A journal of Dayton Children’s Hospital

COVER STORY

3T MR Imaging: It Matters for Kids

Winter | Volume 27 | Number 1

One Children’s Plaza Dayton, Ohio 45404-1815 937-641-3000 childrensdayton.org

Pediatric Forum is produced for the professional staff and referring physicians of Dayton Children’s by the marketing communications department.

The purpose of Pediatric Forum is to provide information and news about pediatric health care issues and to provide information about clinical services and management issues of Dayton Children’s.

WINTER 2016

Editorial BoardSherman Alter, MD, Chairperson

Lucinda Brown, MSN, RN, CNS Lisa Coffey, FACHE L. David Mirkin, MD Kelly Sandberg, MD

Sherman Alter, MD Director, Continuing Medical Education

Deborah A. Feldman President and Chief Executive Officer

Adam G. Mezoff, MD, CPE, AGAF Vice President for Medical Affairs Chief Medical Officer

Gregory Eberhart, MD Chair of the Professional Staff

Dr. Alter is on the speaker’s bureau for SanofiPasteur. The activity has been peer reviewed by the remainder of the planning committee to ensure the absence of bias. The remainder of the editorial board/planning committee members have nothing to disclose.

Sponsorship/Accreditation Information

Author information

It is the policy of Wright State University to ensure balance, independence, ob-jectivity and scientific rigor in all educational activities.

All authors contributing to our programs are expected to disclose any relationships they may have with com-mercial companies whose products or services may be mentioned so that partic-ipants may evaluate the objectivity of the program. In addition, any discussion of off-label, experimental or investigational use of drugs or devices will be disclosed by the authors. Contribut-ing authors reported the following:

Susan Peña-Almazan, MD almazans@childrensdayton.org Dayton Children’s Hospital

Dr. Peña-Almazan has nothing to disclose with regard to commercial support. Dr. Peña-Almazan does not plan on discussing unlabeled/investigational uses of a commercial product.

Beverly Comer, CIP comerb@childrensdayton.org Dayton Children’s Hospital

Ms. Comer has nothing to disclose with regard to commercial support. Ms. Comer does not plan on discussing unlabeled/investi-gational uses of a commercial product.

Elizbeth Ey, MD eye@childrensdayton.org Dayton Children’s Hospital

Dr. Ey has nothing to disclose with regard to commercial support. Dr. Ey does not plan on discussing unlabeled/investigational uses of a commercial product.

Gogi Kumar, MD kumarg@childrensdayton.org Dayton Children’s Hospital

Dr. Kumar has nothing to disclose with regard to commercial support. Dr. Kumar does not plan on discussing unlabeled/investigational uses of a commercial product.

Stephanie J. Smith, MS, RN CPNP-AC/PC smithsj@childrensdayton.org Dayton Children’s Hospital

Ms. Smith has nothing to disclose with regard to commercial support. Ms. Smith does not plan on discussing unlabeled/investigational uses of a commercial product.

William Spohn, MD, CIP William.Spohn@wright.edu Dayton Children’s Hospital

Dr. Spohn has nothing to disclose with regard to commercial support. Dr. Spohn does not plan on discussing unlabeled/investigational uses of a commercial product.

Physician accreditation statement and credit designation

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME)through the joint provider-ship of Wright State Univer-sity (WSU) and DaytonChildren’s Hospital.

WSU designates this Journal-based CME Activity for a maximum of 4 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of theirparticipation in the activity.

Obtaining CME credit To obtain CME credit, read, reflect on articles, complete the evaluation and answer at least 70 percent of the quiz correctly. Send the answer sheet and program evaluation to:

Sue Strader, CoordinatorDepartment of Continuing Medical EducationDayton Children’sOne Children’s PlazaDayton, OH 45404-1815Fax 937-641-5931Email straders@childrens-dayton.org

Take test online: childrensdayton.org/ providers

The answer sheet and program evaluation must be received by December 30, 2016, for the credit to be awarded.

Target audience This education activity is designed for pediatricians, family physicians and related child health care providers.

Print date: February 2016

The content and views presented are those of the author and do not necessarily reflect those of the publisher, Dayton Children’s. Unlabeled use of products may be mentioned. Before prescribing any medicine, primary references and full prescribing information should be consulted. All planning committee members have disclosed that they do not have any financial relationships with commercial entities that may impact the content of this publication.

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Educational objectives

4 Identify the four pediatric issues covered in this journal and develop appropriate intervention.

4 Appropriately use the resources of Dayton Children’s Hospital to improve patient care.

It Matters for Kids

3T MR Imaging

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by Elizabeth Ey, MD

Cor T1 image of wrist arthrogram demonstrates small tear of the triangular fibrocartilage complex with flow of contrast into distal radioulnar joint.

Since 2002, an increas-ing number of very high field strength magnetic res-onance (MR) systems have been installed for clinical use. In February 2014, Dayton Children’s Hospital installed a 3 Tesla (3T) MR system. When imag-ing children, the greatest advantages of higher field strength include improved image quality and faster scan times, even when scanning smaller, more detailed anatomy.

A 3T MR system has a magnetic field strength of approximately 10,000 times the magnetic field strength of the earth. (For reference, the magnets used to lift heavy metallic objects in junk yards, such as cars and trucks, operate at approximately 2 Tesla.) The main advan-tages of scanning at 3T are higher signal-to-noise ratio relative to lower field strength systems. The sig-nal-to-noise ratio is the ratio of usable information relative to noise in the sys-tem. (Think of the number of important email relative to the number of spam email in your inbox.) The signal-to-noise ratio

increases linearly with the strength of the magnet; therefore, a 3T MR system has nearly twice the sig-nal-to-noise ratio of a 1.5T MR system.

Why Does This Matter?

The higher signal-to-noise ratio can be used to create images with greater detail. This is especially useful when studying very small anatomic structures in children such as the ligaments in the wrist (Fig-ure 1), inner ear anatomy or cranial nerves at the base of the brain (Figure 2). Subtle abnormalities of brain development and structure can also be better demonstrated (Figure 3). Additionally, the higher signal-to-noise ratio of a 3T MR system can be used to scan more quick-ly without impacting the resolution of the image. Shorter scan times mean less chance of patient motion and potentially less sedation needed. In most cases, the radiologist must strike a balance between a shorter scan time and higher resolution.

Objectives

Following the completion of this article, the reader should be able to:

1. Identify the advantages of 3T MR imaging in children.

2. State several clinical situations for which 3T imaging is preferred.

Figure 1

Figure 2

Demonstrates a large schwannoma in the right jugular foramen extending into the right cerebellopontine angle and right internal auditory canal. Note normal cranial nerves VII and VIII in the left internal auditory canal.

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Child who presented with transient weakness of the left upper extremity with localized seizure activity on EEG. (3a)Diffusion weighted image showing a tiny region of acute brain ischemia as a focus of restricted diffusion in the right superior temporal gyrus.

(3b) T2 FLAIR sequence.

(3c) T1 sequence which further localize and characterize the area of abnormality.

Figure 3aFigure 3b

Figure 3c

Higher signal-to-noise ratio is also important in situations that require very rapid imaging, such as creating images of flow-ing blood in MR angi-ography. Functional MR imaging (fMRI) in the brain depends on the relative blood oxygen level in the region of the brain used when a child completes a particular function, such as a visual task or a motor task (Figure 4, next page). The higher field strength at 3T helps us to accomplish each of these specialized MR exams.

Is a 3T MR System More Dangerous?

With the many benefits come risks. Higher mag-netic fields introduce a greater risk to our patients because of the strength

of the 3T magnet. Some medical equipment or implants are safe at 1.5T but are not safe at 3T because of their ferromag-netic content (the majority of metals are ferromag-netic). As there are fewer 3T magnets in service, many implants have yet to be proven completely safe at 3T field strength. Ferromagnetic materials can be not only dangerous to the patient at 3T, but will also distort the quality of the image to a greater extent. This sensitivity can be used to detect extreme-ly small areas of previous hemorrhage in the brain (iron from the hemoglobin deposited), but can be very problematic when trying to image the pitu-itary gland in a child with

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orthodontic braces (Figure 5). The staff at Dayton Children’s carefully screen all MRI patients for metal implants twice: first as they schedule the appointment, and again in person prior to entering the MR scan room. The type of implants (including braces and retainers) often determines which patients are safe for 3T scanning and which are better imaged at 1.5T. Tattoos can also contain metal pigments and pose serious risk for skin burns at 3T.

