Intraventricular hemorrhage in the full-term neonate.

Intraventricular hemorrhage (IVH) can occur in full-term newborns with a variety of clinical pictures. We studied five full-term infants who suffered IVH in the neonatal period and survived. No apparent cause for hemorrhage could be found in four. All had normal results of neurologic examinations at birth, and four had no major antecedent perinatal or postnatal difficulties. In 19 previously described full-term infants with IVH, no perinatal problems were noted in 45% of those who survived. Although more common in premature infants, IVH can occur in full-term infants and should be suspected when there is a sudden change in the neurologic status. In subsequent examinations, three of our five infants had mild spasticity and two appeared to be normal. The grading system developed for IVH in premature infants, while indicating severity of the hemorrhage, does not predict clinical outcome in full-term infants. A more definitive statement of outcome will require a longer period of observation.

Treatment of status epilepticus in children.

In children, seizures associated with status epilepticus (SE) include a number of types that are age-related. These types of seizures are not associated with SE in older patients. Likewise, etiologies of SE in children are also unique to this patient population, in particular those responsible for SE in the neonate. Consequently, therapy must address specific treatment of any possible underlying condition in addition to appropriate interventional and supportive measures.

Phenobarbital maintenance dose requirements in treating neonatal seizures.

We studied the pharmacokinetics of phenobarbital in 15 neonates after a single intramuscular dose. The mean apparent distribution volume, half-life, and apparent total body clearance were 0.81 liter per kilogram, 103.4 hours, and 6.4 ml per hour per kilogram, respectively. Substantial interpatient variation was observed in the half-life and apparent total body clearance. Maintenance doses of 3.1 and 3.8 mg per kilogram per day were projected from the mean apparent total body clearance to produce plasma concentrations of 20 and 25 micrograms per milliliter, respectively. These recommendations provide initial maintenance dosage guidelines, which should be adjusted according to plasma concentrations and clinical effects.

Characteristics of the dementia in late-onset metachromatic leukodystrophy.

Patients with metachromatic leukodystrophy (MLD) of juvenile or adult onset present with behavioral abnormalities. In nine patients, diagnosed between ages 11 and 33 years, behavior and neuropsychological test results disclosed a pattern of dementia combining features associated with both frontal and white matter abnormalities. All the patients had been considered to have a psychiatric disorder prior to the diagnosis of MLD, even though none had any of the cardinal features of schizophrenia or other major psychosis. Early diagnosis of late-onset MLD is important to provide access to appropriate effective therapy.

Phenobarbital dosage for control of neonatal seizures.

The relationship of the initial phenobarbital dose to weight, gestational age, blood level, and seizure control was studied in 39 neonates. The blood proportional to the dosage per kilogram, and was not related to weight or gestational age. Seizures remitted only at blood phenobarbital concentrations above 16.9 micrograms per milliliter. Therapeutic levels can be achieved by the intravenous or intramuscular administration of 16 to 23 mg per kilogram of phenobarbital.

Sea-blue histiocyte and posterior column dysfunction: a familial disorder.

This is a report of a new familial neurologic disorder characterized by ceroid-lipofuscin storage, sea-blue histiocytes, and associated neurologic findings. Neurologic manifestations in the family members examined were varied, but posterior column involvement was the most common finding. The presence of sea-blue histiocytes was genetically determined by an autosomal dominant trait. Vitamin E blood concentrations were decreased in the absence of absorption difficulties in two sisters who were most seriously affected. The relationship of ceroid-lipofuscin, lipid peroxidation, and vitamin E is discussed.

Dural venous sinus thrombosis in acute lymphoblastic leukemia.

Three children with acute lymphoblastic leukemia developed sagittal sinus thrombosis. One patient was in peripheral remission. One patient survived. In neither patient who died were the walls of the dural sinuses infiltrated with leukemic cells. Attention is drawn to this potentially treatable cause of central nervous system symptoms in childhood leukemia. Angiography is the diagnostic test of choice and can also demonstrate intracerebral hematoma and subdural hematoma, if present. Sinus thrombosis can occur either during exacerbation or remission of the basic leukemic process. The possibility that chemotherapeutic techniques predispose toward this complication is raised.

