Neonatal Metabolic Encephalopathy

RAKESH VERMA

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2Neonatal Encephalopathy

• The American College of Obstetricians and Gynecologists (ACOG) describes neonatal encephalopathy • as a clinically defined syndrome of disturbed neurologic function

in the earliest days of life • born at or beyond 35 weeks of gestation, • manifested by a subnormal level of consciousness or seizures,

and often accompanied by difficulty with initiating and maintaining respiration and depression of tone and reflexes.

3Etilogies• HYPOXIC -ISCHEMIC ENCEPHALOPATHY (HIE)• PERINATAL STROKE • PROGRESSIVE ENCEPHALOPATHY

• metabolic, • infectious or • toxic etiologies

• OTHERS• Brain anomalies, • Intracranial hemorrhage,• Genetic mutations, syndromes

• MATERNAL TOXINS • passive addiction to narcotics, barbiturates, alcohol, tricyclic antidepressants etc.

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• Acute encephalopathy due to metabolic disorders usually result from • accumulation of a toxic substance e.g. ammonia or • deficiency of an essential product e.g. ATP.

• Most of these metabolites are able to cross the placenta and therefore the baby is usually well at birth. A typical history would be a baby who was well initially, but only to present with poor feeding, lethargy or seizures after a few days.

5Presentation of IEM

IEMAcute encephalopathy• Urea cycle disorders• Non ketotic

hyperglycinemia• Organic academia• Maple syrup urine

disease• Mitochondrial disease

Metabolic academia• Organic academia• Fatty acid oxidation

defect• Congenital lactic

acidosis

Hypoglycemia• Galactosemia• GSD• Carnitine deficiency• Fatty acid oxidation

defect

6Presentation of IEM

• Inborn errors of metabolism presenting withencephalopathy can broadly be divided into 2 main groups,

1. One with significant biochemical abnormalities and 2. Another with NO significant biochemical abnormalities

7Encephalopathy with Significant BiochemicalAbnormalities

1. Hyperammonia2. Metabolic acidosis3. Hypoglycemia

81. Hyperammonemia

• When there is significant hyperammonemia, the main metabolic disorders to exclude are • urea cycle defects and• organic acidurias

• As these disorders mainly affect the protein metabolism, they often present after the baby has established full feeds.

• Other rare causes of hyperammonemia to consider are fattyacid oxidation disorders and transient hyperammonemia ofthe newborn.

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• Ammonium is neurotoxic. • Neurological damage and prognosis is dependent on the duration

and severity of hyperammonemia.• All protein intake should be stopped. • Treatment includes intravenous sodium benzoate or sodium

phenylbutyrate.• Severe or refractory cases may require hemodialysis• Other medications may be required depending on the metabolic

disorder suspected

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112. Metabolic Acidosis

• A common feature during an acute illness is metabolic acidosis with an increased anion gap. These can be divided into the mainanions that cause the acidosis.

A. Lactic acidosisB. Organic aciduria

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13A. Lactic acidosis

• Lactic acidosis can be a common acute feature in critically ill neonates, often as a result of poor circulatory perfusion or seizure activity.

• However, persistent lactic acidosis or increased lactate in the cerebrospinal fluid is suggestive of metabolic disease.

• In a neonate with encephalopathy and persistent lactic acidosis, one needs to exclude mitochondrial defects or pyruvate metabolism defects.

14B. Organic acidurias• Organic acidurias such as methylmalonic acidaemia (MMA) and propionic

acidaemia (PA) are disorders of branched-chain amino acid metabolism. • Metabolic decompensation occurs around in the first week of life after

establishing feeds with marked metabolic acidosis. This is also usually accompanied by hyperammonemia as a result of a secondary inhibition of the urea cycle.

• Urine organic acid analysis would show excretion of the abnormal organic acid and is often diagnostic

• Administration of carnitine facilitates the excretion of the organic acids.• In addition, cofactors such as vitamin B12 or biotin are often given • Treatment for secondary hyperammonemia may be necessary

153. Hypoglycaemia

• Hypoglycaemia can be a presenting feature in many metabolic diseases. • The timing of hypoglycaemia in relation to feeds can be very useful

in directing the next line of investigations. If hypoglycaemia occurs shortly after a feed, one should always suspect hyperinsulinism. Disorders of gluconeogensis can present after fasting of a few hours.• Fatty acid oxidation defects are also an important group of conditions

to consider in hypoglycaemia. Urine organic acid analysis, measurement of plasma carnitine and acylcarnitine profile are the main line of investigations.

