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

The Clinic INSIDE THIS ISSUE The Challenge Most thyroid nodules—about 95%—are entirely Points to Remember benign. However, identifying the occasional 2 Perspectives on requires careful evaluation of every • Thyroid nodules are common, with the Continuing nodule found, using a combination of clinical palpable nodules found in 4% to 7% of Evolution of Therapy assessment, neck , imaging the adult US population and solitary or for Atrial Fibrillation (Figure 1), and, in many cases, analysis of a biopsy multiple nodules found at much higher specimen (Figure 2, see page 2). rates during ultrasonographic screening. Sometimes, thyroid nodules are noticed by 4 Advances in Seizure the patient or a family member or are discovered • Early diagnosis improves the likelihood Prevention and Prediction during a routine physical examination. They rarely that a cancer can be discovered while still cause symptoms, unless they are large enough contained within the thyroid gland and to interfere with swallowing. Thyroid cancer can amenable to surgery. 6 Childhood Fractures: invade and damage the recurrent laryngeal nerve, When to Worry causing hoarseness. Such invasion and damage are • Mayo Clinic endocrinologists opened the infrequent, however. Most nodules are incidental Thyroid Nodule Clinic in 2009, providing A discoveries, and now many more such nodules are coordinated care, a thorough assessment, discovered because of the increased use of imaging and a definitive diagnosis completed at a performed for other reasons, including carotid single visit. ultrasonography, neck or chest computed tomog- raphy, magnetic resonance imaging, and even positron emission tomography. Early and prompt diagnosis improves the likelihood that a cancer can be discovered while still contained within the thyroid gland and amenable to surgery. Once soft tissue invasion has occurred or lymph nodes are extensively involved, the chance of surgical cure drops substantially and there is a much higher incidence of meta- static spread of these late-stage cancers. Prompt diagnosis is also important for the patient because the finding of a nodule often raises fears about cancer and a delay in diagnosis fuels the concern and anxiety. The most recent set of guidelines from the American Thyroid Association specifies that the evaluation of a thyroid nodule should include clinical assessment to determine the number, size, and location of all nodules within the gland; mea- surement of serum thyrotropin (TSH) to exclude Figure 1. Ultrasound-guided fine-needle aspiration ; ultrasonography to assess the of a thyroid nodule. nodule for features of malignancy; and fine-needle aspiration (FNA) of nodules that meet the appro- priate size and ultrasound criteria. However, not every nodule needs to be biopsied, so the clinical scenario and ultrasound features are important in selecting the appropriate nodule for biopsy. Mayo Clinic endocrinologists opened the Thyroid Nodule Clinic in 2009 to streamline this evaluation and provide a coordinated approach that meets the needs of patients with thyroid nod- ules. The Thyroid Nodule Clinic provides a 1-stop thyroid nodule evaluation that includes a focused clinical assessment, ultrasound evaluation, and FNA—all typically performed within a 60-minute appointment at a single visit. The ultrasound allows Mayo staff to select both palpable and impalpable nodules for biopsy and target the most suspicious nodule, which is not always the largest nodule. Using ultrasound guidance for those biopsies, Mayo Clinic endocrinologists typically perform more than 600 biopsies per year and expect a clear diagnosis in more that 95% of cases at the first attempt. Because of the coordinated assessment provided through the Thyroid Nodule Clinic, FNA Figure 2. Thyroid cytology of a specimen of papil- results are typically available within 2 hours, so the lary thyroid carcinoma showing papillary archi- patient usually receives a definitive result of the tecture and nuclear enlargement with crowding of entire assessment within 4 hours. Patients with a classic papillary thyroid cancer (Papanicolaou stain, benign nodule can be reassured, and those with original magnification ×100). a malignant or suspicious nodule can be offered an appropriate surgical referral, often within 24 provide for these patients, while lowering costs, hours. Mayo Clinic endocrinologists believe that improving efficiency, and providing a better service the Thyroid Nodule Clinic improves the care they to referring physicians.

