2. Estimated rates of kernicterus (per
100,000 live births)
Hyperbilirubinemia
1. Prematurity
- yellow bars.
2. G6PD deficiency
-green.
3. Hemolytic and
idiopathic
conditions-blue
4. Rhesus (Rh)
disease -red.
3. Number of infants with major impairments due to kernicterus as presented
for
1. Hearing loss-
white bar.
2. Athetoid
cerebral palsy-
black bar.
4. Shah Z, Chawla A, Patkar D, Pungaonkar S. MRI in kernicterus.
Australasian Radiology 2003;47:55–57
5. • The syndrome of Bilirubin-induced Neurologic Dysfunction
[BIND] represents a spectrum of minor neurologic
manifestations among vulnerable infants who have
experienced an exposure to bilirubin of lesser degree than
generally described
• Can occur in the absence of classical kernicterus
• When total serum/plasma bilirubin (TB) levels exceed an
infant's neuroprotective defenses
BIND
6. Confounding effects include
• Prematurity,
• Hemolysis,
• Perinatal-neonatal complications,
• Altered bilirubin-albumin binding,
• Severity and duration of bilirubin exposure,
• Individual vulnerability of the infant related to genetic,
family, social, and educational predilection, regardless
of the cause of neonatal jaundice
7. Clinical neuro-motor manifestations extend to a range of ;
• Subtle processing disorders
• Objective disturbances of visual-motor,
• Auditory,
• Speech,
• Cognition,
• Language
**Previous history of moderate-to-severe hyperbilirubinemia of
varied duration
8. Features of BIND
1. Neuromotor signs
2. Muscle tone
abnormalities
3. Hyperexcitable
neonatal reflexes
4. Variety of
neurobehavior
manifestations
5. Speech and language
abnormalities
6. Evolving array of
central processing
abnormalities, such as
sensorineural
audiological and visuo-
motor dysfunctions.
10. Protective factors
1. Bilirubin transporters- ATP-binding cassette
transporter B1 (ABCB1) at the luminal (blood-side)
face of capillary endothelial cells of the blood–brain
barrier and ATP-binding cassette transporter C1
(ABCC1) at the basolateral face of the choroid
plexus epithelium of the blood–cerebrospinal fluid
barrier may facilitate bilirubin efflux from the CNS
and bilirubin clearance from the brain.
2. Unbound bilirubin in the CNS may also be cleared
by bilirubin oxidase and cytochrome P-450
isoenzymes.
3. Tissue-binding capacity varies- there is less tissue-
binding capacity in preterms than in term neonates.
17. Neuroanatomical vulnerability
• Globus pallidus- kernicterus
• Other vulnerable areas- cerebellum,
hippocampus, and subthalamic nuclear bodies,
cranial nerves.
• Increased neuromotor activity level in infants
with BIND at age 18 months may be a reflection
of minor dysfunction in subcortical circuitries,
especially in the networks of the basal ganglia
and cerebellum.
18. Injury to areas and outcomes
• Hippocampus- functional deficits leading to
age-related cognitive decline.
• Limbic-striatal-thalamic circuitry- autism
spectrum disorders and schizophrenia.
• Putamen for autism.
19. Acute Bilirubin Encephalopathy (ABE)
• The signs and symptoms of ABE may be
• Subtle requiring a high index of suspicion,
• Or Apparent with overt neurologic
abnormalities.
• Spectrum of manifestation-3 phases.
20. • Phase 1 (early ABE) manifests early usually at 3–5 days of life with
decreased alertness, poor feeding, hypotonia and weak Moro.
• Phase 2 (intermediate ABE) has variable onset and duration,
usually presenting in the 1st week but can be later with
stupor, irritability, hypertonia of extensor muscles, which may
alternate with hypotonia, opisthotonos, retrocollis and high-
pitched cry.
• Phase 3 (advanced ABE) often presents after the
1st week and is typically characterized by hypotonia. Other
features include coma, pronator spasm of upper extremities, sun
setting eyes, fever, inability to feed and apnea.
**Mortality may be as high as 21%, usually due to
respiratory failure or refractory seizures
23. Prevention of ABE and Kernicterus
Spectrum Disorders(KSD)
• An anticipatory and individualized approach with
the goal of avoiding excessive hyperbilirubinemia
is the key to preventing severe neonatal jaundice,
ABE and its subsequent progression to KSD.
• Using a systematic tiered approach, targeted
preventive strategies are essential at each level
during the assessment of newborn infants to
prevent these complications.
24. Primary Prevention
• Programs Aimed At Promoting
And Supporting Successful Breast Feeding,
• Documentation Of The Mother’s Blood Group During
Care With Cheap And Available And Appropriately Used
Rhesus Immunoglobulin(rhogam™),
• Meticulous Risk Assessment
• Providing The Parents With Written
And Oral Information About Jaundice Are Paramount.
25. • Similarly, recognizing that visual estimation of the
severity of jaundice may be misleading
• Establishing protocols for the identification and
evaluation of hyperbilirubinemia are of prime
importance.
