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Inborn errors of metabolism (IEM) are individually rare but collectively common disorders, occurring in 1:800 to 1:1000 births. There are more than 1000 known inherited disorders characterized by disruption of metabolic pathways which may present with diverse symptoms affecting any organ at any age, including with psychiatric symptoms mimicking primary psychiatric disorders. This review is intended to help psychiatrists and other physicians suspect an inborn error of metabolism in a patient presenting with psychiatric symptoms. A comprehensive literature review was undertaken, using Index Medicus and resources at the University of Southern California Norris Medical Library to identify specific information for each individual disorder described. Those inborn errors of metabolism most likely to present with psychiatric symptoms primarily impact the brain, acting either directly on biochemical pathways in the central nervous system or indirectly reflecting dysfunction in other organs. Symptoms may occur episodically under stress when metabolic demands are highest or progressively evolve over time reflecting gradual neuropsychiatric deterioration. Cognitive impairment and psychosis appear to be the most frequently reported psychiatric problems. Noting age of onset, patterns of psychiatric presentation, and associated symptoms in other organ systems can increase suspicion and facilitate diagnosis of psychiatric symptoms due to an inborn error of metabolism. Psychiatric problems can be seen with multiple inborn errors of metabolism with associated systemic dysfunction or as isolated symptoms. It is important for physicians to be aware of clues that might increase suspicion of an underlying genetic disorder, and to recognize that consultation with a medical geneticist is recommended for diagnosis and to provide the patient optimal care in either situation.

Background The management of psychiatric disorders in neurological diseases (PDND) creates special challenges that cannot be adequately addressed by either psychiatry or neurology alone. However, the literature on clinician-friendly recommendations on how to coordinate neurological and psychiatric care is limited. Objective This narrative review will provide practical instructions on how to efficiently integrate psychiatric and neurological care in inpatient management of PDND. Methods We reviewed articles published as recently as January, 2021 in five electronic databases. We included articles that assessed human care, focused on adults, and examined how to better coordinate care between different medical specialties, particularly, between psychiatry and neurology. Results Eighty-four manuscripts were included in this review, of which 23 (27%) discussed general principles of well-coordinated care of PDND in inpatient settings (first part of this review), and 61 (73%) were used to provide recommendations in specific neurological diseases (second part of this review). Conclusions General principles of well-coordinated care of PDND include recommendations for both the primary team (usually neurology) and the consulting team (psychiatry). Primary teams should delineate a specific question, establish roles, and follow up on the recommendations of the consulting team. Consultants should do their independent assessment, be organized and specific in their recommendations, and anticipate potential problems. One of the most important aspect to develop well-coordinated care is the establishment of clear, frank and, preferably oral, communication between the teams. Practical difficulties in the management of PDND include pharmacodynamic and pharmacokinetic interactions as well as mutual dependency between psychiatry and neurology.

Delirium is a neuropsychiatric disorder characterized by acute disturbances in attention, consciousness, cognitive processing, perception, and the sleep-wake cycle. The few studies investigating treatment of delirium in critically ill children and adolescents have used differing diagnostic criteria, and have not employed control groups or procedures to blind observations. The objective of this study was to examine the efficacy of olanzapine for the treatment of delirium in the pediatric intensive care unit (ICU) using methodological procedures to reduce bias and allow greater generalization. Psychiatric records of 59 patients admitted to the pediatric ICU or cardiothoracic ICU over a 4 yr period with the diagnosis of delirium were examined. The delirium rating scale was used to assess delirium severity at the time of initial psychiatric evaluation and five days later. Raters were blinded to medication administration. Patients who were diagnosed with delirium, but did not receive olanzapine, or any other antipsychotic medication, served as the control group. Greater improvement of delirium symptoms was found for the olanzapine group (n = 31) than the control group (n = 28) (F ((1,40)) = 4.86, r = 0.33, 95% confidence interval = 0.020–0.58). This finding remained statistically significant after controlling for initial delirium severity (F ((1, 20)) = 28.62, r = 0.77, 95% confidence interval = 0.50–0.90). This study demonstrates patients with delirium administered olanzapine had greater reduction of delirium symptom severity than controls. It supplements the existing literature by using a study design that reduces expectancy effects and allows examination of the natural history of delirium symptoms without medication administration.

This review seeks to provide an update on the diagnosis, management, and outcome of pediatric delirium. Care of patients with delirium depends on correct diagnosis and treatment of its underlying cause. A variety of instruments are available to aid diagnosis. Management of delirium currently depends on atypical antipsychotics, while avoiding agents that may precipitate or exacerbate it. While most critically ill children survive delirium, many children die or have worsening function after their illness. The longer the duration of delirium, the more severe its subsequent problems including postintensive care syndrome and posttraumatic stress disorder. Possible serious long-term consequences emphasize the importance of efforts to improve diagnosis and outcome in critically ill children suffering from delirium.

