What type of IEM or Hypoxic Injury does this infant have?

Question: What is it that this infant boy born on 5/9/00 has? Is it an IEM? Hypoxic Injury?

An infant boy was born 5/9/00 to a 34 year old, A pos, gravida 2, para 1, white female after a 38 week gestation. Complications of pregnancy included PIH last 5 days of pregnancy. The EDC was 5/4/00. Membranes were ruptured 2 hrs. PTD. The amniotic fluid was clear. Delivery was spont. vag. delivery under epidural/local anesthesia. 1 min. apgar was 6, the 5 min. apgar was 7. Resuscitation included: blowby oxygen.

Neuro: The child developed seizures almost immediately after birth, requiring TX with Phenbarb, Dilantin and Activan. LP done which was bloody. Initial CT showed subarachnoid blood. EEG showed burst suppression pattern. EEGs on 5/10, 5/11, 5/15, 5/26 and 6/5 all showing persistence of burst suppression. MRI on 5/18 showed scattered areas of subarachnoid blood, increased signal intensity and some hemorrhage within the Basal Ganglia. The child received Ativan 5/10, 5/25 - PRN) Phenobarb since 5/1 0; Pyridoxine - 100 mg on 5/11, 5/25, 5/26; Felbatol started 5/26 to 6/1. Still on Phenobarb 6/8/00.

Resp: The child was intubated for sedative effects of seizure meds as well as neuro status from 5/10 to 6/1. Off ventilator on 6/1 with some episodes ofshallow breathing. Seizures can cause infant to stop breathing but recovers if stimulated.
CV: The child received pressors from 5/10 - 5/12. He also received Albumin X2 during that time for Hypotension.
ID: The child was placed on empiric amp/gent after birth; more recently he received a course of anco for positive blood culture for staph EPI on 5/24.

Physical exam: wt: 3540 grams, hc: 36.2 cms, length: 50cms, hr: 132, rr: 33, temp: 99.1, bp: 61/33, mean:42
Gen. App: Pink, SGA Heent: AF- open flat, eyes: red, reflex bilaterally, ear canals: patent, palate: intact, neck: supple without masses, lungs: BS clear bilaterally, heart: RR without murmur, sounds normal, abdomen: soft  without masses or organoegaly, genitalia: normal, rectal: anus patent, extremities: FROM, pulses 2+, hips and clavicles intact. Infant can hear and see.

Neonatal Metabolic Screening Lab results from sample date 5/11/00, a partial listing of some of the high levels (umole / L):  Glutamic Acid = 8, Asparagine = 11, Glycine = 12, Glutamine = 624, Threonine = 48, Alanine = 25, Tyrosine = 28, Valine = 23, Methionine = 6. On 6/1 an Amino Acid Qunt. Serum was borderline elevation in Serum Glycine to 528uM. The CSF serum ratio is also borderline elevated at 0.032.

Is there anything else we could look for? Maybe narrow down our search to a specific area? Thank you for time.

[CCF Neuro[P] MD, RPS]

Dear Mark:

Very interesting case, but as always it is of someone's child.  SGA is often a marker for some metabolic etiology.  The fact that there were early seizures is also worrisome.  I am assuming that B6 did not correct the EEG.  All the electrolytes were normal? this would especially be true of the glucose and ketones?  Persistent hypoglycemia can be due to a glucose transporter defect and easily corrected by the ketogenic diet. As CPT is induced during birth, the brain requires mostly glucose during the initial hours of birth.  The high glycine is interesting and should be worked up further, this is especially true since it was found in the CSF and blood.  We have seen similar cases in the past and although alot depends on where you trained and who you trained with, I think we would do the full court press on this child.  Is the head circumference normal?  Is the child acidotic?  Is the child dysmorphic?

I think I would send: serum and urine amino acids to Marvin Natocwicz (sp?) at U. Mass, urine organic acids to Richard Kelly at Kennedy Krueger, long chain fatty acids (peroxisome defect) to Moser's lab, carnitines both free and acyl to CIDEM at Case Western as an initial starting point.

If the child is acidotic with a high lactate then I would begin high glucose in the fluids and reduce lipids and protein until you get some results back.  

Let us know what happens and if we can do anything to help.

Sincerely,

CCF Neuro MD

[Mark]

Dear CCF, Neuro MD,

Thank you for your response. You were correct in your assumption that the B6 did not correct the EEG. An early inject of B6 (within 3 days after birth) during an EEG showed no change. B6 was also used on 5/26 with no change.
All electrolytes were normal including the glucose and ketones. Repeat tests were done at a later date with a different lab and showed same results, normal.
Head circumference is normal. Early seizure activity was 35 minutes after birth, and intermittent lasting approx. 25 seconds every 12-24 hours. Phenobarb levels were in the 40s early on, dropping to 15-25 levels currently. I will need to consult on acidotic and dysmorphic question and get back to you.
Several factors point to NKH but the Glycine level is not elevated enough to confirm.
Thank you for the additional references amino acid, etc. testing I will follow up on that. Thank you very much.

