metabolic disorders, pyidoxine dependent, folinic acid dependent seizure, metabolic syndromes

1. Neonatal Metabolic
Encephalopathy
RAKESH VERMA
1

2. Neonatal 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.
2

3. Etilogies
• 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.
3

4. • 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.
4

5. Presentation of IEM 5
IEM
Acute 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

6. Presentation of IEM
• Inborn errors of metabolism presenting with
encephalopathy can broadly be divided into 2 main groups,
1. One with significant biochemical abnormalities and
2. Another with NO significant biochemical abnormalities
6

7. Encephalopathy with Significant Biochemical
Abnormalities
1. Hyperammonia
2. Metabolic acidosis
3. Hypoglycemia
7

8. 1. 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 fatty
acid oxidation disorders and transient hyperammonemia of
the newborn.
8

9. • 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
9

10. 10

11. 2. Metabolic Acidosis
• A common feature during an acute illness is metabolic acidosis
with an increased anion gap. These can be divided into the main
anions that cause the acidosis.
A. Lactic acidosis
B. Organic aciduria
11

12. 12

13. A. 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.
13

14. B. 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
14

15. 3. 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.
15

16. 16
Present Absent
Hypoglycemia
Urine for reducing substances
Urinary ketone
GSD
Organic academia
Gluconeogenic defect
Fatty oxidation defect
Ketogenesis defect
Hyperinsulinism
Present Absent
Galactosemia

17. Encephalopathy with no obvious biochemical
abnormality
• 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
17

18. • 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.
18

19. Epileptic 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.”
19

20. Epileptic 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)
20

21. Different metabolic disorder with similar
epilepsy correlate
Type of seizure Metabolic disorder
Infantile 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
21

22. • 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.
22

23. Group 1 type of neurological intoxication
1. Pyridoxal dependency
2. Pyridoxal phosphate deficiency
3. Folinic acid responsive seizure
4. Serine deficiency
5. GLUT-1 deficiency
6. DEND syndrome ( Developmental delay, Epilepsy and Neonatal
Diabetes)
7. Non ketotic hyperglycinemia
23

24. Pyridoxin 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
24

25. Pyridoxal 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
25

26. Folinic 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
26

27. Serine synthesis defect
• Due to deficiency of phosphoglycerate dehydrogenase (mostly)
• Low CSF serine
• Treatment - Serine therapy
27

28. Glucose 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
28

29. DEND 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
29

30. MRI findings in metabolic encephalopathy
Disorder 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 Normal
Serine deficiency Cortical and subcortical atrophy,
hypomylination
30

31. Treatment summary
Disorder Drugs
Pyridoxine dependent seizures Trail 100mg IV to max 500mg
15-30mg/kg/day oral
Pyridoxal 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
31

32. Others
• 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
32

33. General management during acute stage
Supportive care Admit
Venous/arterial line
Adequate respiratory support
Correct hypothermia/hypoglycemia/dehydration
Correction 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 output
Peritoneal 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
33

34. Precautions 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
34

35. Normal 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
35

36. Costs 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)
36

37. Baby shield packages TMS
Package 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 ₹
37

38. References
• 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
38