How Does a 3T System Work?

MR imaging is based on the behavior of protons as they align with the main magnetic field. With higher field strength, the protons align more quickly and also spin faster. This spinning is called reso-nance frequency. To create the necessary images, the protons are subjected to radiofrequency pulses that cause the protons to fall out of alignment. As they return to alignment with the main magnet field, small radiofrequency pulses are generated and detected by the MR system coils. The coils used for clinical imaging are tuned to the specific resonance

Axial (4a) and coronal (4b) images from a functional MRI for a child with partial complex seizures found to have a small tumor in the left temporal lobe. The functional MRI was performed to localize speech and language areas. The child was asked to silently name objects presented in her visual field. The areas of cortical activation (red) localize to Broca’s area in the left inferior temporal gyrus.

Figure 4a and b

a b

Metal artifact created by braces. (5a) Midline sagittal T1 image of the pituitary gland in a child without braces. (5b) The same sequence in a child with braces. Notice the loss of definition of the pituitary gland as well as the entire lack of signal information from the facial area due to the metal in the patient’s mouth.

Figure 5a and b

a b

frequency of the protons, which is determined by the field strength of the magnet. Therefore, the coils are not interchange-able between various MR systems.

At higher field strength, the radiofrequency pulses used to create an image are higher frequency and deposit a greater amount of energy into a patient’s tissues. The energy absorp-tion per kilogram of body weight and per unit time is called the specific absorp-tion rate (SAR). To avoid heating tissue more than 1 degree Celsius, SAR thresholds have been set at less than 4 Watts/kg over a 15-minute period. As you might expect, the SAR limit will be reached much sooner at 3T than at 1.5T. Therefore, we take

special care to separate pulse sequences with high SAR with less intensive sequences, especially while scanning children and infants at 3T.

Why Should I Send my Patient for a 3T Scan?

Some clinical indications are better evaluated at 3T including seizure disorders, demyelinating disease and musculoskel-etal anatomy. Patients who need MR angiogra-phy, MR spectroscopy or functional MR imaging at Dayton Children’s are also scanned at 3T whenever possible. On the other hand, cardiac and fetal MR imaging are generally performed at 1.5T. Pa-tients are scheduled on the magnet that best suits their

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clinical indication as well as their MR safety needs.

What Can Patients Expect When Receiving a 3T Scan?

For safety reasons (as well as for image quality), we ask all Dayton Children’s patients to change into a hospital gown and to remove their shoes prior to their MR imaging. We also provide all of our patients ear protec-tion because the 3T MR system has a considerably louder noise level. This ear protection includes headphones, earplugs or padding around the ears. Some people experience dizziness and/or nausea when in a high magnetic field. This can be avoided by moving the head slowly as it nears the center of the magnet. The MR technol-ogists are mindful to move the patient slowly into and out of the magnet.

Current Research

3T MR imaging opens the doors to new discover-ies too. The new 3T MR system at Dayton Chil-dren’s has allowed us to partner with researchers at Wright State University, the Neuroscience Institute and the Air Force Research Institute. Neurologists, psy-chiatrists, neurosurgeons, physicists, engineers and radiologists are currently collaborating on several projects that study brain structure and function in a variety of areas including neural assessment, mod-eling and performance enhancement capabilities.

CME Questions

1. A metal implant that is determined safe in the 1.5T environment is automatically determined to be safe in the 3 Tesla environment.

True or False

2. Heating of patient tissues is a greater risk when scanning at 3T than when scanning at 1.5T.

True or False

3. Which of the following are clinical indications where 3T MRI has a potential advantage over 1.5 T MRI?

a. Musculoskeletal imaging

b. Imaging for seizure disorders

c. Functional MR imaging

d. All of the above

Conclusion

3T MR imaging presents us with many exciting opportunities to better care for patients and collabo-rate with local researchers. 3T MR imaging can be the best option for the right people under the right conditions. Children can’t always be scanned at 3T because of metal implants or the patient’s condition, but when possible, 3T can help produce a more detailed image in a short-er amount of time. When caring for children, these opportunities can make all the difference.

References

1. Chavhan GB, Babyn PS, Singh M, Vidarsson L, Shroff M. MR imaging at 3.0 T in children: Technical differences, safety issues, and initial experience. RadioGraph-ics. 2009;29:1451-1466.

2. Kuhl CK, Traber F, Schild HH. Whole-body high-field-strength (3.0-T) MR imaging in clinical practice part I. Technical considerations. Radiolo-gy. 2008;246(3): 675-696.

3. Kuhl CK, Traber F, Gieseke J, et al. Whole-body high-field-strength (3.0-T) MR imaging in clinical practice part II. Technical considerations and clinical applications. Radiology. 2008;247(1): 16-35.

Author

Elizabeth Ey, MD

Elizabeth Ey, MD, is medical director of medical imaging at Dayton Children’s. Dr. Ey is board certified in diagnostic radiology and has a certificate of added qualification in pediatric radiology. She performs fetal MRI and interventional studies such as drainages, biopsies and intraopera-tive image guidance.

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HumanSubject Researchand OtherActivities

Needing Dayton Children’s Hospital Institutional Review

Board (IRB) Review

A patient participates in one of the 145 IRB-approved human subject research investigations currently active at Dayton Children’s Hospital.

Research being offered at Dayton Children’s includes studies in the areas of asthma, cystic fibrosis, hemophilia, infectious disease, obesity, oncology, inflammatory bowel disease, secondhand smoking exposure in children, and surgery. Dayton Children’s also collaborates with Wright State University and Premier Health Neuroscience Institute for neuroscience research in children.

by William Spohn, MD, and Beverly Comer

Objectives

Following the completion of this article, the reader should be able to:

1. Identify the purpose of Dayton Children’s Hospital’s Institutional Review Board (IRB).

2. Identify research and other activities that need to be submitted to the IRB for review.

Dayton Children’s Institutional Review Board (IRB)

The Dayton Children’s IRB oversees all human subject research approved at the hospital. It ensures that fed-eral, state and institutional guidelines are met for the protection and welfare of all research participants. The IRB also makes non-re-search determinations and ensures that both human subject research and cer-tain non-research activities are Health Insurance Por-tability and Accountability Act (HIPAA) compliant.

The IRB has recently ex-perienced an increase in research and other activ-ities requiring IRB review. The hospital’s Destination 2020 goal to promote human subject research has helped fuel this new surge.

Dayton Children’s has obtained a Federalwide Assurance (FWA) through the Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP). In the FWA Dayton Children’s assures compliance with federal regulations for the pro-tection of human subjects in research, including a subpart requiring addition-al safeguards for children involved in research.

The IRB is primarily com-posed of scientific health professionals, as well as nonscientific and commu-nity members who conduct scientific, ethical and regulatory compliance re-views. IRB reviews include prospective initial applica-

use of a marketed drug in the course of medical practice. IDE regulations apply when it involves the use of a medical device to determine safety or effectiveness [21 CFR 812.2(a)].

A human subject is a liv-ing individual about whom an investigator conducting research obtains data through intervention or in-teraction with the individu-al or by use of identifiable private information, either:

A. Directly through exam-ination, treatment, inter-view, or questionnaire, or

B. Indirectly through observation, or through ac-cess to records/files, data banks or other depositories [45 CFR 46.102(f)].

Investigators and IRB Submissions

At least one investigator must be a member of Dayton Children’s pro-fessional staff and/or a Dayton Children’s employ-ee. The research study principal investigator is responsible for IRB submis-sions and for compliance with all applicable rules and regulations. Subinves-tigators and other study team members report to the principal investigator.

tions, modifications and continuations. The review process is administered through Dayton Children’s IRB Office.

