Mad as a Hatter

1. Mad as a Hatter Deepti Deshpande, MBBS, MPH, FAAP Assistant Professor, Pediatrics and Public Health University of Arizona June 2013

2. Initial Presentation 20 month old girl admitted with: • Intermittent abdominal pain for 7 weeks. • Diarrhea off and on for 4 weeks. • Increased fussinessand fatigue. • Tactile low grade fevers off and on for 7 weeks. Night sweats. • 5 lbsweight loss. • Brought to the ER because her hands/ toes were turning cold and purpleover past day.

3. Initial Presentation • Several PCP, Urgent care and ER visits during this time. • Diagnosed with a viral illness, constipation, ear infection. Received 1 course of antibiotics. Entire family treated for parasites in Mexico a few weeks prior. • No sick contacts, No animal exposure. • Travels to Mexico frequently but no other travel.

4. Initial Thoughts: Differential Diagnoses • Infectious: infectious gastroenteritis, parasitic illness, pyelonephritis, intra-abdominal abscess, coccidiodomycosis, tuberculosis. • Non-infectious: nutritional deprivation and deficiencies, inflammatory bowel disease, thyroid disorder, malignancy, other systemic illness.

5. Additional History On further directed questioning/ ROS: • Regression of motor milestones: Over past 7 weeks, stopped running, started walking very slowly and over time stopped walking. Poor balance and falls. Lack of interest in play. • No suggestion of pain. • Scalp hair loss and hair pulling for ~ 2 weeks

6. Physical Exam • Temp 36.8, HR 162, RR 30, BP 122/74, Sats 100% on RA. • Weight= 9.6 kg (10th percentile), height and head circumference 10-25thpercentiles. • Irritable. Consolable for brief periods. Pulling her hair. • Cool hands and feet with a dusky bluish-purple color. Centrally well perfused and warm. Distal pulses 2+. • Abnormal neurological exam: Walks few steps very slowly with some gait instability. Loses balance easily when tries to squat to pick up a toy. Moves all extremities well but unable to stoop and recover. Patellar deep tendon reflexes 2+ but unable to elicit ankle reflexes. Normal tone and strength in the upper body. Fine motor exam appears normal. Tone decreased in the lower extremities. Follows some commands inconsistently. Says a few words. • Remaining exam within normal limits.

7. Clinical Presentation in a Nutshell • Neurological: B/L lower extremity weakness and hypotonia and regression of motor milestones. Gait instability. Inability to elicit ankle reflexes. • Cardiovascular: Hypertension and Tachycardia. • Gastrointestinal: Intermittent abdominal pain and diarrhea for several weeks. • Constitutional: Irritability, weight loss, sweating and dusky hands/ feet. Low grade fever.

8. Differential Diagnoses • GuillianBarresyndrome, ADEM, transverse myelitis, encephalitis, intracranial process. • Endocrine disorders. • Neuroendocrine disorders. • Neuro-degenerative or muscle disorders. • Toxic ingestions. • Genetic disorders. • Metabolic disorders.

9. Workup • MRI Brain and Spine: Normal. • Lumbar Puncture: Normal CSF cell counts, protein and glucose. CSF myelin basic protein neg. • Complete blood count, complete metabolic panel, electrolytes, urinalysis unremarkable. ESRand CK normal. • Cocciand PPD negative. Celiac disease screen negative. • Blood culture, urine culture, CSF culture, stool studies negative (occult blood, stool culture, stool ova and parasites negative.

10. Workup • Thyroid tests: Initially slightly low TSH with high normal free T4, but normalized on repeat testing. • Cortisol normal. • Renin and Aldosterone normal. Imaging: • Abdominal and Chest X-rays normal. • Abdominal/ Renal US normal. • ECHO with mild subjective LVH with age appropriate measurements.

