14 yr old Male With Altered Mental Status

David Josey Jr. M.D. April 1, 2008

HPI
14 yr old male presented to the RWJ ED with a
1 day history of headache, slurred speech, confusion, problems walking, and dizziness. Patient was in Gym class and experienced a sudden onset of these symptoms.
Headache-B/L temporal area, pounding in nature (-) photophobia/phonophibia Speech-inability of school nurse to understand him Walking- unable to walk in a straight line

Symptoms continued at his PMDs office.

Review of Systems
(+) 10 lb weight loss over an 8 month
period despite increased appetite (+) increased thirst (-) increased urine output (+) easy fatigability (+) tremors (+) increased watery stools

ROS cont.

(-) chest pain/palpitations (-) preceding behavioral changes (-) history of ingestion of any over the counter or prescription drugs or medications (-) exposure to carbon monoxide (-) trauma (-) fever (-) neck stiffness (-) night sweats

PMH
Born full term by normal delivery Diagnosed with ADHD as a child
Not treated with medications as patient able to function well in school without it. Normal baseline function

History cont.

Allergic to Penicillin : rash Immunizations: UTD Meds: MVIs Diet: Regular Family HX:
Mom GERD 16 yr old brother with eczema and ADHD (-) family hx of medical problems

Soc hx: lives with parents and brother, (+) parakeet,

plays basketball and baseball, attends 9th grade, (-) alcohol, illicit drug use, tobacco, denies sexual activity Development: appropriate

In the ED
Initial vitals:
T 99.2 HR 160 BP 145/84 RR 22 Sats 99% RA

Awake, alert, anxious appearing, diaphoretic but speech

normal, headache decreased, dizziness resolved Eyes: PERRL, EOM intact, fundi not observed Ears: TM clear B/L Throat: MMM, orapharynx clear

Neck:
supple thyroid which was diffusely enlarged and firm to palpation, (-) bruit

CV: NL S1,S2, tachycardic, I-II/VI SEM LLSB

Physical Exam cont.

Chest: NL breathing easily ABD: NL Genitalia: Tanner IV pubic hair, L gynecomastia Extremities: WWP, FROM, (-) C/C/E Neuro: CN II-XII grossly intact, fine peripheral tremor of fingers, 5/5 muscle strength U/L, 2-3/4 DTR patellar tendon, (+) clonus at Achilles tendon, finger to nose NL, gait nl, toe walk nl, heel walk nl, some difficulty with toe to heel walking.

Summary
14 yr old male without significant past medical
history who presents with sudden onset of headache, slurred speech, confusion, problems walking, and dizziness, Symptoms are associated clinically with tachycardia and hypertension on the background of an 8th month history of weight loss despite polyphagia, fatigue, and polydyspia.

Physical exam.on the floor

All the same except the following:
HR 132 with BP now 119/61

Neuro: (-) Romberg, (-) dysmetria (-)

ataxia nl muscle tone

Differential

Differential
Psyche

Neoplasm

Anxiety/panic attack ADHD Brain tumor Lymphoma TIA/Stroke Intracranial hemorrhage Meningitis/encephalitis Porphyria Concussion/increased ICP

Endocrine Hyperthyroidism DIABETES Pheochromocytoma Hypercalcemia Hypoglycemia Drug ingestion Cocaine Amphetamines Steroids Phenylepherine Ephedrine MAO Inhibiters PCP Mushrooms Lead poisoning Carbon monoxide poisoning

Neurologic

Diagnostic testing
Blood/urine:
CBC CMP ESR UA Urine Drug Screen Thyroid function studies (TFTs)

Radiology: EKG
Head CT

Diagnostic Test Results

13.3 10.7 39.2 347
60 N 0B 26 L 11 M

137
4.2

102 27.2

11 0.5

103 10.0

Prot: 6.1

Tbili 1.0

AST: 27 ALT:32

Albumin 4 Allk Phos: 224

UDS: (-) barbiturates, Benzodiazepines, Cocaine , opiates, PCP, THC UA: 1.018, trace protein, (-) blood, nitrite, bilirubin, ketones ESR: 12

 TFTs: pending EKG: sinus tachycardia, incomplete

RBBB, LVH, normal axis deviation Head CT: normal

Differential

Psyche
Anxiety/panic attack ADHD Coarctation of the Aorta Arrhythmia Renal Artery Stenosis Polycystic kidney disease Glomerulonephritis Concussion/increased ICP TIA/Stroke Sub-dural hemorrhage Brain tumor Meningitis