IRB policies and submis-sion forms are available on Dayton Children’s intranet or through the IRB office.

IRB personnel include Adam Mezoff, MD, CPE, AGAF, IRB institutional official; William Spohn, MD, CIP, IRB chair; and Bev Comer, CIP, IRB coor-dinator (email: comerb@childrensdayton.org). The IRB office telephone num-ber is 937-641-4218.

What Is Human Subjects Research?

Research, as defined by the U.S. Department of Health & Human Services (HHS), is a systematic investigation, including research development, testing and evaluation, designed to contribute to generalizable knowledge [45 CFR 46.102(d)].

Research, as defined by the Food and Drug Administration (FDA), is an experiment that involves a test article and one or more human subjects that is subject to the Investiga-tional New Drug (IND) or Investigational Device Exemption (IDE) regulations or which collects data to be submitted to or held for inspection by the FDA [21 CFR 50.3(c)]. IND regulations apply when research involves any use of a drug except for the

The principal investigator (PI) is required to obtain certain approvals before IRB submission as de-scribed on the IRB new protocol submission check-list. Once these approvals have been obtained, the PI is required to submit a new research study application to the IRB prior to initiating the study. The new study application forms available on Dayton Childrens intranet include a checklist as an aid in determining required pre-approvals as well as IRB forms and documents to be submitted for review.

Types of IRB Research Submissions

I. Minimal Risk Research

Minimal Risk Research means that the probability and magnitude of antici-pated harm or discomfort to participants in the research are not greater, in and of themselves, than those ordinarily encoun-tered in daily life or during the performance of routine physical or psychological examinations or tests [45 CFR 46.102(i)]. The re-search must meet this defi-nition and fall within one

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6. Research on non-sensi-tive group characteristics or behaviors employing survey, interview and quality assurance method-ologies.

IRB Review: Minimal risk research studies meeting the criteria for exempt or expedited status are performed by the IRB chair or his designee. These reviews are normally performed within three weeks of submission to the IRB office. The IRB chair or designee will review and provide an approval/determination letter to the principal investigator. The IRB reviewer has authority to refer review to the full board if deemed necessary.

II. Greater than Minimal Risk Research

Research studies not meeting the criteria for exempt or expedited status are reviewed by the full IRB. These are usually research/clinical investi-gations involving greater than minimal risk but presenting the prospect of direct benefit to the individual participants (45 CFR 46.405 and 21 CFR 50.52).

All trials regulated by the FDA require full IRB review. These studies will often have an outside study sponsor (e.g., a pharma-ceutical company). They can also be investigator initiated.

IRB Full Board Review: Greater than minimal risk new research protocols require full IRB review at a convened meeting.

Studies being submitted for full board review must be turned into the IRB office at least two weeks prior to the IRB meeting in which it is to be reviewed. IRB meetings are scheduled the second Wednesday of each month. Upon review, a letter with IRB determina-tion(s) will be provided to the principal investigator.

Reliance on an Outside IRB for Human Subject Research Reviews

Dayton Children’s can rely on an external IRB for re-view of human subject re-search. In order for this to occur an Institution Autho-rization Agreement (IAA), signed by the institutional official of both the relying institution and the institution being relied upon, must first be executed. Investiga-tors are to contact the Day-ton Children’s IRB office for

guidance. Once the IAA is in place, the local princi-pal investigator can submit a new study application for Dayton Children’s IRB review/approval to open the study with reliance on the outside IRB.

Non-research Activities to be Submitted to the IRB

The IRB additionally makes non-research activity determinations. At Dayton Children’s the IRB makes final determinations as to whether a project qualifies as being non-research for the following activities:

• Quality Improvement: This type of project is designed to bring about immediate, positive chang-es in the delivery of health care or organizational effectiveness at Dayton Children’s.

or more of the following classifications that qualify for exempt or expedited IRB review.

Exempt Research:

1. Normal educational practices and settings.

2. Anonymous education tests, surveys, interviews or observations.

Note: Surveys and inter-views involving children are not exempt.3. Identifiable study participants in special circumstances.

4. Collection or study of existing data.

Note: Information must be in existence prior to starting the research.5. Public benefit or service programs.

6. Taste and food evaluation.

Expedited Research:

1. Collection of blood samples from children no more than twice weekly.

2. Prospective collection of biological specimens for research purposes by noninvasive means.

3. Collection of data by noninvasive procedures routinely employed in clini-cal practice, except X-rays.

4. Research involving non-sensitive materials (data, documents, records, specimens) that have been previously collected or will be collected solely for non-research purposes.

5. Collection of non-sen-sitive data from voice, video, digital or image recordings made for research purposes.

The IRB is primarily composed of scien-tific health profes-sionals, as well as nonscientific and community mem-bers who conduct scientific, ethical and regulatory compliance reviews.

Authors

William Spohn, MD, CIP

Dr. Spohn has served as the Dayton Children’s IRB chair for the past 10 years. He is board-certi-fied in pediatrics, pedi-atric pulmonology and pediatric critical care. He is a clinical professor of pediatrics at Wright State University Boonshoft School of Medicine.

Beverly Comer, CIP

Beverly Comer is the IRB coordinator at Dayton Children’s. She is a Certified IRB Professional (CIP) and a member of the Public Responsibility in Medicine and Research (PRIM&R).

CME Questions

4. Dayton Children’s Institutional Review Board (IRB):

a. Oversees human sub-ject research approved at Dayton Children’s.

b. Is comprised of both scientific and nonscien-tific members.

c. Provides ethical and regulatory compliance reviews.

d. All of the above

5. IRB Approval is required before beginning a new research study.

True or False

6. Research with greater than minimal risk is reviewed by:

a. The IRB Chair

b. The IRB Chair’s designee

c. The full IRB at a convened meeting

Submission form: The investigator is to submit the Quality Improvement Non-research Project Petition for IRB Determination Form.

• Case Report: This is an activity to develop information to be shared for medical/educational purposes. It can review no more than three patients, describes observations and is not presented as a systematic investigation to contribute to generalizable knowledge.

Submission form: The lead reporter is to submit the Case Report/Non- research Project Petition Form to the IRB.

• Not Engaged in Research: In order to be engaged in a research study, Dayton Children’s IRB must be responsible for the research. Examples of activities to be submitted: 1) Research approved by an external IRB and only utilizing Dayton Children’s services (a determination will be made as to wheth-er or not it will also require oversight by Dayton Chil-dren’s IRB); 2) Recruitment materials to be provided to individuals about an opportunity to participate in a study not conducted at Dayton Children’s.

Submissions: Contact the IRB office for information on documents required, depending on the activity.

• Emergency Use of an Investigational Drug, Biologic or Medical Device: Contact the IRB office prior to the use of any of these procedures.

• Other: Check with the IRB office if you have questions or concerns about any other investigative activity.

Additional Information

• HHS 45 CFR 46, in-cluding Subpart D: http://www.hhs.gov/ohrp/humansubjects/guidance/ 45cfr46.html

• FDA 21 CFR 50 and 56: http://www. accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?CFR

• Available on Dayton Children’s FOCUS intranet or by contacting the IRB office: 937-641-4218

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Updates in Management

of Pediatric Epilepsy

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by Gogi Kumar, MD

Objectives

Following the completion of this article, the reader should be able to:

1. Describe the latest advances in the diagnosis of epilepsy in children.

2. Identify the latest therapies available for treating children with epilepsy.

Epilepsy serves as the fourth most common neurological disorder with statistics demonstrating 0.6% of children aged 0 to 17 years with diagno-sis of epilepsy.1 Nearly 460,000 children, 2.9 million people total within the United States, are pur-suing epilepsy treatment.2 While an estimated 50% respond to implemented anti-epileptic management, an approximate 20% to 30% are refractory to medication therapy.

