Ira Bergman

Cause of hearing loss in the high-risk premature infant

Bilateral hearing loss occurred in 9.7% of infants who survived despite very low birth weight (less than or equal to 1500 gm), 16.7% of infants who survived neonatal seizures, and 28.6% of infants who survived both low birth weight and neonatal seizures. All neonates received treatment in a single neonatal intensive care unit between 1976 and 1980. Twenty-two of 36 hearing-impaired children were normal physically and mentally, with IQ scores of greater than or equal to 85. Significant neonatal predictors of hearing loss in high-risk premature infants (less than or equal to 36 weeks gestation), as determined by multivariable testing, were prolonged respirator care, high serum bilirubin concentration, and hyponatremia. Exchange transfusions were associated with a decreased risk of hearing loss.

Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration

An encephalopathy developed in three infants in the intensive care unit after heavy sedation with midazolam and fentanyl for 4 to 11 days. The affected infants had poor social interaction, decreased visual attentiveness, dystonic postures, and choreoathetosis. Symptoms cleared completely in 5 days to 4 weeks. Retrospective review of records of all children treated in the intensive care unit with prolonged intravenous administration of midazolam revealed that 45 children could be assessed neurologically on withdrawal of sedation. Three children had definite and two had possible neurologic sequelae (5/45, 11.1%). All had received concomitant intravenous fentanyl therapy. Neurologic sequelae were significantly associated with young age, female gender, low serum albumin concentration, and concomitant administration of aminophylline. This encephalopathy may represent a benzodiazepine withdrawal syndrome, a prolonged agonist action on the benzodiazepine receptor, or the combined effects of multiple toxic, metabolic, and infectious insults to the central nervous system of infants in the intensive care unit. Prolonged use of intravenous midazolam sedation necessitates careful dosing, monitoring, and discontinuation, particularly in infants and young children.

Glutaric acidemia A metabolic disorder causing progressive choreoathetosis

A boy with glutaric acidemia had psychomotor retardation first noted at age 6 months, recurrent metabolic acidosis, and a progressive quadriparesis with choreoathetosis. He died at age 31/2 years. Cultured skin fibroblasts lacked glutaryl-CoA dehydrogenase activity. There was a biochemical, but not a clinical, response to dietary restriction of lysine and tryptophan. The caudate and putamen of the brain showed severe loss of nerve cells and fibers with proliferation of astrocytes, as well as markedly reduced γ-aminobutyric acid and glutamate decarboxylase activity.

Outcome in children with enteroviral meningitis during the first year of life

The neurologic, psychologic, language, and academic skills were evaluated and compared in children who had had enteroviral meningitis in infancy and their siblings. The study population consisted of 45 children in whom enteroviral meningitis developed between the ages of 4 days and 12 months. Three died of heart failure caused by viral myocarditis. Thirty-three survivors and 31 siblings were comprehensively evaluated with physical and neurologic examinations; hearing, vision, and achievement tests; and tests of cognitive, perceptual-motor, language, memory, and emotional-behavioral functions. The remaining nine survivors of meningitis and eight of their siblings were assessed by telephone interviews and analysis of school and medical records. None of the survivors had major adverse neurologic sequelae. In addition, they performed as well as their siblings on all tests administered. Our study did not demonstrate either overt or covert impairments of neurologic function or development in survivors of infantile enteroviral meningitis.

Recombinant vesicular stomatitis virus targeted to Her2/neu combined with anti-CTLA4 antibody eliminates implanted mammary tumors

Vesicular stomatitis virus (VSV) is being developed for cancer therapy. We created a recombinant replicating VSV (rrVSV) that preferentially infected Her2/neu expressing breast cancer cells. We now used this rrVSV to treat macroscopic peritoneal tumor implants of a mouse mammary tumor cell line stably transfected to express Her2/neu. rrVSV therapy alone prolonged survival but did not cure any animals. rrVSV therapy combined with antibody to TGFb or antibody to IL-10 receptor (IL-10R) each produced cure in one of six animals. Strikingly, rrVSV therapy combined with anti-CTLA4 monoclonal antibody (MAb) produced cure in four of five animals. Anti-CTLA4 MAb was only effective when administered within one day of rrVSV therapy. Cure required CD4 T-cells early (<7 days) and late (>7 days) after rrVSV therapy whereas CD8 T-cells were required only late (>7 days) after rrVSV therapy. Surviving animals were resistant to re-challenge with D2F2/E2 suggesting a memory immune response. Histopathologic analysis demonstrated a dense inflammatory infiltrate of tumor nodules within days of therapy and foamy histiocytes replacing the tumor nodules 2 weeks following therapy. These studies demonstrate that targeted rrVSV combined with anti-CTLA4 MAb can eliminate established macroscopic tumor implants by eliciting an anti-tumor CD4 and CD8 T-cell immunologic response.

