What is the Remission Rate for Antithyroid Drug Treatment for Hyperthyroidism in Children?

Patient Presentation
A 12-year-old female came to clinic for her health maintenance examination. She had no complaints and her mother had no concerns until her daughter was weighed and there was a slower increase in her weight over the year. The patient had normal eating and activity and they denied weight loss. She was sleeping well without night sweats, had normal elimination and was doing well in school. She had a history of being a more anxious child but this was unchanged. The family also denied any skin or hair changes. The past medical history was negative except for some normal acute illnesses. The family history was positive for diabetes, stroke and arthritis. The review of systems was otherwise normal.

The pertinent physical exam showed a well-appearing Asian female with a heart rate of 108 beats/minute, blood pressure of 106/56, respiratory rate of 20 and she was afebrile. Her height was 90% and tracking normally. Her weight had always been at the 95% and was now at the 90%. HEENT revealed very subtle proptosis with the eyelids still covering part of the irises. Her thyroid was diffusely enlarged without palpable nodes and there was no murmur over the organ. She had some shoddy anterior cervical adenopathy. Heart was mildly tachycardic without a murmur. She had normal skin without hair loss or increased perspiration. Neurological examination found a mild tremor of her hands when they were outstretched and she seemed somewhat anxious to the examiner. She also had mild hyperreflexia in all extremities. The laboratory evaluation showed a thyroid stimulating hormone of < 0.1 microU/mL (normal 0.5-4.7 microU/mL), and a free T4 of 3.9 ng/dL (normal 0.8-2.7 ng/dL).

The diagnosis of hyperthyroidism with thyrotoxicosis was made and pediatric endocrinology was consulted by telephone. An appointment for evaluation was made for 2 days later. The radiologic evaluation of a thyroid ultrasound found a mildly diffusely enlarged organ without nodules. Additional laboratory testing was positive for TSH receptor antibodies consistent with Grave’s disease. She began treatment with the antithyroid drug methimazole.

Discussion

The thyroid gland secrets two hormones – T4 which is a prohormone and T3 which is the biologically active hormone. Receptors for T3 are found in nearly all body tissues. T3 regulates metabolism and energy production. Organs most affected are the heart, liver and central nervous system as well as growth of the fetus and child. Hyperthyroidism is common with a prevalence rate of about 1-2% for women and 0.2% for men. The most common cause of thyrotoxicosis is Grave’s disease where autoantibodies to thyroid stimulating hormone (TSH) exist. These autoantibodies attach to thyroid tissue TSH receptors and increase the production of T4 and T3. Grave’s disease often co-occurs with other autoimmune diseases such as diabetes, Hashimoto’s thyroiditis, rheumatoid arthritis and also with Turner’s, Down’s and Di George syndromes. Children only account for about 1-2% of all patients with Grave’s disease.

Signs and symptoms of thyrotoxicosis include:

  • Cardiovascular – tachycardia, palpitations, shortness of breath, arrhythmias, hypertension and high output failure
  • Eyes – soreness and irritation, staring, eyelid retraction, periorbital edema, ophthalmoplegia, conjunctival injection
  • Gastrointestinal – weight loss, increased appetite
  • Genital system – Oligomenorrhea, decreased fertility, reduced libido in men
  • Musculoskeletal – muscle weakness or tremor, muscle wasting
  • Neck – neck swelling
  • Nervous system – hyperactivity, anxiety, concentration problems, fatigue and nervousness, hyperreflexia
  • Skin and Hair – heat intolerance, increased perspiration, warm, moist skin, thinning or hair loss

Treatment options for thyrotoxicosis includes:

  • Antithyroid drugs (ATD) – The most common drugs used are carbimazole and its active metabolite methimazole (MMI) and propylthiouracil. Propylthiouracil is usually not used because of the risk of severe hepatitis.
    MMI is the most common first line drug used and is taken orally daily. Side effects include hives, rashes, gastrointestinal problems and arthritis.
    The goal is to create a euthyroidism condition which then stops the autoimmune response and the thyrotoxicosis. This is defined as the clinical remission.

  • Radioactive iodine (RAI) – it is often used as a more radical treatment if clinical remission cannot be obtained or sustained with ATDs. It may be used as a first line treatment for patients with a large goiter or opthalmopathy.
    A single dose if often used, but the patient may need additional treatments. It is not used in young children, or pregnant or lactating mothers because of the potential risk of neoplasia.

  • Surgery – total or near total thyroidectomy is the most common surgery. RAI may be needed if hyperthyroidism continues after surgery. Surgery causes hypothyroidism and the need for lifelong replacement thyroid medication.

