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Available online at www.sciencedirect.com
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Subtle bilirubin-induced neurodevelopmental dysfunction (BIND) in the term and late preterm infant: Does it exist? Roelineke J. Lunsing, PhD, MD Department of Neurology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands
article info
abstra ct Subtle bilirubin-induced neurological dysfunction (BIND) is defined as disturbances in sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone in the absence of the classical findings of kernicterus. This review is restricted to the (sensori)motor signs of BIND associated with unconjugated hyperbilirubinemia in term and late preterm neonates. The diagnosis of BIND at follow-up requires validated, age-specific techniques that are designed to identify these disturbances in infancy and later childhood. The (sensori)motor signs of BIND are compatible with the pathological substrate of unconjugated hyperbilirubinemia and its known effects on the brain. & 2014 Elsevier Inc. All rights reserved.
Introduction Free unconjugated bilirubin is the neurotoxin that can damage the newborn brain. The classic and most overt form of bilirubin encephalopathy is kernicterus,1 originally a pathologic term referring to the yellow staining (icterus) of the deep nuclei of the brain (kern—relating to the basal ganglia).2 Currently kernicterus is also used to describe the clinical picture of chronic bilirubin encephalopathy,2 a tetrad of auditory impairment (including deafness), a movement disorder (dystonia and/or athetosis), ocular movement impairment (especially impaired upward gaze), and dental enamel dysplasia of the deciduous teeth.3 Shapiro has suggested that the clinical manifestations of kernicterus can be divided into 4 main subtypes: (1) classical kernicterus—as described above; (2) auditory predominant kernicterus—characterized by a predominance of auditory symptoms with minimal or no motor symptoms; (3) motor predominant kernicterus—a predominance of motor E-mail address: [email protected] http://dx.doi.org/10.1053/j.semperi.2014.08.009 0146-0005/& 2014 Elsevier Inc. All rights reserved.
symptoms with minimal or no auditory symptoms; and (4) subtle kernicterus or bilirubin-induced neurologic dysfunction (BIND).2 The incidence of BIND is not known nor is the precise threshold at which bilirubin may be neurotoxic in a given infant.4 The published literature yields conflicting results with respect to the occurrence of BIND at different bilirubin levels and at different ages. For example, Rubin et al.5 found no differences in neurological examination at the age of 7 years in children whose neonatal total serum bilirubin (TSB) levels were r171 μmol/L (10 mg/dL) vs those with TSB 274– 393 μmol/L (16–23 mg/dL) whereas Newman and Klebanoff6 reported a stepwise increase in abnormal or suspicious neurological findings from 14.9% of 7-year-old children whose neonatal TSB levels were o171 μmol/L (10 mg/dL) to 22.4% in those with TSBs Z342 μmol/L (20 mg/dL). Although BIND occurs in premature infants, this review will deal exclusively with BIND in healthy term and late preterm neonates of Z34 weeks gestational age.
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Defining BIND BIND was defined by Shapiro2 as subtle neurodevelopmental disabilities without classical findings of kernicterus that, after careful evaluation and consideration, appear to be due to bilirubin neurotoxicity. These may include disturbances of sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone.2 The central auditory processing problems can be reliably assessed by auditory measures. However, auditory responses to acoustic stimuli cannot be used for all ages and cognitive abilities.3 Middle ear measures and cochlear measures are used to rule out confounding factors3 but the auditory brain stem evoked response is an objective method that can be applied at all ages.7 On the other hand, our ability to detect the more subtle neurological signs of BIND, such as disturbances in sensorimotor integration, coordination, and muscle tone at different ages, is less clear.
BIND in the newborn and in infancy Soorani-Lunsing et al.8 used the techniques by Prechtl9 at age 3–8 days and by Touwen10 at 12 months to evaluate 40 previously healthy Dutch infants at Z36 weeks of gestation who were born between 1997 and 1998 (Table 1). The Prechtl and Touwen techniques identify minor neurological dysfunction (MND), mild deviations in muscle tone regulation or mild asymmetries in infantile reactions, and tendon reflexes, i.e., mild disturbances of sensory and sensorimotor integration, and thorough training in these techniques is necessary to achieve reliable and reproducible results. At the age of 3 months, the investigators also studied the quality of general
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movements, a sensitive tool for evaluating brain function in young infants.11 To do this, they made a 20-min video recording of spontaneous motility in supine infants, while the infant was in an alert, active, non-crying ehavioral state. The recordings were then assessed blindly. The quality of the movements was classified as normal-optimal (perfectly and acceptably complex, fluent, and variable general movements), mildly abnormal or MND (insufficiently complex and variable movements, which are not fluent), or definitely abnormal (virtual lack of complexity, variation, and fluency). Inter-scorer agreement was good (κ value 40.80).12 Overall, 20 newborn infants who had non-hemolytic hyperbilirubinemia, with TSB levels of 233–444 μmol/L (13.6–26 mg/dL) were compared with 20 non-jaundiced controls, matched for sex and gestational age. Of the 20 jaundiced newborns, 14 (70%) had evidence of MND compared with 5 of 20 (25%) controls [odds ratio (OR) ¼ 6.62; confidence interval (CI): 1.59–27.51; P o 0.05]. Differences between these groups in MND were also seen at the ages of 3 and 12 months. Those with MND at 12 months were further divided into 2 sub classifications: MND type 1 and MND type 2. MND type 1 is the simple form of MND, which implies normal, yet non-optimal neurological function, with only 1 item being deviant. MND type 2 is a more complex, and clinically relevant, form in which more than 1 item is mildly abnormal.13 MND occurred significantly more often in the jaundiced group compared with controls (OR ¼ 9.47, CI: 1.67–53.65 adjusted for sex). Remarkably, all children with complex MND had a TSB Z335 μmol/L (19.6 mg/dL). The same group of investigators subsequently followed up with 43 healthy neonates at Z37 weeks gestation with TSB Z220 μmol/L (12.9 mg/dL) and 70 controls with TSB o 220 μmol/L born between 2002 and 2007.14 Using similar methods, they evaluated the infants at the ages of 3–8 days
Table 1 – BIND defined by lower Bayley motor scores or signs of MND in infancy. References
Group(s) (n)
Bilirubin (μmol/L)
FU age
Method or minor (neurological sign)
Results (BIND)
Boggs et al.17
22.566
8 mo
Bayley motor
Scheidt et al.18
27.270
171 Every 24 h measured 171 Every 24 h measured
1 yr
Neur. abnormality
Increase bilirubin - 0.5% increase; n with low score Correlates with bilirubin, P ¼ 0.02
Scheidt et al.19 Rubin et al.5
Wong et al.20 SooraniLunsing8 Lunsing14
ph (121) c (117) s1 (153) s2 (69) c (120) s1 (30) s2 (63) s (20) c (20) s (43) c (70) s (10) c (100)
4222 4222 188–257 274–393 r171 300–341 342–427 233–444 Non-icteric 220–366 o220 Z300 o300
1 yr 8 mo 1 yr 3 yr 3 mo 12 mo 3 mo
Correlates with bilirubin, P ¼ 0.05 ns ph ¼ 0.8% and c ¼ 0% ph ¼ c ¼ 0% Covariance P o 0.05 Covariance P o 0.007
Failure to stand Other signs Hypotonia Abnormal movements Bayley motor 122 Neurological items Neurological evaluation General movements Touwen General movements
s ¼ 55%, c ¼ 25% and P ¼ 0.05 s ¼ 50%, c ¼ 10% and P o 0.05 s ¼ 33%, c ¼ 41% and ns
Hempel
s ¼ 40%, c ¼ 13% and P o 0.05
All normal
18 mo
BIND ¼ bilirubin-induced neurologic dysfunction, MND ¼ minor neurological dysfunction, n ¼ number, yr ¼ years, FU ¼ follow-up, mo ¼ months, h ¼ hours, neur. ¼ neurological, ns ¼ non-significant, ph ¼ phototherapy group, c ¼ control or comparison group (only in the study by Lunsing), s ¼ study group, s1 and s2 ¼ sub study groups with specific bilirubin levels.