Perspectives on the Continuing Evolution of Therapy for Atrial Fibrillation

Scope of the Problem ing heart disease, may have more persistent or Atrial fibrillation (AF) remains the leading even chronic AF. Nevertheless, the previously arrhythmia in North America, both in num- held belief that most paroxysmal AF ultimately bers of patients affected and the frequency progresses to a chronic form has been ques- of accompanying sequelae. The prevalence tioned. Recent studies have suggested that pro- continues to increase, despite progress in the gression occurs in only 20% to 40% of patients treatment of contributing factors. Although over the course of 3 to 5 years, although longer- 1% of individuals in their 60s may have AF, the term data are lacking. prevalence increases to 10% to 12% in individ- uals older than 80 years. Currently 2.5 million Drug Therapy for AF Americans have AF, but with the aging popula- Because of stroke risk, most patients require tion and improved cardiovascular survival, this some form of antithrombotic therapy in the number may increase to 5 million or 6 million form of aspirin, warfarin, or dabigatran. Those by the year 2050. patients with no risk factors may completely In most patients, AF is initially paroxysmal; forgo antithrombotic therapy, while recently other patients, particularly those with underly- published guidelines suggest that therapy with

2 MAYO CLINIC | ClinicalUpdate aspirin alone is adequate in patients at low risk with a CHADS score less than 1. Patients Points to Remember with several risk factors (age >75 years, hyper- tension, diabetes, prior stroke or transient • Atrial fibrillation (AF) is an increasing ischemic attack, left ventricular dysfunction) burden on the global health care system are at higher risk, necessitating anticoagulation because of the numbers of patients therapy with warfarin. affected, the impact of stroke, and the While relatively rare in the absence of other cost of both inpatient and outpatient heart disease, the possibility of an AF contribu- therapy. tion to ventricular dysfunction should be con- sidered in patients who have a rapid ventricular • Because of stroke risk, most patients response rate and reduced ejection fraction. with AF require some form of anti- Establishing appropriate rate control, however, thrombotic therapy in the form of requires some assessment of rate during rest aspirin, warfarin, or the newer direct and exertion. While most guidelines recommend antithrombin agents such as dabigatran. that resting rates during AF be less than 90 to 100 bpm, a recent large clinical trial has shown • A number of observational studies have that a resting rate less than 110 bpm is adequate shown that ablation is of benefit in for rate control. During exercise, the heart rate eliminating AF, reducing its frequency, should be maintained at less than 120 bpm. and improving patients’ quality of life. Restoration of normal sinus rhythm may be the most effective means of rate control. A number of studies have shown the useful- tality may accompany AF, comparative studies ness of membrane-active, antiarrhythmic drug examining the utility of rate vs rhythm control therapy for maintaining sinus rhythm. Approxi- therapy have had disappointing results. mately 30% to 40% of patients treated with antiarrhythmic therapy achieve control over the Nonpharmacologic Therapy for AF course of 1 year of follow-up. These data have A number of observational studies have shown been validated by larger comparative clinical that AF ablation is of benefit in eliminating AF, trials. Similar results have been reported in reducing its frequency, and improving patients’ studies designed to compare rate and rhythm quality of life (Figure). In most studies, 75% control therapy. Although an increase in mor- to 85% of patients with paroxysmal AF have been rendered free of this arrhythmia over the course of 1 year of observation. Even in patients with persis- tent or chronic AF after ablation, the incidence of the arrhythmia is significantly decreased in 10% to 20%. When Mayo researchers reviewed outcomes of ablation performed at Mayo Clinic, they found (over 2 years of follow- up) that the response to ablation was excel- lent in more than 75% of patients with par- oxysmal AF. Patients with persistent and chronic AF likewise have shown enhanced Figure. Computer-generated map of left atrial activation. Red dots indicate benefit, although ablation sites. a more aggressive

