Published online November 1, 2005
PEDIATRICS Vol. 116 No. 5 November 2005, pp. 1226-1230 (doi:10.1542/10.1542/peds.2004-2468)
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EXPERIENCE AND REASON

Clinical (Video) Findings and Cerebrospinal Fluid Neurotransmitters in 2 Children With Severe Chronic Bilirubin Encephalopathy, Including a Former Preterm Infant Without Marked Hyperbilirubinemia

Stephanie L. Merhar, MD* and Donald L. Gilbert, MD{ddagger},§

* University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
{ddagger} Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
§ Department of Neurology, University of Cincinnati School of Medicine, Cincinnati, Ohio


   ABSTRACT
TOP
 ABSTRACT
CASE REPORTS
 DISCUSSION
 REFERENCES
 
Chronic bilirubin encephalopathy, characterized clinically by extrapyramidal movement abnormalities, vertical gaze abnormalities, and hearing loss, results from neuronal injury after marked hyperbilirubinemia in term and preterm infants. In premature infants, bilirubin staining of specific brain structures has been described at autopsy after only moderate hyperbilirubinemia, but classic chronic bilirubin encephalopathy without marked hyperbilirubinemia has been reported only rarely. We report a case of a 7-year-old, former 29-weeks' gestation, gravely ill premature infant with a peak bilirubin level of 13.3 mg/dL in the neonatal period. We compare this case with a 12-year-old, former term infant with a peak bilirubin level of 49.4 mg/dL on day 10 of life. Both children have dystonia, athetosis, upward gaze palsy, and sensorineural hearing loss, with MRIs showing characteristic abnormal signal in the globus pallidus. We add previously unreported cerebrospinal fluid neurotransmitter levels that show a mild decrease in the dopamine metabolite homovanillic acid in the former premature infant only.

Key Words: bilirubin • bilirubin-albumin binding • cerebrospinal fluid • kernicterus • neuroimaging

Abbreviations: CSF, cerebrospinal fluid • TPN, total parenteral nutrition

The prevention of bilirubin encephalopathy in both term and preterm infants continues to be a hotly debated topic.1–3 There seems to be no threshold total bilirubin level above which all or most infants have chronic neurologic sequelae, and many studies have been unable to demonstrate a significant association between peak total serum bilirubin level and neurodevelopmental outcome.4–7 However, case reports of kernicterus and chronic bilirubin encephalopathy continue to appear in the literature. A few cases have been reported in premature infants with low peak serum bilirubin levels and no acute symptoms.8–10 We report a case of chronic bilirubin encephalopathy in a preterm infant without marked hyperbilirubinemia and compare it to a classic case in a term infant with a high peak total serum bilirubin. We review the histories, neurologic findings, and MRI results, and provide the first report of cerebrospinal fluid (CSF) neurotransmitter levels in this condition.


   CASE REPORTS
TOP
 ABSTRACT
 CASE REPORTS
DISCUSSION
 REFERENCES
 
Patient 1
Patient 1 is a female born at 29 weeks' gestation by emergency cesarean section resulting from fetal distress. At birth, she was noted to have bruising of her back, hand, and legs. Her birth weight was 1370 g. Maternal blood type was A positive, and the infant's blood type was O positive. Apgar scores were 6 at 1 minute and 9 at 5 minutes. The patient was intubated and received surfactant on the day of birth. A patent ductus arteriosus was ligated on day 10. She had a difficult respiratory course with many episodes of apnea requiring bagging and a period of high-frequency oscillatory ventilation. On day 7, a left grade 1 germinal matrix hemorrhage was noted on ultrasound. A follow-up head ultrasound on day 21 was interpreted as showing bilateral grade 1 germinal matrix hemorrhages. An MRI on day 25 was interpreted as normal. On day 59, because of persistent apneic spells, an electroencephalogram was obtained to rule out seizures. This was interpreted as showing excessive right temporal, sharp transients, and therefore the patient was placed on phenobarbital. However, because no additional clinical evidence of seizures occurred, she was weaned off of the phenobarbital after a normal electroencephalogram on day 106.