Children with refractory epilepsy are more likely to have developmental regression, cognitive and behavioral problems, and often require comprehen-sive multidisciplinary care.

There have been unprec-edented advances in the diagnosis and treatment of epilepsy in the past de-cade, which have enabled us to better diagnose and manage children with epilepsy.

Etiological Diagnosis

When a child is diag-nosed, most parents want to know why their child has epilepsy. The most important advances in elucidating the causative factors for epilepsy have come from our increased understanding of epilepsy genetics. Genetic testing can improve diagnosis and enable us to provide accurate prognosis and recurrence risk information. For some conditions ge-netic diagnosis can guide therapy, greatly improving the lives of patients.

Single gene testing should be used only if the diagno-sis is clinically certain, as in Rett syndrome or Dravet syndrome. For any child suffering from epilepsy and developmental disabil-ity, autism or congenital anomalies, a chromosom-al microarray test to detect copy number variations should be sent. If the mi-croarray does not give us an answer, specific gene panels and then whole ex-ome genome sequencing can be used.3

Epilepsy Biomarkers

Researchers are trying to identify reliable biomark-ers for the epilepsies so we can predict the onset of epilepsy, monitor the course of epilepsies, as well as confirm remission.

Advances in neuroimaging including diffusion tensor imaging, a type of mag-netic resonance imaging (MRI) that shows micro-structural detail of tissues based on the diffusion of water molecules, has shown abnormal structural connectivity during focal and generalized seizures.

Implantable microelec-trodes are revealing com-plex brain activity during seizures. Using microelec-trodes, researchers are able to better characterize high-frequency oscillations (HFOs) that have been linked to seizure onset zones and may serve as a biomarker of epileptogene-sis; this could help identify people at risk for develop-ing epilepsy after an initial insult to the brain.4

Medical Therapy

In terms of therapy, the number of antiepileptic agents used in the market approved for epilepsy treatment has tripled in the last two decades. Table 1 demonstrates the number of antiepileptic medications approved for the treatment of epilep-

sy with the more recent ones referred to as third generation antiepileptic medications. Compared to the first generation antie-pileptic medications, the second and third genera-tion tend to have a safer adverse effect profile and are better tolerated.

First generation antiepileptic drugs

Second generation antiepileptic drugs

Third generation antiepileptic drugs

Ethosuximide(Zarontin)

Oxcarbazepine(Trileptal)

Eslicarbazepine acetate (Aptiom)

Carbamazepine(Tegretol)

Levetiracetam(Keppra)

Lacosamide (Vimpat)

Phenytoin (Dilantin) Lamotrigine (Lamictal)

Sodium Valproate(Depakote)

Topiramate(Topamax)

Perampanel (Fycompa)

Phenobarbital Felbamate(Felbatol)

Retigabine (Ezogabine)

Clonazepam(Klonipin)

Gabapentin(Neurontin)

Rufinamide (Banzel)

Clobazam (Onfi) Pregabalin (Lyrica)

Vigabatrin (Sabril)

Tiagabine (Gabitril)

Zonisamide (Zonegran)

Table 1. Three generations of antiepileptic medications (brand name in parentheses)

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Neuromodulation

Neuromodulation devices use electrical stimulation to decrease the excitability of the brain and thereby decrease the frequency or duration of seizures. The best known neurostimula-tion device is the Vagal Nerve Stimulator (VNS) (Figure 1). It has been FDA approved for children and acts on the vagus nerve with stimulation ascending through brainstem nuclei and modulating the excit-ability of the cortex diffuse-ly. VNS has to be implant-ed surgically under the skin and is used in patients with intractable epilepsy when surgical cure is not an option. VNS delivers stimulation on a scheduled basis, activated by the patient or in response to heart rate. The advantage of VNS is the relative lack of side effects. The other modality of FDA approved neuromodulation is responsive neurostimu-lation Neuropace® RNS system, which is implanted intracranially and delivers stimulation only when epileptiform activity is detected.

Deep brain stimulation and trigeminal nerve stimulation are other neuromodulation techniques that are being explored but are not FDA approved yet.4

Metabolism-Based Therapies

Ketogenic diet is a high-fat, very low carbohydrate diet often used to treat medication-resistant epilep-sies and has become very popular in recent years. Some studies show that more than 50% of people who try the diet have a greater than 50% improve-ment in seizure control and 10% experience seizure freedom. It is the first line treatment for some child-hood onset epilepsies like GLUT1 deficiency syndromes.

The diet induces a state known as ketosis, meaning the body shifts to break-ing down fats instead of carbohydrates to survive. Some children are able to discontinue the ketogenic diet after several years and remain seizure free, but this is done with strict supervision and monitoring by a physician.

The ketogenic diet requires a strong commitment from the family and is not easy to maintain, as it requires strict adherence to a lim-ited range of foods. Pos-sible side effects include impaired growth due to nutritional deficiency and a buildup of uric acid in

the blood, which can lead to kidney stones.

Recently the modified Atkins diet and low-glyce-mic-index diets which are less restrictive have been tried in small trials and have been found to be effective.

Epilepsy Surgery

Any child with intractable focal seizure needs to be evaluated for epilepsy sur-gery to determine whether a lesion in the brain is causing the seizures that can be surgically removed so the epilepsy can be cured without causing major deficits.

Epilepsy surgery should be performed as soon as possible once the determi-nation has been made that surgery could be poten-tially curative for the child. This saves unnecessary polytherapy as well as im-proves the developmental outcome as many of the childhood epilepsies are associated with adverse cognitive and develop-mental outcomes.

Surgical evaluation takes into account the seizure type, the brain region in-volved and the importance

of the area of the brain where seizures originate for everyday behavior.

The initial evaluation includes video EEG monitoring, MRI of brain and neuropscyhological testing. Other modalities used are PET scan, ictal SPECT and MEG to better localize the epileptiform activity.

Implanted electrodes may be used to record activity from the surface of the brain, which yields more detailed information than an external scalp EEG. Surgeons usually avoid operating in areas of the brain that are necessary for speech, movement, sensation, memory and thinking, or other important abilities. fMRI can be used to locate such eloquent brain areas involved in an individual.

Surgery for epilepsy does not always successfully reduce seizures, and it can result in cognitive or personality changes as well as physical disability. It also carries a risk for permanent neurological deficit.

Surgical procedures for treating epilepsy disorders include lesionectomy, temporal lobe resection, multiple subpial transec-tions, corpus callosotomy and hemispherectomy.

Cannabinoids in the Treatment of Epilepsy

Children who suffer from intractable epilepsy are often on multiple antisei-zure medications. The availability of newer

Figure 1. Vagal Nerve Stimulator

medications with a more benign side effect profile may have provided us with more treatment options, but side effects related to the central nervous system remain unchanged. This forces parents and families to look toward alternative treatment options.

Cannabis as a treatment for epilepsy has received widespread media atten-tion with some reports of it being effective for some patients with intractable epilepsy. Preclinical and preliminary data from studies in humans suggest that cannabinoids and tet-rahydrocannabinol (THC) may be effective in some patients with epilepsy. In a recent abstract presented at the American Epilepsy Society annual meeting based on a multicenter clinical trial it was report-ed that cannabis-based drug Epidolex was found to be useful in treatment of intractable epilepsy where the median overall seizure frequency reduction was 45.1% in all patients and 62.7% in those with Dravet syndrome.5

Epidolex is awaiting approval by the FDA at present, however once the drug is approved, it will be considered as a viable option for treatment of the various forms of intracta-ble childhood epilepsy syndromes.

CME Questions

7. Metabolism-based therapies include:

a. Ketogenic diet

b. Sodium valproate

c. Cannabinoids

d. Vagal nerve stimulator

8. Which of the following statements about the use of cannabinoids in epilepsy in children is true?

a. Cannabinoids are approved for the treatment of epilepsy.

b. There is robust scientific evidence to suggest the efficacy of cannabinoids in epilepsy.

c. There are ongoing clinical trials to evaluate the efficacy of cannabi-noids in epilepsy.

d. Smoking marijuana is an effective treatment for epilepsy.