Learning Point
Only about 30% of children achieve clinical remission with ATD treatment, whereas 60-70% of adults achieve remission.
Longer term ATD may be necessary to achieve and keep children in clinical remission. If remission cannot be achieved or sustained, then other treatment is necessary.

Favorable predictors of Grave’s disease remission are older age group, presence of other autoimmune conditions and duration of ATD treatment more than 2 years.
Unfavorable predictors are younger age, large goiter, non-Caucasian race, biochemical severity and ATD medication non-compliance.

Questions for Further Discussion
1. How is Hashimoto’s thyroiditis different from Grave’s Disease?
2. What causes thyrotoxicosis?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Hyperthyroidism

.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet. 2012 Mar 24;379(9821):1155-66.

Leger J, Carel JC. Hyperthyroidism in childhood: causes, when and how to treat. J Clin Res Pediatr Endocrinol. 2013;5 Suppl 1:50-6.

Leger J, Kaguelidou F, Alberti C, Carel JC. Graves’ disease in children. Best Pract Res Clin Endocrinol Metab. 2014 Mar;28(2):233-43.

Author

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What Are Considerations for a Dancer to Begin Pointe Training?

Patient Presentation
During a discussion among several pediatricians about readiness for various sports training, one pediatrician asked what her colleagues did for young girls who wanted to start ballet dancing on pointe. There were a few general comments but nothing substantial except one person said that she thought there was a recent paper about the topic. Through a literature search, the pediatrician found a paper and then shared the information with her colleagues.

Discussion
Ballet dancing originated in Italy and was patronized by Queen Catherine de Médici of France who began the first ballet school in 1581. King Louis XIV of France was a major patron as he founded the Académie Royale de Danse in 1661. The Sun King was a performing dancer himself. The first documentation of a dancer performing en pointe (ie on pointe or on the tips of the toes) was in 1832 by Marie Talioni performing in La Sylphide.

Dancers are highly trained athletes and when dancing on pointe have the special appeal of appearing to effortlessly defy gravity. Ballet dancing shoes are slippers (made of soft leather, canvas, or satin, that has flexible, thin usually leather soles that that hug the foot), demi-pointe (similar to pointe shoes except for a smaller toe box and no shank in the arch, used more in Europe than United States) and pointe shoes. Pointe shoes have a toe box made of layers of paper, fabric and glue with a squared off end on the toe (i.e. the platform) that the dancer stands on and which provides the majority of the support. The shank is usually made of leather and supports the arch. Fabric (usually satin) surrounds these main pieces and the shoe is attached to the foot by elastic near the ankle and satin ribbons. A professional ballerina once described it to the author as “dancing in a Dixie® cup”. Pointe shoes are highly specialized equipment that needs a trained specialist to properly fit. The fit is extremely important for long-term injury prevention.

When dancing in ballet slippers, the relevé (elevated) foot position places the pressure on the metatarsals at 4x body weight. In demi-pointe or pointe shoes, the pressure is on the toes at 12 times body weight. The “ideal” foot is the “Giselle” foot where the first 3 toes are of relatively the same length allowing for distribution of the force across a greater area. Dancers with different anatomy still can be successful though. Dancing on pointe requires complete plantarflexion of the foot and ankle to 90° or more and is stabilized as the ankle “locks” into position with the subtalus locking between the tibia and calcaneus.

The change from dancing on the metatarsal heads to dancing on the toes seems like it should increase the likelihood of injuries but studies have not shown this. Specifically one study which looked at recreational (non-professional but serious) dancers before pointe shoes and after pointe shoe use did not find an increase in the likelihood of injuries during the past month or past 3 years. Longer term data was not evaluated. Also no studies have found that dancing on pointe before growth plate closure is linked to growth plate arrest, therefore radiographs are unnecessary to use as a factor for determining pointe readiness. Also the growth plates in these bones do not close until 18-20 years well after most dancers are already successfully dancing on pointe.

The quality of the preparatory training is paramount and experienced, ballet-specific instructors are important for preparation, decision making for placement into pointe shoes and training dancers using them. European ballets schools tend to be more rigorous with formalized systems of training and qualified instructors. This is not always true in the United States where dance studios may provide instruction in many different dance types and may not have instructors with specific training as ballet instructors. Studios can be placed under pressure to place dancers into pointe shoes because of the psychological aspirations of the dancer and family, and because of the financial pressures to do so.
As with any athletic activity, training and coaching under the direction of professional dancers with ballet-specific training is the most appropriate for dancers going on pointe.

