October 2007

 CC: “I keep vomiting”  HPI: 9 yo male presents with one week history of intermittent vomiting. He was punched in the head one week prior but had no outward signs of injury, though he did have emesis on the day of the injury.  Since then he has vomited on and off. The emesis was NB NB.

 Three days prior to this visit he stayed home from school because of decreased appetite and malaise.  He went to school the next day but was sent home because of nausea.  That evening he was well until after dinner when he had multiple episodes of emesis.  Of note… no headaches and no visual changes

 Mom finally called the pediatrician and was sent to the ER.  The patient had a head CT done and was given IVF. The CT was read as normal.  He was discharged home.

 During your shift in the CHER, the patient is brought in by his mom for lethargy.  She said he was watching cartoons and was slow to answer questions.  He became listless and lethargic. He required lots of stimulation to answer questions.  He was noted to have one (small) episode of bilious emesis as well.

 PMH: mild intermittent asthma. No recent illnesses  Meds: Albuterol PRN, last use 1 month ago  Imm: UTD  Dev: Normal, does well in school  Fam Hx: noncontributory  Social: Lives with mom, dad and brother in Metairie.  Travel Hx: none, occasionally goes camping with sibling.

 Ht: 143 cm (95%) Wt: 27 kg (50%)  T 98.9 HR 86 RR 22 BP 100/70  Gen: pale, thin, does not open his eyes when you ask him to but follows other motor commands “raise your leg”  HEENT: no nuchal rigidity or meningeal signs  CV: rrr no murmur  Chest: CTAB  Abd: benign  Skin: no rash, icterus, track marks, petechiae, etc

 Neuro: ◦ MS: responds to painful stimuli, nonverbal, follows some commands ◦ CN: PERRL, no photophobia, EOMi, symmetrical face, tongue midline ◦ Tone: normal ◦ Motor: 5/5 in all extremities when pt would cooperate ◦ Sensory: Appeared intact ◦ DTR: 2+ everywhere except 3+ patellar B and 4-5 beats of ankle clonus B

Top 3 Differentials & Top 3 Tests

Intermittent Vomiting x 1 wk Acute Mental Status Changes In an otherwise well child

 Encephalopathy ◦ Hypoxic ischemia ◦ Hypoglycemia ◦ Cerebral Edema ◦ Increased ICP ◦ Toxins  Acute CNS infection ◦ Bacterial ◦ Viral  Postinfectious ◦ Mycoplasma ◦ Varicella ◦ Etc  Toxins ◦ Exogenous ◦ Endogenous  Renal failure?  Liver failure?  IEM ◦ Urea metabolism ◦ Inherited Organic acidemias  Reye Syndrome  Complex migraine  Temporal lobe epilepsy

Bolus given. Sent HomeBolus given. Admitted.  ER visit day prior: ◦ BUN 17, Cr 0.7 ◦ HCO 3 20 ◦ Other electrolytes, LFTs, Amylase, Lipase, CBC was normal ◦ UA: SG 1.030,1+ ketones ◦ KUB: wnl ◦ Head CT: wnl  Today: ◦ All the same labs were repeated  Results were the same! ◦ Utox: negative ◦ LP:  CSF was normal

 Patient becomes more alert after bolus.  He asks for food and is loving the Children’s Hospital TV channels.  Speech is dysarthric ◦ Mom says that this is NOT his normal speech ◦ BUT she is happy that he is acting more like himself

 You’re called because the patient becomes agitated.  He is kicking, screaming, and pulling at his IV.  Why this acute decompensation???

What do you do? Any further tests? Has anything entered into your index of suspicion?

 CMP ◦ normal  Ammonia ◦ 220 umol/L (nl <30) ◦ This level was repeated and confirmed

9 yo male with acute mental status changes, vomiting and hyperammonemia.

 Ammonia released from catabolism of amino acids ◦ Cell breakdown ◦ Excess dietary protein  Excreted as urea (kidney) via urea cycle as conversion of glutamate to glutamine (liver)  Increased ammonia almost exclusively toxic to the brain

 NH3 must be measured in every sick child who is encephalopathic for an apparently unknown cause  Otherwise hyperammonemia may be missed and the child deprived of treatment.  Signs and Symptoms (> umol/L) ◦ Lethargy ◦ Confusion ◦ Vomiting ◦ Acute ataxia ◦ Hyperactivity ◦ Coma (>300)

 In healthy neonates, NH3 is <100 ◦ If sick can be up to 180umol/L ◦ Suspect IEM in neonates if >200umol/L  In older children, NH3 is <80umol/L (nl=<35) ◦ Think IEM if >100umol/L

 Blood sample must be taken as uncuffed venous or arterial, kept on ice, and analyzed immediately.  It’s put in a green or purple top tube  False elevations are common ◦ Hemolysis ◦ Delay in processing ◦ Exposure to room temp

Any guesses?