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and 3 months. At 18 months, the standardized age-specific neurologic examination of Hempel15 was carried out. Five domains are examined: visuomotor function, posture and muscle tone, fine motor function, gross motor function, and reflexes. Simple MND stands for the presence of 1 deviant domain, representing a non-optimal yet normal form of brain function.13 Complex MND denotes the presence of more than 1 deviant domain. Inter-scorer agreement was satisfactory (κ value ¼ 0.62–1.00).16 They did not find any difference in the rates of complex MND at any age, although the jaundiced infants were more lethargic as neonates (OR ¼ 3.66, CI: 1.33– 10.04) and more active at 18 months (OR ¼ 0.31, CI: 0.07–0.55). They also compared a subgroup of 10 children whose TSB levels were Z300 mmol/L (17.5 mg/dL) with 100 with TSB o 300 mmol/L. At 18 months, the hyperbilirubinemic infants were more likely to have MND (OR ¼ 4.21, CI: 1.02–17.37). Boggs et al.17 and Scheidt et al.18 analyzed the data from the Collaborative Perinatal Project (CPP), which included the followup of some 27,000 infants. In the CPP, all infants had a TSB measured at 48 7 12 h. If the TSB was Z171 μmol/L (10 mg/dL), the test was repeated every 24 h until it was o171 mmol/L (10 mg/dL). Outcome was assessed at 8 months using the Bayley scales of mental and motor development. In addition, Scheidt et al.18 performed a detailed neurologic examination at the age of 1 year. Boggs et al.17 found a linear relationship between the maximum TSB and the percentage of total motor Bayley scores below 27. In the group with birth weights Z3000 g, the estimated increase in percentage of infants with a low score was 0.5% for each mg/dL (17 mmol/L) rise in TSB. Scheidt et al.18 found a significant relationship (P r 0.05) between the peak TSB and lower mean Bayley motor scale results in white infants with a birth weight 42500 g and gestational age Z37 weeks. However, the authors note that although statistically significant, the correlation coefficients were small because of the effect of a disproportionally large number of infants with low bilirubin values. In the black infants, no significant relationship was found. To examine for more subtle effects, the mean Bayley motor scores were compared for infants with maximum bilirubin levels r154 μmol/L (9 mg/dL) vs 155– 240 μmol/L (9.1–14 mg/dL) in the same birth weight and gestational age group. Again, a significant difference was present only in the white group (P r 0.02). At the age of 1 year, there was a significant correlation for neurological abnormality (P o 0.02) and failure to stand (P o 0.05) with the maximum TSB. In a 6-year follow-up of the NICHD Collaborative Phototherapy Study, 2 child neurologists, blinded to group assignment, reviewed and classified records of the neurological examinations for analysis of neurological abnormalities.19 The diagnosis of cerebral palsy was based on observed defects in posture, movement, tone, and reflexes. In infants with birth weight Z2500 g and TSB 4 222 μmol/L (13.0 mg/dL) randomly assigned to the phototherapy (n ¼ 121) or control groups (n ¼ 117), there was no significant difference between groups in the incidence of hypotonia, abnormal movements, or cerebral palsy. Rubin et al.5 followed up with 1613 participants of the educational follow-up study in the Minnesota section of the Collaborative Perinatal Project (CPP) and divided them into 3 groups based on their peak TSB levels: o171 μmol/L (10 mg/dL, n ¼ 120), 188 257 μmol/L (11.0–15.0 mg/dL, n ¼ 153), 274– 393 μmol/L (16.0–23 mg/dL, n ¼ 69). A neurological examination
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was performed at 1 year of age. The physician reported his overall clinical impression of the neurologic status of the child on the basis of extensive protocols consisting of 122 items. Neurologic status was coded as 0 ¼ normal, 1 ¼ suspect, and 2 ¼ abnormal. At 1 year, if controlled for gestational age, the higher bilirubin groups scored significantly lower on the Bayley Motor Scale compared with the lower bilirubin group (P o 0.05) and neurological abnormalities were more often present in the higher bilirubin groups than the lower bilirubin group (P o 0.007). Wong et al.20 followed up with Chinese full-term infants with peak TSBs of 300–341 μmol/L (17.5–19.9 mg/dL, n ¼ 30), 342–428 μmol/L (20–25 mg/dL, n ¼ 63), and Z428 μmol/L (25 mg/dL, n ¼ 6). A neurologist evaluated the infants every 3–6 months until the age of 3 years, and all had normal neurodevelopmental status at the age of 3 years. Two infants, one in each of the higher TSB groups, showed transient mild motor delay and hypotonia at the age of 3 months, but both returned to normal by 6 and 11 months, respectively.
BIND at preschool and school age Rubin et al.5 followed up with 318 of the participants in the educational follow-up study and the Minnesota section of the CPP and evaluated their neurological status at the age of 7 years using the same 122 items employed at 1 year. They found no significant differences among the 3 bilirubin groups (Table 2). Newman and Klebanoff6 reanalyzed the data from the CPP of infants with birth weights Z2500 g who had neonatal TSB recorded. At the age of 7 years, 33,272 had been examined using a detailed, standardized neurological examination consisting of 82 items. The examination was performed by project staff pediatric neurologists or by specially trained pediatricians at each center who were blinded to the neonatal TSB levels. The risk of abnormal or suspicious examinations increased in a stepwise manner from 14.9% in the group whose maximum TSB had been o171 μmol/L (10 mg/dL)–22.4% in the highest bilirubin group [TSB Z 342 μmol/L (20 mg/dL) adjusted OR ¼ 1.12, 95% CI: 1.06–1.20]. They also looked for associations between peak TSB level and each of the 82 items of the neurological examination. Significant relationships were reported between gait abnormalities (P o 0.001), awkwardness (P o 0.001), equivocal Babinski reflexes (P o 0.001), abnormal cremaster (P ¼ 0.001) or abdominal (P ¼ 0.008) reflexes, failure at fine stereognosis (P ¼ 0.008), questionable hypotonia (P values ranging from 0.005 for the right upper extremity to 0.07 for the trunk), and gaze abnormalities (P ¼ 0.001–0.05). Athetosis was not associated with peak TSB levels. Valaes et al.21 followed up with a group of 415 jaundiced neonates, with birth weight 42500 g, from the island of Lesbos. They found that 233 of the mothers had received phenobarbital during the last few weeks of pregnancy to decrease their neonatal TSB levels and there were 182 controls. The neurological examination described by Touwen and Prechtl22 was used at the of ages 5 and 6 years and examiners were blinded to the neonatal TSB levels. A high proportion of the children performed non-optimally in the following areas: associated movements during walking tip toe and on heels,
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Table 2 – BIND (defined by MND or signs of MND) at preschool and school age. References
Rubin et al.5
Group(s) (n)
Valaes et al.21
s1 s2 c s1 s2 s3 c s1
Grimmer et al.23
s2 (13) s3 (11) s (16)
Newman and Klebanoff6
Ozmert et al.24
Newman et al.25 Heimler and Sasidharan26 Vandborg et al.27
c sI sII sIII sIV sV c s c s c s c
(142) (63) (113) (2876) (870) (268) (29258) (21)
(18) (13) (26) (27) (19) (19) (27) (82) (168) (39) (36) (162) (146)
Bilirubin (μmol/L)
FU age
Method
Results (BIND)
188–257 274–393 r171 171–255 256–341 Z340 o171 274–342
7 yr
122 Neurological Items
ns Difference
7 yr
82 Neurological Items
s1 ¼ 16%, s2 ¼ 18%, s3 ¼ 22% and c ¼ 15% P o 0.001
5–6 yr
Touwen and Prechtl
ns Difference between s groups
5–15 yr
Touwen
ns Difference except for choreiform dyskinesia P ¼ 0.03
8–13 yr
Neurological Examination
sI ¼ 8%, sII ¼ 23%, sIII ¼ 7% and sIV ¼ 0% sV ¼ 29% and c ¼ 4%
5 yr
Neurological Examination Neurological Examination Questionnaire Fine/gross motor
s ¼ 17% and c ¼ 29% P ¼ 0.04 s ¼ 18% and c ¼ 8% P ¼ 0.2 ns Difference
343–428 4428 342–513 o205 290–341 342–375 376–426 Z426 Z342 (Coombsþ) No icterus 428–511 o428 342–513 no icterus Z428 ?