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Present Absent

Hypoglycemia

Urine for reducing substances

Urinary ketone

GSDOrganic academia

Gluconeogenic defect

Fatty oxidation defectKetogenesis defectHyperinsulinism

Present Absent

Galactosemia

17Encephalopathy with no obvious biochemicalabnormality

• Non-ketotic hyperglycinemia (NKH) typically presents in the first few hours or days of life with refractory seizures and progressive obtundation. The presence of hiccups may be a clue.• Diagnosis is based on an increased CSF:plasma glycine ratio. • Treatment in classical NKH is often disappointing and mortality is

high. Survivors will have profound neurological sequelae.• Molybdenum cofactor deficiency or isolated sulphite oxidase

deficiency can also present with encephalopathy

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• GLUT-1 deficiency syndrome can also present with intractable seizures in the first week of life. • Diagnosis is suggested by a CSF: blood glucose equal or less than

1/3 blood glucose.• Treatment involves a ketogenic diet to provide alternative fuel to

the brain.

• Vitamin-responsive seizures are another rare cause.E.g.Pyridoxine-dependent, pyridoxal phosphate and folinic acid.

19Epileptic encephalopathy

• The term epileptic encephalopathy describes a heterogeneous group of epilepsy syndromes associated with severe cognitive and behavioural disturbances. 

• The ILAE defined an epileptic encephalopathy as a condition in which “the epileptiform EEG abnormalities themselves are believed to contribute to a progressive disturbance in cerebral function.”

20Epileptic encphlaopathy includes

• Early myoclonic encephalopathy• Early infantile epileptic encephalopathy (Ohtahara

syndrome)• Infantile Spasm ( West Syndrome)• Severe myoclonic epilepsy in infancy (Dravet syndrome)• Migrating partial seizures in infancy• Myoclonic status in nonprogressive encephalopathies• Lennox-Gastaut syndrome ( LGS)• Landau-Kleffner syndrome ( LKS)

21Different metabolic disorder with similar epilepsy correlate

Type of seizure Metabolic disorderInfantile spasm Biotinase deficiency, Menke disease, Organic

aciduria, Aminoacidopathies, Mitochondrial disorders

Epilepsy with myoclonic seizure

Non Ketotic Hyperglycenimia, GLUT-1 deficiency, Mitochondrial disorders

Progessive myoclonic epilepsy

Sialodosis, Mitochondrial disorders, Lafora disease

Epilepsy with generalized tonic clonic seizure

GLUT-1 deficiency, Neuronal ceroid lipofuscinosis

Epilepsy partialis continua

Alper’s disease, Mitochondrial disorders

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• The approach to neonatal seizure will be same in all cases. It is only after routine workup and management, we find either no cause or no response the we start thinking of Neonatal epilepsy syndromes.• Most of these disorders will have normal findings on routine

screening e.g. normal ammonia, lactate or mildly elevated due to convulsions, no significant hypo or hyperglycemia, normal calcium and magnesium, normal ABG and anion gap, normal CBC. • Thus in short no clue to diagnosis then we call it as “Group

1 type of neurological intoxication” profile.

23Group 1 type of neurological intoxication

1. Pyridoxal dependency2. Pyridoxal phosphate deficiency3. Folinic acid responsive seizure4. Serine deficiency5. GLUT-1 deficiency6. DEND syndrome ( Developmental delay, Epilepsy and

Neonatal Diabetes)7. Non ketotic hyperglycinemia

24Pyridoxin dependent seizures (PDS)

• Severe intractable seizure not controlled by AEDs but promptly stop on pyridoxine administration• Markers – elevated plasma and CSF pipecolic acid

- urinary Alpha Aminoadipic Semialdehyde (AASA)• Gene locus 5q31• Pregnant women given birth to previous PDS should receive 50-

100mg pyridoxine daily for later half of pregnancy

25Pyridoxal phosphate deficiency

• Suspected when there is partial or no response pyridoxine • CSF shows – reduced HVA and 5HIAA

- elevated Ser, Thr, Gly• Biomarker – Methoxytyrosine in CSF• Gene locus 17q21• Treatment – oral administration of pyridoxal phosphate

26Folinic acid responsive seizure

• Similar presentation as pyridoxine dependent seizures• Suspected when no response to pyridoxine administration• Markers – elevated plasma and CSF pipecolic acid

- urinary Alpha Aminoadipic Semialdehyde (AASA)• Treatment – Folinic acid. Pyridoxin is always given

alongwith

27Serine synthesis defect

• Due to deficiency of phosphoglycerate dehydrogenase (mostly)• Low CSF serine• Treatment - Serine therapy

28Glucose transporter type 1 deficiency

• Low CSF sugar – hallmark- CSF glucose is equal or less than 1/3 blood glucose• 3 phenotypes described• SCL2A1 mutation• Treatment – Ketogenic diet + carnitine