Delirium describes a syndrome of acute brain dysfunction with severe consequences on patient outcomes, medical cost, morbidity, and mortality. It represents a final common pathway of numerous pathophysiologic disturbances disrupting cerebral homeostasis. The diagnosis is predicated on recognition of the clinical features of the syndrome through ongoing clinical assessment. Early identification can be aided by routine screening, particularly in high-risk populations. Evaluation and management are continuous and simultaneous processes involving a multidisciplinary care team including child psychiatry consultation. Prevention, early identification and management are critical in alleviating symptoms, improving outcomes, and reducing distress for patients, families, and care teams. This review highlights our current understanding regarding pediatric delirium, its mechanisms, clinical manifestations, detection and management.

Delirium is a serious and common problem in severely medically ill patients of all ages. It has been less addressed in children and adolescents. Treatment of delirium is predicated on addressing its underlying cause. The management of its symptoms depends on the off-label use of antipsychotics, while avoiding agents that precipitate or worsen delirium. Olanzapine, quetiapine, and risperidone are presently considered first-line drugs, usually replacing haloperidol. Other agents have shown promise, including melatonin to address the sleep disturbance characteristic of delirium, and dexmedetomidine, an α2-agonist, that may facilitate lower doses of benzodiazepines and opioids that may worsen delirium.

Atypical antipsychotics have been documented to be effective in the management of delirium in adults and older children, but despite considerable need, their use has been less studied in the very young. A retrospective chart review was undertaken to describe the use of atypical antipsychotics in controlling symptoms of delirium in infants and toddlers.All psychiatric inpatient consultations performed during a 3 year period were reviewed to identify children36 months old diagnosed with delirium. Delirium Rating Scale (DRS) scores were retrospectively calculated when the antipsychotic was initiated and discontinued, to confirm the diagnosis of delirium and evaluate symptom severity, and then to assess symptom response to pharmacologic intervention.There were 10 boys and 9 girls in the study population (ages 7-30 months, mean 20.5 months). Olanzapine (n=16) and risperidone (n=3) were used, and length of treatment and response were comparable for both medications. Mean DRS scores decreased significantly (p0.001) with antipsychotic administration, without significant adverse side effects.Although randomized placebo controlled studies are needed to better characterize the indications, risks, and benefits, these atypical antipsychotic medications appeared to be effective and safe for managing delirium symptoms in very young pediatric patients.

Atypical antipsychotics have been documented to be effective in the management of delirium in adults, but despite considerable need, their use has been less studied in pediatric patients.A retrospective chart review was done to describe the use of atypical antipsychotics in controlling symptoms of delirium in children and adolescents.Pharmacy records at Children's Hospital Los Angeles were reviewed to identify patients to whom antipsychotic agents were dispensed over a 24-month period. Psychiatric inpatient consultations during the same 24-month period were reviewed. Patients 1-18 years old diagnosed with delirium given antipsychotics constituted the study population. Delirium Rating Scale-Revised-98 (DRS-R98) scores were retrospectively calculated, when possible, at time antipsychotic was started to confirm the initial diagnosis of delirium and evaluate symptom severity, and again when antipsychotic was stopped, to assess symptom response.Olanzapine (n=78), risperidone (n=13), and quetiapine (n=19) were used during the 2 years of the study. Mean patient age, length of treatment, and response were comparable for the three medications. For patients with two DRS-R98 scores available (n=75/110), mean DRS-R98 scores decreased significantly (p0.001) with antipsychotic without significant adverse side effects.Although randomized placebo-controlled studies are needed, atypical antipsychotic medications appeared to be effective and safe for managing delirium symptoms in pediatric patients while underlying etiology was addressed.

The posterior fossa syndrome (PFS) is common after cerebellar tumor resection in pediatric patients. It is characterized by postoperative mutism and ataxia and associated with persistent abnormalities in mood and cognition. Method: A 2-year prospective study of children and adolescents with cerebellar tumors identified by neuroimaging was performed at the Children’s Hospital Los Angeles. Results: There were 8 girls and 14 boys in the study, aged 14 months to 17 years. The tumor sizes ranged from 2 to 6.5 cm in diameter. The patients presented with ataxia, headache, vomiting, depressed or irritable mood and inattention. Symptoms of PFS were present postoperatively in all except for the 2 patients with lateral tumors. The symptoms began before resection, were most prominent immediately after surgery, and improved over time. Neuropsychological assessment of 10 patients documented a persistent cognitive decrement. Conclusion: This small, descriptive study provides information on the natural history of pediatric posterior fossa tumors from before surgery through the postoperative period.

With the advent of new treatments for pediatric disorders, more chronically ill children and adolescents are surviving into adulthood than ever before. This article is aimed at helping psychiatric consultants understand how medical, developmental, and psychosocial needs are altered in adults who have grown up chronically ill as children. Congenital heart disease, cystic fibrosis, and rheumatologic disorders are discussed in detail as models to illustrate the impact of congenital malformations, genetic disorders, and typically adult disorders occurring in the pediatric age group.