3 yr 18 mo– 6 yr
BIND ¼ bilirubin-induced neurologic dysfunction, MND ¼ minor neurological dysfunction, FU ¼ follow-up, mo ¼ months, yr ¼ years, n ¼ number, s ¼ study group, s1, s2, s3 and sI, sII, sIII, sIV, sV ¼ sub study groups with specific bilirubin levels, c ¼ control, ns ¼ non-significant.
standing with the eyes closed, mouth opening–finger spreading phenomenon, diadochokinesis and associated movements, finger–nose test, finger opposition test, and knee– heel test. Optimal performance was given a score of 1, the least adequate performance was 3 or 4. Right and left sides were scored separately. The TSB was 4274 μmol/L (15.7 mg/ dL) in 6.6% of the control group vs 1.1% in the phenobarbital group. They also evaluated 44 children with TSB Z 274 μmol/ (16 mg/dL) and those with TSB levels of 274–342 μmol (16– 20 mg/dL, n ¼ 21), 343–428 μmol/L (20.1–25.0 mg/dL, n ¼ 13), and 4428 μmol/L (25 mg/dL, n ¼ 11) and found no differences in neurological outcome or IQ scores. Grimmer et al.23 followed up with healthy jaundiced term neonates (Z2500 g and Z37 weeks) with peak TSB levels of 342–513 μmol/L (20–30 mg/dL) who were admitted to the Berlin Free University Children's Hospital from 1978 to 1988. Of them, 16 with TSB of 342–513 mmol/L (20–30 mg/dL) were examined according to Touwen between 5 and 15 years and compared with 18 controls, matched for sex, whose TSB never exceeded 205 mmol/L (12 mg/dL). They used the qualitative subscales in evaluating sensorimotor apparatus, posture, balance of the trunk, coordination of the extremities, fine manipulative abilities, choreiform dyskinesia, gross motor function, quality of movements, and associated movements to compare outcome between groups. The study group showed no significant difference in cluster profiles compared with the controls, except that the study infants had a worse subscale score for choreiform dyskinesia (P ¼ 0.028)
Ozmert et al.24 performed a retrospective follow-up of 102 jaundiced, Turkish infants at Z37 weeks gestation born between 1980 and 1985 and admitted with hyperbilirubinemia. Birth weight was 43000 g. They divided the infants into 5 groups: group I Z290–341 μmol/L (n ¼ 13), group II 342– 375 μmol/L (n ¼ 26), group III 376–426 μmol/L (n ¼ 27), group IV Z426 μmol/L (n ¼ 19), group V Z342 μmol/L (n ¼ 17) and group VI, a control group randomly chosen without hyperbilirubinemia (n ¼ 27). All had negative Coombs tests, except for group V. At 8–13 years of age, they were examined by a pediatric neurologist and grouped according to the findings as normal or with minor or prominent neurological abnormalities. The minor neurological abnormalities reported were mild choreoathetosis, abnormal stereognosis, strabismus, and dysdiadochokinesis. Minor neurological findings were seen in 23% in group II and 29.4% in group V compared with 3.7% in the control group. Newman et al.25 conducted a prospective study of healthy term and late preterm infants (Z2000 g and Z34 weeks) born between 1995 and 1998 in northern California. Of them, 82 infants with TSB Z 428 mmol/L (25 mg/dL) and 168 controls with TSB o 428 mmol/L or who had no TSB measured were examined at a mean age of 5.1 7 0.12 years. Child neurologists and a clinical nurse specialist in child neurology, blinded to the TSB levels, conducted a standardized neurologic examination. They gave their overall impression using a 5point scale, with 1 point indicating normal result, 2 points indicating normal or questionable results, 3 points indicating
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abnormal results with minimal functional disability, 4 points indicating abnormal results with moderate functional abnormality, and 5 points indicating abnormal results with severe functional disability. The neurologists were instructed to select the category “normal or questionable” for anything that was slightly suspicious in order to maximize sensitivity. Furthermore, research assistants assessed motor skills with the use of a motor performance checklist. They used a validated 12-item screening instrument that includes items such as catching a ball and cutting out a square and that assigns each item a score of pass (0) or fail (1). “Questionable” or abnormal findings were seen in 29% of the control group compared with 17% in the study group (OR ¼ 0.47; 95% CI: 0.23–0.98; P ¼ 0.04). The groups did not differ on a validated 12-item motor performance checklist. At a mean age of 3 years, Heimler and Sasidharan26 compared 39 term infants with non-hemolytic jaundice [TSB 342–513 μmol/L (20–30 mg/dL)] with a control group of 36 children who did not develop jaundice in Wisconsin, USA. The authors used a motor Bayley 2 test of motor development and the neurological examination was performed by a pediatrician. The latter exam included deep tendon reflexes, muscle tone, quality of gait, finger–nose pointing, posture with arms extended (eyes open), and upward gaze. No differences were found between the groups with respect to the motor Bayley 2 test and the neurological examination, with special emphasis on minor abnormal neurological items. Vandborg et al.27 did a descriptive follow-up study of infants in the Danish national cohort born between 2004 and 2007. Infants Z35 weeks' gestation with TSB Z428 μmol/ L (25 mg/dL) were compared with controls matched for gender, age, gestational age, and municipality. The development was estimated by the Ages and Stages Questionnaire (ASQ) completed by the parents at 18, 24, 33, 48, and 60 months. The ASQ is validated and compared with other developmental tests such as the Bayley Mental Development Intelligence Scale. The ASQ consists of 5 domains: communication, gross motor skills, fine motor skills, problem solving, and personal social skills. Parents of 162/206 (79%) in the study group and 146/208 (70%) in the control group completed the ASQ. No differences were found in gross motor and fine motor scores at any age.
The evolution of BIND and its effect on daily life Soorani-Lunsing et al.8 reported MND in neonates with unconjugated hyperbilirubinemia and Wolf et al.28 found a significant correlation between the Prechtl neonatal exam9 and motor characteristics tested by the infant motor screen at the age of 4 months (P o 0.0001). Hadders-Algra13 reported that in neonates with MND, 10% have complex MND and 2% manifest cerebral palsy at the age of 9 years. Soorani-Lunsing et al.8 found MND in infants aged 3 months following neonatal hyperbilirubinemia. Mildly abnormal general movements at 3 months of age are correlated with neurological and/or behavioral sequelae at a later age.29 Complex MND at preschool and school age is associated with attention and cognitive deficits,13 and others have reported that MND at school age often interferes with the child's or teenager's
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activities in daily life.30 Thus, although follow-up studies of BIND or MND following hyperbilirubinemia report a low incidence of neurological problems such as cerebral palsy or movement disorders, the more subtle sequelae may, later, have an important impact on daily life. Data concerning the effect of unconjugated hyperbilirubinemia in adults are scarce.
BIND and the adult Seidman et al.31 described a relationship between neonatal hyperbilirubinemia in full-term newborns and lower IQ scores (o85) at 17 years in Israeli males but not in females. Hokkanen et al.,32 in Finland, evaluated 128 adults of 30 years of age who, as full-term neonates, had been exposed to at least 2 TSB levels of 4340 μmol/L (20 mg/dL). They were compared with 82 controls who had no perinatal risk factors. As adults, the hyperbilirubinemic group were significantly more likely than the controls to have difficulties in academic achievement and the ability to complete secondary and tertiary education. Of the total hyperbilirubinemic group, 45% had neurobehavioral problems diagnosed at the age of 9 years. These individuals had persistent cognitive problems, lower scores in parameters reflecting life satisfaction, and less controlled drinking, but no increase in substance abuse. Ebbesen et al.33 found no relationship between neonatal hyperbilirubinemia and neurological or psychiatric disorders or low IQ in male conscripts. There are no data extant on the relationship between neonatal hyperbilirubinemia and BIND in adulthood.