Total bilirubin on day of life 1 was 5.9 mg/dL. On day 2, jaundice was noted, her total bilirubin was found to be 8.9 mg/dL, and phototherapy was started and continued until day 4. Total parenteral nutrition (TPN) was initiated on day 2. On day 8, total bilirubin was 11.7 mg/dL (direct fraction: 1.1 mg/dL) and albumin was 2.0 g/dL (molar ratio: 0.67). On day 9 total bilirubin was 13.3 mg/dL, but phototherapy was not restarted at this time. Total bilirubin was 6.6 mg/dL (direct fraction: 4.7 mg/dL) on day 15. On day 23, total bilirubin was 15.4 mg/dL (direct fraction: 10.8 mg/dL), and the patient was diagnosed with TPN cholestasis and started on ursodiol.

The patient was discharged from the hospital at 114 days of age. Developmental delay was first noted at 6 months of age, and examination at 11 months showed marked delay and hypotonia. Auditory brainstem responses at 16 months showed no measurable waveforms. The patient was subsequently treated with botulinum toxin injections and baclofen in a cerebral palsy clinic, where it was felt that her symptoms were far out of proportion to the pathology seen on early imaging. Encephalopathy caused by kernicterus was not suspected.

The patient was referred to a movement-disorder clinic at 6 years of age, and examination showed spasticity, dystonia, ballismus, and abnormalities of vertical gaze. We scheduled an MRI and performed metabolic testing on her CSF during the same sedation. MRI showed bright T2 signal and volume loss in globus pallidus interna (Fig 1) and extension of abnormal signal into midbrain seen on T2, proton density, and fluid-attenuated inversion-recovery sequences. In retrospect, we reviewed the MRI from day of life 25, which shows subtle hyperintensity in the globus pallidus in T1 but not T2 sequences, as has been described recently.9 The CSF showed a decreased level of the dopamine metabolite homovanillic acid of 199 nmol/L (normal range: 218–852 nmol/L). Levels of the CSF neurotransmitter metabolites 5-hydroxyindoleacetic acid and 3-O-methyldopa were within the normal range for age. Currently the patient is 7 years old with severe global impairment, dystonia, athetosis, ballism, upward gaze palsy, and sensorineural hearing loss (see Video 1 , which is published as supporting information on www.pediatrics.org/content/full/116/5/1226).


Figure 1
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  		Fig 1. T2-weighted axial MRI scan showing increased signal and volume loss in the bilateral globus pallidus interna. There was also subtle signal change in the midbrain.

 

Figure 1
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  		Video 1. Chronic bilirubin encephalopathy in a 7-year-old, former 29-weeks’ gestation premature infant. Note opisthotonus, ballism, and dystonia.

 
Patient 2
Patient 2 is a female born by spontaneous vaginal delivery at 38 weeks' gestation with a birth weight of 3033 g. Early history and radiologic findings were described previously.11 Apgar scores were 9 at 1 and 5 minutes. She was discharged from the hospital on day 2 of life with a bilirubin level of 12 mg/dL. Over the next several days, her parents noted progressive lethargy, arching of the back, decreased stooling, and decreased breastfeeding. Outpatient bilirubin levels tested during this time were repeatedly "normal." On day 10, she presented to the Cincinnati Children's Hospital Medical Center with the symptoms noted above and severe jaundice. Her bilirubin level at that time was 49.4 mg/dL (direct fraction: 5.7 mg/dL). Two double-volume exchange transfusions reduced the bilirubin level to 13.6 mg/dL. Evaluation for the cause of the hyperbilirubinemia was inconclusive. No hemolytic disorder was identified. A brain MRI and ophthalmologic examination were nondiagnostic. Auditory brainstem responses were evaluated and were consistent with severe hearing loss or severe brainstem pathology. The patient was discharged from the hospital on day of life 20.