9. Neuromodulation for epilepsy includes all except:

a. Vagal nerve stimulator

b. Responsive neurostimulation

c. Deep brain stimulation

d. Epilepsy surgery

Author

Gogi Kumar, MD

Gogi Kumar, MD, is medical director of child neurology at Dayton Children’s. Dr. Kumar is board certified by the American Board of Psy-chiatry and Neurology with special qualifica-tions in child neurology. She is also an assistant professor of pediatrics at Wright State Univer-sity Boonshoft School of Medicine.

Summary

Childhood epilepsy is a spectrum disorder with long-term developmental consequences. There have been tremendous ad-vances in diagnostic and therapeutic modalities for management of epilepsy; however, the management of children with intractable epilepsy remains challeng-ing.

References

1. Russ SA, Larson K, Halfon N. A national profile of childhood epilepsy and seizure disorder. Pediatrics. 2012;129:256–64. DOI: 10.1542/peds.2010-1371

2. US Census Bureau, Population Division [database online]. Annual estimates of the resident population by sex, age, race, and Hispanic origin for the United States, States, and Counties: April 1, 2010, to July 1, 2013. Release Date: June 2014. Accessed February 2, 2015.

3. Mefford HC. Clinical genetic testing in epilepsy. Epilepsy Currents. 2015;15(4): 197-201.

4. Nune G, DeGiorgio C, Heck C. Neuromodulation in the treatment of epilep-sy. Curr Treat Options Neurol. 2015;17:43.

5. Abstract at AES 2015 Devinski et al NYU 2015

15

16

Chiari malformation (CM), also referred to as Arnold-Chiari malformation, was first described by patholo-gist Dr. Hans Chiari in 1891 as a downward herniation of the cau-dal cerebellum into the spinal canal.6 Persons with CM often have a significantly smaller posterior fossa than those of the same age and sex.2

There are six clas-sifications of Chiari malformation with Type-I being the most prevalent. CM Type-0 is crowding at the level of the foramen mag-num with no definite tonsillar herniation and may also have web-bing at the outlet of the fourth ventricle.6 CM Type-I is the cerebellar tonsil descent >3-5mm below the level of the foramen magnum in which the tonsils may appear flattened, beak-

like or rhomboid in shape.2 The universally accepted radiograph-ic diagnosis of CM Type-I is cerebellar tonsil descent below the foramen magnum ≥ 5 mm.2 CM Type-I.5 includes cerebellar tonsil descent and me-dulla herniation without basilar invagination.6 CM Type-II includes cerebellar descent with elongation of the vermis and other pos-terior fossa structures

and is associated with myelomeningocele. CM Type-III is rare with a poor progno-sis and is associated with high-level cervical meningocele that often contains neural tissue. CM Type-IV is the most severe. It includes cere-bellar hypoplasia and is often associated with malformations of the brain and brain stem and most patients do not survive infancy.2

by Ste

phanie

Smith,

MS, RN,

CPNP-A

C/PC

17

Epidemiology

The true prevalence of Chiari Type-I malformation is unknown due to lack of universal neuroimaging but is reported to range between 1/1,280 and 1/18,000.5 There is a gender predominance of four females to one male diagnosed with CM-Type I.2 Familial associations of CM Type-I is reported as high as 12%.5 CM can have non-syndrom-ic associations such as craniosynostosis, myelome-ningocele, hydrocephalus, idiopathic intracranial hypertension, anxiety, depression, scoliosis and syringomyelia.3,4,5 The prevalence of psychiatric disorders such as anxiety and depression have been estimated to be as high as 43%.1 The prevalence of syringomyelia and scolio-sis in CM Type-I is as high as 80%.5 Syringomyelia is a fluid-filled collection or cyst with the spinal cord.

Several inherited syn-dromes are associated with CM Type-I including Pfeiffer, Williams, Crou-zon, Klippel-Feil, Gold-enhar, Shprintzen-Gold-berg, Albright hereditary osteodystrophy, achon-droplasia, Angelman, hypophosphatemia rickets

Objectives

Following the completion of this article, the reader should be able to:

1. Define Chiari malformation and the distinction between the six classifications.

2. List specific symptoms and comorbidities associated with Chiari Type-I malformation.

3. Understand workup for Chiari Type-I malformation and concerning clinical and radiographic findings that lead to the decision for surgery.

and velocardiofacial syndrome.5 CM Type-I can also be acquired second-ary to intracranial tumor, post-traumatic hemorrhage and alteration of cerebro-spinal fluid (CSF) dynamic secondary to lumbar shunting.2,4

Symptomology

Patients with Chiari Type-I malformation can be asymptomatic or symptom-atic with varying degrees of symptoms. Trauma such as a neck or head injury may induce or worsen symptoms in patients with CM. Consider obtaining a brain MRI on a patient with prolonged concussive symptoms greater than or equal to three months. Symptoms may vary ac-cording to age.

Diagnostic Workup

Primary care provid-ers (PCPs) should refer patients whose initial imaging is suggestive of Chiari malformation to neurosurgery for further evaluation. In addition to the neurosurgery referral, if the patient is experienc-ing headaches, he or she should also be referred to neurology for medi-cal management of the headaches. A brain MRI without contrast is ordered to confirm cerebellar tonsil descent, evaluate the pos-terior fossa structures and to assess cerebral spinal fluid flow at the level of the Chiari Malformation

by Ste

phanie

Smith,

MS, RN,

CPNP-A

C/PC

18

foramen magnum using CINE sequencing. A spine MRI without contrast is ordered to assess for syrin-gomyelia. Scoliosis films are ordered if scoliosis is suspected on clinical exam. If both syringomye-lia and scoliosis are pres-ent, repeat radiographic imaging will be obtained in four to six months to assess for progression of the syrinx or scoliosis. The following tests may be ordered depending on symptomology: elect-ronystagmogram (ENG), somatosensory evoked potentials, barium swallow study, sleep study and tilt table test. A lumbar punc-ture may be warranted if visual changes and pap-illedema are found on the

neurologic exam to assess for idiopathic intracranial hypertension. The follow-ing referrals may also be warranted: ophthalmolog-ic exam, otolaryngology referral and psychological counseling.

Medical Management

Headaches are the primary complaint in patients with Chiari Type-I malformation with the vast majority being occipital headaches. These head-aches are often chronic headaches and require aggressive medical man-agement under the direc-tion of neurology. Activity modifications can be ben-eficial for those patients who experience increased symptoms during sports or other physical activity.

Symptoms for Chiari patients less than 3 years of age

Sleep apnea

Stridor

Gait or motor impairment

Abnormal movements of postures such as arching of neck

Developmental delay

Impaired oropharyngeal function: persistent irritability, aspiration,

regurgitation, dysphagia, choking and abnormal vocal cord function4

Symptoms for Chiari patients greater than or equal to

3 years of age

Tussive headache that has a sudden onset with coughing,

sneezing, valsalva-like activity or physical exertion

Neck pain, especially with hyper flexion

Vertigo and/or cerebellar ataxia

Tinnitus, hearing loss, whooshing or clicking sounds

unilateral or bilateral

Paresthesia

Extremity weakness

Incontinence

Neuro-ophthalmologic manifestations: blurred vision, nystagmus, diplopia, scotoma

and ocular bobbing4

Table 1.

Key Points

Most patients diagnosed with CM Type-I will not require surgery.

The diagnosis of CM Type-I can provoke signifi-cant anxiety with individu-als and families. Education regarding CM Type-I, support and reassurance is essential for each patient and his or her family mem-bers. A Child Health Infor-mation (CHI) sheet on the Dayton Children’s website (www.childrensdayton.org) can be printed and given to the family at the time the referral to neurosurgery is made.