[Mark]

Here is some more information and test results as of 6/11. Anyone with a guess as to what this infant has is welcome to reply. I would greatly appreciate it! Guesses are encouraged!

1. Infant is nonacidotic or dysmorphic.
2. Head circumference is normal.
3. CSF Glycine is only slightly elevated.
4. Ammonia and Ketones are normal.
5. Does not have cherry red spot.
6. The Pyridoxine (B-6) had no effect.
7. CT and MRI show nothing abnormal.
8. Electrolytes are normal, except sodium was slightly high.
9. No atrophy.
10. All other tests, urine, blood, CSF showed nothing abnormal in standard testing for deficiencies or elevated levels.
11. Infant is in otherwise good condition and healthy.

[CCF Neuro[P] MD, RPS]

Dear Mark:

The mild elevations of glycine is still what I would pursue.  I would check some problem with it's metabolism.  If a pediatric epileptologist read the EEG as burst suppression I would believe it, but trace alterans is normal for a 34 weeker and it is a burst suppression pattern.  As you know, ketones are not normal, so did you find ketones in the serum? urine?  The alanine does not seem high to me, what was the alanine to lysine ratio?  The urine organic acids, what was the 2-ketoglutaric acids?  The basal ganglia findings are also interesting.  There was no hint of in utero infection (HIV, mycoplasm)?  Did you say that there were no elevations of lactate or pyruvate?  One thinks of Leigh disease with bilateral basal ganglia changes.  Were the changes confined to the striatum or was it lenticular nuclei?  Let me know.

CCF Neuro MD

[Mark]

Sorry for the delay in answering your questions.

1. Test results did not find ketones the serum or urine.
2. Alanine to lysine ratio is normal, not elevated.
3. The first urine organic acid test indicated nothing abnormal, however we are awaiting additional test results.
4. No utero infection. No HIV or mycoplasm.
5. The bilateral basal ganglia changes were confined to the lenticular nuclei.
6. The lactate and pyruvate are not elevated.
7. Autosomal recessive myopathy is not being considered.
8. There might be a possibility that this is a BH4 deficiency so an analysis of pterins is being done.
9. The original thought was NKH, however glycine levels were only slightly elevated.

They are considering switching from Phenobarb to Tegretol due to depressed breathing, what is your opinion on Tegretol?

Thank you again for your time, I value your opinion.

[CCF Neuro[P] MD, RPS]

Dear Mark:

Since the EEG would indicate that the process is generalized in nature, I don't think I would switch to carbamazepine.  The problem is one of efficacy.  As you have probably read, there are really not good AEDs for infantile seizures.  Phenobarbitol has been used for such a long time that most of it's side effects are well known and most neurologists are familiar enough with it to manage the levels and side effects appropriately.  What is the current level (we usually will titrate it up until efficacy with seizure control) and are the seizures under control?  What is the EEG currently? still in burst suppression or is it trace alternans?  

Hypoxia usually affects the lenticular more that the caudate in my experience.  The bouts of apnea and hemmorrhage might suggest this also.  

Let us know how things are progressing.  Thanks for your updates.

Sincerely,

CCF Neuro MD

[Mark]

Here is the anticonvulsant history; 5/10 - Phenobarb level taken to 47 with no seizure activity noted, very sedated, intubated. Phenobarb stopped completely. 5/19 Phenobarb level at 12, pt very active, some seizure activity every 2-3 hrs. 5/20 - seizure activity intensity increasing, Phenobarb started again. 5/23 - Phenobarb at 38.6, pt seizure activity minimal. 5/26 - Phenobarb reduced, started Felbatol, pt moderate activity, seizure activity every hour. 6/1 - Felbatol stopped, Phenobarb brought back to 28, seizure activity moderate, ventilator removed. 6/7 - Phenobarb increased to 32, seizure activity minimal. 6/9 - pt had respiratory failures after daily Phenobarb dose. 6/15 - pt had respiratory failures after daily Phenobarb dose, CO2 levels @70+, put pt on C-PAP, minimal seizure activity. 6/16, 6/17, 6/18 - Phenobarb switched from alcohol-base to water-based crushed tablets. Small seizures. No respiratory failures. pt is very sleepy. Tongue & eye rhythmic movement noted frequently, possible seizure activity.
Last EEG on 6/5 showed some background activity, abnormal multifocal sharp waves. Diffuse encephalopathy. Any anticonvulsant recommendations? Thank you.

[CCF Neuro[P] MD, RPS]

Dear Mark:

The EEG is difficult to assess in a 34 weeker (my opinion).  But, I think I would still use the phenobarbitol and push the level alittle.  Alittle higher level might stop the seizures (apneas likely seizures) and should be able to maintain the seizure control.  I would think levels near 40 - 50 should be good.  If seizure control is maintained at this level then you might want to see if dropping the level alittle might still produce seizure control.  Don't forget that phenobarbitol half life in a neonate is very long.  I would load initially using the volume of distribution (phenobarbitol is about 0.6) X weight in kilograms X the desired new level (desired level - current phenobabitol level).  Get a total and free phenobarbitol level in about 2 - 3 hours and redose if necessary.

Sincerely,

CCF Neuro MD