BIND and CNS pathology The clinical manifestations of BIND are consistent with the pathological spectrum of brain damage attributed to unconjugated hyperbilirubinemia. The motor neurological signs of BIND include disturbances in muscle tone, sensorimotor integration, and coordination. In newborns and infants, MND secondary to hyperbilirubinemia manifests as subtle abnormalities in muscle tone and mild disturbances in the sensorimotor apparatus.8,14 At school age, the motor signs secondary to hyperbilirubinemia include strabismus, questionable hypotonia, gait abnormalities, awkwardness, abnormal stereognosis, mild choreiform dyskinesia, athetosis, and dysdiadochokinesis.6,23,24 These minor neurological abnormalities are compatible with the knowledge that bilirubin encephalopathy damages the basal ganglia, particularly the globus pallidus and subthalamic nucleus, various cranial nerve nuclei, such as the oculomotor, and other brain stem nuclei, including the inferior olivary nuclei, certain cerebellar nuclei, and the dentate nucleus and the anterior horn cells of the spinal cord.34,35 The neurological signs of MND might also be the result of a non-optimally wired brain, a concept suggested by Rakic36 who notes that competitive cell interactions are crucial in shaping the final structure of the CNS. In line with this, unconjugated bilirubin reduces the viability of precursors, decreases neurogenesis, increases cellular dysfunction in differentiating cells, decreases the number of
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dendritic and axonal branches at 3–9 days, and decreases the density of dendritic spines and synapses at 21 days.37 Thus, the pathologic substrate of BIND matches the image of a nonoptimally wired brain, although, at the micro level, these abnormalities are not visible with the current techniques of brain imaging.
Discussion As illustrated by the above discussion and as shown in Tables 1 and 2, the findings in these studies are remarkably inconsistent. Some of this inconsistency can likely be attributed to differences in the methodologies and examination techniques employed, as well as the different study designs. In addition, essentially all of the data are based on peak TSB levels, with no information on the length of exposure to elevated bilirubin levels. If promptly treated, it seems reasonable to assume that the potential toxicity of an elevated TSB is likely to be ameliorated, although the published data are not consistent in this respect.24,26 At neonatal age and infancy, the studies that utilize neurological techniques designed to detect minor neurological signs5,8,14 report a higher incidence of minor neurological problems than the those that apply more traditional neurological examination techniques.18–20 The minor neurological problems mentioned, such as hypotonia, mild asymmetries in infantile reactions, and tendon reflexes, are compatible with the signs mentioned by Shapiro2 in the definition of BIND. Therefore, to diagnose BIND and minor neurological dysfunction in infancy and childhood, it is necessary to use specialized examination techniques developed specifically for each age group. These include an assessment of general movements11 at the age of 3 months and the use of 122 neurological items5 or the techniques of Touwen10 or Hempel15 for examinations at 8– 18 months. Furthermore, it appears from the data by Lunsing et al.14 and Wong et al.20 that BIND can be transient at this age. In line with this, Hadders-Algra13 notes that the findings in complex MND, i.e., MND type 2, evolve with time and might not be expressed for several years. Although Newman and Klebanoff,6 Grimmer et al.,23 and Ozmert et al.24 (the latter in only 2 of the 5 jaundiced groups) found that minor neurological signs occurred more frequently in children with neonatal hyperbilirubinemia than in controls, other investigators did not. In some of the studies listed in Table 2, specialized techniques5,6,21,23 were used in order to detect minor neurological signs or dysfunction, while others used specific findings obtained by traditional neurological examination24–26 and 1 used a questionnaire.27 The conflicting results include the finding of fewer minor neurological abnormalities in the groups with higher TSBs24 or more frequent “questionable” or abnormal neurological findings in the controls than the hyperbilirubinemic group25 or no difference between groups.26 The classical neurological examination is directed towards the diagnosis of overt abnormalities, such as spasticity or ataxia. More subtle neurological signs, such as hypotonia and mild coordination problems, are often underestimated and/or cannot be reliably reproduced. But these subtle signs are the ingredients of MND, and age-specific, standardized, neurological
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examinations with a focus on minor neurological abnormalities are therefore necessary to identify the possible effects of moderate hyperbilirubinemia. Nevertheless, although Rubin et al.5 used an extensive protocol consisting of 122 neurological items, they did not find a significant difference in the neurological outcome between the jaundiced and the control groups and neither did Valaes et al.21 Unfortunately, neither of these authors report that the examination was done by specially trained examiners, a necessary requirement if we are to detect minor neurological dysfunction. Nevertheless, it is apparent that, even in the case of high neonatal TSBs of Z450 μmol/L (26.3 mg/dL), there can be no subsequent neurological sequelae,38 and this is certainly also the case for BIND. Genetic and environmental factors such as sex, socioeconomic status, and interval complications can also influence the development of MND in either direction.13
Conclusions The (sensori)motor signs of BIND can be defined as minor neurological abnormalities manifesting in the newborn and at school age and beyond. These (sensori)motor signs are consistent with the pathological substrate of unconjugated hyperbilirubinemia and its effects on neurological structures at the micro level. If we are to identify subtle neurodevelopmental disabilities at follow-up, these infants and children must be evaluated by examiners who are specifically trained in the use of validated, age-specific examination techniques designed to uncover these disturbances. BIND has an impact later in life but seldom in the form of overt neurological sequelae. Some will show minor neurological problems from birth onwards, while others will have a silent period in infancy but manifest later attention and cognitive defects.
re fe r en ces
1. Volpe JJ. Bilirubin and brain injury. In: Volpe JJ, ed, Neurology of the Newborn, 5th ed. Philadelphia: WB Saunders, Elsevier Inc; 2008. 619–646. 2. Shapiro SM. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med. 2010;15(3):157–163. 3. Shapiro SM, Popelka GR. Auditory impairment in infants a risk for bilirubin-induced neurologic dysfunction. Semin Perinatol. 2011;35(3):162–170. 4. Johnson L, Buthani VK. The clinical syndrome of bilirubininduced neurologic dysfunction and neurologic dysfunction. Semin Perinatol. 2011;35(3):101–113. 5. Rubin RA, Balow B, Fisch RO. Neonatal serum bilirubin levels related to cognitive development at ages 4 through 7 years. J Pediatr. 1979;94(4):601–604. 6. Newman TB, Klebanoff MA. Neonatal hyperbilirubinemia and long-term outcome: another look at the collaborative perinatal project. Pediatrics. 1993;92(5):651–657. 7. Saluja S, Agarwal A, Kler N, Amin S. Auditory neuropathy spectrum disorder in late preterm and term infants with severe jaundice. Int J Pediatr Otorhinolaryngol. 2010;74(11):1292– 1297.
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8. Soorani-Lunsing RJ, Woltil H, Hadders-Algra M. Are moderate degrees of hyperbilirubinemia in healthy term neonates really safe for the brain? Pedriatr Res. 2001;50(6):701–705. 9. Prechtl HFR. The Neurological Examination of the Full Term Newborn Infant, Clinics in Developmental Medicine, No. 63, 2nd ed. London: Heinemann; 1–68. 10. Touwen BCL. Neurological Development in Infancy. Clinics in Developmental Medicine, No.58. London: Heinemann; 0–150. 11. Prechtl HFR, Einspieler C, Cioni G, Bos AF, Ferrari F, Sontheimer D. An early marker of developing neurological handicap after perinatal brain lesions. Lancet. 1997;339: 1361–1363. 12. Hadders-Algra M, Klip-Van den Nieuwendijk A, Martijn A, van Eykern LA. Assessment of general movements: towards a better understanding of a sensitive method to evaluate brain function in young infants. Dev Med Child Neurol. 1997;39 (2):89–99. 13. Hadders-Algra M. Two distinct forms of minor neurological dysfunction perspectives emerging from a review of data of the Groningen Perinatal Project. Dev Med Child Neurol. 2002;44 (8):561–571. 14. Lunsing RJ, Pardoen WFH, Hadders-Algra M. Neurodevelopment after moderate hyperbilirubinemia at term: a prospective study. Pediatr Res. 2013;73(5):655–660. 15. Hempel MS. The neurological examination technique for toddler-age. PhD Thesis, University of Groningen, 1993; digital ID 4947a28682278:0-232. 16. Hadders-Algra M. The neuromotor examination of the preschool child and its prognostic significance. Ment Retard Dev Disabil Res Rev. 2005;11(3):180–188. 17. Boggs TR, Hardy JB, Frazier TM. Correlation of neonatal serum total bilirubin concentrations and developmental status at age eight months. J Pediatr. 1967;71(4):553–560. 18. Scheidt PC, Mellits ED, Hardy JB, Drage JS, Boggs TR. Toxicity to bilirubin in neonates: infant development during first year in relation to maximum neonatal serum bilirubin concentration. J Pediatr. 1977;91(2):292–297. 19. Scheidt PC, Bryla DA, Nelson KB, Hirtz DG, Hoffman HJ. Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial. Pediatrics. 1990;85(4):455–463. 20. Wong V, Chen W, Wong K. Short- and long-term outcome of severe neonatal nonhemolytic hyperbilirubinemia. J Child Neurol. 2006;21(4):309–315. 21. Valaes T, Kipouros K, Petmezaki S, Solman M, Doxiadis SA. Effectiveness and safety of prenatal phenobarbital for the prevention of neonatal jaundice. Pediatr Res. 1980;14(8): 947–952. 22. Touwen BCL, Prechtl HFR. The Neurological Examination of the Child With Minor Nervous Dysfunction. Clinics in Developmental Medicine, No.38. London: Heinemann; 1971.