Outcome of second hematopoietic cell transplantation in Hurler syndrome.

Hurler syndrome (HS) is an autosomal recessive, inherited metabolic storage disorder due to deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. Untreated patients develop progressive mental retardation and multisystem morbidity with a median life expectancy of 5 years. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and even improvement of intellect, with long-term survival. However, children with HS have an increased incidence of graft failure, usually with concomitant autologous marrow reconstitution. Between 1983 and 2000, 71 Hurler children underwent HCT at the University of Minnesota. Of these 71, 19 (27%) experienced graft failure. We report HCT outcomes in all 11 Hurler patients receiving a second HCT at the University of Minnesota. Median age at second HCT was 25 months (range, 16 to 45 months); median time from first HCT was 8 months (range, 4 to 18.5 months). The conditioning regimen consisted of cyclophosphamide/TBI/ATG (n = 8) or busulfan/cyclophosphamide/ATG (n = 3). The source of bone marrow was an unrelated donor in six, matched sibling in four, and mismatched related in one. Five of the 11 grafts were T cell depleted prior to infusion. Overall, 10 of 11 patients showed donor-derived engraftment, of whom three developed grade 3 to 4 acute GVHD. Five of 11 patients are surviving a median of 25 months (range, 2 months to 12 years) with an overall actuarial survival of 50% (95% CI, 27% to 93%) at 4 years. All five show sustained donor engraftment with normalization of IDU activity levels. Three of five evaluable patients demonstrated stabilization of neuropsychological function after second HCT. Currently, allogeneic donor-derived hematopoiesis provides the only chance for long-term survival and improved quality of life in Hurler patients. While graft failure in Hurler patients requires further investigation, a timely second HCT can be well-tolerated and beneficial.

Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases.

Treatment and potential cure of lysosomal and peroxisomal diseases, heretofore considered fatal, has become a reality during the past decade. Bone marrow transplantation, (BMT), has provided a method for replacement of the disease-causing enzyme deficiency. Cells derived from the donor marrow continue to provide enzyme indefinitely. Several scores of patients with diseases as diverse as metachromatic leukodystrophy, adrenoleukodystrophy, globoid cell leukodystrophy, Hurler syndrome (MPS I-H), Maroteaux-Lamy (MPS VI) Gaucher disease, and fucosidosis have been successfully treated following long-term engraftment. Central nervous system (CNS) manifestations are also prevented or ameliorated in animal models of these diseases following engraftment from normal donors. The microglial cell system has been considered to be the most likely vehicle for enzyme activity following bone marrow engraftment. Microglia in the mature animal or human are derived from the newly engrafted bone marrow. Graft-v-host disease activation of the microglia is also of importance. This article will summarize some of the pertinent literature relative to the role of microglia in such transplant processes.

Factors influencing serum levels of carbamazepine and carbamazepine-10,11-epoxide in children.

Carbamazepine-10,11-epoxide (CBZ-E), the principal metabolite of carbamazepine (CBZ), is reported to have antiepileptic and toxic effects similar to CBZ. Steady-state CBZ and CBZ-E levels (high performance liquid chromatography, HPLC assay) were reviewed in 225 outpatient children and young adults taking CBZ with or without other antiepileptic drugs (AEDs). In patients on CBZ alone, mean serum concentration of CBZ was 7.9 +/- 1.9 micrograms/ml and of CBZ-E was 1.5 +/- 0.6 micrograms/ml. The CBZ-E/CBZ ratio was 19.6 +/- 2.4%. Serum CBZ increased with increasing age and with CBZ dose. CBZ-E increased with increasing CBZ dose but was unaffected by age. The CBZ-E/CBZ ratio progressively declined with age. Co-medication with barbiturates or valproic acid significantly increased CBZ-E. Phenytoin showed a similar trend while ethosuximide caused the least change. Patients on CBZ and two or more other AEDs had highest CBZ-E levels and CBZ-E/CBZ ratio. CBZ and CBZ-E levels are variably affected by age, CBZ dose, and co-medication with other AEDs. When other AEDs are administered, careful monitoring is especially indicated in order to avoid toxicity.