11. Workup • Neuroendocrine workup • Urinary metanephrines, urinary catecholamines, plasma metanephrines elevated. • Urinary VMA and HVA: Normal • Urinary 5-HIAA: Normal • This raised concern for Pheochromocytoma: • Abdomen/ Pelvis CT negative • MIBG scan negative

12. What have we ruled out? Now what? • GBS, ADEM, intracranial or spine abnormality • Infectious etiologies • Thyroid disorders • Hyperaldosteronism states • Pheochromocytoma, carcinoid tumor, neuroblastoma Further Testing revealed…

13. ELEVATED MERCURY LEVELS

14. (Ref < 35) (Ref 0-10)

15. Diagnosis: Mercury Toxicity • Mercury toxicity • Clinical syndrome suggestive of mercury toxicity. • Elevated urinary and blood mercury levels. • Elevated urinary beta2 microglobulin levels indicate possible early kidney injury. • No chelation therapy recommended. • Mercury levels not too high and clinical symptoms not severe with spontaneous improvement. • Etiology unclear but suspected due to excessive seafood intake. • Child ate 2-3 servings of shrimp/ tuna almost daily. • No other exposure sources identified on detailed questioning.

16. Hospital Course • Admitted to the Pediatric Floor for 23 days. • Hypertension and Tachycardia: Hypertension controlled using PRN Hydralazine and subsequently started on Propranolol. • Followed by Nephrology, Endocrinology, Neurology, Toxicology, Ophthalmology, Cardiology, PT/ OT.

17. 95th percentile: 104 mm

18. Normal Range

19. Hospital Course • Lower extremity weakness improved. Walking well prior to discharge. PT ongoing. • Dusky hands and feet resolved. • Abdominal pain, diarrhea, sweating resolved. Afebrile during stay. • Irritability resolved and child more playful and interactive.

20. Discharge Plan • Recommended avoiding all seafood. • Propranolol for hypertension. • Outpatient management • PCP follow up • Nephrology follow up • Toxicology follow up • Repeat mercury levels in 6 months.

21. Long Term Outcome • Mercury levels decreased spontaneously without any further seafood exposure. • Hypertension and tachycardia resolved over the next 2 months. Propranolol stopped. Repeat ECHO normal. • All systemic, gastrointestinal, cardiovascular and neurological symptoms resolved and back to baseline within about 2-3 months post discharge. • Meeting age appropriate developmental milestones.

22. Mercury Poisoning

23. Forms of Mercury • Elemental or metallic mercury • Highly volatile- vapors inhaled. • Pulmonary manifestations most severe. • Sources: Thermometers, sphygmomanometers, metallurgy. • Inorganic salts: Mercurous/ Mercuric salts • Well absorbed through skin, some via GI tract. • Gastrointestinal and Renal manifestations. • Sources: Paints, topical antiseptics, bleaching creams etc. • Organic: methyl/ ethyl/ phenyl mercury • Almost 100% absorbed via GI tract. • Primarily neurological manifestations. • Sources: Seafood, vaccinations etc.

24. Mercury Toxicity: Clinical Features Clinical presentation depends on the type of mercury, route, dose and duration of exposure. • Acrodynia: Rare idiosyncratic reaction in children. • Neurological: CNS/ Peripheral nerves • Gastrointestinal • Pulmonary • Renal • Skin/ Gingiva/ Eyes

25. Acrodynia • Rare idiosyncratic syndrome of mercury toxicity in young children. • Symptoms may include irritability, erythema of hands and feet, photophobia, hypotonia, painful extremities, hypertension and tachycardia etc.

26. Mercury Toxicity • Laboratory Diagnosis • Urinary lead levels • Blood lead levels • Pheochromocytoma like syndrome • Elevated plasma and urine catecholamines and metanephrines • Inactivates COMT • Treatment: Chelation used in severe symptomatic children. • DMSA commonly used.

27. Consider Mercury Toxicity in your differential Unexplained hypertension with a pheochromocytoma like presentation, neurological symptoms, developmental regression, renal, gastrointestinal or skin symptoms.

28. Questions? Mad as a Hatter!