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23. Grimmer I, Berger-Jones K, Bührer C, Brandl U, Obladen M. Late neurological sequela of non-hemolytic hyperbilirubinemia of healthy term neonates. Acta Paediatr. 1999;88 (6):661–663. 24. Ozmert E, Erden G, Topçu M, et al. Long term follow-up of indirect hyperbilirubinemia in full-term Turkish infants. Acta Paediatr. 1996;85(12):1440–1444. 25. Newman TB, Liljestrand P, Jeremy RJ, et al. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. New Engl J Med. 2006;354(18):1889–1900. 26. Heimler R, Sasidharan P. Neurodevelopmental and audiological outcome of healthy term newborns with moderately severe non-haemolytic hyperbilirubinemia. J Paediatr Child Health. 2010;46(10):588–591. 27. Vandborg PK, Hansen BM, Greisen G, Jepsen M, Ebbesen F. Follow-up of neonates with total serum bilrubin levels Z25 mg/dl: a Danish population-based study. Pediatrics. 2012;130(1):61–66. 28. Wolf M, Beunen G, Casaer P, Wolf B. Neonatal neurological examination as a predictor of neuromotor outcome at 4 months in term low-Apgar-score babies in Zimbabwe. Early Hum Dev. 1998;51(2):179–186. 29. Hadders-Algra M, Groothuis AMC. Quality of general movements in infancy is related to neurological dysfunction, ADHD, and aggressive behaviour. Dev Med Child Neurol. 1999;41(6):381–391. 30. Soorani-Lunsing RJ, Hadders-Algra M, Huisjes HJ, Touwen BCL. Neurobehavioural relationships after the onset of puberty. Dev Med Child Neurol. 1994;36(4):334–343. 31. Seidman DS, Paz I, Stevenson DK, Laor A, Danon YL, Gale R. Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years. Pediatrics. 1991;88(4):828–833. 32. Hokkanen L, Launes J, Michelsson K. Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates—a 30 year prospective follow-up study. PeerJ. 2014;294:1–20. 33. Ebbesen F, Ehrenstein V, Traeger M, Nielsen GL. Neonatal non-hemolytic hyperbilirubinemia: a prevalence study of adult neuropsychiatric disability and cognitive function in 463 male Danish conscripts. Arch Dis Child. 2010;95(8):583–587. 34. Connolly AM, Volpe JJ. Clinical features of bilirubin encephalopathy. Clin Perinatol. 1990;17(2):371–379. 35. Turkel SB. Autopsy findings associated with neonatal hyperbilirubinemia. Clin Perinatol. 1990;17(2):381–394. 36. Rakic P. Defects of neuronal migration and the pathogenesis of cortical malformations. Progr Brain Res. 1988;73:15–73. 37. Fernandes A, Falcao AS, Abranches E, et al. Bilirubin as a determinant for altered neurogenesis, neuritogenesis, and synaptogenesis. Dev Neurobiol. 2009;69(9):568–582. 38. Ebbesen F, Bjerre JV, Vandborg PK. Relation between bilirubin levels Z450 μmol/l and blirubin encephalopathy: a Danish population-based study. Acta Paediatr. 2012;101:384–389.
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Available online at www.sciencedirect.com
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Subtle bilirubin-induced neurodevelopmental dysfunction (BIND) in the term and late preterm infant: Does it exist? Roelineke J. Lunsing, PhD, MD Department of Neurology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands
article info
abstra ct Subtle bilirubin-induced neurological dysfunction (BIND) is defined as disturbances in sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone in the absence of the classical findings of kernicterus. This review is restricted to the (sensori)motor signs of BIND associated with unconjugated hyperbilirubinemia in term and late preterm neonates. The diagnosis of BIND at follow-up requires validated, age-specific techniques that are designed to identify these disturbances in infancy and later childhood. The (sensori)motor signs of BIND are compatible with the pathological substrate of unconjugated hyperbilirubinemia and its known effects on the brain. & 2014 Elsevier Inc. All rights reserved.
Introduction Free unconjugated bilirubin is the neurotoxin that can damage the newborn brain. The classic and most overt form of bilirubin encephalopathy is kernicterus,1 originally a pathologic term referring to the yellow staining (icterus) of the deep nuclei of the brain (kern—relating to the basal ganglia).2 Currently kernicterus is also used to describe the clinical picture of chronic bilirubin encephalopathy,2 a tetrad of auditory impairment (including deafness), a movement disorder (dystonia and/or athetosis), ocular movement impairment (especially impaired upward gaze), and dental enamel dysplasia of the deciduous teeth.3 Shapiro has suggested that the clinical manifestations of kernicterus can be divided into 4 main subtypes: (1) classical kernicterus—as described above; (2) auditory predominant kernicterus—characterized by a predominance of auditory symptoms with minimal or no motor symptoms; (3) motor predominant kernicterus—a predominance of motor E-mail address: [email protected] http://dx.doi.org/10.1053/j.semperi.2014.08.009 0146-0005/& 2014 Elsevier Inc. All rights reserved.
symptoms with minimal or no auditory symptoms; and (4) subtle kernicterus or bilirubin-induced neurologic dysfunction (BIND).2 The incidence of BIND is not known nor is the precise threshold at which bilirubin may be neurotoxic in a given infant.4 The published literature yields conflicting results with respect to the occurrence of BIND at different bilirubin levels and at different ages. For example, Rubin et al.5 found no differences in neurological examination at the age of 7 years in children whose neonatal total serum bilirubin (TSB) levels were r171 μmol/L (10 mg/dL) vs those with TSB 274– 393 μmol/L (16–23 mg/dL) whereas Newman and Klebanoff6 reported a stepwise increase in abnormal or suspicious neurological findings from 14.9% of 7-year-old children whose neonatal TSB levels were o171 μmol/L (10 mg/dL) to 22.4% in those with TSBs Z342 μmol/L (20 mg/dL). Although BIND occurs in premature infants, this review will deal exclusively with BIND in healthy term and late preterm neonates of Z34 weeks gestational age.
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Defining BIND BIND was defined by Shapiro2 as subtle neurodevelopmental disabilities without classical findings of kernicterus that, after careful evaluation and consideration, appear to be due to bilirubin neurotoxicity. These may include disturbances of sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone.2 The central auditory processing problems can be reliably assessed by auditory measures. However, auditory responses to acoustic stimuli cannot be used for all ages and cognitive abilities.3 Middle ear measures and cochlear measures are used to rule out confounding factors3 but the auditory brain stem evoked response is an objective method that can be applied at all ages.7 On the other hand, our ability to detect the more subtle neurological signs of BIND, such as disturbances in sensorimotor integration, coordination, and muscle tone at different ages, is less clear.