Endocrine

Cardiac Renal

Hyperthyroidism Diabetes Pheochromocytoma Pituitary Tumor Hypoglycemia Hypercalcemia Neuroblastoma

Cocaine Amphetamines Steroids Phenylepherine Epherdrine MAO Inhibiters PCP

Neoplasm Drug ingestion

Trauma Neurologic

Other
Lead poisoning Carbon monoxide poisoning

Hospital Course: Day #1

Admitted to the PICU for CR monitoring Initially tachycardic to the 130s Echo ordered 2 to LVH on EKG TFTs reordered with thyroid antibodies for both Hashimotos Thyroditis and Graves Disease

Hospital Course: Day #2

Patient remained tachycardic but mostly normotensive Echo: Results of initial TFTs:
TSH 0.08 [0.35-5.5 miu/L] T4 21.8 [5.0/12.0 mcg/dl] F T4 7.22 [0.90-1.80 ng/dl] T3 >800 [60-181 ng/dl] normal study

Results of repeat TFTS:

TSH T4 FT4 T3 <0.01 [0.35-5.5 Miu/L] 5.61 [5.0/12.0 mcg/dl] 5.61 [0.90-1.80 ng/dl] 718 [60-181 ng/dl]

Thyroid ultrasound:

enlarged hyper vascular thyroid gland (-) nodules

Hospital Course: Day #2 cont.

Pediatric Endocrinology consulted
Diagnosis of hyperthyroidism presenting with thyrotoxicosis made Thought to be secondary to Graves Disease until proven otherwise Confirmatory antibodies pending

Therapy initiated
Methimazole 10 mg bid Propanalol 10mg bid

Hospital Course: Day #3

HR decreased to <100 while patient remained
normotensive DISCHARGED home on Methimazole and Propanolol with follow up with endocrinology in 2 weeks

Hyperthyroidism

Thyroid anatomy

Hyperthyroidism
Hyperthyroidism and thyrotoxicosis are used
synonymously However they refer to different aspects of the same condition as follows: Hyperthyroidism- BIOCHEMICALLY over activity of thyroid gland leading to excessive synthesis of thyroid hormones and accelerated metabolism in the peripheral tissues Thyrotoxicosis- CLINICALLY Clinical effects of unbound thyroid hormone whether to not the thyroid gland is the primary source

Pathophysiology

Controlled by a complex feed back mechanism The release of TSH from the anterior pituitary gland is stimulated by low circulating levels of thyroid hormones TSH is under the influence of thyrotropin-releasing hormone (TRH), somatostatin, or dopamine. TSH then binds to TSH receptors on the thyroid gland to release mostly t4 and some T3 Elevated levels of these T4 and T3 act on the hypothalamus and anterior pituitary decreasing synthesis of TSH.

TSH receptor
G-proteincoupled receptors. Large protein embedded in
the cell membrane. Contains an extracellular domain binds TSH and intracellular domain that acts via a G-protein second messenger system to activate thyroid adenyl cyclase, yielding cyclic adenosine monophosphate (cAMP).

Thyroid Hormone Synthesis

Synthesis of thyroid hormone is dependent
on an adequate supply of iodine. Dietary inorganic iodide is transported into the gland by an iodide transporter Iodide is then converted to iodine and bound to tyrosine residues on thyroglobulin by the enzyme thyroid peroxidase in a process called organification.

Synthesis cont.
The result is the formation of monoiodotyrosine
(MIT) and diiodotyrosine (DIT). Coupling of MIT and DIT results in the formation of T3 and T4, which are then stored within the thyroglobulin in the extracellular thyroid follicular lumen. Unlike other endocrine glands, the thyroid has a large supply of stored preformed hormone.

Causes of Thyrotoxicosis
Graves Disease Chronic Lymphocytic Thyroditis (Hashimotos
Thyroditis) Toxic Adenoma McCune Albright Syndrome Subacute Viral Thyroditis TSH Secreting Pituitary Adenoma Exogenous Thyroid Hormone hCG Secreting Tumor

Chronic Lymphocytic Thyroditis

Autoimmune disorder characterized by thyroglobulin
and thyroid peroxidase antibodies Most common cause of acquired thyroid disease Typically results in hypothyroidism However, hyperthyroid phase (Hashitoxicosis) may occur self limited phase although may last up to 6 months recent study showed 11.5% of pts with Hashimotos Thyroditis present with thyrotoxicosis

