CNS Hemorrhage Research Articles

Idiopathic (Immune) Thrombocytopenic Purpura in Children: Pathogenesis and Treatment

On the basis of available evidence it seems that "idiopathic" thrombocytopenic purpura, in children as in adults, should more properly be termed immune thrombocytopenic purpura. Although therapy is often employed because of the fear of CNS hemorrhage, the incidence of this dreaded complication is actually very low. New treatments may permit the physician to induce a safe platelet count while awaiting spontaneous remission. The indications for splenectomy in children may have to be reevaluated and here, too, new forms of therapy may permit the operation to be deferred and, in some cases, avoided entirely.

1379 RATES AND ASSOCIATED RISK FACTORS FOR DLOW INDUCED HYPERGLYCEMIA (HG) IN NEONATES

We have identified rates and associated risk factors for D10W-induced HG among 636 newborns exposed to IV D10W in 2 neonatal ICU's monitored by an intensive Pediatric Drug Surveillance (PeDS) Program. DIOW-induced HG (range 110-774 mg %) was observed in 23 exposed infants (3.6%). There was a highly significant trend (X2=52.5) toward an increasing risk of HG with decreasing admission weight:Infants ≥ 1000 gm who were under stress (ie., asphyxia, sepsis, RDS and/or pneumonia) were 7 times more likely to have HG than non-stressed infants of similar weight (2.7% vs 0.4% respectively); however, stress did not appear to increase the risk of HG among infants ≥ 1000 gm. Similarly, among infants ≥ 1000 gm, increases in the average daily dextrose dose/kg of all dextrose-containing infusions increased the risk of HG, but this effect was not observed among the smaller (< 1000 gm) infants. Since HG may alter fluid balance and cerebral blood flow, it may also affect the risk of CNS bleeding or infarct. Admission weight and stress are risk factors for HG which cannot be altered; to reduce the risk of HG in very low birth weight infants or in larger infants who are under stress, physicians should carefully consider the total amount of dextrose administered (independent of fluids and electrolytes) and carefully monitor the neonate's blood glucose.

Gastroschisis: Primary closure or Silon pouch

There has been a substantial increase in the incidence of gastroschisis in the last few years, and total parenteral nutrition has enabled many of these neonates to survive the long post-operative course. From 1969 to 1976 inclusive, 44 neonates with gastroschisis were treated with either primary closure or the application of a Silon pouch. Fifteen neonates were managed by primary closure. Three of these neonates developed clinical sepsis, but no other intraabdominal complications ensued. There were two deaths (13%) in the early postoperative period, due to CNS hemorrhage and aspiration. This gorup of 15 babies had 17 abdominal operations and the survivors averaged 32 days of parenteral intravenous nutrition before complete oral alimentation could be successfully started. Two ventral hernias required late repair. Twenty-nine neonates were managed primarily with a Silon pouch. Eighteen of these newborns developed sepsis, three Silon sacs had to be removed because of necrotic bowel within, and two other infants developed small bowel fistulae. There were 12 deaths (35%). These 12 infants had prolonged intestinal malfunction that lasted an average of 67 days. This group of 29 babies had 64 abdominal operations and the survivors averaged 46 days of parenteral intravenous nutrition prior to full oral feeds. Four ventral hernias required later repair. The comparison of results in these two groups of newborns reveals a striking difference in their post-operative course and survival. Although the Silon sac has until now become the accepted surgical procedure for gastroschisis, these results conclusively indicate the advantage of primary reduction and closure of the abdominal wall defect.

1008 THE ASSOCIATION OF KERNICTERUS (KI) WITH BACTERIAL SEPSIS

The only cases of KI detected at autopsy in neonates at this institution from 1971 through 1976 occurred in 3 infants with antemortem culture proven sepsis. During this period there were 14,210 deliveries, 387 transferred-in babies, 250 neonatal deaths and 178 autopsies. All 3 of the infants with KI weighed more than 2250 grams and had gestational ages of 36 or 37 weeks. Group B beta hemolytic streptococcal sepsis and meningitis was diagnosed in one infant, but the baby was never icteric. The second infant developed Klebsiella sepsis following spontaneous gastric perforation. The peak total serum bilirubin concentration (SBC) in this baby was 8.6 mg/dl. The third infant manifested E.coli sepsis at 8 hours of age and deteriorated despite appropriate antibiotic therapy; the peak total SBC was 15.6 mg/dl. The direct-reacting SBC in cases 2 and 3 never exceeded 1 mg/dl. All Apgar scores were at least 7 at 1 minute and 9 at 5 minutes. During this period of time only 4 cases (3 with KI) were documented in which sepsis was proven prior to death and a subsequent autopsy was performed. The 3 infants with KI all died with their infection as the primary cause of death. The infant without KI, a 32 week 1850 gram baby, died of a massive CNS hemorrhage. This suggests that persistant bacterial sepsis may be a critical predisposing factor in the development of KI even in the presence of low serum bilirubin concentrations.