BIND in the newborn and in infancy Soorani-Lunsing et al.8 used the techniques by Prechtl9 at age 3–8 days and by Touwen10 at 12 months to evaluate 40 previously healthy Dutch infants at Z36 weeks of gestation who were born between 1997 and 1998 (Table 1). The Prechtl and Touwen techniques identify minor neurological dysfunction (MND), mild deviations in muscle tone regulation or mild asymmetries in infantile reactions, and tendon reflexes, i.e., mild disturbances of sensory and sensorimotor integration, and thorough training in these techniques is necessary to achieve reliable and reproducible results. At the age of 3 months, the investigators also studied the quality of general
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movements, a sensitive tool for evaluating brain function in young infants.11 To do this, they made a 20-min video recording of spontaneous motility in supine infants, while the infant was in an alert, active, non-crying ehavioral state. The recordings were then assessed blindly. The quality of the movements was classified as normal-optimal (perfectly and acceptably complex, fluent, and variable general movements), mildly abnormal or MND (insufficiently complex and variable movements, which are not fluent), or definitely abnormal (virtual lack of complexity, variation, and fluency). Inter-scorer agreement was good (κ value 40.80).12 Overall, 20 newborn infants who had non-hemolytic hyperbilirubinemia, with TSB levels of 233–444 μmol/L (13.6–26 mg/dL) were compared with 20 non-jaundiced controls, matched for sex and gestational age. Of the 20 jaundiced newborns, 14 (70%) had evidence of MND compared with 5 of 20 (25%) controls [odds ratio (OR) ¼ 6.62; confidence interval (CI): 1.59–27.51; P o 0.05]. Differences between these groups in MND were also seen at the ages of 3 and 12 months. Those with MND at 12 months were further divided into 2 sub classifications: MND type 1 and MND type 2. MND type 1 is the simple form of MND, which implies normal, yet non-optimal neurological function, with only 1 item being deviant. MND type 2 is a more complex, and clinically relevant, form in which more than 1 item is mildly abnormal.13 MND occurred significantly more often in the jaundiced group compared with controls (OR ¼ 9.47, CI: 1.67–53.65 adjusted for sex). Remarkably, all children with complex MND had a TSB Z335 μmol/L (19.6 mg/dL). The same group of investigators subsequently followed up with 43 healthy neonates at Z37 weeks gestation with TSB Z220 μmol/L (12.9 mg/dL) and 70 controls with TSB o 220 μmol/L born between 2002 and 2007.14 Using similar methods, they evaluated the infants at the ages of 3–8 days
Table 1 – BIND defined by lower Bayley motor scores or signs of MND in infancy. References
Group(s) (n)
Bilirubin (μmol/L)
FU age
Method or minor (neurological sign)
Results (BIND)
Boggs et al.17
22.566
8 mo
Bayley motor
Scheidt et al.18
27.270
171 Every 24 h measured 171 Every 24 h measured
1 yr
Neur. abnormality
Increase bilirubin - 0.5% increase; n with low score Correlates with bilirubin, P ¼ 0.02
Scheidt et al.19 Rubin et al.5
Wong et al.20 SooraniLunsing8 Lunsing14
ph (121) c (117) s1 (153) s2 (69) c (120) s1 (30) s2 (63) s (20) c (20) s (43) c (70) s (10) c (100)
4222 4222 188–257 274–393 r171 300–341 342–427 233–444 Non-icteric 220–366 o220 Z300 o300
1 yr 8 mo 1 yr 3 yr 3 mo 12 mo 3 mo
Correlates with bilirubin, P ¼ 0.05 ns ph ¼ 0.8% and c ¼ 0% ph ¼ c ¼ 0% Covariance P o 0.05 Covariance P o 0.007
Failure to stand Other signs Hypotonia Abnormal movements Bayley motor 122 Neurological items Neurological evaluation General movements Touwen General movements
s ¼ 55%, c ¼ 25% and P ¼ 0.05 s ¼ 50%, c ¼ 10% and P o 0.05 s ¼ 33%, c ¼ 41% and ns
Hempel
s ¼ 40%, c ¼ 13% and P o 0.05
All normal
18 mo
BIND ¼ bilirubin-induced neurologic dysfunction, MND ¼ minor neurological dysfunction, n ¼ number, yr ¼ years, FU ¼ follow-up, mo ¼ months, h ¼ hours, neur. ¼ neurological, ns ¼ non-significant, ph ¼ phototherapy group, c ¼ control or comparison group (only in the study by Lunsing), s ¼ study group, s1 and s2 ¼ sub study groups with specific bilirubin levels.
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and 3 months. At 18 months, the standardized age-specific neurologic examination of Hempel15 was carried out. Five domains are examined: visuomotor function, posture and muscle tone, fine motor function, gross motor function, and reflexes. Simple MND stands for the presence of 1 deviant domain, representing a non-optimal yet normal form of brain function.13 Complex MND denotes the presence of more than 1 deviant domain. Inter-scorer agreement was satisfactory (κ value ¼ 0.62–1.00).16 They did not find any difference in the rates of complex MND at any age, although the jaundiced infants were more lethargic as neonates (OR ¼ 3.66, CI: 1.33– 10.04) and more active at 18 months (OR ¼ 0.31, CI: 0.07–0.55). They also compared a subgroup of 10 children whose TSB levels were Z300 mmol/L (17.5 mg/dL) with 100 with TSB o 300 mmol/L. At 18 months, the hyperbilirubinemic infants were more likely to have MND (OR ¼ 4.21, CI: 1.02–17.37). Boggs et al.17 and Scheidt et al.18 analyzed the data from the Collaborative Perinatal Project (CPP), which included the followup of some 27,000 infants. In the CPP, all infants had a TSB measured at 48 7 12 h. If the TSB was Z171 μmol/L (10 mg/dL), the test was repeated every 24 h until it was o171 mmol/L (10 mg/dL). Outcome was assessed at 8 months using the Bayley scales of mental and motor development. In addition, Scheidt et al.18 performed a detailed neurologic examination at the age of 1 year. Boggs et al.17 found a linear relationship between the maximum TSB and the percentage of total motor Bayley scores below 27. In the group with birth weights Z3000 g, the estimated increase in percentage of infants with a low score was 0.5% for each mg/dL (17 mmol/L) rise in TSB. Scheidt et al.18 found a significant relationship (P r 0.05) between the peak TSB and lower mean Bayley motor scale results in white infants with a birth weight 42500 g and gestational age Z37 weeks. However, the authors note that although statistically significant, the correlation coefficients were small because of the effect of a disproportionally large number of infants with low bilirubin values. In the black infants, no significant relationship was found. To examine for more subtle effects, the mean Bayley motor scores were compared for infants with maximum bilirubin levels r154 μmol/L (9 mg/dL) vs 155– 240 μmol/L (9.1–14 mg/dL) in the same birth weight and gestational age group. Again, a significant difference was present only in the white group (P r 0.02). At the age of 1 year, there was a significant correlation for neurological abnormality (P o 0.02) and failure to stand (P o 0.05) with the maximum TSB. In a 6-year follow-up of the NICHD Collaborative Phototherapy Study, 2 child neurologists, blinded to group assignment, reviewed and classified records of the neurological examinations for analysis of neurological abnormalities.19 The diagnosis of cerebral palsy was based on observed defects in posture, movement, tone, and reflexes. In infants with birth weight Z2500 g and TSB 4 222 μmol/L (13.0 mg/dL) randomly assigned to the phototherapy (n ¼ 121) or control groups (n ¼ 117), there was no significant difference between groups in the incidence of hypotonia, abnormal movements, or cerebral palsy. Rubin et al.5 followed up with 1613 participants of the educational follow-up study in the Minnesota section of the Collaborative Perinatal Project (CPP) and divided them into 3 groups based on their peak TSB levels: o171 μmol/L (10 mg/dL, n ¼ 120), 188 257 μmol/L (11.0–15.0 mg/dL, n ¼ 153), 274– 393 μmol/L (16.0–23 mg/dL, n ¼ 69). A neurological examination
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was performed at 1 year of age. The physician reported his overall clinical impression of the neurologic status of the child on the basis of extensive protocols consisting of 122 items. Neurologic status was coded as 0 ¼ normal, 1 ¼ suspect, and 2 ¼ abnormal. At 1 year, if controlled for gestational age, the higher bilirubin groups scored significantly lower on the Bayley Motor Scale compared with the lower bilirubin group (P o 0.05) and neurological abnormalities were more often present in the higher bilirubin groups than the lower bilirubin group (P o 0.007). Wong et al.20 followed up with Chinese full-term infants with peak TSBs of 300–341 μmol/L (17.5–19.9 mg/dL, n ¼ 30), 342–428 μmol/L (20–25 mg/dL, n ¼ 63), and Z428 μmol/L (25 mg/dL, n ¼ 6). A neurologist evaluated the infants every 3–6 months until the age of 3 years, and all had normal neurodevelopmental status at the age of 3 years. Two infants, one in each of the higher TSB groups, showed transient mild motor delay and hypotonia at the age of 3 months, but both returned to normal by 6 and 11 months, respectively.