Survivors of pediatric intracranial malignancies are at recognized high risk for neurocognitive and psychosocial dysfunction, endocrinopathies, growth abnormalities, and second neoplasms. The late onset of persistent psychosis may represent an additional serious psychiatric consequence of childhood intracranial malignancies. The authors report eight survivors of pediatric intracranial malignancies whose course was complicated by the delayed onset of hallucinations, delusions, and bizarre behavior 2 to 12 years after diagnosis and treatment of brain tumors. The purpose of this report is to alert others to the generally unrecognized risk of psychosis following the treatment of brain tumors in children and adolescents.

Delirium is presumed to be the same syndrome in all ages. Comparing pediatric and adult studies, the authors found many of the same symptoms reported, but often at significantly different rates. Sleep-wake disturbance, fluctuating symptoms, impaired attention, irritability, agitation, affective lability, and confusion were more often noted in children; impaired memory, depressed mood, speech disturbance, delusions, and paranoia, more often in adults; impaired alertness, apathy, anxiety, disorientation, and hallucination occurrence were similar. These may represent true differences in the presentation of delirium across the life-cycle, or may be attributable to inconsistent methodologies. Prospective studies are needed to resolve this question.

While the cerebellum is not traditionally thought of as having an important role in respiratory control, breathing involves cyclic motor acts that require cerebellar coordination. We postulate that children with partial cerebellar resections have disordered respiratory control due to altered synchronization of ventilatory muscles. We reviewed the records of 36 children following partial cerebellar resections due to neoplasms confined to the cerebellum. P values were elevated in 19% of patients. Six patients had apneic or bradypneic events documented within the first month after resection. Two patients required intubation with assisted ventilation, and one needed assisted ventilation for 7.3 weeks. Those with apnea had lower oxygen saturations, and a longer need for supplemental oxygen. Patients with apnea were older than those without apnea. Swallowing, which uses many of the same muscles as those needed to maintain upper airway patency, was dysfunctional in 50% of those with apneas. We conclude that children with cerebellar resections have an increased incidence of apnea, hypoventilation, and hypoxemia not otherwise explained by pulmonary disease, and some require prolonged assisted ventilation. We speculate that these abnormalities are manifestations of altered respiratory control caused by dysfunctional cerebellar coordination of ventilatory muscles. © 2005 Wiley-Liss, Inc.

Rarely reported in pediatric patients, the characteristic symptoms and course of delirium are well known in adults. This retrospective study was undertaken to describe the clinical presentation, symptoms, and outcome of delirium in children and adolescents. Eighty-four patients age 6 months to 18 years were identified with delirium, from 1,027 consecutive psychiatric consultations during a 4-year period. Mortality was high (20%), and length of stay was prolonged. Symptoms of psychosis and disorientation were less characteristic, but overall the presentation and course of delirium were similar to adults, and the current Diagnostic and Standard Manual of Mental Disorders (DSM) criteria were found applicable in the pediatric population.

The study of delirium has been neglected in pediatric patients, and there are no diagnostic criteria or rating scales adapted for use in this age group. The Delirium Rating Scale is widely used to diagnose and rate the severity of delirium in adults. It was retrospectively administered to 84 children and adolescents diagnosed with delirium to evaluate its applicability in pediatric patients. Delirium Rating Scale scores were comparable to those reported for delirium in adults, although single cross-sectional Delirium Rating Scale scores did not predict length of hospital stay or mortality outcome. Therefore, the Delirium Rating Scale can be used to evaluate delirium in the pediatric population.