• Improvement on older screening methods are needed
and being effectively pursued.
• It is essential to screen for jaundice (pre-discharge) and
G6PD deficiency as part of a systemic evaluation on all
babies for the risk of severe hyperbilirubinemia before
discharge.
26. Secondary Prevention
• Measuring bilirubin levels (TSB
orTcB) in jaundiced babies, interpreting all bilirubin
levels based on hour-specific modified country-specific
Bhutani type nomogram is advocated.
• Additionally, providing appropriately timed and
effective treatment using gestational age, weight
appropriate threshold for risk assessment and country-
specific guidelines is urgently needed.
27. • Combined with effective phototherapy,
health care facilities also need to be able to
quickly refer to tertiary centers that are able
to do emergent exchange blood transfusions
when needed.
• Finally, close post-discharge follow-up strategies
are critical in preventing bilirubin neurotoxicity.
28.
29. ET-CO Measurement at Hospital Discharge
• High Risk ….>2 PPM
• CoSense ET-CO monitoring (nasal canula)
done in 18 babies at MHB with low risk pre-
discharge TSB ( Bhutani Nomogram)
• 8 found to have ET-CO>2 PPM
• 3 re-admitted for severe Jaundice needing
Intensive Phototherapy, inspite of low pre-
discharge TSB
30. ABE in Preterms
• The clinical features are the same as term
neonates albeit more subtle, mainly due to
neuronal immaturity and masking clinical
conditions.
31. Risk factors for BE-Total Serum Bilirubin (TSB)
• High TSB levels have been long associated with a risk
of BE in a dose-dependent pattern
• TSB levels have been used in management guidelines of
neonates with hyperbilirubinemia to define critical values
for interventions
• TSB measures both conjugated and unconjugated bilirubin
in the blood.
• Unconjugated bilirubin is largely bound to
albumin
• A small proportion remains as free/unbound
32. TSB
• High TSB levels correlate with high free unbound
unconjugated bilirubin levels at the membrane
surfaces as a result of saturating the albumin
binding sites
• Free bilirubin is hence available to permeate
membranes, including brain cells, and cause
neuronal injury
33. TSB
• However, reports of ABE occuring at TSB levels
considered to be nonhazardous, that is, below
critical values for exchange blood transfusion
(low bilirubin KSD) have highlighted the need
to establish a critical value of TSB below which
BE is unlikely to occur.
34. Peak TSB is a useful test, but relatively poor measure
of the toxic potential of unconjugated bilirubin.
Consideration must be given to such other factors as
• Duration Of Exposure,
• Concomitant Level Of Serum Albumin,
• Bilirubin-binding Reserve.
• Level Of “Unbound” Bilirubin
• Presence Or Absence Of Acidosis,
• Immaturity/Compromise Of The Blood- Brain Barrier
• Constitutional/Genetic Factors
35. American Academy of Pediatrics. Management of hyperbilirubinemia
in the newborn infant 35 or more weeks of gestation. Pediatrics.
2004;114:297–316
36. American Academy of Pediatrics. Management of hyperbilirubinemia
in the newborn infant 35 or more weeks of gestation. Pediatrics.
2004;114: 297–316.
37. Maisels MJ. Jaundice. In: Avery GB, Fletcher MA,
MacDonald MG (eds), Neonatology: Pathophysiology
and Management of the Newborn. Philadelphia, PA:
J.B. Lippincott; 1999, pp. 765–819.
38. Morris BH, Oh W, Tyson JE, et al. Aggressive vs. conservative
phototherapy for infants with extremely low birth weight. N Engl J
Med. 2008;359:1885–1896.
39. Bilirubin-Albumin Ratio
• Low bilirubin ABE is possible in the context of
hypoalbuminemia or impaired albumin
binding.
• Bilirubin is transported bound to albumin in a
largely predictable way.
• Bilirubin bound to albumin is water soluble
and does not cross the blood–brain barrier
(BBB)
40. Bilirubin-Albumin Ratio
• Unbound (free) bilirubin is expected to be a more
appropriate measure of the risk for BE than TSB.
• However, it is currently not practical to assay UB
in clinical settings.
• Bilirubin:albumin (B:A) molar ratio, on the other
hand,is easily assayed and has previously been
proposed as a surrogate for UB and, consequently,
CNS exposure to bilirubin.
41. American Academy of Pediatrics. Management of hyperbilirubinemia
in the newborn infant 35 or more weeks of gestation. Pediatrics.
2004;114: 297–316.
42. Hulzebos CV, Diljk PH, van Imhoff DE, et al. The
bilirubin albumin ratio in the management of
hyperbilirubinemia in preterm infants to improve
neurodevelopmental outcome: a randomized
controlled trial – BARTrial. PLoS One. 2014;9:e99466.
