Neonatal encephalopathy

A newborn (typically term, within the first hours to days of life) with altered consciousness, poor feeding, abnormal tone, seizures, or autonomic instability. Hypoxic-ischemic encephalopathy (HIE) dominates the differential numerically, but a fraction of "HIE" babies have an unrecognized inborn error of metabolism or genetic epileptic encephalopathy that will only worsen if you treat them like HIE alone. Cooling protocols are time-sensitive; so is the metabolic workup. Both run in parallel.

Three questions structure the bedside reasoning:

1. Is this HIE or something else? Sentinel event (cord prolapse, abruption), low Apgars, multisystem injury (renal, hepatic, cardiac, coagulation), and a typical MRI pattern (basal ganglia / thalami / posterior limb of internal capsule, watershed) point to HIE. A well-grown, well-Apgar newborn who suddenly deteriorates at 24-72 hours, sometimes after the first feed, is the metabolic emergency template: this is when the protective maternal placenta stops clearing the toxin.
2. What pattern of metabolic decompensation? The four big patterns:
   • Hyperammonemia without acidosis → urea cycle disorder.
   • Severe metabolic acidosis with high anion gap, hyperammonemia, ketosis → organic acidemia (propionic, methylmalonic, isovaleric).
   • Hypoglycemia with ketosis or hypoketosis → see hypoglycemia in the neonate and infant.
   • Lactic acidosis disproportionate to clinical picture → mitochondrial disease, pyruvate dehydrogenase deficiency, gluconeogenesis defect.
3. Refractory seizures? Any neonate with seizures that fail two appropriate anticonvulsants should get a pyridoxine trial (and pyridoxal-5-phosphate, and folinic acid) on the table. Pyridoxine-dependent epilepsy (ALDH7A1) responds dramatically; nonketotic hyperglycinemia does not. Genetic epileptic encephalopathies (KCNQ2, CDKL5, STXBP1, SCN2A) need rapid genetic diagnosis because some respond to channel-targeted therapy.

Hypoxic-ischemic encephalopathy

The dominant cause statistically. Sentinel perinatal event, low Apgars, cord gas pH < 7, multiorgan injury, and a characteristic MRI pattern. Therapeutic hypothermia (33.5°C for 72 hours, started within 6 hours of birth) is standard of care for moderate-severe HIE in term and late-preterm infants. Recognizing a metabolic mimic of HIE is critical because cooling without addressing the underlying metabolic block will not rescue the baby.

Metabolic emergencies (the urgent IEMs)

Urea cycle disorders (hyperammonemia without acidosis)

• Ornithine transcarbamylase deficiency (X-linked): the most common UCD. Boys present in the first week of life with vomiting, lethargy, encephalopathy, severe hyperammonemia. Heterozygous females can present anytime from infancy to adulthood depending on X-inactivation.
• CPS1 deficiency, NAGS deficiency, ASS1 (citrullinemia type I), ASL (argininosuccinic aciduria): similar urea-cycle presentations distinguished by amino acid pattern (citrulline absent in OTC/CPS1/NAGS, elevated in citrullinemia, mildly elevated with elevated ASA in ASL deficiency).

Organic acidemias (severe acidosis + hyperammonemia + ketosis)

• Maple syrup urine disease (BCKDH deficiency): ketoacidosis without lactate, sweet-smelling urine, elevated branched-chain amino acids. Encephalopathy starts 4-7 days after birth.
• Propionic acidemia, methylmalonic acidemia, isovaleric acidemia: the "big three" organic acidemias. Severe acidosis, hyperammonemia (sometimes high), ketosis, encephalopathy, pancytopenia possible. Isovaleric acidemia: sweaty-feet odor.

Fatty acid oxidation defects and gluconeogenesis defects: present as hypoketotic or fasting hypoglycemia rather than encephalopathy alone; see hypoglycemia in the neonate and infant.

Mitochondrial and pyruvate metabolism

• Leigh syndrome: lactic acidosis, encephalopathy, brainstem and basal ganglia T2 lesions. Many causative genes.
• Pyruvate dehydrogenase deficiency: severe lactic acidosis, structural brain abnormalities (agenesis of corpus callosum), encephalopathy. Ketogenic diet is treatment.

Sulfite oxidase / molybdenum cofactor deficiency: intractable neonatal seizures, dislocated lenses, dysmorphism. Urine sulfite positive on dipstick (refrigerate sample). cPMP replacement for type A.