Objective. Opsoclonus-ataxia, also called “dancing eye syndrome,” is a serious neurologic condition that is often a paraneoplastic manifestation of occult neuroblastoma in early childhood. Despite resection of tumor and immunosuppressive therapy, outcome generally includes significant developmental and behavioral sequelae. There is controversy about how treatment alters outcome. The goals of this study were to understand the ongoing neurologic and developmental deficits of children who are treated for opsoclonus-ataxia with associated neuroblastoma; to relate treatment history to outcome; and to quantify objectively the acute changes in motor function, speech, mood, and behavior related to intravenous immunoglobulin (IVIg) treatment. Methods. Patients were children with opsoclonus-ataxia caused by neuroblastoma, regardless of interval since diagnosis. Records were reviewed, and children underwent comprehensive evaluations, including neurologic examination and tests of cognitive and adaptive function, speech and language, and fine and gross motor abilities. Psychiatric interview and questionnaires were used to assess current and previous behavior. In 6 children, a videotaped standardized examination of eye movements was performed. Additional examinations were performed immediately before and 2 to 3 days after treatment with IVIg in 5 children. Results. Seventeen children, ages 1.75 to 12.62 years, were examined. All had a stage I or II neuroblastoma resected 3 months to 11 years previously. None received any other treatment for the tumor. All but 1 had received at least 1 year of either oral corticosteroids or corticotropin (ACTH); 12 had received 1 or more courses of IVIg, 2 g/kg. Three had received other immunosuppressive treatment, including cyclophosphamide. Cognitive development and adaptive behavior were delayed or abnormal in nearly all children. Expressive language was more impaired than receptive language. Speech was impaired, including both intelligibility and overall output. Fine and gross motor abilities were impaired. Increased age was strikingly associated with lower scores in all areas. Behavioral problems early in the course included severe irritability and inconsolability in all; later, oppositional behavior and sleep disorders were reported. Opsoclonus abated in all, but abnormalities in pursuit eye movements were found in all 6 children cooperative with standardized examination. Outcome did not differ in children who were treated with ACTH versus oral steroids. Three children who had received cyclophosphamide fared poorly. Immediate versus delayed treatment was not associated with better outcome. IVIg improved both gross and fine motor and speech function acutely, but we could not confirm long-term benefit of IVIg. Total number of courses of IVIg was not associated with outcome. Conclusions. Opsoclonus-ataxia caused by neuroblastoma causes substantial developmental sequelae that are not adequately prevented by current treatment. The increased deficits in older children raise concern that this represents a progressive encephalopathy rather than a time-limited single insult. Although the study is cross-sectional and neither randomized nor blinded, we were unable to confirm a purported advantage of either ACTH over corticosteroids or of cyclophosphamide. A randomized study is needed but is difficult for this rare condition.

Objective To describe the psychiatric presentation, serologic findings, and neuroimaging patterns in children and adolescents with central nervous system involvement with systemic lupus erythematosus (CNS-SLE). Method Pediatric patients with psychiatric symptoms who fulfilled the 1997 revised diagnostic American College of Rheumatology criteria for SLE were studied. Complement levels, and anti-double-stranded DNA, anti-Smith, anti-phospholipid, and anti-neuronal antibodies were evaluated. Computed tomography, magnetic resonance imaging, and single photon emission computed tomography (SPECT) neuroimaging studies were reviewed. Results The 10 patients with CNS-SLE presented with psychosis, mood disturbance, or confusion, and 8 patients had concomitant neurologic symptoms. The 8 girls and 2 boys ranged in age from 7.5 to 17 years. Serum anti-neuronal antibodies were positive with onset of symptoms and declined with improvement. Initial SPECT was abnormal in all 10 patients and remained abnormal. Conclusion SPECT and anti-neuronal antibodies help confirm CNS involvement in patients with SLE and neuropsychiatric symptoms.

Delirium is an acute neuropsychiatric syndrome reflecting serious cerebral dysfunction. The characteristic core symptoms of delirium include the inability to direct, focus, sustain, and shift attention; abnormalities of the sleep-wake cycle; impaired consciousness and awareness; disturbance of thought processes; and behavioral dyscontrol. Delirium is particularly prevalent in critically ill and post-operative patients in the intensive care unit, and may result from hypoxia or infection. It is most likely in the most severely ill, and length of stay is prolonged, and morbidity and mortality and higher with delirium. A variety of clinical instruments have been developed to facilitate the diagnosis of delirium. The Delirium Rating Scale, and its 1998 revision (DRS and DRS-R98) are for psychiatrists to use and are based on DSM criteria. The Pediatric Confusion Assessment Method, adapted for pediatric patients in the ICU (pCAM-ICU), is designed for non-psychiatrists and nurses in the intensive care unit. The Pediatric Anesthesia Emergence Delirium scale (PAED) is the basis for the Cornell Assessment of Pediatric Delirium (CAP-D), and both are for nurses and doctors in the pediatric ICU to use to identify delirium in their patients. Delirium is typically multifactorial and its pathogenesis reflects neurotransmitter changes associated with metabolic and inflammatory processes. Benzodiazepines and anticholinergic drugs, including opioids and antihistamines, are widely used in the pediatric ICU and may precipitate or exacerbate delirium. Benzodiazepines especially are best used sparingly, in the lowest dose possible, if at all. The treatment of delirium is predicated on detecting and addressing its underlying cause, which usually results in its rapid resolution. Environmental interventions may ameliorate the risk for delirium, and drugs which may precipitate or worsen delirium should be avoided. Antipsychotics can provide benefit in managing agitation, perceptual disturbances, sleep-wake cycle abnormalities, and behavioral dyscontrol. Atypical antipsychotics, including olanzapine, risperidone, and quetiapine, have largely replaced haloperidol in newer approaches to management because of lower risk for adverse side effects. The risk for delirium may be mitigated by vigilance, and awareness of its presentation, pathogenesis, and management. Its prevention will be of significant benefit in reducing morbidity, improving outcome, and providing comfort to these very ill and fragile children.

