evidence that seizures may begin beforethey are evident clinically. In the future, devicesmay be able to provide patients with warningsthat a seizure is about to occur or, possibly, toprevent a seizure.

Future Applications

The future of seizure prevention rests onunderstanding the mechanisms underlying

seizure generation. As knowledge in these areasadvances, future clinical applications includeimprovements in epilepsy surgery and thedevices delivering neurostimulation and thepossible development of algorithms that identifyperiods of increased probability of seizures.

A B C

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ation of inherited conditions, such as osteogenesisimperfecta.

Unexplained fractures, especially in infants,mandate consideration of nonaccidental traumaif an underlying bone disorder is not clearly

identified. Poor fracture healing also should raisesuspicion of an underlying bone disease. Mostfractures in children show radiographic evidenceof callus formation by 3 to 6 weeks. By 8 to 12weeks, most fractures are united radiographi-cally and no longer require any form of externalimmobilization.

Evaluation

A basic laboratory evaluation includes suchtests as serum calcium, phosphorus, creatinine,parathyroid hormone, 25-hydroxyvitamin D,and urine calcium determination. The serum

concentration of 25-hydroxyvitamin D is the besttest to determine whether adequate vitamin Dstores are present. The serum concentration ofthe active metabolite of vitamin D (1,25-dihy-droxyvitamin D) can be variable in children withnutritional vitamin D deficiency (low concentra-tion of 25-hydroxyvitamin D) and is usually nothelpful in determining vitamin D status. Growingchildren have a markedly greater serum alkalinephosphatase concentration than adults, andan appropriate reference range for age and sex

should be used. Alkaline phosphatase level willusually be elevated in the context of a recentlysustained, healing fracture. Clinical findings sup-porting a secondary cause of poor bone health(Box) should also guide the evaluation.

Dual-energy x-ray absorptiometry (DXA) is awidely available technique for determining bonedensity. Children with frequent, low-trauma, oratypical fractures are good candidates for bone

density measurement. Children with disordersassociated with low bone density, such as inflam-matory bowel disease, may also benefit frombone density determination. DXA measurementsin children should be performed in centers withexperience obtaining and interpreting the scan.

Prevention

Adequate intake of calcium and vitamin D is thefoundation of any treatment program to promotebone health. The American Academy of Pediatricscurrently recommends that all children receive400 IU of vitamin D daily, which can be obtained

through the diet (mainly milk), supplementation,or both. The optimal amount of vitamin D intakeor serum vitamin D concentration for children hasnot yet been clearly defined. Avoiding excessivecaffeine and soda intake should also be advised.

Bisphosphonates may be beneficial in selectchildren with low bone density and fractures. Theyare not approved by the Food and Drug Admin-istration for use in children and should only begiven under the supervision of a clinician experi-enced with their use in children.

For consultation about childhood fractures and

whether further evaluation is needed, please con-tact the Mayo Clinic Referring Physician Service(see page 8 for contact information).

MAYO CLINIC|ClinicalUpdate

Box. Conditions Associated With LowBone Density or Fractures in Children

Anorexia nervosa

Anticonvulsant use

Dietary calcium deficiency

Glucocorticoid excess

Growth hormone deficiency

Homocystinuria

Hyperthyroidism

Hyperparathyroidism

Idiopathic juvenile osteoporosis

Immobilization

Leukemia

Malabsorption (eg, celiac disease,inflammatory bowel disease)

Neuromuscular disorders

Osteogenesis imperfecta

Osteoporosis pseudoglioma syndrome

Vitamin D deficiency

Figure 2.Incidence of specific fracture types in children.Tib-Fib indicates tibia and/or fibula. Data from Cooper C,Dennison EM, Leufkens HGM, Bishop N, van Staa TP.Epidemiology of childhood fractures in Britain: a study usingthe general practice research database. J Bone Miner Res. 2004Dec;19(12):1976-81.

Girls

Fractures

per10,0

00P

ersonsyears

Boys

Childhood Bone Fractures

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Mayo ClinicClinical Update

Medical Editor:

cott C. Litin, MD

Editorial Board:

Robert P. Shannon, MD

Douglas M. Peterson, MD

linical Updateis written for physicians and should

e relied upon for medical education purposes only.

does not provide a complete overview of the topics

overed and should not replace the independent

udgment of a physician about the appropriateness

r risks of a procedure for a given patient.

MC2024-0311

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PatientCare

InpatientVideo-EEGMonitoringforEpilepsyContinuousvideo-EEGmonitoring(inpatient)helpslocalizeseizurefocus,determine

seizuretype,andquantifythenumberofseizuresinpatientswithintractablerecurrentseizuresandthosewithanunconfirmedseizurediagnosis.

OptimizingtheFunctionalPerformanceofCancerSurvivors

Thereisagrowingunderstandingof theimportanceofexerciseandrehabilitationfor

cancersurvivors.Physical Medicinespecialistscanhelppatientsmanagethenegativelong-termsequelaeofcanceranditstreatmentsandobtainamoresatisfying,high-qualityrecovery.

NewEndoscopicTreatmentforSevereGastrointestinalBleeding

Endoscopicultrasound-guidedtherapyappearstobeasafeandeffectivetreatment

forpatientswithseveregastrointestinalbleedingforwhomconventionaltherapies

havefailed.Thetherapyinvolvesinjectingvariousagentsdirectlyintothesourceto

stopthebleeding.

LessCanBeMoreWhenTreatingSomeKidneyCancersAMayoClinicstudysuggeststhatremovingtheentirekidneyfromyounger patients

withsmall kidneytumorsmayleadtodecreasedoverall survival comparedwithan

operationthat removesthetumorbutleavesthekidneyintact.

Research

ProtectingKidneyCellsfromInjuryIn1992,Dr.KarlNath'sresearchteamdiscoveredthecapacityofhemeoxygenase

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