MAYO CLINIC | ClinicalUpdate 3 ablative approach has been required. In those notable benefit in patients with underlying with paroxysmal AF, ablation for the isola- dilated cardiomyopathies. In many patients, tion of pulmonary veins may be sufficient, not only was AF eliminated, but a substantial while wider-area circumferential ablation with improvement in ejection fraction was observed, additional linear ablation or energy delivery particularly in those with nonischemic left directed at the underlying substrate has been ventricular dysfunction. required. Additional review demonstrated

Clinical Trials

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

Advances in Seizure Prevention and Prediction

The earlier seizure activity is detected, the better captures the activity of millions of neurons and the chance of preventing it. For several years, hundreds of cortical columns (Figure). Mayo Clinic neurologists and their neurosurgi- This research revealed that isolated brain cal colleagues have been working to pinpoint regions the size of cortical columns do, indeed, the exact moment and the precise location of show evidence of seizure activity (microsei- seizure generation. zures) in humans. The investigators found that microseizures occurred most often in patients Isolating the Where and When of Microseizures with epilepsy but also occurred, although Three years ago, using microelectrodes 40 rarely, in control patients without epilepsy. This microns in diameter, or thinner than a human latter finding demonstrates that pathologic hair, Mayo Clinic researchers began recording oscillations can occur even in people who do electroencephalographic (EEG) activity from not have epilepsy. brain regions the size of cortical columns at How do microseizures transition to clinical frequencies beyond the limits of standard EEG seizures in patients with epilepsy? Mayo Clinic recordings. Cortical columns, the smallest func- research findings support the hypothesis that in tional unit in the cortex, are approximately 300 patients with epilepsy, individual microdomains microns across and contain from 1,000 to 7,500 the size of cortical columns generate frequent neurons. In perspective, a typical EEG electrode hypersynchronous discharges, which recruit

4 MAYO CLINIC | ClinicalUpdate 40 µm

150 µm

Clinical contact Microwire a e e l t l m s p Multiunit p a p DC Ultraslow Berger bands m p i i

F activity a r R G

10-3 10-2 10-1 100 101 102 103 104

Figure. Top, The large volume sampled by the millimeter-scale clinical electrode (about 1 million neurons) vs a 0.04-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. other columns of neurons. Similar, noncolumnar groupings of neurons have been identified in Points to Remember the rat hippocampus by researchers at UCLA and are known as pathologically interconnected • Mayo Clinic neurologists and neurosur- neuron (PIN) clusters. These PIN clusters can geons have been working to pinpoint the be considered microdomains of epileptogenesis exact moment and the precise location of or seizure initiation. When a critical volume of seizure generation. microdomain activity is reached, a large-scale seizure is generated. This explanation can be • The recent discovery that seizurelike referred to as the sick column hypothesis. events can occur in pathologic micro- Clinical EEG recordings do not probe the domains (ie, microseizures) in humans spatial and temporal scales of microdomain adds to a growing body of evidence activity, which makes early detection difficult. that seizures may begin before they are This hypothesis may explain why some patients evident on clinical recording systems and do not respond to first-generation responsive well before patients have symptoms. stimulation devices designed to detect and abort seizures. • Initial results from 2 pivotal multicenter trials have demonstrated the efficacy and Update on Implanted Devices to safety of implantable epilepsy devices Detect and Abort Epileptic Seizures that use electrical stimulation for reduc- Two new implantable epilepsy devices that use ing seizure frequency in patients with electrical stimulation are undergoing multi- medically intractable partial epilepsy. center trials for treatment of medically refractory epilepsy. One device uses electrical stimula- tion of the anterior nucleus of the thalamus seizures. Another device under investigation is to modulate the brain activity and prevent the responsive neurostimulator system. Initial