Opsoclonus-myoclonus ataxia syndrome is a paraneoplastic syndrome of cerebellar damage associated with neuroblastoma. The authors assessed psychiatric symptoms of opsoclonus-myoclonus ataxia syndrome in 17 children, who were 16 months to 12(1/2) years of age. Psychiatric symptoms examined included disruptive behavior, affective dysregulation, irritability, impulsivity, cognitive impairment, and poor attention.

Congenital central hypoventilation syndrome (CCHS) is a rare disorder where there is failure of automatic control of breathing. With improved recognition of CCHS, more children are appropriately diagnosed and treated in infancy, allowing survival into adult years. Because most of these children are able to participate in regular school, they are exposed to common adolescent behaviors, such as abusing alcohol and drugs. Alcohol and many illicit substances are known respiratory depressants. We report on 3 cases of adolescents/young adults with CCHS who had severe adverse events related to alcohol, including coma and death. This series illustrates the dangers of alcohol abuse in CCHS. We speculate that adolescents with CCHS may be less able to perceive the risks of substance abuse and impulsive behavior, leading to increased morbidity and mortality. Patients with CCHS appear to lack anxiety and the awareness that their inability to perceive physiologically dangerous levels of hypercarbia and hypoxia deprives them of important protective mechanisms.

The objective of this article is to describe a case of recurrent delirium after cardiac surgery in an infant.Case report. The institutional review board at Children's Hospital Los Angeles waived the need for informed consent.Cardiothoracic intensive care unit in a freestanding children's hospital.A male infant with hypoplastic left heart syndrome who developed delirium on consecutive admissions to the cardiothoracic intensive care unit after cardiac surgery.Pharmacologic intervention using the atypical antipsychotic olanzapine.The symptoms of delirium resolved with the initiation and continuation of olanzapine on both occasions.Delirium is a common, but often unrecognized, diagnosis in the intensive care unit. Its early recognition and treatment may prevent unnecessary use of narcotics and benzodiazepines, decrease length of stay and may improve long-term neurocognitive function. This case report describes an infant who developed discrete, consecutive episodes of delirium following surgery for congenital heart disease. Both episodes were treated effectively with olanzapine.

The serotonin syndrome results when serotonergic activity increases to abnormally high levels. It occurs with selective serotonin reuptake inhibitors (SSRIs), opioids, and other serotonergic agents when the serotonin system has been modulated by another serotonergic agent or compromised by illness. Although the symptoms are quite variable, the syndrome is characterized by a triad of altered mental status, neuromuscular abnormalities, and autonomic dysfunction. The authors report the probable occurrence of the serotonin syndrome with serotonin receptor subtype 3 (5-HT 3 ) antagonist therapy when used to control nausea associated with chemotherapy in two seriously ill children. The first case involves combined use with mirtazapine and the second with fentanyl. These agents may pose a potential risk when used in such combination in seriously ill patients.

Evaluation of suspected alcohol withdrawal should start by obtaining a complete alcohol use history. Symptom-triggered treatment of alcohol withdrawal using assessment scales such as the Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar) is the preferred method. A score of less than ten indicates the need for continued monitoring of the patient. A score of 10 to 15 indicates mild withdrawal, 16 to 20 moderate withdrawal, and greater than 20 severe withdrawal. Sedative/hypnotic (benzodiazepine, barbiturate, and related drug) withdrawal is managed by the same principles used to treat alcohol withdrawal. The consultant may be called upon to assist in managing opioid withdrawal related to illicit use, problems with prescription analgesics, or ongoing opioid agonist therapy (OAT) for addiction. Federally accredited opioid treatment programs (OTPs) can administer methadone or buprenorphine for detoxification or maintenance as part of a comprehensive treatment program.

This article summarizes the autopsy findings in infants dying with hyperbilirubinemia. Changes in both the brain and viscera are described. The meaning of these findings is controversial and may represent either direct toxic effects of bilirubin or secondary bilirubin staining in areas already damaged by other causes.

Cerebellar mutism is a rare finding associated with resection of posterior fossa tumors or cerebellar hemorrhages. We reviewed the medical records of six children, aged 6 to 12 years, who developed cerebellar mutism after resection of a posterior fossa mass or as a result of posterior fossa trauma. From 1989 to 1994, 210 children underwent posterior fossa resection at our institution, and four developed mutism (an incidence of 1.6%). All four patients had primitive neuroectodermal tumors. The fifth patient experienced trauma, and another patient had an arteriovenous malformation (AVM). In four children, hydrocephalus developed as a result of their tumor or AVM. Four developed cerebellar mutism 24 to 48 hours after surgery or trauma, and one developed cerebellar mutism 5 days after surgery, coincident with hydrocephalus. In one, mutism occurred after a second resection was performed for a recurrence of his posterior fossa tumor. Cerebellar mutism lasted 10 days in one patient and 2 to 8 weeks in the other four. Dysarthria was apparent in four patients during the recovery phase. We suggest trauma to the dentate nucleus and/or its outflow tract, the superior cerebellar peduncle, as a cause of reversible mutism. Because posterior fossa tumors are common in children, mutism should be recognized as an important side effect of surgery.