Intracranial hemorrhages in kittens: Hypernatremia versus hypoxia

Although CNS hemorrhages have long been observed in infants with hyaline membrane disease, the etiology of these hemorrhages is still unknown. Two proposed etiologies are hypoxia with acidosis and iatrogenic hypernatremia secondary to sodium bicarbonate therapy. An experiment on kittens comparing these two hypotheses suggested that intracranial hemorrhages were related only to elevated serum sodium concentrations. The CNS hemorrhages were independent of experimentally induced hypoxemia and its consequent acidosis.

Diagnostic significance of CSF spectrophotometry in cerebrovascular diseases

Different spectrophotometric “patterns” of xanthochromic compounds in the CSF may be found in cerebrovascular diseases. In about 1000 such cases the CSF was examined spectrophotometrically. Specific clinical diagnoses of thrombo-embolic or haemorrhagic disorders were verified (autopsy, operation or radiological examinations) or diagnosed with a high degree of probability on clinical grounds (excluding the CSF signs) in only about 20% of the cases. The diagnoses in these cases (about 200) corresponded extremely well with the spectrophotometric patterns found. It must be specially emphasized that this examination performed at a time interval of between 24 hr to 7 days after the onset of symptoms reveals a haemorrhagic component in nearly 100% of cases, as judged by cases with verified or highly probable CNS haemorrhage. A few cases had normal CSF spectra, obviously since the lumbar puncture had been performed too late or too early after the ictus. The times of appearance and disappearance of the pathological CSF patterns, and the optimal test times were also studied. Difficulties in the interpretation of CSF spectrophotometry and methods of overcoming them are described. In conclusion, direct spectrophotometry of the CSF is a simple, fast and extremely sensitive method, which in our opinion should be used routinely in the diagnosis of suspected vascular diseases of the CNS. CSF spectrophotometry may well provide a valuable guide for the clinician in the rational therapy of cerebrovascular disorders.

Ligation of the patent ductus arteriosus in premature infants: Report of 45 cases

Ligation of the PDA in premature infants is well tolerated when there is no underlying pulmonary or CNS hemorrhage or bronchopulmonary dysplasia. Many premature infants require interruption of the large left-to-right shunting PDA in the management of intractable cardiorespiratory failure. Prompt interruption of large left-to-right shunts through the PDA in mechanically ventilated premature infants with severe RDS may prevent the development of severe bronchopulmonary dysplasia, a major cause of mortality among these infants.

High-dose cyclophosphamide therapy for malignant disease.Toxicity, tumor response, and the effects of stored autologous marrow

Twenty-five patients with disseminated malignant disease received single or multiple courses of cyclophosphamide (CY) 60 to 120 mg/kg. Stored autologous marrow was infused following 120 mg/kg of CY in 6 instances. One patient received 240 mg/kg of CY over a 4-day period followed by autologous marrow infusion. Patients receiving 60 mg/kg showed a moderate leukopenia (mean nadir of 500/mm3), anemia (mean hematocrit decline of 8.2 vol%) and variable thrombocytopenia that ranged from no change to 34,000/mm3 with a mean nadir of 127,000/mm3. Increasing the dose to 120 mg/kg produced leukopenia to below 500 cells/mm3 with a mean nadir of 120 cells/mm3. Thrombocytopenia was severe with a mean nadir of 37,000/mm3. Hematocrit values in this group fell by 15.2 vol%. Infectious complications occurred following 1 of 10 courses at 60 mg/kg and 18 of 35 courses at 120 mg/kg. In the latter group, there were 7 episodes of septicemia including one death from pseudomonas septicemia. A second patient, with cerebral metastases, died of a CNS hemorrhage. The patient receiving 240 mg/kg died as a consequence of myocardial necrosis. The infusion of autologous marrow had no apparent effect on hemopoietic recovery or infectious complications. Of the responding patients, 3 had ovarian carcinoma, 3 had testicular tumors, 1 had adenocarcinoma of the bowel, and 1 had an undifferentiated malignancy.