The degree of tonsillar herniation is not directly related to the degree of symptomology as up to 30% of CM-Type I patients are completely asymptom-atic and many with symp-toms can be successfully managed with aggressive

Surgical Management

Surgical decompression is considered if there is progressive syringomye-lia, progressive scoliosis associated with syringomy-elia and headaches that fail aggressive medical management, and in infants with sleep apnea or impaired oropharyn-geal dysfunction. Chiari Type-I malformations may be treated surgically with only local decompression of the overlying bones and release of the dura, or decompression of the bone and dura and some degree of cerebellar tonsil resection. Patients are typically seen 14 days fol-lowing surgery for removal of the clips or nonabsorb-able sutures. If the patient has syringomyelia, repeat imaging is obtained in four to six months follow-ing surgery for further assessment.

medical management and/or activity modifica-tions.

There is a prevalence of psychiatric disorders in patients with CM Type-I that should be identified and treated to increase the patient’s quality of life and improve pain perception. This is especially true for individuals and families who have ineffective coping skills.

PCPs should consider ob-taining a brain MRI with-out contrast to assess for the presence of CM Type-I in children or adolescents with prolonged concussive symptoms (greater than three months).

If not being managed by orthopedics, the PCP should consider obtaining a spine MRI without con-trast for patients with rapid progression of scoliosis or atypical curvature particularly if there is a pain element.

The PCP should also consider obtaining a brain MRI without contrast to assess for CM Type-I in infants with history of aspiration, multiple URIs, stridor, concern for sleep apnea and persistent GER.

References

1. Bakim B, et al. The quality of life and psychi-atric morbidity in patients operated for Arnold-Chiari malformation type I. International Journal of Psychiatry in Clinical Practice. 2013;17: 259-263.

2. Boyd J, Cartwright C, Ledet D, Szatkowski, M, Wallace D. Pediatric and developmental disorders. In: Bader M, Littlejohns L, eds. AANN Core Curric-ulum for Neuroscience Nurses. 5th ed. Glenview, IL: American Association of Neuroscience Nurses; 2010.

3. Greenlee J, Donovan K, Hasan D, Menezes A. Chiari I malformation in the very young child: The spectrum of presen-tations and experience in 31 children under age 6 years. Pediatrics. 2002;110(6):1212-1219.

4. Horne J, Shaughnessy F. Chiari I malformation: An overview. International Journal of Academic Research. 2013;5(2): 274-280.

5. Schanker B, et al. Familial Chiari malfor-mation: Case series. Neurosurgery Focus. 2011;31(3):e1-6.

6. Sungjoon L, et al. Surgical outcome of Chiari I malformation in children: Clinico-radiological factors and technical aspects. Childs Nervous System. 2014;30: 613-623.

CME Questions

10. At what point should a PCP consider obtaining a brain MRI on a patient with prolonged concussive symptoms?

a. 10 days post-concussion

b. 3 months post-concussion

c. 4 weeks post-concussion

d. 6 weeks post-concussion

11. Chiari Type-I malformation is more likely to be associated with which of the following syndromes?

a. Crouzon’s syndrome

b. Turner’s syndrome

c. Smith-Magenis syndrome

d. Down syndrome

12. Which infant should the PCP consider obtaining a brain MRI?

a. An infant with gastric reflux that is well managed with ranitidine and one prior episode of RSV.

b. A 5-month-old infant with tracheomalacia who is feeding well and has no history of aspiration.

c. An infant with persistent stridor, frequent choking during feeds and failure to thrive.

Author

Stephanie Smith, MS, RN, CPNP-AC/PC

Stephanie Smith, MS, RN, CPNP-AC/PC, is a certified pediatric nurse practitioner in the pediatric neurosurgery department at Dayton Children’s. Stephanie received her advanced practice degree from Wright State University Boonshoft School of Medicine and is a member of the American Association for Neuroscience Nurses and Ohio Chapter of the National Association for Pediatric Nurse Practitioners.

19

20

Objectives

Following the completion of this article, the reader should be able to:

1. Recognize the relationship between elevated TSH level and obesity.

2. Understand the genetic conditions related to congenital hypothyroidism.

3. Identify the most recent recommendation regarding management of thyroid nodules and thyroid cancer in children and adolescents.

U P D A T E

Thyroid Disorders in Children and Adolescentsby Susan Peña-Almazan, MD

21

The 100-year anniversary of the isolation of thyroid hormone (TH) was cele-brated in 2014. It has been almost a century since thyroid surgery was successfully done by Drs. Charles Mayo and Henry Plummer to treat a patient with exophthalmic goiter.1 For the past century, count-less individuals including children had been afflicted with and been treated for thyroid disorders. And throughout these years, vast amounts of knowl-edge about disorders of the thyroid gland and its hormones had been elucidated. Nevertheless, there is new information regarding the pathophysi-ology and management of thyroid disorders in pediat-ric patients and these will be the focus of this article.

Obesity and Elevated TSH Level

Thyroid function is checked frequently in the obese child by pediatricians as part of investigation for increased weight gain. In situations where the test result shows mild elevation of thyroid-stimulating hor-mone (TSH) with normal free thyroxine (FT4), there has been a debate wheth-er thyroid hormone supple-mentation is needed.

Studies revealed that 10% to 23% of all obese children had mild TSH elevation. It is hypothe-sized that the elevated TSH results from increased leptin-mediated production of thyrotropin-releasing hormone (TRH) from the hypothalamus. Leptin is a hormone synthesized by

adipose cells and its serum level is proportional to the amount of body fat. It acts on the TRH-synthesiz-ing neurons in the hypo-thalamus which causes increased TSH production in the pituitary gland. The mild TSH level elevation in obese children may be regarded as an adaptive response to increased body weight. Increased BMI then alters TSH level rather than being a result of thyroid gland dysfunc-tion. Normalization of TSH has been observed follow-ing weight loss either due to diet or bariatric surgery. With these findings, it is the consensus not to provide thyroid hormone supplementation to obese children with mild TSH elevation.2-3

Congenital Hypothyroidism Associated with Genetic Conditions

The majority of cases of congenital hypothyroidism (CH) in iodine-sufficient areas are sporadic. CH associated with genetic etiology are rare, yet these are worth knowing since these can occur in several family members and some have extrathyroidal in-volvement. CH associated with genetic mutations are shown in Table 1 and are generally grouped into the following:

Mutations in genes for TTF-1(NKX2.1), TTF-2(FOXE-1), NKX2.5, PAX-8, and Gsα causing syndromic CH

The development of the embryonic thyroid gland and its normal migration

to its normal position in the anterior neck is dependent on the interplay between several transcription factors. These transcription factors are TTF-1, TTF-2, NKX2.5, and PAX-8. Mutations in the genes for these transcription factors lead to CH with associat-ed syndromic disorders.

Mutation in the thyroid transcription factor-1 or TTF-1 gene (also known as NKX 2.1 gene) is associ-ated with normally located and normal-sized thyroid gland with neurologic abnormalities such as hy-potonia, persistent ataxia, dysarthria, microcephaly, choreoathetosis, develop-mental delay and respi-ratory distress syndrome. Thyroid transcription fac-tor-2 or TTF-2 gene (also

Etiology of CH Gene Involved Inheritance

Thyroid Transcription Factor-1 mutation

TTF-1 (aka NKX2.1) Autosomal recessive

Features

Normal anatomy and location of TG associated

with neurologic and respiratory conditions

Thyroid Transcription Factor-2 mutation

TTF-2 (aka FOXE-1) Autosomal recessive Thyroid agenesis associated with cleft

palate, choanal atresia, bifid epiglottis, kinky hair

NKX2.5 mutation NKX2.5 Autosomal recessive Thyroid agenesis associated with

congenital heart defect

PAX-8 mutation PAX-8 Autosomal recessive Ectopic and hypoplastic TG with cysts associated

with renal agenesis

Gsα subunit mutation GNAS1 Autosomal dominant Normal TG anatomy and location associated with TSH resistance and

pseudohypoparathyroidism

TSH Resistance TSHR Autosomal recessive Normal or hypoplastic TG

Monocarboxylase Transporter-8 mutation

MCT-8 X-linked Mild CH and usually diagnosed beyond infancy associated with neurologic and respiratory disorders

Table 1. Congenital Hypothyroidism (CH) with Genetic Mutations and Mode of Inheritance

22

known as FOXE-1 gene) mutation is associated with thyroid agenesis and cleft palate, bilateral choanal atresia, hypoplastic bifid epiglottis and spiky hair. NKX2.5 mutation presents with thyroid agen-esis and congenital heart defects. PAX-8 mutation is associated with hypoplas-tic and sometimes ectopic thyroid gland with cysts in the thyroid remnants, and genitourinary abnormalities including renal agenesis.