** Intensive Phototherapy-
Irradiance of at least 30
μW/cm2 per nm
43. Maisels MJ, Watchko JF, Bhutani VK, et al. An approach to the
management of hyperbilirubinemia in the preterm infant less than 35
weeks of gestation. J Perinatol. 2012;32:660–664
44. Chronic Bilirubin Encephalopathy or
Kernicterus- Diagnosis
Tetrad of
1. Abnormal motor control, movements and
muscle tone
2. Auditory processing disturbance with or
without hearing loss
3. Oculomotor impairments, especially
impairment of upward vertical gaze, and
4. Dysplasia of the enamel of deciduous (baby)
teeth
45. Diagnosis of BIND
• In the past, it was erroneously believed that the
diagnosis of BE could only be made by autopsy.
• Using history, a focused physical examination, the
BIND score and Electrophysiological And
Neuroimaging studies, the diagnosis can be
ascertained with reasonable certainty.
• Assessment of the encephalopathy must be
individualized, taking into account predisposing risk
factors.
46. 1. MENTAL STATUS
3. MUSCLE TONE
4. CRY PATTERN
5. OCCULOMOTOR OR EYE MOVEMENTS
“BIND score is a tool to objectify and
facilitate a clinical diagnosis of ABE as well as
to monitor the neonatal neurological exam in
infants with progressive hyperbilirubinemia as
a predecessor to encephalopathy”
47. MRI in Diagnosis of BIND
• Cranial Magnetic Resonance Imaging (cMRI) can be used to
detect bilirubin neurotoxicity.
• In ABE-T1-hyperintense involvement of the globus pallidus
and subthalamic nuclei, while
• KSD demonstrates increased signal intensity on T2-weighted
images of the same regions, especially in children with
classical and motor predominant kernicterus.
48. BAER
• Emerging evidence suggests that the auditory
neural pathways are the most sensitive system
• In bilirubin neurotoxicity, the BAER is absent
or abnormal (prolonged inter-wave intervals
and/or diminished amplitudes) indicating
damage to the auditory nerve (wave l) and/or
more likely auditory brainstem nuclei.
• Auditory evaluation may improve
detection of bilirubin-induced neurotoxicity in
neonates.
49. Assessing Outcome
1. Neonatal and early infancy assessment
2. Clinical assessment during infancy and
childhood
3. Late infancy (1-2 years) assessment
4. Childhood (age 5-9 years) assessment
5. Long-term impact
50. Better Tools available now to better BIND specific
domains of multisensory processing disorders:
• Pyscho-metric,
• Audiologic,
• Speech,
• Language
• Visual-motor
• Neuromotor examination
** Will allow for prospective surveillance of infants ‘at risk’ for the syndrome
51. Evolution in Thinking
• Moving from beyond just survival and
understanding the importance of quality of
life; prevention of even the most subtle
problems is now important!!
• Early Intervention
52. Neonatal and early infancy assessment
1. Disorders of movement
2. Neuromotor movement dysfunction was still
present at ages 3 and 12 months. Dose-
response correlation to severity of
hyperbilirubinemia among the infants
exposed to “moderate” hyperbilirubinemia
53. Clinical assessment during infancy and
childhood
1. Various methods have been used to evaulate infants-
ASQ, BSID, Newman scale and Prechtl standardized
technique.
2. At 3 months of age, neurological status by assessment
of the quality of general movements is classified as:
“normal-optimal” and “suboptimal” (perfectly and
acceptably complex, variable and fluent general
movements, respectively), “mildly abnormal”
(insufficiently complex and variable movements,
which are not fluent), and “definitely abnormal”
(virtual lack of complexity, variation, and fluency).
54. Clinical assessment during infancy and
childhood
1. 18 months- five domains of function are assessed:
fine motor function, gross motor function, posture
and muscle tone, reflexes, and visuomotor function.
Normal-> Minor dysfunctions -> Complex MND
2. Toddler Behavior Assessment Questionnaire- 111
items evaluating temperament. Answers are coded on
a scale from 1 to 7, where 1 is “never”, 2 is “very
rarely”, and progresses to 7, which is equivalent to
“always”. Scales of temperament included activity
level, pleasure level, falling reactivity, soothability,
interest, anger, and sadness.
55. Late infancy (1-2 years) assessment
1. Complex minor neurologic dysfunction
2. Minor motor problems
3. Children with complex minor neurologic
dysfunction have generally exhibited
disorders of muscle tone regulation. This
dysfunction may also be regarded as a minor
form of BIND.
56. Childhood (age 5-9 years) assessment
1. Subtle signs of neonatal bilirubin
neurotoxicity at ages 5-7 years include:
awkwardness, equivocal Babinski sign, failure
of fine stereognosis, questionable hypotonia,
hyperexcitability, and exaggerated cremastric
and abdominal reflexes.
57. Long-term impact
• 4- 8- point IQ depression related to degree of
hyperbilirubinemia,assuming TB > 25 mg/dL.
• General consensus that there is no direct or
precise dose-dependent relationship between
moderate or severe hyperbilirubinemia and
overall neurologic outcome.