MAYO CLINIC | ClinicalUpdate 5 results from these 2 pivotal multicenter trials body of evidence that seizures may begin before have demonstrated the efficacy and safety of they are evident clinically. In the future, devices these devices. may be able to provide patients with warnings that a seizure is about to occur or, possibly, to Predicting Seizures: Devices on the Horizon prevent a seizure. Not knowing when a seizure will occur is one of the most debilitating aspects of epilepsy. Patients Future Applications may have only 4 or 5 seizures a month, each The future of seizure prevention rests on lasting a few minutes. But those few minutes understanding the mechanisms underlying mean they can’t drive, and they may be afraid seizure generation. As knowledge in these areas to go out in public for fear of having a seizure, advances, future clinical applications include which can lead to social isolation. improvements in epilepsy surgery and the The recent discovery that seizurelike events devices delivering neurostimulation and the can occur in pathologic microdomains (ie, possible development of algorithms that identify microseizures) in humans adds to a growing periods of increased probability of seizures.

Childhood Fractures: When to Worry

Childhood bone fractures are common and often cause concern for patients, parents, and clinicians. Points to Remember Understanding the typical timing and types of fractures is helpful when deciding who needs • Approximately one-third of children further evaluation for potential underlying disease. will sustain a fracture by the age of 18 The rate of fractures increases substantially during years. Most of these children do not puberty for both boys and girls, but to a greater have an underlying metabolic bone degree for boys. The peak incidence of fractures disorder that requires evaluation and in girls occurs around 10 to 12 years of age and in treatment. boys around 13 to 15 years of age. Forearm frac- tures are by far the most common type of fracture • Multiple fractures, unexplained frac- during childhood (Figure 1). However, vertebral tures (especially in infants), atypical compression fractures are distinctly uncommon in fractures (such as vertebral compres- children and should always be a cause for concern sion fractures), low-trauma fractures, and additional evaluation (Figure 2). and a family history of metabolic bone Children with 1 or 2 traumatic fractures are disease are all red flags that should prompt further investigation.

unlikely to have an identifiable disorder and do not routinely require further evaluation. Obtain- ing a detailed history about the circumstances surrounding a fracture is important in determining the level of concern. Multiple fractures, atypical fractures (such as vertebral compression frac- A B C tures), low-trauma fractures, and a family history of metabolic bone disease are all red flags that should prompt further investigation. Children with inflammatory bowel disease, celiac disease, chronic glucocorticoid exposure, neuromuscular disorders, and others (Box) warrant special atten- tion to optimize bone health, since they are at Figure 1. Trauma-related fracture of the distal radius. A, Radius shortly after increased risk for low bone density. A family his- injury. B and C, Subsequent normal bone healing. tory of frequent fractures should prompt consider-

6 MAYO CLINIC | ClinicalUpdate should be used. Alkaline phosphatase level will Box. Conditions Associated With Low usually be elevated in the context of a recently Bone Density or Fractures in Children sustained, healing fracture. Clinical findings sup- porting a secondary cause of poor bone health • Anorexia nervosa (Box) should also guide the evaluation. • Anticonvulsant use Dual-energy x-ray absorptiometry (DXA) is a widely available technique for determining bone • Dietary calcium deficiency density. Children with frequent, low-trauma, or • Glucocorticoid excess atypical fractures are good candidates for bone • Growth deficiency density measurement. Children with disorders associated with low bone density, such as inflam- • Homocystinuria matory bowel disease, may also benefit from • Hyperthyroidism bone density determination. DXA measurements • Hyperparathyroidism in children should be performed in centers with experience obtaining and interpreting the scan. • Idiopathic juvenile osteoporosis • Immobilization Prevention • Leukemia Adequate intake of calcium and vitamin D is the foundation of any treatment program to promote • Malabsorption (eg, celiac disease, bone health. The American Academy of Pediatrics inflammatory bowel disease) currently recommends that all children receive • Neuromuscular disorders 400 IU of vitamin D daily, which can be obtained through the diet (mainly milk), supplementation, • Osteogenesis imperfecta or both. The optimal amount of vitamin D intake • Osteoporosis pseudoglioma syndrome or serum vitamin D concentration for children has • Vitamin D deficiency not yet been clearly defined. Avoiding excessive caffeine and soda intake should also be advised. Bisphosphonates may be beneficial in select children with low bone density and fractures. They ation of inherited conditions, such as osteogenesis are not approved by the Food and Drug Admin- imperfecta. istration for use in children and should only be Unexplained fractures, especially in infants, given under the supervision of a clinician experi- mandate consideration of nonaccidental trauma enced with their use in children. if an underlying bone disorder is not clearly For consultation about childhood fractures and identified. Poor fracture healing also should raise whether further evaluation is needed, please con- suspicion of an underlying bone disease. Most tact the Mayo Clinic Referring Physician Service fractures in children show radiographic evidence (see page 8 for contact information). of callus formation by 3 to 6 weeks. By 8 to 12 weeks, most fractures are united radiographi- cally and no longer require any form of external immobilization. Childhood Bone Fractures