The stimulatory G protein α subunit gene (GNAS1) encodes for the Gsα, the α subunit of the stimulatory G protein which mediate signal transduction across cell membranes, coupling extracellular receptors—in-cluding receptors to TSH and parathyroid hormone (PTH)—to intracellular effector proteins. Heterozy-gous inactivating mutation in the GNAS1 result to end-organ resistance to TSH causing congenital hypothyroidism as well as end-organ resistance to PTH causing pseudo-hypoparathyroidism 1a(PHP1A). In addition to hypothyroidism and hypocalcemia, patients with PHP1A present with recognizable dysmorphic features referred to as Albright Hereditary Osteo-dystrophy (AHO), which consists of short stature, shortened fourth and fifth metacarpals and metatar-sals, obesity, subcutaneous ossification, intracranial calcification and variable mental retardation. These patients may be detected by newborn screening to have congenital hypothy-roidism and later on are

found to have hypocal-cemia and the stigmata of AHO. The degree of hypothyroidism, however, tends to be mild.4

Mutation in TSH receptor gene causing non-syndromic CH

The TSH receptor gene (TSHR) encodes a trans-membrane receptor present on the surface of the thyroid follicular cells that mediates the effects of TSH. Mutations in the human TSHR gene result in TSH resistance leading to reduced sensitivity to TSH and were first described in 1995. Variable TSH resistance are observed and may present with normally formed or with hypoplastic thyroid gland. Some affected individuals present with compensated TSH resistance (elevated TSH and normal free T4) while in some cases, severe hypothyroidism (el-evated TSH with low free T4) occur.

Mutations in genes for components of thyroid hormone synthesis

Genetic mutations involv-ing components of thyroid hormone synthesis are

mostly autosomal reces-sive disorders and may present with goiter. These include conditions due to mutations in the genes for thyroid peroxidase, thyroglobulin, sodium-io-dide symporter, SLC26A4, thyroid oxidase 2 and iodotyrosine deiodinase.

Thyroid peroxidase (TPO) catalyzes the oxidation, organification and cou-pling reactions involved in the synthesis of thyroid hormone. Defects in the TPO gene are the most frequent cause of inherited thyroid dyshormogene-sis causing permanent congenital hypothyroidism. Lack of TPO activity caus-es iodide organification defect leading to impaired binding of tyrosine resi-dues in thyroglobulin, thus interfering with the synthe-sis of iodotyrosine which is the building block of the thyroid hormone.

Thyroglobulin (TG) is exclusively synthesized in the thyroid gland and is a critical binding protein to tyrosine residues with which iodine is bound with for the formation of iodotyrosines. Mutations in the TG gene are asso-

ciated with moderate to severe CH associated with low serum TG concentrations.

Sodium-iodide symport-er (NIS) transports into the thyroid follicular cell iodide from the circula-tion under the stimulation by TSH binding to the TSH receptor. The first demonstration of a loss of function in the NIS gene was reported in 1997. The hypothyroidism is of variable severity (ranging from fully compensated to severe hypothyroidism) and goiter is not always present. Individuals with a higher dietary intake of iodine are less likely to have severe hypothyroid-ism than those with iodine deficiency.

Mutation in the SLC26A4 gene causes Pendred syndrome which is char-acterized by sensorineural deafness and diffuse or multinodular goiter. Despite the goiter, individuals are likely to be euthyroid and only rarely present with CH. TSH levels, however, are often in the upper

Affected Process Substance/Gene Involved Characteristic Features

Iodine Trapping Sodium Iodide symporter Reduced thyroidal iodide

Iodide efflux into follicular lumen SLC26A4 Sensorineural deafness

Matrix protein for hormone synthesis Thyroglobulin Goiter

Absent or very low TG level

Iodide organification/ coupling reaction Thyroid peroxidase Partial or total iodide

organification defect

Intrathyroidal iodide recycling Iodotyrosine deiodinase(aka DEHAL1)

Negative CH screenGoiter, hypothyroidism after neonatal period

Table 2: Known Gene Defects Causing Thyroid Dyshormogenesis (Adapted from Reference #5)

23

end of normal range, and hypothyroidism of variable severity may eventually develop.

NADPH oxidases are encoded by two recently cloned genes, THOX1 and THOX2, located at the apical membrane of the thyroid cell and are involved in the H2O2 generation in the thyroid. TPO has no biological activity in the absence of H2O2. Defects in the THOX2 gene present with mild transient hypothyroid-ism (partial organification defect) to severe CH (with complete iodide organi-fication defect). Goiter is absent in affected patients.

Iodotyrosine deiodinase (IYD) is important in recy-cling or recirculation of iodide, thus its deficiency can lead to excessive uri-nary loss of MIT and DIT. Mutation in the IYD gene (aka DEHAL1 gene) can lead to iodide deficiency, which may manifest at birth or may present with hypothyroidism at 1.5 to 8 years of age.5

Mutation in the gene for Monocarboxylase Transporter-8 (MCT8)

T3 is the biologically ac-tive thyroid hormone and it exerts its effect by acting on nuclear receptors, necessitating its transmem-brane passage across the nuclear membrane. MCT-8 is a membrane thyroid hor-mone transporter and its gene has been mapped to the X chromosome. Males with MCT-8 mutation present with neurological abnormalities presenting in early infancy consisting

of hypotonia, nystagmus, feeding difficulties, recur-rent aspiration and severe delay in motor and mental development. Hypothyroid-ism tends to be mild and is usually diagnosed beyond infancy. So far, this is the only example of congeni-tal hypothyroidism with an X-linked inheritance as well as hypothyroidism resulting from a defect in target tissue rather than in the pituitary-thyroid biosynthet-ic pathway.4

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer

A landmark guideline about the management of children with thyroid nodules and differentiated thyroid cancer was just released in July of this year by the American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer. For years, pediatric practitioners followed management of thyroid nodules and can-cer in adults when dealing with these problems in children. Thus, this is a much-awaited work since the guidelines are tailored specifically for the needs of the pediatric population with thyroid nodule and thyroid cancer.

The difference between the pathophysiology and prognosis of differentiat-ed thyroid cancer (DTC) in adults and children prompted the development of these pediatric guide-lines. Thyroid nodules are uncommon in children compared to adults. How-ever, there is greater risk

of malignancy in thyroid nodules diagnosed in chil-dren compared nodules in adults (22% to 26% in chil-dren versus 5% to 10% in adults). Although children with DTC have extensive disease at clinical pre-sentation (i.e., presence of regional lymph node involvement, extra-thyroidal extension and pulmonary metastasis), they are much less likely to die from the disease than adults and many children with pulmo-nary metastases develop

persistent although stable disease following I-131 therapy. Thus, differen-tiated thyroid cancer is associated with a more favorable progression-free survival in children com-pared to adults with persistent DTC.

These guidelines provided recommendations for the evaluation and manage-ment of thyroid nodules in children and adolescents, including the role and in-terpretation of ultrasound,

It is the expectation

that, following these

guidelines, diagno-

sis of differentiated

thyroid cancer will

be prompt and

management

will not cause

unnecessary and

serious morbidities

in the affected child

or adolescent.