Intracranial injury after moderate head trauma in children

We retrospectively evaluated the records of 459 children who had normal findings on a neurologic examination after moderate head injury characterized by brief loss of consciousness. Skull x-ray examination had been performed in 358 children, and 52 (14%) had fractures. Intracranial complications developed in six children (1.3%); five had extradural hematomas and one had bifrontal contusions. All six had skull fractures. Three children required surgical evacuation of hematomas between approximately 24 and 72 hours after injury. On the basis of these results, we conclude that in the absence of a skull fracture, most alert children without symptoms who have sustained moderate head injury may be safely discharged from the emergency department in the care of a competent observer.

Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat and human effectors

Abstract Antibodies can direct tumor cell lysis by activating complement-mediated and cell-mediated cytoxicities (antibody-dependent cell-mediated cytotoxicity, ADCC). Clinical translation of these effects into successful cancer therapy has been slow. Choosing an appropriate animal model to test new therapeutic strategies is difficult because of species differences in immunological effector functions. In previous work, we found that an unmodified anti-ganglioside mouse IgG3 monoclonal antibody (mAb), 3F8, could successfully treat clinical tumors in humans and experimental tumors in rats but not experimental tumors in mice. We explored the reasons for this species difference by performing in vitro antibody-dependent cytotoxicity assays comparing the potency of polymorphonuclear neutrophils (PMN), natural killer (NK) cells and complement from the three species: mouse, rat and human. 3F8-dependent complement-mediated cytotoxicity produced more than 70% specific release when human and rat sera were used and only 20% with mouse serum. PMN-mediated ADCC was 35%–70% with human effectors, 25%–60% with rat and undetectable with mouse. Human eosinophils did not contribute to this ADCC. Cytotoxicity utilizing interleukin-2-activated NK cells was antibody-independent in all three species but the specific release was 60%–70% with human and rat NK cells and 10% with mouse NK cells. These data suggest that, for mouse IgG3, the rat may provide a more relevant rodent model than the mouse for testing the in vivo antitumor effects of monoclonal antibodies.

Outcome of Children With Cerebral Edema Caused by Fulminant Hepatic Failure

Mortality is high in patients with fulminant hepatic failure (FHF). Neurologic complications of encephalopathy and cerebral edema are major contributors to mortality. Orthotopic liver transplantation has improved survival in these patients. However, the complexity of medical and surgical problems in this patient population, coupled with a severe shortage of organs, requires careful patient selection. The aim of this study was to describe the neurologic outcome of children with FHF who developed radiologically apparent cerebral edema. The hospital and outpatient records and radiologic studies of 20 children with FHF admitted to Childrens Hospital of Pittsburgh from 1981-1995 who developed encephalopathy and computed tomographic evidence of cerebral edema were reviewed. Fourteen patients died (70%), three were left with severe neurologic deficits (15%), and three were left with moderate deficits (15%). Survival was correlated with a lesser degree of coma. Histopathologic examination of eight brains demonstrated cerebral edema and widespread ischemic neuronal necrosis in all eight. The presence of radiographic cerebral edema in children with FHF is an objective measure that indicates a very poor prognosis. Termination of care is a reasonable option. Comprehensive monitoring of cerebral function and intracranial pressure is required in children with FHF. Orthotopic liver transplantation should be performed in children with severe and worsening encephalopathy before the development of radiographically apparent cerebral edema.

Connatal brain tumors in patients with tuberous sclerosis.

Two neonates with tuberous sclerosis and giant cell astrocytomas diagnosed soon after birth are described. During attempted surgical resection of their tumors, both infants developed refractory intraoperative cardiac arrhythmias and died. At autopsy, both patients had multiple cardiac rhabdomyomas. Subependymal giant cell astrocytomas rarely present in the neonate, but genetic implications and associated cardiac hamartomas warrant special consideration of these connatal tumors. Surgical considerations suggest that an operative approach to these tumors should be delayed beyond the neonatal period.

Treatment of implanted mammary tumors with recombinant vesicular stomatitis virus targeted to Her2/neu

Vesicular stomatitis virus (VSV) is being developed for cancer therapy. We have created a recombinant replicating VSV (rrVSV) that targeted to Her2/neu expressing breast cancer cells and expresses mouse GM‐CSF. We now tested the efficacy of this rrVSV in the treatment of peritoneal tumor implants of D2F2/E2 cells, a BALB/c mouse mammary tumor cell line, which was stably transfected to express Her2/neu. Mice were treated 1 day following tumor implantation with either 2 × 108 infectious doses rrVSV or conditioned media (CM). All control animals developed massive peritoneal tumor with a median survival of 16 days. Nine of 10 rrVSV treated mice survived long term with no evidence of tumor. rrVSV had much less efficacy in treating implants of the parent D2F2 cells that did not express Her2/neu. The median survival was 13.5 days in mice treated with CM and 21 days in those treated with rrVSV. There was one long term survivor in the rrVSV treated group. None of the rrVSV treated animals showed evidence of viral toxicity. Three of 7 long term survivors did not develop tumor when rechallenged first with D2F2/E2 and then with D2F2 cells. Both successful therapy and resistance to rechallenge were T‐cell dependent. These studies demonstrate that targeted rrVSV eliminated peritoneal implants of Her2/neu expressing tumor and elicited an anti‐tumor T‐cell immunologic response.