Evaluation Boys Girls A basic laboratory evaluation includes such tests as serum calcium, phosphorus, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and urine calcium determination. The serum concentration of 25-hydroxyvitamin D is the best test to determine whether adequate vitamin D stores are present. The serum concentration of Fractures per 10,000 Persons–years Fractures the active metabolite of vitamin D (1,25-dihy- droxyvitamin D) can be variable in children with nutritional vitamin D deficiency (low concentra- Figure 2. Incidence of specific fracture types in children. tion of 25-hydroxyvitamin D) and is usually not Tib-Fib indicates tibia and/or fibula. Data from Cooper C, helpful in determining vitamin D status. Growing Dennison EM, Leufkens HGM, Bishop N, van Staa TP. children have a markedly greater serum alkaline Epidemiology of childhood fractures in Britain: a study using phosphatase concentration than adults, and the general practice research database. J Bone Miner Res. 2004 an appropriate reference range for age and sex Dec;19(12):1976-81.

MAYO CLINIC | ClinicalUpdate 7 Physician Update Mayo Clinic Clinical Update

Medical Editor: Scott C. Litin, MD

March 2008 Regional News Editorial Board: Welcome to the first issue of Physician Update e-mail newsletter. This newsletter will offer access to articles from the Clinical Update print publication, plus other items of � Mayo Clinic in Arizona Robert P. Shannon, MD general interest to a physician audience. � Mayo Clinic in Florida Douglas M. Peterson, MD � Mayo Clinic in Minnesota Patient Care Clinical Trials Inpatient Video-EEG Monitoring for Epilepsy Clinical Trials Open to Patient Continuous video-EEG monitoring (inpatient) helps localize seizure focus, determine Recruitment seizure type, and quantify the number of seizures in patients with intractable Clinical Update is written for physicians and should recurrent seizures and those with an unconfirmed seizure diagnosis. Referring a Patient be relied upon for medical education purposes only. Arizona Referrals Optimizing the Functional Performance of Cancer There is a growing understanding of the importance of exercise and rehabilitation for (866) 629-6362 It does not provide a complete overview of the topics Survivors cancer survivors. Physical Medicine specialists can help patients manage the Florida Referrals negative long-term sequelae of cancer and its treatments and obtain a more covered and should not replace the independent (800) 634-1417 satisfying, high-quality recovery. judgment of a physician about the appropriateness Minnesota Referrals (800) 533-156 or risks of a procedure for a given patient. 4 New Endoscopic Treatment for Severe Gastrointestinal See Medical Professionals Endoscopic ultrasound-guided therapy appears to be a safe and effective treatment Bleeding page for more physician for patients with severe gastrointestinal bleeding for whom conventional therapies have failed. The therapy involves injecting various agents directly into the source to resources. stop the bleeding. Comments?

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