Learning Point
There is no specific testing that can determine when a dancer can successfully transition to on pointe. One study found that 3 functional tests that help evaluate strength, flexability, alignment, postural control and balance correlated with teacher subjective rating for on pointe dancing readiness. These 3 are:

  • Airplane test – The dancer stands on one leg. The trunk is bent forward while the non-weight bearing leg is elevated behind them. The arms are extended in front creating the look of an airplane flying, or the letter “T” from the side or a Warrior III yoga pose.
    The arms are lowered toward the ground, and the weight bearing leg is bent or folded in a controlled manner (i.e. plié) (<a href="View images here)

  • Sauté test – The dancer stands in a neutral pelvis, upright stable trunk position with arms at the side. The knees are bent and the dancer does a short jump into the air landing with control and a appropriate bending on the knees to absorb the shock. (<a href="View video here)
  • Topple test – a pirouette or turn is performed on one leg. The non-weight bearing leg’s hip is abducted and flexed with the foot aligned next to the weight being leg’s knee. The dancer should be able to do this in the relevé (elevated) foot position.(<a href="View video here“)

The great ballet choreographer George Balanchine once said that it took 4 or more years of serious training before a dancer was ready and with serious training starting around 7-8 years, this would be around 11-12 years or more.

A 2009 study ended with these considerations for pointe readiness. “A dancer should have adequate mental maturity and physical capability to begin dancing on pointe, rather than requiring a specific age or number of years. The dancer should have adequate flexibility in the foot and ankle complex to achieve full pointe, sufficient training to achieve proper placement, strength to achieve postural control and balance, proprioception, alignment, technique, mastery of movement, the ability to learn and perform choreography, and the ability to listen to apply corrections.” These ideas seem appropriate for any athlete including dancers.

Questions for Further Discussion
1. What resources do you have available locally to evaluate dancers for on pointe readiness?
2. What history questions should be gathered to evaluate dancers for on pointe readiness?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Exercise and Physical Fitness.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Nunes NM, Haddad JJ, Bartlett DJ, Obright KD. Musculoskeletal injuries among young, recreational, female dancers before and after dancing in pointe shoes. Pediatr Phys Ther. 2002 Summer;14(2):100-6.

Shah S. Determining a young dancer’s readiness for dancing on pointe. Curr Sports Med Rep. 2009 Nov-Dec;8(6):295-9.

Richardson M, Liederbach M, Sandow E. Functional criteria for assessing pointe-readiness. J Dance Med Sci. 2010;14(3):82-8.

Pearson SJ, Whitaker AF. Footwear in classical ballet: a study of pressure distribution and related foot injury in the adolescent dancer. J Dance Med Sci. 2012;16(2):51-6.

Author

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What Causes Muscle Cramps?

Patient Presentation
A 10-year-old female came to clinic for her health maintenance examination. Her mother reported that she had night leg pain about 2-3 times per year over the past couple of years, but she had had one episode during the week before. The daughter would cry out and her mother would get there within 1-2 minutes. The girl would just say that her legs hurt and wanted them rubbed after which she would sleep without re-awakening. Once the mother was able to come to the bedside sooner and she was having unilateral muscle cramping. Again the mother massaged her leg and the daughter went back to sleep. She had no other sleep problems and had no problems during the day. Her mother said she didn’t seem to be restless when sleeping when she checked on her at night. She was a dancer but they were not aware of any increase in activity or changes in dietary intake on the days the episodes occurred. She and her mother denied that she sat or slept in abnormal positions. She had a good general diet and seemed to drink an appropriate amount of fluid. The past medical history showed a healthy female with some xerosis. The family history was negative for any neurological problems, sleep disorders, or leg cramping or pain. The review of systems was otherwise negative.

The pertinent physical exam showed a healthy female with normal vital signs. Her growth parameters showed a weight and height of 10-25% with normal velocities. HEENT was normal including her thyroid. Pubertal development was Tanner stage 1. Musculoskeletal examination was normal including muscle bulk. Palpation of the muscles did not produce any pain. Chvostek’s sign was negative and a Trousseau’s sign was not attempted.

The diagnosis of intermittent nocturnal leg pain possibly due to muscle cramping was made. The pediatrician discussed with the family that most leg pain and muscle cramps are idiopathic. Her history and physical examination did not reveal any other obvious causes of leg pain or muscle cramps and so the pediatrician recommended to monitor her. He recommended continuing to make sure she ate a healthy diet with calcium, potassium and magnesium foods and to drink an appropriate amount of fluid. He showed them some gentle stretching exercises that she could do before bed and told her to untuck the bedding to prevent the legs from having undue pressure put on them. They were to also keep a diary of the episodes and to call after the next one to discuss it.