Early neurovascular abnormalities underlying 6-aminonicotinamide (6-AN)-induced congenital hydrocephalus in rats.

AbstractDefects in the rat central nervous system during retarded brain development and congenital hydrocephalus were studied following single maternal injections of the niacinamide antimetabolite 6‐aminonicotinamide (6‐N) late in development. Histological and histochemical analyses indicated CNS hemorrhage and growth retardation of fetal brains 24 hours after treatment; fluid movement into cerebral ventricles was evidenced by secretionlike, circular “blebs” along the ependymal lining. There was transitorily increased glycogen in hypoplastic choroid plexuses with disruption of cerebral layering of neuroblasts. Despite thinned cerebral cortex and increased ventricular surface area, associated with cranial distortion and communicating, compensatory ventricular enlargement, normal intracranial pressure was recorded by day 21 of gestation. During the pathogenetic process macrophagic cells removed cellular debris and RBC's so that by term little evidence of early hemorrhage was apparent.

The binding of xanthochromic compounds in the cerebrospinal fluid: Preliminary report

Xanthochromic compounds in the CSF were studied with direct spectrophotometry (650-350 nm) as well as with spectrophotometry of the concentrated (ultrafiltered) CSF, the CSF ultrafiltrates, and the electrophoretically-separated CSF. The xanthochromic substances are apparently bound in a non-ultrafilterable form, probably attached to CSF proteins. Spectrophotometric examination of CSF concentrates seems to be valuable in cases with low concentrations of xanthochromic substances, e.g. methaemoglobin in many cases of subdural haematoma. The “normal” CSF bilirubin concentration, as determined from CSF concentrates, has been estimated as 1–5 μ g 100 ml . An equation is given for the approximate calculation of CSF bilirubin of non-haemorrhagic origin. The equation seems to be of diagnostic value in the case of children with neonatal hyperbilirubinaemia and suspected CNS haemorrhage. The results of a limited number of electrophoretic examinations are given and discussed. CSF bilirubin seems, like serum bilirubin, to be almost exclusively bound to albumin. The oxyhaem has been found in the β 1-globulin region, probably bound as oxyhaemoglobin. Most of the methaem has been observed in the albumin fraction, probably bound as methaemalbumin. It has also appeared in the β 1-globulin position, probably as methaemoglobin. Systematic studies on the binding of xanthochromic CSF compounds are now in progress.

DIAGNOSIS AND TREATMENT: MANAGEMENT OF IDIOPATHIC THROMBOCYTOPENIC PURPURA

THE TERM idiopathic thrombocytopenic purpura (ITP) should be reserved for that hemorrhagic disorder characterized by a subnormal platelet count (usually below 50,000/cu mm) in the presence of a normal marrow containing normal or increased megakaryocytes and the absence of systemic disease capable of inducing thrombopenia. Bone marrow examination is mandatory to rule out leukemia, other infiltrative disorders, and hypoplastic and aplastic states; an L.E. preparation is indicated as are the careful search for systemic infection and renal disease and the detailed inquiry concerning drug ingestion. Although no specific antecedent event can be identified in most cases of ITP, it is recognized that some of the common childhood exanthemata may occasionally be followed by thrombocytopenic purpura (e.g., rubella, rubeola, varicella). The rational approach to treatment must be based upon understanding of the natural history of the disease. Acute ITP has an excellent prognosis and approximately 80% affected children will make a complete and permanent recovery without specific therapy. Of these, three-quarters will recover within 3 months of onset, most within 4 to 6 weeks. Approximately 20% of cases will persist longer than 6 months and are then usually designated as chronic. The mortality rate in acute ITP is extremely low and most of the urgency for treatment stems from concern over central nervous system hemorrhage. It seems clear that the incidence of CNS bleeding is no greater than 2-4% and that in most series reporting a greater incidence cases were not limited to ITP but included instances of thrombotic thrombocytopenic purpura and purpura fulminans, i.e., disease states associated with vasculitis.