Candida osteomyelitis of the spine and intervertebral disc developed in three patients without evidence of back trauma or overlying cutaneous infection. Two patients were prone to the development of disseminated candidlasis by the use of multiple antibiotics and other predisposing modalities following abdominal surgery. One patient had no identifiable cause for development of the infection. The diagnosis was established in all three cases by x-ray evidence of osteomyelitis and culture from needle aspirate. Two patients had bone scans consistent with infection. Each patient received different therapy. One was treated with amphotericin B, one with spinal fusion and 5-fluorocytosine, and one with no antifungal therapy. All patients had complete healing of the involved vertebrae. Candida organisms have the potential to cause destructive bone infection following hematogenous dissemination. The presence of Candida osteomyelitis may be helpful In diagnosing disseminated candidiasis.

In recent years kernicterus at autopsy has been observed in sick premature infants in the absence of markedly elevated levels of serum bilirubin. Potentiating factors have been suggested to explain kernicterus in such a setting. In order to establish which factors are associated with increased risk for kernicterus in these small babies, this retrospective matched control study was undertaken. Thirty-two infants with kernicterus at autopsy were matched for gestational age, birth weight, length of survival, and year of birth to 32 control infants without kernicterus. Multiple historical, clinical, and laboratory factors were compared, including therapy, sepsis, hypothermia, asphyxia as reflected by Apgar score, hematocrit, acidosis, hypercarbia, hypoxia, hypoglycemia, and hyperbilirubinemia. No statistically significant differences between the kernicteric and nonkernicteric infants were demonstrated for any of these factors, including peak total serum bilirubin levels. Multivariant analysis also failed to determine a group of factors associated with increased risk for kernicterus. It was not possible to separate those infants with and without kernicterus at autopsy on the basis of the clinical factors evaluated.

Kernicterus at autopsy, traditionally associated with hyperbilirubinemia, is now often observed in the absence of markedly elevated levels of serum bilirubin. Attempts to document clinically predictive risk factors for kernicterus have been largely unsuccessful in the current population of sick neonates. In a study of 32 pairs of newborns with and without kernicterus at autopsy and matched for gestational age, weight, length of survival, and year of birth, no differences were found when multiple clinical factors thought to potentiate risk for kernicterus were compared. Microscopic sections of brains from these same matched pairs were then evaluated without knowledge of the clinical or gross findings according to prearranged criteria. Statistical analysis of the microscopic findings was done, comparing each observed change in each anatomic site, all changes in each site, and each change in all sites. Although the gross pattern of staining followed that of classic kernicterus, the expected, specific histologic changes characteristic of kernicterus were found in only three patients. Spongy change, or edema, was significantly more common in the grossly stained brains (P

The author examines a number of disorders associated with nonimmune hydrops fetalis; included are hematologic, cardiovascular, pulmonary, renal, gastrointestinal, and hepatic disorders, congenital neoplasms, chromosomal disorders, heritable disorders, congenital infections, disorders of the placenta and cord, and gestational disorders.

Findings in a six-year-old boy with a virilizing tumor of the left testis are presented. His bone age was 14 years. Serum testosterone (5.9 nglml), urinary 17-ketosteroid (29 mg/24 hr), and pregnanetriol (14 mg/24 hr) excretion was elevated. These values were not suppressed after the administration of dexamethasone. Spermatic-peripheral vein concentration differences showed that the tumor secreted 17-hydroxy-pregnenolone, dehydroeplandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, estrone, estradiol, 11-desoxycortisol, and corticosterone. The tumor did not secrete cortisol. Electron microscopy study of the tumor revealed a dimorphic population of light and dark cells with many features seen in Leydig cell tumors. However, these were not distinct from those of adrenal rest tumors. Reinke crystalloids were not found. True precocious puberty developed five months after tumor removal, ie, the right testis increased in size, and serum gonadotropins increased. Seven months after tumor removal, the patient was demonstrated not to have impaired cortisol synthesis, ie, urinary 17-hydroxysteroids increased from 1.8 to 38.0 mg/24 hr In response to adrenocorticotropic hormone (ACTH) administration. The differential diagnosis of virilizing testicular tumors lies between Leydig cell adenoma and adrenal rest tumor in California congenital adrenal hyperplasla. The demonstration that the patient did not have Impaired cortisol synthesis is consistent with his tumor being a Leydig cell adenoma.