BIND at preschool and school age Rubin et al.5 followed up with 318 of the participants in the educational follow-up study and the Minnesota section of the CPP and evaluated their neurological status at the age of 7 years using the same 122 items employed at 1 year. They found no significant differences among the 3 bilirubin groups (Table 2). Newman and Klebanoff6 reanalyzed the data from the CPP of infants with birth weights Z2500 g who had neonatal TSB recorded. At the age of 7 years, 33,272 had been examined using a detailed, standardized neurological examination consisting of 82 items. The examination was performed by project staff pediatric neurologists or by specially trained pediatricians at each center who were blinded to the neonatal TSB levels. The risk of abnormal or suspicious examinations increased in a stepwise manner from 14.9% in the group whose maximum TSB had been o171 μmol/L (10 mg/dL)–22.4% in the highest bilirubin group [TSB Z 342 μmol/L (20 mg/dL) adjusted OR ¼ 1.12, 95% CI: 1.06–1.20]. They also looked for associations between peak TSB level and each of the 82 items of the neurological examination. Significant relationships were reported between gait abnormalities (P o 0.001), awkwardness (P o 0.001), equivocal Babinski reflexes (P o 0.001), abnormal cremaster (P ¼ 0.001) or abdominal (P ¼ 0.008) reflexes, failure at fine stereognosis (P ¼ 0.008), questionable hypotonia (P values ranging from 0.005 for the right upper extremity to 0.07 for the trunk), and gaze abnormalities (P ¼ 0.001–0.05). Athetosis was not associated with peak TSB levels. Valaes et al.21 followed up with a group of 415 jaundiced neonates, with birth weight 42500 g, from the island of Lesbos. They found that 233 of the mothers had received phenobarbital during the last few weeks of pregnancy to decrease their neonatal TSB levels and there were 182 controls. The neurological examination described by Touwen and Prechtl22 was used at the of ages 5 and 6 years and examiners were blinded to the neonatal TSB levels. A high proportion of the children performed non-optimally in the following areas: associated movements during walking tip toe and on heels,
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Table 2 – BIND (defined by MND or signs of MND) at preschool and school age. References
Rubin et al.5
Group(s) (n)
Valaes et al.21
s1 s2 c s1 s2 s3 c s1
Grimmer et al.23
s2 (13) s3 (11) s (16)
Newman and Klebanoff6
Ozmert et al.24
Newman et al.25 Heimler and Sasidharan26 Vandborg et al.27
c sI sII sIII sIV sV c s c s c s c
(142) (63) (113) (2876) (870) (268) (29258) (21)
(18) (13) (26) (27) (19) (19) (27) (82) (168) (39) (36) (162) (146)
Bilirubin (μmol/L)
FU age
Method
Results (BIND)
188–257 274–393 r171 171–255 256–341 Z340 o171 274–342
7 yr
122 Neurological Items
ns Difference
7 yr
82 Neurological Items
s1 ¼ 16%, s2 ¼ 18%, s3 ¼ 22% and c ¼ 15% P o 0.001
5–6 yr
Touwen and Prechtl
ns Difference between s groups
5–15 yr
Touwen
ns Difference except for choreiform dyskinesia P ¼ 0.03
8–13 yr
Neurological Examination
sI ¼ 8%, sII ¼ 23%, sIII ¼ 7% and sIV ¼ 0% sV ¼ 29% and c ¼ 4%
5 yr
Neurological Examination Neurological Examination Questionnaire Fine/gross motor
s ¼ 17% and c ¼ 29% P ¼ 0.04 s ¼ 18% and c ¼ 8% P ¼ 0.2 ns Difference
343–428 4428 342–513 o205 290–341 342–375 376–426 Z426 Z342 (Coombsþ) No icterus 428–511 o428 342–513 no icterus Z428 ?
3 yr 18 mo– 6 yr
BIND ¼ bilirubin-induced neurologic dysfunction, MND ¼ minor neurological dysfunction, FU ¼ follow-up, mo ¼ months, yr ¼ years, n ¼ number, s ¼ study group, s1, s2, s3 and sI, sII, sIII, sIV, sV ¼ sub study groups with specific bilirubin levels, c ¼ control, ns ¼ non-significant.
standing with the eyes closed, mouth opening–finger spreading phenomenon, diadochokinesis and associated movements, finger–nose test, finger opposition test, and knee– heel test. Optimal performance was given a score of 1, the least adequate performance was 3 or 4. Right and left sides were scored separately. The TSB was 4274 μmol/L (15.7 mg/ dL) in 6.6% of the control group vs 1.1% in the phenobarbital group. They also evaluated 44 children with TSB Z 274 μmol/ (16 mg/dL) and those with TSB levels of 274–342 μmol (16– 20 mg/dL, n ¼ 21), 343–428 μmol/L (20.1–25.0 mg/dL, n ¼ 13), and 4428 μmol/L (25 mg/dL, n ¼ 11) and found no differences in neurological outcome or IQ scores. Grimmer et al.23 followed up with healthy jaundiced term neonates (Z2500 g and Z37 weeks) with peak TSB levels of 342–513 μmol/L (20–30 mg/dL) who were admitted to the Berlin Free University Children's Hospital from 1978 to 1988. Of them, 16 with TSB of 342–513 mmol/L (20–30 mg/dL) were examined according to Touwen between 5 and 15 years and compared with 18 controls, matched for sex, whose TSB never exceeded 205 mmol/L (12 mg/dL). They used the qualitative subscales in evaluating sensorimotor apparatus, posture, balance of the trunk, coordination of the extremities, fine manipulative abilities, choreiform dyskinesia, gross motor function, quality of movements, and associated movements to compare outcome between groups. The study group showed no significant difference in cluster profiles compared with the controls, except that the study infants had a worse subscale score for choreiform dyskinesia (P ¼ 0.028)
Ozmert et al.24 performed a retrospective follow-up of 102 jaundiced, Turkish infants at Z37 weeks gestation born between 1980 and 1985 and admitted with hyperbilirubinemia. Birth weight was 43000 g. They divided the infants into 5 groups: group I Z290–341 μmol/L (n ¼ 13), group II 342– 375 μmol/L (n ¼ 26), group III 376–426 μmol/L (n ¼ 27), group IV Z426 μmol/L (n ¼ 19), group V Z342 μmol/L (n ¼ 17) and group VI, a control group randomly chosen without hyperbilirubinemia (n ¼ 27). All had negative Coombs tests, except for group V. At 8–13 years of age, they were examined by a pediatric neurologist and grouped according to the findings as normal or with minor or prominent neurological abnormalities. The minor neurological abnormalities reported were mild choreoathetosis, abnormal stereognosis, strabismus, and dysdiadochokinesis. Minor neurological findings were seen in 23% in group II and 29.4% in group V compared with 3.7% in the control group. Newman et al.25 conducted a prospective study of healthy term and late preterm infants (Z2000 g and Z34 weeks) born between 1995 and 1998 in northern California. Of them, 82 infants with TSB Z 428 mmol/L (25 mg/dL) and 168 controls with TSB o 428 mmol/L or who had no TSB measured were examined at a mean age of 5.1 7 0.12 years. Child neurologists and a clinical nurse specialist in child neurology, blinded to the TSB levels, conducted a standardized neurologic examination. They gave their overall impression using a 5point scale, with 1 point indicating normal result, 2 points indicating normal or questionable results, 3 points indicating
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abnormal results with minimal functional disability, 4 points indicating abnormal results with moderate functional abnormality, and 5 points indicating abnormal results with severe functional disability. The neurologists were instructed to select the category “normal or questionable” for anything that was slightly suspicious in order to maximize sensitivity. Furthermore, research assistants assessed motor skills with the use of a motor performance checklist. They used a validated 12-item screening instrument that includes items such as catching a ball and cutting out a square and that assigns each item a score of pass (0) or fail (1). “Questionable” or abnormal findings were seen in 29% of the control group compared with 17% in the study group (OR ¼ 0.47; 95% CI: 0.23–0.98; P ¼ 0.04). The groups did not differ on a validated 12-item motor performance checklist. At a mean age of 3 years, Heimler and Sasidharan26 compared 39 term infants with non-hemolytic jaundice [TSB 342–513 μmol/L (20–30 mg/dL)] with a control group of 36 children who did not develop jaundice in Wisconsin, USA. The authors used a motor Bayley 2 test of motor development and the neurological examination was performed by a pediatrician. The latter exam included deep tendon reflexes, muscle tone, quality of gait, finger–nose pointing, posture with arms extended (eyes open), and upward gaze. No differences were found between the groups with respect to the motor Bayley 2 test and the neurological examination, with special emphasis on minor abnormal neurological items. Vandborg et al.27 did a descriptive follow-up study of infants in the Danish national cohort born between 2004 and 2007. Infants Z35 weeks' gestation with TSB Z428 μmol/ L (25 mg/dL) were compared with controls matched for gender, age, gestational age, and municipality. The development was estimated by the Ages and Stages Questionnaire (ASQ) completed by the parents at 18, 24, 33, 48, and 60 months. The ASQ is validated and compared with other developmental tests such as the Bayley Mental Development Intelligence Scale. The ASQ consists of 5 domains: communication, gross motor skills, fine motor skills, problem solving, and personal social skills. Parents of 162/206 (79%) in the study group and 146/208 (70%) in the control group completed the ASQ. No differences were found in gross motor and fine motor scores at any age.