Absence seizures and variants.

Absence seizures include classic absence, impulsive petit mal, juvenile absence seizures with myoclonic phenomena, and atonic-astatic seizures. Proper diagnosis requires careful historical elucidation of the actual seizure events, family history of seizures, and of other neurologic abnormalities. Electroencephalographic studies must include proper activation techniques. Treatment is initiated with antiepileptic drugs likely to be effective against generalized discharges: ethosuximide and valproate.

Management of generalized seizures in childhood.

The management of generalized seizures, the most common in childhood, depends upon accurate diagnosis, choice of appropriate antiepileptic drug, and attention to detail in the choice of diagnostic and therapeutic modalities. Most patients with generalized seizures can achieve control but the long-term prognosis may be less favorable than is widely believed.

Massive focal brain swelling as a feature of MELAS.

Two patients are reported with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes in whom CT documented massive focal brain swelling with midline shift concurrent with exacerbations of their conditions. Brain swelling producing mass effect should be recognized as a feature of MELAS.

Acute parkinsonian syndrome with demyelinating leukoencephalopathy in bone marrow transplant recipients.

A syndrome of rigidity, bradykinesia, spasticity, and often myoclonus and dementia developed acutely in 5 patients who had undergone successful engraftment of bone marrow transplants for the treatment of various hematologic diseases. Magnetic resonance imaging demonstrated widespread changes in white matter; brain biopsy disclosed mild demyelination associated with active phagocytosis of myelin. One patient, who was not treated, remains severely demented. Patients treated with very high-dose methylprednisolone had complete clinical recovery.

CSF findings in adrenoleukodystrophy: correlation between measures of cytokines, IgG production, and disease severity.

The childhood-onset cerebral form of adrenoleukodystrophy has a devastating neurologic prognosis. Unfortunately, there is no early method of distinguishing it from the more benign forms of adrenoleukodystrophy, such as adrenomyeloneuropathy. To evaluate the manner in which this disease entity may be reflected in the cerebrospinal fluid, we studied a consecutive series of 19 patients, all with biochemically proved adrenoleukodystrophy. total protein, immunoglobulin production, cytokine levels, and cerebrospinal fluid pressure were measured. In this single sample of cerebrospinal fluid, a significant correlation existed between clinical stage of the illness and cerebrospinal fluid myelin basic protein. No correlation existed with total protein, cytokines, or measures of immunoglobulin production.

Prevention of deterioration in metachromatic leukodystrophy by bone marrow transplantation.

The first girl in a family was affected with late infantile metachromatic leukodystrophy (MLD) and had the expected characteristic central nervous system progressive deterioration, which resulted in decerebration and death. The second girl (propositus) demonstrated similar symptoms and signs at the same age. Both girls had characteristically low arylsulfatase A levels. The propositus underwent allogeneic bone marrow transplantation (BMT) from a normal histocompatible sibling. Two and a half years later, the propositus has not developed the intellectual and neurologic impairment demonstrated by the first sibling, although nerve conduction has continued to worsen. These results suggest that the induction of normal enzyme levels by BMT may be retarding or inhibiting CNS deterioration. These results, confirming earlier results of others, are sufficiently promising to warrant a larger scale critical trial of BMT early in the course of MLD.

Absence, myoclonic, and atonic seizures.

This article describes the typical absence attack, as well as the typical manifestations of myoclonic and atonic seizures. It reviews the usual treatment, including pharmacology, and gives the prognosis for these entities.