Many of the stresses contributing to brain injury in the intrapartum or neonatal period may also exist prenatally. To define this problem, we reviewed the clinical features and neuropathologic findings in 433 consecutive stillbirth autopsies. Twenty-five had evidence of periventricular/intraventricular hemorrhage or gliosis. Twenty infants had died in utero before active labor and five during delivery. Nine stillbirths were infected. Ten cases had periventricular/intraventricular hemorrhage alone, five had the hemorrhage with parenchymal hemorrhage, five had parenchymal hemorrhage only, and five had gliosis. This group of 25 cases establishes that intrauterine brain injury is not rare. Separation of antepartum events occurring in utero from those imposed during labor, delivery, resuscitation, and the neonatal period is very important and has significant medical and legal implications.

Pseudomonads are common causes of nosocomial infections but are rarely implicated in perinatal disease. In a retrospective autopsy study we found that 9% of all acute congenital bacterial infections were due to Pseudomonas species. Premature rupture of membranes occurred in half the cases and clinical maternal amnionitis in two-thirds. One case was apparently nosocomial in origin. No known risk factors were implicated in any other case. Seven infants were stillborn and two died within a few hours. Congenital pneumonia, funisitis, and chorioamnionitis were found at autopsy. Intrauterine infection due to the pseudomonads poses a serious problem that has not been previously recognized.

A pericentric inversion of chromosome 8, inv(8)(p23q22), in a male carrier resulted in an unbalanced recombinant, rec(8)dup q, inv(8)(p23q22), which was diagnosed prenatally. The features seen in the aborted fetus resembled the features seen in a previously affected child who received the identical recombinant from her carrier mother. In this particular inversion involving chromosome 8, both male and female carriers risk producing an unbalanced progeny. Different familial pericentric inversions are reviewed for the presence or absence of unbalanced recombinants.

Coagulation studies were performed on 13 children with clinical diagnoses of Reye syndrome. Four had abnormalities so severe that transfusion of coagulation factors and platelets were required prior to percutaneous liver biopsy. In one of these, abnormalities frequently found in association with acute hepatic failure were present. Disseminated intravascular coagulation was noted in two, while in the fourth child laboratory data were most consistent with that process. Although the coagulation defect associated with Reye syndrome is most often due to decreased production of all coagulation factors except VIII, these patients demonstrate that consumption can also occur. The severity of the coagulopathies found indicates that bleeding can become a major complication in the diagnosis and management of Reye syndrome.

• Improved obstetrical and neonatal care has increased survival for many small premature infants. However, there remains a distinct group who die of complications later in infancy. The autopsy findings associated with these "postponed neonatal deaths" were the subject of our retrospective study of 18 premature infants (mean estimated gestational age, 28.6±0.6 weeks) who survived from 4 weeks to 4 months of age (mean, 70±11 days). All 18 infants required prolonged artificial ventilatory support and parenteral nutrition. The major findings at autopsy were similar in all cases and included bronchopulmonary dysplasia, hepatic cholestasis and fibrosis, abnormalities of endochondral ossification, and diffuse cerebral gliosis and infarction. Infection was the most common cause of death, and most of the infants died with acute bronchopneumonia. These postponed neonatal deaths, while they do not appear in standard neonatal mortality statistics, represent a problem of concern. ( AJDC 1986;140:576-579)

There is general agreement that pregnant women with active tuberculosis require immediate treatment with some combination of isoniazid (INH), ethambutol, rifampin or streptomycin. Other than the possibility of fetal ototoxicity from streptomycin none of these drugs in normal dosages has proved teratogenous to the human fetus (1). We therefore report here a possible association between fetal malformations and excessive early maternal ingestion of INH.

Adherence of E. coli to bladder cells was studied by mixing E. coli with cells scraped from the surface of the normal mouse bladder. E. coli adherence to bladder epithelium did not correlate with renal infection, the ability of E. coli to resist phagocytosis, the growth of the strains, the presence of K-antigen or dulcitol fermentation. There was also no correlation with proportion of deaths, motility, or rough mutation. Pili were observed in three of the 22 strains of E. coli and their presence was not associated with increased virulence. In this model of renal infection neither adherence of E. coli to bladder epithelial cells nor the presence of pili were significant virulence factors.

Major advances have been made in the identification and prevention of perinatal factors that lead to long-term handicap or neurologic deficits. When the infant or child exhibits a major handicap, scrutiny of the pregnancy management often occurs in an attempt to define the causal factors. The medical goal of this inquiry is to prevent injuries and, when possible, to eliminate these factors. In the litigious sense, any deviation from optimal, ideal care or any unusual observations, such as unusual or atypical fetal heart rate patterns, are often causally linked to the adverse outcome. There are at least four categories of major fetal injury that probably occur prior to labor. An awareness of, and a diligent search for, details will no doubt clarify the legitimate origins of many so-called birth injuries. Hence the common tendency to fixate on minor deviations and/or deficiencies of labor and delivery management as causing catastrophic injuries will be successfully challenged.