Discussion
Leg pain is a relatively common problem in children. Usually it is idiopathic in origin but can be the sign of organic pathology. The differential diagnosis can be found here.

Noctural legs cramps have been found to occur in about 7% of healthy children. They start after age 8 and peak at 16-18 years of age. Cramps that are idiopathic are unilateral, and those with organic causes can be uni- or bi-lateral. Most episodes last only a few minutes but those lasting longer than 10 minutes are more likely to have an organic etiology.

Learning Point
The differential diagnosis of nocturnal muscle cramping in children includes:

  • Idiopathic – most common
  • Endocrine
    • Diabetes
    • Hypothyroidism
    • Hyperthyroidism
  • Exercise
    • Myalgia due to overuse
    • Compartment syndrome
    • Myoglobinuria
  • Fluids and Electrolytes
    • Poor fluid intake
    • Hypocalcemia
    • Hypokalemia
    • Hypomagnesemia
    • Metabolic alkalosis
  • Neurological
    • Contracture
    • Neuropathy
    • Sleep disorders
      • Restless legs syndrome – causes brief sustained muscle contractions
      • Periodic limb movement disorder
  • Other
    • Growing pains
    • Medication
    • Positioning, abnormal
    • Pregnancy
    • Vascular disease

Growing pains are a common problem but do not have hard muscular contraction. Growing pains are chronic pain of both legs that occur in the evening and night with normal physical examination and laboratory testing.
The pain is in the thigh or calf muscles. The pain can occur over weeks or months.

Questions for Further Discussion
1. What are indications for a sleep study for possible sleep disorders?
2. What laboratory testing could be done for muscle cramps and why?

Related Cases

    Symptom/Presentation: Pain

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Leg Injuries and Disorders

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Leung AK, Wong BE, Chan PY, et al. Nocturnal leg cramps in children: incidence and clinical characteristics. J Natl Med Assoc. 1999;91:329-332.

Picchietti D, Allen RP, Walters AS, Davidson JE, Myers A, Ferini-Strambi L. Restless legs syndrome: prevalence and impact in children and adolescents–the Peds REST study. Pediatrics. 2007 Aug;120(2):253-66.

Guideline Development Group on Sleep Disorders in Childhood and Adolescence in Primary Care. Clinical practice guideline on sleep disorders in childhood and adolescence in primary care. Madrid (Spain): Health Technology Assessment Unit, Lain Entralgo Agency, Ministry of Health, Social Services and Equality (Spain); 2011.

Gingras JL, Gaultney JF, Picchietti DL. Pediatric periodic limb movement disorder: sleep symptom and polysomnographic correlates compared to obstructive sleep apnea. J Clin Sleep Med. 2011 Dec 15;7(6):603-9A.

Author

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

Is A Specific Corticosteroid Better for Treatment of Asthma Than Another?

Patient Presentation
An 11-year-old known-asthmatic male came to clinic for his health supervision visit. He was doing well in school, but his mother was concerned because he seemed to need his albuterol inhaler more and was coughing more at night. During the fall he had been playing soccer and although he took his inhaler before practices and games, he seemed to need the inhaler again during practices and games most days. Usually he also had no problems at night but his coughing was now waking the mother up at night at least 2-3 times per week. She had started giving him his inhaler before school on some days also. None of the symptoms improved as the fall frosts occurred. He said he had problems keeping up with the kids on the playground and had several episodes where his chest got tight at school.

The past medical history showed seasonal allergic rhinitis that was usually well controlled with cetirizine. He had never been hospitalized for asthma, and took oral steroids ~ 2 times a year for acute exacerbations. The family history was positive for asthma and allergies in multiple family members. The pertinent physical exam showed a healthy appearing male with normal vital signs and growth parameters. HEENT showed slightly pale mucous membranes and allergic shiners. Lungs were clear but after exercise in the room, he had some mild end expiratory wheezing. The rest of his examination was normal.

The diagnosis of uncontrolled asthma was made. An office peak flow meter reading was diminished from previous results. The resident seeing the child knew that he should probably start on an inhaled corticosteroid for better management, but he asked if one steroid was better than another. The staff pediatrician said that she didn’t think so because professional guidelines offered many different options plus the local pulmonologist seemed to use 2-3 different ones usually. “I’ll have to look at the guidelines again but I think if we use what the pulmonologist uses, he should get better,” she said. At follow-up in 4 weeks, the mother said that he was not coughing at night and he was using less albuterol although she could not quantify it. The physician did re-teaching about how to use the spacer and inhaler properly and had the mother start a symptom diary. The mother would contact the office with the amount of albuterol use over the next two weeks.