Peroxisomal

• Zellweger spectrum disorders: profound hypotonia, seizures, hepatomegaly, dysmorphism (high forehead, large fontanelle). VLCFAs first-line.

Genetic epileptic encephalopathies

Neonatal seizures that are not explained by HIE, stroke, or metabolic disease.

• KCNQ2-related disorders (KCNQ2-related disorders): tonic seizures starting in the first week, encephalopathy, characteristic burst-suppression or multifocal EEG. Sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin) are often effective, which is why the genetic diagnosis matters acutely.
• STXBP1 (early infantile epileptic encephalopathy 4): Ohtahara-like presentation, burst-suppression EEG, refractory seizures.
• CDKL5: female-predominant; early infantile spasms, hypsarrhythmia evolution.
• SCN2A: can be early-onset with sodium channel blocker response (gain-of-function variants), or later with loss-of-function and refractory features.
• SCN1A / SCN1A seizure disorders (Dravet): generally presents later (6-18 months) with fever-sensitive seizures, but mentioned here because sodium channel blockers worsen Dravet and the diagnosis influences anticonvulsant choice across the broader population.
• GNAO1, SCN8A, KCNT1: additional epileptic encephalopathy genes with varying treatment responses.

Treatable specific entities

• Pyridoxine-dependent epilepsy (ALDH7A1, antiquitin): refractory neonatal seizures that respond dramatically to IV pyridoxine. Diagnostic and therapeutic trial: 100 mg IV pyridoxine with EEG monitoring (cardiorespiratory monitoring is required because brief apnea can occur). Continue lifelong pyridoxine. Diagnostic biomarkers: elevated alpha-aminoadipic semialdehyde (AASA) and pipecolic acid.
• Pyridoxal-5-phosphate (PLP)-responsive epilepsy (PNPO): responds to PLP, not pyridoxine.
• Folinic acid-responsive seizures: clinically and biochemically overlap with pyridoxine-dependent epilepsy.
• GLUT1 deficiency (SLC2A1): low CSF glucose with normal plasma glucose (CSF:plasma ratio < 0.4). Ketogenic diet is treatment.
• Nonketotic hyperglycinemia (GLDC, AMT): intractable neonatal seizures, profound hypotonia, hiccups, burst-suppression EEG. CSF glycine elevated; CSF:plasma glycine ratio > 0.08 is diagnostic. No definitive disease-modifying therapy.
• Biotinidase / holocarboxylase synthetase deficiency: rare neonatal presentation; biotin replacement.

Send the critical sample before treatment when possible, and start empiric protection in parallel:

1. Blood gas, lactate, ammonia, glucose, electrolytes (anion gap). Ammonia must be free-flowing, on ice, processed immediately.
2. Plasma amino acids, urine organic acids, acylcarnitine profile, free and total carnitine. These three together cover urea cycle, organic acidemia, and FAOD.
3. Urine ketones, urine reducing substances, urine sulfite (refrigerated sample).
4. CSF studies if seizures or possible IEM: glucose (paired with plasma; GLUT1), lactate, amino acids (glycine for NKH; CSF:plasma ratio), neurotransmitters, 5-MTHF.
5. Targeted biomarkers: plasma AASA / urinary AASA + pipecolic acid (pyridoxine-dependent epilepsy), VLCFAs (peroxisomal), 7-dehydrocholesterol (Smith-Lemli-Opitz), uric acid.
6. EEG (continuous when possible). Burst-suppression is a high-information pattern (Ohtahara, NKH, KCNQ2, STXBP1, severe HIE).
7. MRI brain. HIE pattern (basal ganglia + thalami + posterior limb of internal capsule, watershed) vs metabolic / mitochondrial pattern (symmetric basal ganglia / brainstem in Leigh; corpus callosum agenesis in PDH; cysts and gyral abnormalities in Zellweger).
8. Therapeutic trials at the bedside:
   • IV pyridoxine 100 mg, with cardiorespiratory monitoring and EEG.
   • PLP if pyridoxine fails.
   • Folinic acid if both fail.
   • High-dose biotin if biotinidase a concern.
9. Rapid trio exome / genome in any neonate with unexplained encephalopathy, refractory seizures, or atypical course; many NICUs have 5-7 day turnaround.
10. Empiric protective measures while testing pends: stop protein intake, provide glucose at 8-10 mg/kg/min, address hyperammonemia (sodium phenylacetate/benzoate; arginine or citrulline; hemodialysis if NH3 > 500), and cool if HIE criteria met.