Les auteurs rapportent deux cas d'enfants mort-nes chez qui on a decouvert a l'autopsie des kystes epidermoides ovariens. Ces kystes peuvent survenir par metaplasie squameuse: soit des restes epitheliaux cœlomiques (kystes sous-corticaux et medullaires), soit des reliquats des tubes mesonephriques (kystes hilaires et ceux du ligament large)

Since it was first described several years ago, yellow bilirubin staining of the pulmonary membranes in neonatal hyaline membrane disease has apparently become more common. In a retrospective study of neonatal autopsy experience, it was found that as more of the premature infants survived longer, yellow hyaline membrane disease was a more frequent finding, increasing from 7% of all newborns having hyaline membrane disease at autopsy in 1970 to 50% in 1980. In comparing 499 cases with eosinophilic hyaline membranes with 168 cases of yellow membranes, newborns with bilirubin staining of the pulmonary membranes were found to be more premature (P < .02), had smaller autopsy weight (P < .002), and survived longer (P < .00001). When multiple clinical parameters were compared between a group of infants with yellow membranes and a group of infants with pink membranes who were matched for gestational age, year of birth, and length of survival, no differences were found between the two groups. No correlation was found between kernicterus and yellow staining of the pulmonary hyaline membranes in the first years of the study, but there was a strong correlation in the last 5 years, coincident with the increase in the rate of yellow hyaline membrane disease found at autopsy. The gross bilirubin staining of the brain was the secondary type of kernicterus, not toxic bilirubin encephalopathy. The observation of bilirubin staining in the lung and in the brain correlates with prolonged survival in some very small premature infants. This does not appear to be a manifestation of bilirubin toxicity, but rather a marker of prior tissue damage.

Elevated serum bilirubin in the neonatal period has been related to the occurrence of kernicterus at autopsy. The level of bilirubin believed to be critical has been decreasing, especially for the small premature. To our knowledge, a controlled study of those factors potentiating kernicterus at relatively low levels of bilirubin has not been done. Thirty infants found at autopsy to have kernicterus (gross bilirubin staining of the basal ganglia) were matched with 30 other autopsied infants for gestational age, birthweight, life span and year of birth. These infants were collected from January 1971 to January 1977. In each group, 6 weighed 2,500. Gestational age ranged from 25 to 41 weeks and length of survival from 1 to 28 days. Autopsy findings, clinical histories and laboratory profiles were examined for known potentiating factors and no significant differences were found for serum pH, pO2, pCO2, hematocrit, glucose, Apgar scores, temperature, blood group incompatibility and hydration. The average peak level of bilirubin was low in both groups and while slightly higher in the group with kernicterus, this difference was only minimally significant (paired t-test, p-0.05). The presence of kernicterus in these infants may not be preventable by controlling serum bilirubin to low levels. The levels of bilirubin demanding therapeutic intervention in the high risk infant needs re-evaluation.

We wish to thank Drs Valaes and Gellis for their comments on our paper, in general, we agree with them. We have just completed the second half of our study of the same matched infants with and without kernicterus at autopsy, in which we addressed the neuropathologic changes observed in both groups of infants. Our findings support the conclusions of Valaes and Gellis and emphasize that kernicterus may not always be "the definitive evidence of bilirubin toxicity," as has been previously thought.

In Reply.— Ours was a retrospective, controlled study of the clinical-pathologic correlates of kernicterus. Cases with kernicterus at autopsy were matched by gestational age, weight, and length of survival with paired control infants. The same neuropathologist was responsible for the initial processing and diagnosis of all the cases. On review, we found the expected histologic features of toxic bilirubin encephalopathy in only two of 32 cases with characteristic gross bilirubin staining at autopsy. Spongy change was found in no predictable anatomic location in the remaining cases.

Kernicterus, or bilirubin staining of specific nuclei of the brain in newborns, is traditionally considered to represent a deleterious manifestation of hyperbilirubinemia. All infants (32) from January, 1970 through January, 1977 found at autopsy to have characteristic gross bilirubin staining were identified. They were matched with 32 other infants without gross staining for gestational age, weight, length of survival and year of birth. In our initial clinical review we found no differences when multiple factors thought to potentiate risk for kernicterus were compared between the matched pairs. The neuropathologic changes in these two groups were evaluated without knowledge of the clinical or gross findings. While the pattern of gross bilirubin staining followed that classically described for kernicterus, specific histologic changes were found in only two kernicteric and one non-kernicteric infant. The nonspecific finding of diffuse spongy change was more common in the grossly stained brains (p

• Two unrelated children were born with severe congenital malformations: a girl now seven years old and a boy who died in the newborn period. Both had severe cervical hyperextension, severe flexion deformities of the limbs, and bilateral popliteal pterygia. Postmortem examination of the second case showed small, well-formed thoracic vertebrae with mild epidural fibrosis and hemorrhage. These birth defects are rare and usually occur separately. We postulate that they are related in these two cases; that the arthrogryposis and popliteal pterygia were probably the result of the spondylohypoplasia and associated changes; and that together, these related defects may constitute a new malformation complex. ( Am J Dis Child 134:42-45, 1980)