24

CME Questions

13. The finding of mild TSH elevation in obese children:

a. is always indicative of hypothyroidism.

b. needs thyroid hor-mone supplementation.

c. all of the above

e. none of the above

14. Congenital hypo-thyroidism related with genetic mutations include the following conditions, except:

a. Thyroid dysgenesis with respiratory distress syndrome, developmental delay, hypotonia, ataxia and choreoathetosis

b. Absent TG with cleft palate, choanal atresia, and kinky hair

c. Goiter with sensorineural hearing loss

d. Lingual thyroid gland

15. Differentiated thy-roid cancer in children and adolescents have the following features compared to adults except:

a. It is more common.

b. It is associated with increased invasiveness at diagnosis.

c. Children are less likely to die from the disease compared to adults.

d. There is greater risk for it in the presence of a thyroid nodule.

Author

Susan Peña-Almazan, MD

Susan Peña-Almazan, MD, is a pediatric endocrinologist at Dayton Children’s. Dr. Peña-Almazan is board certified in pediatric en-docrinology and pediat-rics. She is an assistant professor of pediatrics at Wright State Univer-sity Boonshoft School of Medicine, a fellow of the American Academy of Pediatrics and a member of the Pediatric Endocrine Society.

References

1. The 100-year anniver-sary of the isolation of thy-roid hormone in Rochester, Minnesota. Endocrinology Update. 2014;9(4):1-2.

2. Reihner T. Thyroid function in the nutritionally obese child and adoles-cent. Current Opinion in Pediatrics. 2011;23: 415-420.

3. Stitchel H, l’Allemand D, Gruters A. Thyroid function and obesity in children and adolescents. Horm Res. 2000;54: 14-19.

4. Park SM, Chatterjee VKK. Genetics of congenital hypothy-roidism. J Med Genet. 2005;42:379-389.

5. Grasberger H, Refetoff S. Genetic causes of congenital hypothyroidism due to dyshormogene-sis. Curr Opin Pediatr. 2011;23(4):421-428.

6. Francis GL, Waguespak S, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, et al. The American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer: Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015;1-95.

fine needle aspiration biopsy and cytology, and the management of benign nodules. Most important, the guidelines addressed the evaluation, treatment and follow-up of children and adolescents with DTC including pre-operative and post-operative stag-ing, surgery, the role of radioactive iodine therapy and goals for TSH sup-pression.

Based on the guideline, to workup a thyroid nodule for possible thyroid cancer, ultrasound-guided fine- needle aspiration is the recommended procedure. If malignancy is confirmed, total thyroidectomy should be done including nodal and neck dissection in the presence of positive nodal metastasis. Since there is good prognosis for surviv-al, extensive management including radioactive I-131 therapy involving whole body radiation needs to be considered in-dividually and not general-ly recommended as previ-ously done since there has been increased incidence of secondary malignancy related to this therapy in pediatric thyroid survivors.6 It is the expectation that, following these guidelines, diagnosis of differentiated thyroid cancer will be prompt and management will not cause unnecessary and serious morbidities in the affected child or adolescent.

25

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Pediatric Forum | Volume 27, Number 1

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Read and reflect on each article.

Answer the questions from each article and complete this test. 70 percent correct answers are needed to obtain the full 4.0 AMA PRA Category 1 CreditsTM.

Complete the program evaluation.

Return your completed test and program evaluation by mail or fax to: Sue Strader, coordinator Department of Continuin Medical Education Dayton Children’s One Children’s Plaza, Dayton, OH 45404-1815 Fax: 937-641-5931 Email: straders@childrensdayton.org Take test online: childrensdayton.org/providers

This test must be received by December 31, 2016, for the credit to be awarded.

Your answers to CME questions (Please circle the BEST answer.)1. True False2. True False 3. a b c d4. a b c d5. True False6. a b c7. a b c d8. a b c d9. a b c d10. a b c d11. a b c d12. a b c d13. a b c d14. a b c d15. a b c d

Physician accreditation statement and credit designation

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint provider-ship of Wright State University (WSU) and Dayton Children’s Hospital.

WSU designates this Journal-based CME Activity for a maximum of 4 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

News and updates

Neurosurgery welcomes Robert Lober, MD, PhD

Rober Lober, MD, PhD, recently joined the Dayton Children’s neurosurgery department. As part of his role, he will conduct pediatric research in our partnership with the Wright State University & Premier Health Neurosci-ence Institute.

Dr. Lober plans to create a neuroimaging labora-tory that will analyze the

massive amounts of data from the medical imaging scans of Dayton Chil-dren’s patients, as well as experimental subjects, to guide protocols and better care for future patients. He will work with researchers, physicists and clinicians from around the country to find ways to revolutionize treatment options. Along with advanced imaging, he has special interests in neuro-oncology, hydro-cephalus and epilepsy.

Grand Rounds

Dayton Children’s Pedi-atric Grand Rounds are offered every Wednesday morning at 8:30 am in the auditorium. Can’t attend in person? Many grand rounds are available to watch online at your convenience. One hour of Category 1 CME credit is offered for grand rounds and grand rounds online.

Have a topic request or feedback on grand rounds or grand rounds online? Email Sue Strader at straders@childrensdayton.org.

Visit childrensdayton.org/providers and select the education tab

More locations to help battle childhood obesity

Dayton Children’s is expanding the lipid clinic to more locations. The lipid clinic team, including a registered dietitian, will now see patients:

• Tuesdays, Specialty Care Center in Middletown• Thursdays, Ohio Pediatric Care Alliance in SpringfieldThe lipid clinic provides treatment plans for children with disorders including:• Abnormal cholesterol • Abnormal triglycerides • Insulin resistance syn-drome (this is a prediabet-ic condition involving high triglycerides, high blood pressure, obesity, high fasting insulin level) • Diseases or disorders of obesity

Critical Care welcomes Rasika Venkatraman, MD

Rasika Venkatraman, MD, joins the pediatric intensive care unit at Dayton Chil-dren’s. Dr. Venkatraman comes from Nationwide Children’s in Columbus where she completed a fel-lowship in pediatric critical care and served on the

adverse drug subcommit-tee and the venous-throm-boembolism event reduc-tion committee. She has a strong interest in finding ways to keep sedation at levels that don’t lead to more complications for our most critically ill and injured kids.

26Learn more at childrensdayton.org/providers

Mental Health Services Expansion

Psychiatry welcomes Bethany Harper, MD

Dayton Children’s wel-comes Bethany Harper, MD, to the psychiatry department. Dr. Harper is an assistant professor of psychiatry at Wright State University Boonshoft School of Medicine, where she completed her medical degree, residency and a fellowship in child and adolescent psychiatry. She is also active in taking care of some of the Day-ton area’s most vulnerable children, through work for St. Vincent de Paul and Daybreak.

Dr. Harper joins psychi-atrists Grace Matheson, MD, PhD, and medical di-rector, and Andrew Smith, MD, at Dayton Children’s. They care for patients, ages 4 through 16, who have complex mental health needs with only

limited improvement after taking multiple medica-tions, severe autism and/or developmental delays, and medical conditions in addition to mental health concerns.

Mental Health Community Resources Directory

This directory launched Fall 2015 and is the first of its kind in the Dayton region, bringing together many of the mental health resources available to families in our community in an easy-to-navigate online directory. You can search by zip code, service needed, condition or age range and even select only resources that accept Medicaid. It is located under the mental health services section on Dayton Children’s website, childrensdayton.org/men-talhealthdirectory.

Save the DateUpcoming CME Events

Prevention as the Best Medicine: Strengthening Our Conversation About Vaccines

May 14, 2016

Dayton Children’s Hospital One Children’s Plaza Dayton, OH 45404

*credits include 5 hours of Category 1 CME and 20 points of MOC Part II

2016 Pediatric Update: Pediatric Obesity

A collaboration between Dayton Children’s and Nationwide Children’s

April 19, 2016

6:00 pm - 8:30 pm

Springfield Regional Medical Center 100 Medical Center Drive Springfield, OH 45504

More information on both events will be mailed in the spring.

Visit childrensdayton. org/providers

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Dayton Children’s HospitalOne Children’s PlazaDayton, Ohio 45404-1815

Nonprofit OrganizationU.S. Postage Paid

Permit Number 323Dayton, Ohio