29DEND syndrome

• Channelopathy mutation of KATP involving brain and pancreas

• Insulin is customary given but does not ameliorate the neurological manifestation. However sulphonylureas have better response than insulin. They bind the channel and causes physiological release of insulin

30MRI findings in metabolic encephalopathyDisorder Findings

Pyridoxine dependent seizures Venticulomegaly ±Pyridoxal phosphate dependent seizure

Brain atrophy±, delayed myelination

Folinic acid responsive seizures Increased signal in fontoparietal white matter on T2

GLUT-1 Deficiency NormalSerine deficiency Cortical and subcortical

atrophy, hypomylination

31Treatment summary

Disorder DrugsPyridoxine dependent seizures Trail 100mg IV to max 500mg

15-30mg/kg/day oralPyridoxal phosphate dependent seizures

Pyridoxal phosphate - 30-50mg/kg/day in 3-6 divided doses

Folinic acid responsive seizures 2-5mg IV, 3-5mg /kg/day (with pyridoxine)

GLUT-1 Deficiency Ketogenic diet + Carnitine 50mg/kg/day

DEND Sulphonylurea

32Others

• Early myoclonic epilepsy – seen in• Non ketotic hyperglycinemia• Organic acidemia• GABA transaminase deficiency• Serine deficiency• Sulfite oxidase deficiency• Peroxisomal disorder

• Early infantile epileptic encephalopathy (Ohtahara syndrome)• Nonketotic hyperglycinemia• Mitochondrial disorders

33General management during acute stage

Supportive care AdmitVenous/arterial lineAdequate respiratory supportCorrect hypothermia/hypoglycemia/dehydrationCorrection of acidosis [pH< 7.22, HCO3 < 14mEq/L]Keep NPO/ GIR 6mg/kg/min

Reduce load/ removal of affected metabolites

Ensure adequate hydration and urine outputPeritoneal dialysis• Oligouria/anuria• Serum Sodium >165• Persistant metabolic acidosis• Hyperammonia >400micromol/L

Co-factor administration Vitamin [100 times the daily requirement]Oral carnitine 100-200mg/day

34Precautions while collecting samples

• Should be collected before specific treatment is started or feeds are stopped• Samples for blood ammonia and lactate should be

transported in ice and immediately tested. • Lactate sample should be arterial and should be collected

after 2 hours fasting in preheparinised syringe• Ammonia sample is to be collected approximately after 2

hours of fasting in EDTA vacutainer. • Avoid mixing air and flow should be free flow

35Normal values (Nelson)• Ammonia

• Older childrens 11-35 micromol/L• Healthy newborn <100 micromol/L• Sick newborn <200 micromol/L• Suspected IEM >200 micromol/L• Severe neurologic sequlae >300 micromol/L (>24hours)

• Lactate (L) Blood• 1-12mo 1.1-2.3 mmol/L 10-21 mg/dl• 1-7 yrs 0.8-1.5 mmol/L 7-21 mg/dl• 7-15 yrs 0.6-0.9 mmol/L 5-8 mg/dl• CSF <1.8 mmol/L <16 mg/dl

• Pyruvate (7-17yrs) 0.076±0.026mmol/L

36Costs of investigation

Test Lal path lab

Lab one Expected time

Ammonia 1000 750 3-4 hrs (personally)(lab one)

Lactate 970 1000 (outsource)

3-4 hrs (personally)(lab one)

Pyruvate 3250 1600 ?(outsource)

2 days (lal)

37Baby shield packages TMSPackage MRP Hospital price

1 condition - Heel-prick 250 ₹ 200 ₹2 conditions - Heel-prick 500 ₹ 400 ₹3 conditions - Heel-prick 650 ₹ 500 ₹4 conditions- Heel-prick 990 ₹ 790 ₹6 conditions - Heel-prick 1300 ₹ 1050 ₹7 conditions- Heel-prick 1500 ₹ 1200 ₹7 conditions- Cord-blood 1500 ₹ 1200 ₹

11 conditions- Heel-prick* 2390 ₹ 1790 ₹TMS - 52 2625 ₹ 2100 ₹TMS - 58 5000 ₹ 3100 ₹TMS - 62 6000 ₹ 3800 ₹

111 conditions- urine 3490 ₹ 2790 ₹118 conditions- Cord blood + Urine 4990 ₹ 3990 ₹119 conditions- Heel prick + Urine 4990 ₹ 3990 ₹

38References • Uptodate.com• Nelson textbook of Pediatrics• Inborn errors of metabolism in critically ill newborn – Anil B Jalan• Ee Shien Tan ; Inborn Errors of Metabolism Presenting as Neonatal

Encephalopathy: Practical Tips for Clinicians; Ann Acad Med Singapore 2008;37(Suppl 3):94-6• PGI/AIIMS protocol

Thanks