Toxic Adenoma
Autonomously functioning thyroid nodule
hypersecreting T3 and/or T4 resulting in thyrotoxicosis Aka Plummers disease Very rare in children Almost never malignant

McCune Albright Syndrome

Clinical syndrome that is classically characterized by
polyostotic fibrous dysplasia, cafau-lait hyper pigmentation, and endocrinopathies. Most common endocrinopathy is peripheral precocious puberty Caused by activation mutation in GNAS1 Hyperthyroidism can be observed
can present with a diffuse goiter in addition to other signs of hyperthyroidism associated with mutation in the alpha subunit of the G regulatory protein that links TSH receptor with cAMP

Subacute Viral Thyroditis

Generally associated with a viral URI Classically characterized by tender, warm
thyroid gland Hyperthyroidism caused by inflammation of the thyroid gland and subsequent release of preformed thyroid hormone. Once inflammation resolves, symptoms resolve

TSH Secreting Pituitary Adenoma

Can result in thyrotoxicosis Biochemically:
elevated TSH levels, leading to elevated T4 and T3 levels

Extremely rare

Exogenous Thyroid Ingestion

Ingestion of L thyroxin medications T4 is converted to T3 in the peripheral
tissues, leading to inhibition of TSH Lab studies:
elevated T4 and T3 levels suppressed TSH level

Occasionally T3 is ingested:
similar lab results but T4 is low

hCG Secreting Tumors

Adolescents with tumors such as
hydatiform mole and choriocarcinoma can present with thyrotoxicosis hCG binds directly to the TSH receptor, leading to excessive thyroid hormone release Very rare

Graves Disease

Graves Disease
Most common cause of hyperthyroidism in
children accounts for >95% of childhood cases of hyperthyroidism Prevalence approximately 0.02% in childhood Gets it name from the Irish physician Robert Graves who described it in 1835.

Pathophysiology
Associated with HLA-B8 and HLA-DR3 haplotypes Polygenic inheritance The reasons for the development of Graves Disease are
presently unknown. Some postulated causes include:
Environmental Factors- damage to the thyroid, by radiation or ethanol injection, with liberation of antigens, has been noted, smoking also increases the risk Thymic Selection of Lymphocytes- pre-T lymphocytes may be educated in the thymus to recognize thyroid-related epitopes, and thus to generate self-tolerance against these thyroid-related antigens. Molecular Mimicry- exposure to a particular peptide epitope in an environmental antigen might develop immune reactivity to an amino acid sequence identical to that present in an human endogenous antigen such as TSH receptor, TPO, or TG. Thyroid Injury and Antigen Release- certain types of injury to the thyroid are followed by the development of thyroid autoimmunity, including Graves' disease. i.e. radiation

Pathophysiology cont.
Patients likely have defective immune tolerance, leading to
the development of specific auto antibodies directed against various thyroid antigens The TSH receptor is the most significant thyroid auto antigen in this disorder. However, children with Graves disease also produce immunoglobulin's directed against thyroperoxidase (anti-TPO) and thyroglobulin, as well as TSH receptorblocking antibodies

Morbidity and Mortality

Potentially life threatening Most severe manifestation is thyroid storm Rare in children Can also see signs of CHF

Demographics
Females affected more often than males
3-6:1 ratio Incidence increases throughout childhood with peak incidence in children 10-15 yrs No racial predilection seems to exist

Clinical
Children are usually identified because of
enlarged thyroid, weight loss or behavioral changes Exophthalmos less commonly observed in children Enlarged thyroid may cause dysphasia Symptoms may mimic ADHD

Symptoms
Dysphasia Irritability and emotional liability Sleeplessness and restlessness Inability to concentrate Deterioration of handwriting and school performance Frequent stools or diarrhea
Palpitations Pruritus Weight loss Increased appetite Nocturia, increase in urination and thirst Infrequent or light menses Weakness and tiredness Exercise intolerance Heat intolerance

Frequency of signs and symptoms

The frequency of
symptoms :
Increased appetite (60%) Weight loss (50%) Increased sweating (49%) Hyperactivity (44%) Heat intolerance (33%) Palpitations (30%) Fatigue (16%) Diarrhea (13%)

The frequency of
signs :
Goiter (99%) Tachycardia (82%) Exophthalmos (47%) Tremor (61%) Thyroid bruit (53%) Increased pulse pressure (50%)

Physical
Patients can be thin
with a fixed stare and fidgety behavior Can see multiple ophthalmological, thyroidal, cardiopulmonary, neuromuscular and dermal findings.