The evolution of BIND and its effect on daily life Soorani-Lunsing et al.8 reported MND in neonates with unconjugated hyperbilirubinemia and Wolf et al.28 found a significant correlation between the Prechtl neonatal exam9 and motor characteristics tested by the infant motor screen at the age of 4 months (P o 0.0001). Hadders-Algra13 reported that in neonates with MND, 10% have complex MND and 2% manifest cerebral palsy at the age of 9 years. Soorani-Lunsing et al.8 found MND in infants aged 3 months following neonatal hyperbilirubinemia. Mildly abnormal general movements at 3 months of age are correlated with neurological and/or behavioral sequelae at a later age.29 Complex MND at preschool and school age is associated with attention and cognitive deficits,13 and others have reported that MND at school age often interferes with the child's or teenager's
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activities in daily life.30 Thus, although follow-up studies of BIND or MND following hyperbilirubinemia report a low incidence of neurological problems such as cerebral palsy or movement disorders, the more subtle sequelae may, later, have an important impact on daily life. Data concerning the effect of unconjugated hyperbilirubinemia in adults are scarce.
BIND and the adult Seidman et al.31 described a relationship between neonatal hyperbilirubinemia in full-term newborns and lower IQ scores (o85) at 17 years in Israeli males but not in females. Hokkanen et al.,32 in Finland, evaluated 128 adults of 30 years of age who, as full-term neonates, had been exposed to at least 2 TSB levels of 4340 μmol/L (20 mg/dL). They were compared with 82 controls who had no perinatal risk factors. As adults, the hyperbilirubinemic group were significantly more likely than the controls to have difficulties in academic achievement and the ability to complete secondary and tertiary education. Of the total hyperbilirubinemic group, 45% had neurobehavioral problems diagnosed at the age of 9 years. These individuals had persistent cognitive problems, lower scores in parameters reflecting life satisfaction, and less controlled drinking, but no increase in substance abuse. Ebbesen et al.33 found no relationship between neonatal hyperbilirubinemia and neurological or psychiatric disorders or low IQ in male conscripts. There are no data extant on the relationship between neonatal hyperbilirubinemia and BIND in adulthood.
BIND and CNS pathology The clinical manifestations of BIND are consistent with the pathological spectrum of brain damage attributed to unconjugated hyperbilirubinemia. The motor neurological signs of BIND include disturbances in muscle tone, sensorimotor integration, and coordination. In newborns and infants, MND secondary to hyperbilirubinemia manifests as subtle abnormalities in muscle tone and mild disturbances in the sensorimotor apparatus.8,14 At school age, the motor signs secondary to hyperbilirubinemia include strabismus, questionable hypotonia, gait abnormalities, awkwardness, abnormal stereognosis, mild choreiform dyskinesia, athetosis, and dysdiadochokinesis.6,23,24 These minor neurological abnormalities are compatible with the knowledge that bilirubin encephalopathy damages the basal ganglia, particularly the globus pallidus and subthalamic nucleus, various cranial nerve nuclei, such as the oculomotor, and other brain stem nuclei, including the inferior olivary nuclei, certain cerebellar nuclei, and the dentate nucleus and the anterior horn cells of the spinal cord.34,35 The neurological signs of MND might also be the result of a non-optimally wired brain, a concept suggested by Rakic36 who notes that competitive cell interactions are crucial in shaping the final structure of the CNS. In line with this, unconjugated bilirubin reduces the viability of precursors, decreases neurogenesis, increases cellular dysfunction in differentiating cells, decreases the number of
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dendritic and axonal branches at 3–9 days, and decreases the density of dendritic spines and synapses at 21 days.37 Thus, the pathologic substrate of BIND matches the image of a nonoptimally wired brain, although, at the micro level, these abnormalities are not visible with the current techniques of brain imaging.
Discussion As illustrated by the above discussion and as shown in Tables 1 and 2, the findings in these studies are remarkably inconsistent. Some of this inconsistency can likely be attributed to differences in the methodologies and examination techniques employed, as well as the different study designs. In addition, essentially all of the data are based on peak TSB levels, with no information on the length of exposure to elevated bilirubin levels. If promptly treated, it seems reasonable to assume that the potential toxicity of an elevated TSB is likely to be ameliorated, although the published data are not consistent in this respect.24,26 At neonatal age and infancy, the studies that utilize neurological techniques designed to detect minor neurological signs5,8,14 report a higher incidence of minor neurological problems than the those that apply more traditional neurological examination techniques.18–20 The minor neurological problems mentioned, such as hypotonia, mild asymmetries in infantile reactions, and tendon reflexes, are compatible with the signs mentioned by Shapiro2 in the definition of BIND. Therefore, to diagnose BIND and minor neurological dysfunction in infancy and childhood, it is necessary to use specialized examination techniques developed specifically for each age group. These include an assessment of general movements11 at the age of 3 months and the use of 122 neurological items5 or the techniques of Touwen10 or Hempel15 for examinations at 8– 18 months. Furthermore, it appears from the data by Lunsing et al.14 and Wong et al.20 that BIND can be transient at this age. In line with this, Hadders-Algra13 notes that the findings in complex MND, i.e., MND type 2, evolve with time and might not be expressed for several years. Although Newman and Klebanoff,6 Grimmer et al.,23 and Ozmert et al.24 (the latter in only 2 of the 5 jaundiced groups) found that minor neurological signs occurred more frequently in children with neonatal hyperbilirubinemia than in controls, other investigators did not. In some of the studies listed in Table 2, specialized techniques5,6,21,23 were used in order to detect minor neurological signs or dysfunction, while others used specific findings obtained by traditional neurological examination24–26 and 1 used a questionnaire.27 The conflicting results include the finding of fewer minor neurological abnormalities in the groups with higher TSBs24 or more frequent “questionable” or abnormal neurological findings in the controls than the hyperbilirubinemic group25 or no difference between groups.26 The classical neurological examination is directed towards the diagnosis of overt abnormalities, such as spasticity or ataxia. More subtle neurological signs, such as hypotonia and mild coordination problems, are often underestimated and/or cannot be reliably reproduced. But these subtle signs are the ingredients of MND, and age-specific, standardized, neurological
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examinations with a focus on minor neurological abnormalities are therefore necessary to identify the possible effects of moderate hyperbilirubinemia. Nevertheless, although Rubin et al.5 used an extensive protocol consisting of 122 neurological items, they did not find a significant difference in the neurological outcome between the jaundiced and the control groups and neither did Valaes et al.21 Unfortunately, neither of these authors report that the examination was done by specially trained examiners, a necessary requirement if we are to detect minor neurological dysfunction. Nevertheless, it is apparent that, even in the case of high neonatal TSBs of Z450 μmol/L (26.3 mg/dL), there can be no subsequent neurological sequelae,38 and this is certainly also the case for BIND. Genetic and environmental factors such as sex, socioeconomic status, and interval complications can also influence the development of MND in either direction.13
Conclusions The (sensori)motor signs of BIND can be defined as minor neurological abnormalities manifesting in the newborn and at school age and beyond. These (sensori)motor signs are consistent with the pathological substrate of unconjugated hyperbilirubinemia and its effects on neurological structures at the micro level. If we are to identify subtle neurodevelopmental disabilities at follow-up, these infants and children must be evaluated by examiners who are specifically trained in the use of validated, age-specific examination techniques designed to uncover these disturbances. BIND has an impact later in life but seldom in the form of overt neurological sequelae. Some will show minor neurological problems from birth onwards, while others will have a silent period in infancy but manifest later attention and cognitive defects.
re fe r en ces
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