Bind neuro neocon 2018 - Dr Karthik Nagesh

Bind neuro neocon 2018 - Dr Karthik Nagesh

1. BIND:PRESENTATION AND “PREVENTION” CHRONIC BILIRUBIN ENCEPHALOPATHY:DIAGNOSIS AND OUTCOME Dr. N Karthik Nagesh MD,FRCPCH ( U.K.), FNNF Chairman of Neonatology & NICUs Chairman, Manipal Advanced Children’sCentre, Manipal Hospitals, Bangalore [email protected]

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 Hearing loss- white bar. 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 Neuromotor signs Muscle tone abnormalities Hyperexcitable neonatal reflexes Variety of neurobehavior manifestations Speech and language abnormalities Evolving array of central processing abnormalities, such as sensorineural audiological and visuo-motor dysfunctions.

9. Risk factors for extreme hyperbilirubinemia and their impact

10. Protective factors 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. Unbound bilirubin in the CNS may also be cleared by bilirubin oxidase and cytochrome P-450 isoenzymes . Tissue-binding capacity varies- there is less tissue-binding capacity in preterms than in term neonates.

11. Pathogenesis Complex interplay of protective factors and factors that increase susceptibility.

12. Hypothesized Pathophysiologic Mechanisms in Bilirubin-Induced Neuronal Injury.

13. Damage mechanism

14. Mechanisms Underlying Bilirubin Induced Neuronal Injury

15. Risk factors for Neonatal Jaundice

16. Model for reversible bilirubin neurotoxicity

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

21. Neonate With Features Of Advanced Bilirubin Encephalopathy

22. Prevention Currently, clinical practice is governed by concerns for prevention of kernicterus rather than of BIND.

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. 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

29. ABE in Preterms The clinical features are the same as term neonates albeit more subtle , mainly due to neuronal immaturity and masking clinical conditions.

30. 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

31. 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

32. 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.

33. 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

34. American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316

35. American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114: 297–316.

36. 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.

37. 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.

38. 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)

39. 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.

40. American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114: 297–316.

41. 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

42. 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

43. Chronic Bilirubin Encephalopathy or Kernicterus - Diagnosis Tetrad of Abnormal motor control, movements and muscle tone Auditory processing disturbance with or without hearing loss Oculomotor impairments, especially impairment of upward vertical gaze, and Dysplasia of the enamel of deciduous (baby) teeth

44. 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.

45. MENTAL STATUS MUSCLE TONE CRY PATTERN 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”

46. MRI in Diagnosis of BIND Cranial Magnetic Resonance Imaging ( cMRI ) can be used to detect bilirubin neurotoxicity. In ABE- T1-hyperintense i nvolvement 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.

47. 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.

48. Assessing Outcome Neonatal and early infancy assessment Clinical assessment during infancy and childhood Late infancy (1-2 years) assessment Childhood (age 5-9 years) assessment Long-term impact

49. 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

50. 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

51. Neonatal and early infancy assessment Disorders of movement 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

52. Clinical assessment during infancy and childhood Various methods have been used to evaulate infants- ASQ, BSID, Newman scale and Prechtl standardized technique. 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).

53. Clinical assessment during infancy and childhood 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 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.

54. Late infancy (1-2 years) assessment Complex minor neurologic dysfunction Minor motor problems 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.

55. Childhood (age 5-9 years) assessment 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.

56. 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.