 Inadequate function of urea cycle ◦ Hepatocellular dysfunction ◦ Deficient urea cycle enzymes  Acquired  Reye  Drugs (valproate, chemotherapy)  Inherited  Urea cycle enzyme deficiency  Organic acidemia  Fatty acid oxidation defects  UTI from urease-producing organisms  Increased muscle activity ◦ Respiratory distress and seizures (not >180umol/L)

 Blood gas ◦ Respiratory alkalosis as NH3 stimulates resp center ◦ Metabolic acidosis think organic acidemia vs FAO d/o  Urine ◦ Ketones- organic acidemia  BMP ◦ Anion gap  Liver function tests  Plasma and urinary amino acids  Urine organic acids  Acylcarnitine profile ◦ Fatty acid oxidation defects  Plasma carnitine level

Urine OA came back Elevated orotic acid Plasma AA Elevated glutamine level Low/Absent citrulline

 Most common urea cycle disorder  The ammonia that is not detoxified by the urea cycle is converted to glutamine and glutamate.  Increased glutamine in astrocytes  osmotic shift of fluid into astrocytes  swelling/cerebral edema

 The goal of the urea cycle is to breakdown ammonia into urea.  This process takes place in the hepatocytes.  It’s that simple!

 Is an x-linked disorder (1/30,000) ◦ The other urea cycle defects are AR ◦ Does rarely occur in girls! 10% of female carriers become symptomatic  Typical presentation ◦ Males in first week of life with lethargy, vomiting, hypothermia (looks like sepsis) ◦ Respiratory Alkalosis  Late Onset Disease ◦ Typically females with vomiting, lethargy and behavioral changes

 Symptoms can occur following viral illness, childbirth and use of VPA.  Onset of symptoms frequent at the time of weaning from breast milk  CT/MRI can show evidence of acute ischemia. Generalized high intensity in white matter, brainstem, basal ganglia and bilateral frontal lobes.  EEG- slowing, can show triphasic waves

 Triad of encephalopathy, respiratory alkalosis and hyperammonemia.  NH3 levels (> 500 uM hemizygotes), > 100 uM heterozygotes.  Normal anion gap respiratory alkalosis  Serum amino acids: low citrulline, arginine, increased glutamine. Urine: high orotic acid.  DNA diagnosis available

 Stop protein intake!  Provide adequate calories to prevent catabolism (10% dextrose)  Only use lipids if fatty acid oxidation ruled out  Generous amounts of fluids to promote ammonia excretion

 Sodium benzoate and sodium phenylacetate to promote ammonia excretion  If NH3 >400 or no improvement in 8hrs- hemodialysis or hemofiltration  NO exchange transfusion, blood product transfusion or drugs that impair liver function  Call genetics

 Plasma glutamine is useful marker for effective therapy (<1000umol/L)  Decrease protein intake acutely during infection  Ibuprofen instead of Tylenol  Diet- low protein. Most patients can receive less than the RDA of protein and maintain good growth  Ensure essential amino acids and vitamins/minerals

 What triggered his presentation? ◦ Intermittent vomiting associated with increased protein intake ◦ He was well in the mornings because of overnight fast. ◦ Vomiting occurred later in the day because of eating  Overall trigger was mild viral illness ◦ Not from the school bully!

 June 2007… AG a 7yo female was transferred to the PICU with a 3 day history of lethargy progressing to coma.  Dialysis was started for hyperammonemia  She was diagnosed with OTC deficiency ◦ Confirmed heterozygote by DNA ◦ Apparently, she lived on a vegan commune with her mom and spent the weekend with dad chowing down on burgers. ◦ She was also on valproic acid for epilepsy. ◦ Both factors contributed to the presentation!

Thank you to Dr. Allison Conravey and Dr. Marble for their expertise! Thanks for participating in the pediatric puzzler!