Neurologic Perspectives of Crigler-Najjar Syndrome Type I

Shevell, Michael; Majnemer, Annette; Schiff, David

doi:10.1177/088307389801300605

Cited by 16 publications

(10 citation statements)

References 42 publications

(4 reference statements)

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“…In conclusion, 67 years following its discovery, Crigler‐Najjar syndrome remains a morbid and potentially fatal disorder (Table ) . In developed nations, brain injury occurs in 18%‐26% of patients with Crigler‐Najjar, a figure that has remained essentially unchanged during the last 2 decades.…”

Section: Discussionmentioning

confidence: 99%

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

et al. 2020

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Background and Aims We describe the pathophysiology, treatment, and outcome of Crigler‐Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient‐years. Approach and Results Unbound (“free”) bilirubin (Bf) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT) to albumin (A) and validate their molar concentration ratio (BT/A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT/A at least 30% below intravascular BT binding capacity (i.e., BT/A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (Lf) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to BT (R2 = 0.71) and BT/A (R2 = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin–albumin equilibrium association binding constant (R2 = 0.69), which varied 10‐fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak BT ≥ 30 mg/dL and BT/A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5‐fold. Consistent phototherapy with 33‐103 µW/cm2•nm for 9.2 ± 1.1 hours/day kept BT and BT/A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. Conclusion Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.

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Section: Discussionmentioning

confidence: 99%

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

et al. 2020

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“…Crigler and Najjar's classic description preceded the advent of effective phototherapy, and all of their patients developed brain injury and eventually died [19]. The combined data from four recent surveys [37,[52][53][54] suggest that 23-42% of CND patients suffer neurological injury ranging from mild to severe, 28-50% of patients will need one or multiple exchange transfusions, and 9-38% die of complications related to the disease. In contrast, we had no brain injuries or deaths extending over 200 patient-years and did not perform a single exchange procedure since we began caring for children with CND in 1989.…”

Section: Diagnosis and Management Of Cnd In The Newborn Periodmentioning

confidence: 98%

Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease

et al. 2006

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We summarize the treatment of 20 patients with Crigler-Najjar disease (CND) managed at one center from 1989 to 2005 (200 patient-years). Diagnosis was confirmed by sequencing the UGTA1A gene. Nineteen patients had a severe (type 1) phenotype. Major treatment goals were to maintain the bilirubin to albumin concentration ratio at <0.5 in neonates and <0.7 in older children and adults, to avoid drugs known to displace bilirubin from albumin, and to manage temporary exacerbations of hyperbilirubinemia caused by illness or gallstones. A variety of phototherapy systems provided high irradiance over a large body surface. Mean total bilirubin for the group was 16+/-5 mg/dl and increased with age by approximately 0.8 mg/dl per year. The molar ratio of bilirubin to albumin ranged from 0.17 to 0.75 (mean: 0.44). The overall non-surgical hospitalization rate was 0.12 hospitalizations per patient per year; one-half of these were for neonatal hyperbilirubinemia and the remainder were for infectious illnesses. Ten patients (50%) underwent elective laproscopic cholecystectomy for cholelithiasis. No patient required invasive bilirubin removal or developed bilirubin-induced neurological damage under our care. Visual acuity and color discrimination did not differ between CND patients and age-matched sibling controls. Four patients treated with orthotopic liver transplantation were effectively cured of CND, although one suffered significant transplant-related complications.Conclusions. While patients await liver transplantation for CND, hyperbilirubinemia can be managed safely and effectively to prevent kernicterus. Lessons learned from CND can be applied to screening and therapy of non-hemolytic jaundice in otherwise healthy newborns.

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“…One major point is the best age to transplant CN patients and appropriate timing of the procedure before irreversible neurological damage occurs which also remains an unresolved issue [20,24] . In fact, the literature shows the possibility of a sudden severe clinical neurological damage consisting in cognitive decline, pyramidal, extrapyramidal and cerebellar dysfunction in untreated type I CN patients [12,18,22] , and death or lesions due to kernicterus in severe type II CN patients [3,4,7,8] . All four CN I patients had unremitting very high serum bilirubin values and bilirubin / albumin molar ratios which required continuous intensive phototherapy from the fi rst months of life.…”

Section: Resultsmentioning

confidence: 99%

Clinical Utility of Electrophysiological Evaluation in Crigler-Najjar Syndrome

Perretti

Crispino²,

Marcantonio³

et al. 2007

Neuropediatrics

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We evaluated the neurological and neurophysiological features in ten patients with genetically characterized Crigler-Najjar (CN) syndrome: four with typical type I CN had undergone orthotopic liver transplantation (OLT); six had type II CN, and three of them developed severe hyperbilirubinemia with a limited response to phenobarbital leading to an intermediate phenotype I/II. Clinical neurological and multimodal electrophysiological evaluations [electroencephalogram (EEG), visual (VEPs), motor (MEPs) and brainstem auditory (BAEPs) evoked potentials] were performed. Neurological examinations showed mild hand tremor in four patients (one pre-OLT and one post-OLT type I, two type I/II). EEG revealed high voltage paroxysmal discharges in four patients (three type I/II, and one type I with a marked improvement after OLT). VEPs showed P100 wave increased latency in five patients (three type I, and two type I/II considered for OLT evaluation). MEPs showed prolonged central motor conduction time in five patients (two type I; one type I/II; two type II). Only EEG and VEPs findings showed a correlation with high bilirubin levels. BAEPs were normal. In conclusion, VEPs and EEG contribute to identify and monitor bilirubin neurotoxic effects, and may play a decisional role in some cases of severe hyperbilirubinemia without overt neurologic damage.

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Neurologic Perspectives of Crigler-Najjar Syndrome Type I

Cited by 16 publications

References 42 publications

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease

Clinical Utility of Electrophysiological Evaluation in Crigler-Najjar Syndrome

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