An MRI at 12 months of age showed abnormally high signal and volume loss on T2 in the medial globus pallidus bilaterally (Fig 2). The patient was initially hypotonic but developed choreiform or athetoid movements during the first 2 years of life. She has profound deficits in all developmental spheres and requires total care; she has no language. At the age of 8 she was admitted for intestinal pseudo-obstruction and sepsis and developed complex partial seizures, for which she was treated with valproic acid.


Figure 2
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  		Fig 2. T2-weighted axial MRI showing increased signal and volume loss in the bilateral globus pallidus interna.

 
At the age of 10 she was referred to a movement-disorder clinic for progressive truncal and oromandibular dystonia. Treatment with trihexyphenidyl 16 mg per day led to marked reduction in oromandibular dystonia, truncal dystonia, and limb dyskinesias (see the last segment of Video 2 , which is published as supporting information on www.pediatrics.org/content/full/116/5/1227 ). At the age of 12 she developed thrombocytopenia, anemia, and intestinal pseudo-obstruction leading to dependence on TPN. Discontinuation of trihexyphenidyl did not improve bowel function but led to severe dyskinesias that resolved with resumption of treatment. During this time, she has also had multiple pneumonias and progressive cerebral atrophy of unclear cause, possibly related to sleep apnea or chronic hypoxia. Anemia resolved after the valproic acid was discontinued.


Figure 2
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  		Video 2. Chronic bilirubin encephalopathy in a 12-year-old, former term infant. Initial segments show oromandibular dystonia and limb dyskinesias before treatment with trihexyphenidyl, which improved markedly with treatment and are not seen in the final segment.

 
CSF, obtained during another procedure, showed normal levels of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-O-methyldopa at the age of 11. The patient is currently 13 years old with mildly increased, rigid tone, no language, and no meaningful use of her limbs. She remains partially dependent on TPN.


   DISCUSSION
TOP
 ABSTRACT
 CASE REPORTS
 DISCUSSION
REFERENCES
 
It has been speculated, based on postmortem findings, that chronic bilirubin encephalopathy could occur in premature infants in the absence of marked hyperbilirubinemia,12 but the classic syndrome of extrapyramidal movement abnormalities, hearing loss, and vertical gaze abnormalities had not been described until recently, when 7 cases were reported8–10 with total peak serum bilirubin levels ranging from 8.8 to 14.7 mg/dL. We report an additional case and, in addition, provide the first report of CSF neurotransmitter measurements. The mild reduction in the dopamine metabolite homovanillic acid suggests the possibility of some slight damage to substantia nigra pars compacta not seen in term kernicterus.

Chronic bilirubin encephalopathy in the absence of marked hyperbilirubinemia in former preterm infants may be underdiagnosed for several reasons. First, neurologic signs associated with acute kernicterus in term infants, including lethargy, opisthotonus, and high-pitched cry,13–15 appear less frequently16 or may be difficult to detect in sick neonates. Second, during later childhood, dystonia may go unrecognized because of concomitant spasticity or may be misdiagnosed. Third, the MRI findings are subtle, particularly in the newborn period,9 and may be overlooked. As a result, as our case demonstrates, clinicians may not think of this rare diagnosis.

Kernicterus is a pathologic diagnosis consisting of yellow staining of brainstem nuclei accompanied by neuronal damage, particularly in globus pallidus, subthalamic nucleus, hippocampus, substantia nigra pars reticulata, and cranial nerve and deep cerebellar nuclei.17 In the appropriate clinical setting, the diagnosis of bilirubin brain injury can be inferred both clinically and by MRI.

Both preterm6,18–20 and term infants with high bilirubin levels may develop chronic auditory abnormalities, choreoathetosis, ballismus, and limitation of upward gaze. MRI of patients with chronic bilirubin encephalopathy shows hyperintensity in bilateral globus pallidus plus or minus subthalamic nucleus on T2-weighted imaging.9,10 Selective involvement of the globus pallidus is fairly specific, although there are reports of isolated globus pallidus changes in methylmalonic aciduria.21 Both of our patients seem to exhibit the classic neurologic signs and MRI findings of chronic bilirubin encephalopathy. The former preterm patient, with more ballismus and low dopamine metabolite levels, may have more subthalamic nucleus or midbrain involvement.

Although bilirubin encephalopathy is now rare in the United States because of guidelines for the use of phototherapy and exchange transfusions and the use of Rhogam to prevent hemolytic disease of the newborn, a number of cases in infants of >34 weeks' gestation have been reported in the past decade. Additional risk factors other than environmental exposure to bilirubin have been proposed to exist, because many studies have shown that it is difficult to predict by peak total serum bilirubin alone which infants will go on to develop these sequelae.4–7

It has been hypothesized that premature infants are more susceptible to chronic brain injury from lower bilirubin levels,22 perhaps because of other factors that occur more often in sick premature infants than in term infants. These factors include hypoxia, acidosis, asphyxia, hypothermia, hypercarbia, sepsis, and intraventricular hemorrhage,23 which may allow bilirubin to enter and injure the brain at fairly low levels. Therefore, the standard interventions of phototherapy and exchange transfusion are based on lower levels of total bilirubin in the presence of prematurity, low birth weight, and risk factors such as low Apgar scores, low pH, and clinical deterioration.24

The use of total bilirubin levels to guide intervention is convenient, but other measures may be more physiologically relevant. The fraction of bilirubin not bound to albumin (free bilirubin) can cross the intact blood-brain barrier and cause neuronal damage,25 and bilirubin bound to albumin can enter the brain when the blood-brain barrier is disrupted. There has been much interest in using such measures as the free bilirubin level, bilirubin-binding capacity of albumin, and bilirubin/albumin molar ratio to better predict how much of the total bilirubin is available to enter and damage the brain.26–29 A bilirubin/albumin molar ratio of >0.5 has been suggested as a threshold for decision-making in sick preterm infants.9 The premature infant we describe had a bilirubin/albumin molar ratio of 0.67, consistent with this suggested threshold.

In the former premature infant, had we known that the MRI would show pallidal injury, we would not have measured CSF neurotransmitters levels. The low homovanillic acid level raises the question of partial toxic or ischemic damage to substantia nigra pars compacta, reducing dopamine synthesis. In contrast, the former term infant was subsequently found to have normal-for-age dopamine metabolites in her CSF, consistent with postmortem studies showing damage to substantia nigra pars reticulate, not pars compacta.30 It is possible that the selective susceptibility in midbrain to neuronal injury differs in premature versus term infants.

Symptomatic treatment of these children has been helpful but largely unsatisfactory, because both children require total care. For the premature case, the most effective intervention has probably been botulinum toxin. Dopaminergic medication did not help, possibly because the pallidal lesions are "downstream" from the dopaminergic projections to striatum. The former term patient has experienced clear reduction in oromandibular and neck dystonia and limb athetosis on trihexyphenidyl, an anticholinergic drug that can be useful for pediatric or adult dystonia.31,32

These 2 severe cases demonstrate that clinicians need to be vigilant about treating elevated bilirubin levels in infants, perhaps by using bilirubin/albumin molar ratios in addition to total bilirubin levels in premature infants.33 Pediatricians should be aware that survivors of prematurity with dystonia, hearing loss, or gaze abnormalities may in fact have undiagnosed bilirubin encephalopathy, because early MRI may fail to show the classic findings of globus pallidus scarring. Additional studies for prevention and treatment of long-term complications of neurotoxicity of bilirubin are needed.


   ACKNOWLEDGMENTS
 
We thank Rebecca Ichord, MD, and Marya Strand, MD, for helpful comments.


   FOOTNOTES
 
Accepted Feb 4, 2005.

Address correspondence to Donald L. Gilbert, MD, Division of Neurology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229–3039. E-mail: donald.gilbert{at}cchmc.org

No conflict of interest declared.

Dr Merhar’s current address is: Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, OH 45229-3039.


   REFERENCES
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 ABSTRACT
 CASE REPORTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

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