Labs
Hyperthyroidism
confirmed simply and quickly with measurements of FT4 and TSH

Graves Disease
confirmed by measurement of TSH receptor stimulating immunoglobulins, i.e. TSIgs

Imaging
Diagnostic radioiodine I
131 uptake is rarely performed Either technetium Tc 99m or 123I scan may be useful if the gland does not have a uniform consistency Ultrasound may also be used to image the gland

Treatment
3 main treatments
Medical therapy Radio-iodine Ablation of the thyroid gland Surgery

Antithyroid drugs
2 main medications are used in the U.S.
Propylthiouracil and Methimazole Inhibit thyroid biosynthesis decreasing the oxidation of iodine and iodination of tyrosine. PTU diminishes the peripheral conversion of T4 to T3 PTU is required TID because of shorter half life Methimazole can be administered BID

Therapy cont.
Glucocorticoids
Decrease peripheral T 4to T 3conversion, and may have a more prolonged suppressive effect on thyrotoxicosis Prednisone has been reported to induce remission of Graves' disease, but at the expense of causing Cushing's syndrome potassium iodide acts promptly to inhibit thyroid hormone secretion from the Graves' disease thyroid gland. Used more in congenital Graves disease. blockers- alleviate many of the signs and symptoms of Graves Disease However have little effect on the fundamental disease process Palpitations, excessive sweating, and nervousness improve, and tremor and tachycardia are controlled

Potassium Iodide

Adjunctive Therapy:

Radio-Iodine Ablation
Ablation of the thyroid gland with radio-iodine is the
treatment of choice for most adults. After more than 50 years of widespread use, no evidence of an increased risk of malignancy or genetic damage exists. Nonetheless, because of the theoretical risk, frequency of radioiodine therapy is much lower in pediatric patients. 131 I is administered orally in 1-2 doses. Ablation may take several weeks to months, and hyperthyroid symptoms may continue until that time. Propanalol may be used to ameliorate these symptoms.

Surgery
Surgery is the oldest treatment for Graves Disease Generally, patients are initially treated with antithyroid
medications. Iodide then is added before surgery to decrease the vascularity of the thyroid gland. To minimize risk of recurrence, most of the gland is removed. Surgical complications can include hypoparathyroidism and damage to the recurrent laryngeal nerve

Summary
Graves disease is the most common
cause of hyperthyroidism is children but with proper treatment can be successfully managed.

Follow up
Microsomal Antibody
1:400 [<1:100]

Thyroglobulin Antibody
1:160 [<1:10]

Thyroid Binding Globulin

10.6 [13-30mcg/ml]

Patient remains asymptomatic

The End

References

Dallas J, Foley T. Hyperthyroidism. In: Pediatric Endocrinology. 3rd ed. 1996:401-415 Sugino K, Ito K, Mimura T, et al. Surgical treatment of Graves' disease in children. Thyroid. 2004;14:447-452 Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin North Am. Mar 1998;27(1):109-26 Bahadada S, Bhansali A, et. Al. Juvemile Hyperthyrodism: an Experience . Indian Pediatrics 2006 43: 301-317 Ferry RJ, et al. Graves disease Published online Rivkees, SA, Sklar C, Freemark M, The Management of Graves Disease in Children with Special Emphasis on Radioiodine Treatment. The Journal of Clincical Endocrinology and Metabolism 1998 83: 3767-3776 Stalberg P, Svensson A, et al. Surgical Treatment of Graves Disease: Evidence-Based Approach World Journal of Surgery 2008 Published online Glaser NS, Styne DM. Predicting the Likilihood of Remission in Children with Graves Disease: A Prospective, Multicenter Study. Pediatrics 2008 121: 481-488 www.endotext.com

Objectives
To present an interesting case of altered
mental status Discuss the differential diagnosis of hyperthyroidism Review the Pathophysiology and treatment of Graves Disease.

Questions
1. Are patients with Graves disease who
do not have their thyroid removed at greater risk for thyroid cancer later on in life? 2. What determines which of the antithyroid medications are used in a patient.

Thanks
Dr. Marshall Dr. Kelly Monica and Archana

Differential
Acute/Chronic
IDDM with DKA Brain tumor with seizure/increased ICP Hypertension with hypertensive encephalopathy

Acute
Ingestion Infection Seizure Aneursym Stroke