Discussion
Asthma is a chronic obstructive lung disease that affects many children and adults. There is a wide range of symptoms that people experience from occurring relatively rarely (ie intermittent asthma) to patients having daily symptoms of such intensity that they are life-threatening (ie chronic severe asthma). The goals of asthma management include patient education and medication management so patients have no or minimal symptoms, prevent exacerbations, have no activity restrictions, have normal pulmonary function tests, have no or minimal medication side effects and meet patient and family expectations. Well controlled asthma should have:

  • Asthma symptoms twice a week or less
  • Rescue bronchodilator use twice a week or less
  • No nighttime or early morning awakening
  • Daily, school and work activities should not be limited
  • Patient, family and physician believe asthma is well-controlled.
  • Normal pulmonary function tests

Assessment of asthma should occur routinely and especially if the patient’s symptoms are not well controlled.
This includes:

  • Frequency of
    • Symptoms
    • Night and morning symptoms
    • Rescue inhaler use
    • Activities, school or work limitations
  • Overall patient assessment
    • Pulmonary function tests
    • Assess
      • Psychosocial status
      • Adherence/compliance
      • Potential reasons for non-adherence
        • Tobacco smoke
        • Allergen avoidance and control measures including dust, cockroaches, animal dander etc.
        • Weight reduction for obesity
        • Mental illness
        • Poverty and social stressors
        • Poor technique of inhaler use
        • Poor understanding of disease or management
      • Medication side effects
      • Triggers
      • Asthma action plan knowledge
  • Reconfirm the asthma diagnosis – is there more than 1 diagnosis

A step-wise approach for asthma has been advocated, where patients who are not well-controlled at a particular step, are given medication at the next higher step (ie “stepped-up”) until they are controlled.
Likewise, patients who are well-controlled may be candidates to “step-down” to a lower step in order to minimize the potential medication side effects.

Guidelines for treatment of asthma include:

  • Step 1 Short acting beta-agonist prn
  • Step 2 Low-dose inhaled corticosteroids (ICS), leukotriene modifiers, theophylline, cromolyn or nedocromil
  • Step 3 Medium-dose ICS, Low-dose ICS plus long-acting beta-agonist or a leukotriene modifier or theophylline
  • Step 4 Medium-dose ICS and long-acting beta-agonist, or medium- dose ICS plus a leukotriene modifier or theophylline
  • Step 5 High-dose ICS and long-acting beta-agonist
  • Step 6 High-dose ICS and long-acting beta-agonist plus systemic corticosteroids

Patients at Step 3 or higher should consult with an asthma specialist.

Learning Point
Professional societies do not recommend a particular inhaled corticosteroid (ICS) for asthma.
Different medications have different pharmcological profiles. Equivalency tables are available to assist clinicians at
AAAAI- Table 4-4b. and Scottish Intercollegiate Guidelines Network (SIGN).

The overall efficacy is affected by:

  • Steroid type itself
  • The type of spacer or chamber used. A one-way valve is preferred.
  • Technique of the inhaler use
  • Personal factors and other considerations (i.e. tobacco smoker, African-American, etc.)

The total ICS systemic concentration equals the total amount delivered to the lungs, plus the oral amount that is not deactivated by the liver. Overall, about 10-50% of the ICS is delivered to the lungs. Almost 100% of the ICS dose in the lung is bioavailable and will enter the circulation. Without a spacer or valved holding chamber, about 50-80% of the ICS medication is swallowed. Much of this will be deactivated by the liver, but some will enter the circulation. The overall oral ICS bioavailability (of the swallowed portion of the dose) has been reported as:

  • Flunisolide = 21%
  • Beclomethasone dipropionate = 20%
  • Triamcinolone acetonide = 10.6%
  • Budesonide = 11%
  • Fluticasone propionate = 1%
  • Mometasone = <1%

Questions for Further Discussion
1. How does asthma itself and treatments potentially affect children’s growth?
2. What are other potential side effects of pharmacological treatment of asthma?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Asthma and Asthma in Children.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

National Heart, Lung and Blood Institute. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma – Summary Report 2007.
Available from the Internet at http://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf (rev. 2007, cited 11/18/14).

Rachelefsky G. Inhaled Corticosteroids and Asthma Control in Children: Assessing Impairment and Risk. Pediatrics. 2009;123(1):353-366.

Scottish Intercollegiate Guidelines Network (SIGN), British Thoracic Society. British guideline on the management of asthma. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2011 May.
Available from the Internet at Scottish Intercollegiate Guidelines Network (SIGN)(cited 11/18/14).

Author

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital