Stroke in children with sickle cell anaemia: aetiology and treatment.

Cerebral infarction is a frequent, severe complication of sickle cell anaemia. During childhood, most strokes are due to infarction with the majority resulting from occlusion of the large cerebral arteries. Risk factors include transient ischaemic attacks, acute chest syndrome, severe anaemia and elevated blood pressure. Less certain is the association with leucocytosis, or protection provided by alpha-thalassaemia or fetal haemoglobin. Children who have one stroke are at significant risk for having subsequent events that can be substantially reduced by maintaining haemoglobin S below 30%. It has not yet been possible to identify individuals for whom transfusion can be safely stopped. Haemosiderosis is a consequence of intensive and long term transfusion therapy, which requires chelation with deferoxamine. Iron accumulation can be minimised using erythrocytapheresis but this is technically difficult in children, expensive and results in increased donor exposure. In addition to lesions associated with strokes, an additional 17% of patients can be shown to have clinically silent cerebral infarcts. Although these are termed 'silent', those affected have mild neuropsychological deficits. Their relationship to stroke or risk for recurrence is unknown. Transfusion therapy has been shown to provide primary stroke prevention for children who have elevated cerebral artery velocity. Finally, intracranial haemorrhages, more commonly found in adults, also affect children. Subarachnoid haemorrhage is frequently found to result from cerebral artery aneurysms. A condition that mimics the moyamoya syndrome radiographically, as well as for its risk of haemorrhage, can be found in children with partly occluded cerebral arteries either as a result of stroke or silent infarct.

Multicenter comparison of magnetic resonance imaging and transcranial Doppler ultrasonography in the evaluation of the central nervous system in children with sickle cell disease.

PURPOSE: To compare the results of standardized magnetic resonance imaging (MRI) of the brain and transcranial Doppler (TCD) ultrasonography of cerebral arteries in school-aged children with sickle cell disease to determine the correlation between these two different neurodiagnostic tests. PATIENTS AND METHODS: Data were analyzed from 78 children with sickle cell disease (mean age 11 yrs) who participated in both the Cooperative Study of Sickle Cell Disease (CSSCD) and the Stroke Prevention Trial in Sickle Cell Anemia (STOP). Patients who had experienced an overt stroke were excluded. MRI findings were classified as normal or "silent infarct." Results of TCD were classified as normal, conditional, or abnormal, based on the time-averaged maximum mean flow velocity in the proximal middle cerebral and distal internal carotid arteries. RESULTS: Of 61 patients who had a normal MRI examination, 11 (18%) had either conditional (5 patients) or abnormal (6 patients) TCD results. Among 17 patients in whom silent infarction was seen on MRI, only 5 (29%) had a conditional (1 patient) or abnormal (4 patients) TCD velocity. Thus, discordant results were seen in 23 patients: 12 in which the TCD result was normal and the MRI abnormal; 11 in which the TCD velocity was elevated and the MRI normal. CONCLUSIONS: Abnormal TCD and MRI examinations reveal different aspects of the pathophysiology of central nervous system (CNS) injury in sickle cell disease and are often discordant. Although TCD abnormality is predictive of overt stroke, the lack of concordance between TCD and MRI findings suggests a need to develop more sensitive and specific indicators of early CNS pathology, such as neuropsychometric testing and positron-emission tomography (PET) scans, and to obtain more information about microvascular pathologic processes that may affect CNS function.

Influence of penicillin prophylaxis on antimicrobial resistance in nasopharyngeal S. pneumoniae among children with sickle cell anemia. The Ancillary Nasopharyngeal Culture Study of Prophylactic Penicillin Study II.

PURPOSE: To evaluate the consequences of prolonged prophylactic penicillin use on the rates of nasopharyngeal colonization with Streptococcus pneumoniae and the prevalence of resistant pneumococcal strains in children with sickle cell anemia. METHODS: Nasopharyngeal specimens were obtained from children with sickle cell anemia (Hb SS or Hb S beta degrees thalassemia) at 10 teaching hospitals throughout the United States. These patients were participating in a prospective, randomized, placebo-controlled trial in which they were prescribed prophylactic penicillin before their fifth birthday and were randomized to prophylactic penicillin or placebo after their fifth birthday (PROPS II). The specimens were cultured for S. pneumoniae, and isolates were analyzed for antimicrobial susceptibility to nine commonly prescribed antimicrobial agents. RESULTS: Of the 226 patients observed, an average of 8.4 specimens were collected per patient. From 1,896 individual culture specimens, 5.5% of the specimens were positive for S. pneumoniae; 27% of patients had at least one positive culture. Nine percent of the study patients had at least one isolate of penicillin intermediate or resistant pneumococci. There was no significant difference in the percent of positive cultures for S. pneumoniae in those patients given penicillin prophylaxis after 5 years of age (4.1%) compared with those patients given placebo after 5 years of age (6.4%). Likewise, there was no significant difference (p = 0.298) in the percent of patients with at least one positive culture for S. pneumoniae in the group given prophylactic penicillin after 5 years of age (21.8%) compared with the group given placebo after 5 years of age (28.3%). There was no difference between the penicillin and placebo groups in the proportion of patients with penicillin intermediate or resistant pneumococci, but there was a trend toward increased carriage of multiply drug-resistant pneumococci in children > 5 years of age receiving prophylactic penicillin compared to children > 5 years of age receiving placebo. The increased colonization rate with multiply drug-resistant organisms of children > 5 years of age receiving penicillin prophylaxis is not statistically significant. CONCLUSIONS: The potential for continued penicillin prophylaxis to contribute to the development of multiply resistant pneumococci should be considered before continuing penicillin prophylaxis in children with sickle cell anemia who are older than 5 years of age. Added to the published data from PROPS II, which demonstrated no apparent advantage to continue prophylaxis, the data support the conclusion that, for children with no history of invasive pneumococcal disease, consideration should be given to discontinue prophylactic penicillin after their fifth birthday.

Severe protein C deficiency in a newborn.

An infant presented at birth with a cutaneous lesion that developed the characteristics of purpura fulminans. He sustained a cerebral infarction during the first 4 days of life, which was initially misinterpreted to be cerebral hemorrhage resulting from thrombocytopenia and hypofibrinogenemia. After the diagnosis of Protein C deficiency was made and effective replacement therapy begun, no further cutaneous lesions occurred. Although there was no evidence of further cerebral infarction, the initial insult progressed to severe encephalomalacia and cerebral atrophy. This disorder should be considered in infants with purpura fulminans or those with cerebral infarction, as prompt institution of transfusion therapy to replace the missing protein may prevent further damage.

Experience with a totally implantable venous device in children.

Venous access was attained in 15 children by use of a totally implantable central venous catheter and reservoir. Catheters were in place from 28 to 581 days, giving a cumulative experience of 4,094 days. Although they were well accepted by physicians, parents, and the children, they were not without major complications. These included extravasation of a chemotherapeutic agent in one, migration of the catheter tip to an unacceptable location in another, and catheter thrombosis and catheter-related sepsis in two each. The malpositioned catheter, one of the thrombosed catheters, and both infected catheters were removed. Ease of care, freedom from protruding tubing, and compatibility with normal activities are major positive features of the implantable devices that should be considered when deciding on the type of prolonged central venous access for use in children being treated with cancer.

Endomyocardial biopsy to monitor anthracycline therapy in children.

Evaluation of the ultrastructure of material obtained by endomyocardial biopsy has been proposed as a means to evaluate patients for impending anthracycline cardiotoxicity. Eighteen biopsies obtained from 13 patients (age, 3-18 years) are reported. Twelve biopsy procedures were done to evaluate the cardiac status on reaching a cumulative dose of 400 mg/m2 and three patients had six subsequent biopsies after having received significantly more drug or receiving radiation therapy to the lungs or mediastinum. Scores were assigned to the tissue obtained and used to guide the decision to continue or stop anthracycline therapy. Three patients with abnormal cardiac studies at low cumulative doses, five of whom had received greater than 400 mg/m2 and three of whom had received considerably higher doses and thoracic irradiation were given more drug without incident. Two specimens were interpreted to indicate avoidance of further anthracycline and two patients were cautiously given more despite evidence of mild myocardial damage. These results indicate that endomyocardial biopsies can be performed on a pediatric population with a reasonable complication rate. Further studies should be undertaken to evaluate its usefulness as a means to predict and avoid anthracycline cardiomyopathy.

Cellular and plasma kinetics of daunorubicin given by two methods of administration in a patient with acute leukemia.

Leukemic cell and plasma concentrations of daunorubicin were examined serially in a patient with acute lymphoblastic leukemia following administration of the drug by two different regimens: regimen A-an iv bolus dose of 50 mg/m2, and regimen B-a loading dose of 15 mg/m2 followed by 35 mg/m2 infused over 4 hours. Peak plasma levels were four times higher after regimen A the B, whereas leukemic cell concentrations were not significantly different. No difference in acute toxicity or therapeutic efficacy was seen after either method of administration. However, we have demonstrated that peak plasma levels of daunorubicin can be reduced by continuous infusion without significantly altering target tissue concentrations.