A novel approach to the study of hypoxia-ischemia-induced clinical and subclinical seizures in the neonatal rat.

Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of acute mortality and chronic neurologic morbidity in infants and children. HIE is the most common cause of neonatal seizures, and seizure activity in neonates can be clinical, with both EEG and behavioral symptoms, subclinical with only EEG activity, or just behavioral. The accurate detection of these different seizure manifestations and the extent to which they differ in their effects on the neonatal brain continues to be a concern in neonatal medicine. Most experimental studies of the interaction between hypoxia-ischemia (HI) and seizures have utilized a chemical induction of seizures, which may be less clinically relevant. Here, we expanded our model of unilateral cerebral HI in the immature rat to include video EEG and electromyographic recording before, during and after HI in term-equivalent postnatal-day-12 rats. We observed that immature rats display both clinical and subclinical seizures during the period of HI, and that the total number of seizures and time to first seizure correlate with the extent of tissue damage. We also tested the feasibility of developing an automated seizure detection algorithm for the unbiased detection and characterization of the different types of seizure activity observed in this model.

Proximal femoral growth disturbance in developmental dysplasia of the hip: what do we know?

BACKGROUND: Proximal femoral growth disturbance (PFGD) can be the most devastating complication of the treatment of development dysplasia of the hip. The reported incidence ranges from 0% to 73%. The condition involves varying degrees of growth disturbances of the femoral capital epiphysis, the physeal plate or both. PURPOSE: This manuscript will discuss normal growth and development of the hip, the blood supply to the upper end of the femur, pathological and radiographic changes, classifications used to describe PFGD and, most importantly, the potential causes of these growth disturbances and the authors' strategies for avoiding PFGD.

Adaptive electric field control of epileptic seizures.

We describe a novel method of adaptively controlling epileptic seizure-like events in hippocampal brain slices using electric fields. Extracellular neuronal activity is continuously recorded during field application through differential extracellular recording techniques, and the applied electric field strength is continuously updated using a computer-controlled proportional feedback algorithm. This approach appears capable of sustained amelioration of seizure events in this preparation when used with negative feedback. Seizures can be induced or enhanced by using fields of opposite polarity through positive feedback. In negative feedback mode, such findings may offer a novel technology for seizure control. In positive feedback mode, adaptively applied electric fields may offer a more physiological means of neural modulation for prosthetic purposes than previously possible.

Phosphatidylinositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-beta.

Bacterial lipopolysaccharide (LPS) elicits responses by macrophages that help the body repel infections. Recent evidence indicates that phosphatidylinositol 3-kinase (PI 3-kinase) may mediate some of these responses. Here, we show that exposing macrophages to LPS rapidly increased membrane-associated PI 3-kinase activity and also elevated p70 S6 kinase activity. Inhibitors of PI 3-kinase or the mammalian target of rapamycin (mTOR) fully blocked p70 S6 kinase activation, implying that this kinase is controlled by PI 3-kinase and mTOR. These inhibitors also substantially reduced LPS-induced nitric oxide (NO) production. This inhibition was, in part, attributable to impaired LPS-stimulated secretion of interferon-beta, an autocrine co-factor for NO production. However, the addition of exogenous interferon-beta did not fully restore NO production, indicating that the NO response was being inhibited by another mechanism as well. Together, these data suggest that PI 3-kinase, mTOR, and possibly p70 S6 kinase mediate LPS-induced NO production by regulating the secretion of interferon-beta and by a second undefined mechanism.

Duchenne muscular dystrophy: deficiency of dystrophin-associated proteins in the sarcolemma.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a major component of the subsarcolemmal cytoskeleton and exists in a large oligomeric complex tightly associated with several sarcolemmal glycoproteins which provide a linkage to the extracellular matrix protein, laminin. In the present study, we investigated the status of the dystrophin-associated proteins in the skeletal muscle from 17 DMD patients of various ages. The results revealed a dramatic reduction in all of the dystrophin-associated proteins in the sarcolemma of DMD muscle compared with normal muscle and muscle from a variety of other neuromuscular diseases. This abnormality was common in all 17 DMD patients, irrespective of age. Our results indicate that the absence of dystrophin leads to the loss in all of the dystrophin-associated proteins, which renders DMD muscle fibers susceptible to necrosis. The analysis of dystrophin-associated proteins is important in the assessment of experimental therapies that attempt to replace dystrophin in DMD muscle.

The sudden infant death syndrome and apnea/obstruction during neonatal sleep and feeding.

Respiratory observations made during nutritive feeding and a complete daytime nap within the first week of life on ten newborns who subsequently were victims of sudden infant death syndrome (SIDS) were compared with normative data based on 1,301 infants of comparable ages. Measurements were obtained of all apneic pauses and/or transient respiratory obstructive events at least two seconds in duration. A statistically significant increased number of future SIDS victims were found to have an unusual amount of apnea/obstruction episodes during nutritive feeding when compared with the normative group. Future SIDS victims, as a group, also had an increased frequency of apneic pauses during sleep. Furthermore, all SIDS victims demonstrated either an unusual amount of apnea/obstruction during nutritive feeding or apneic pauses during sleep. None of the airway obstruction measures during sleep differentiated the SIDS infants from the normative group. These results are consistent with the general hypothesis that prolonged apnea or airway obstruction is part of the pathophysiologic process resulting in SIDS and those hypotheses implicating unstable respiratory activity during sleep as well as apnea and pharyngeal/laryngeal dysfunction induced by liquid stimulation of the upper airway. They are also compatible with the growing body of evidence indicating that factors that predispose an infant to SIDS originate in the perinatal period.

Pentasomy X with multiple dislocations.

We describe a pentasomy X (49,XXXXX) patient whose multiple dislocations led to a consideration of the Larsen syndrome. Review of the 11 reported cases of pentasomy X showed that elbow dislocations are known to occur in this syndrome. Our patient is the first to present hypoplasia of the glenoid process with consequent should dislocation. Clinical and radiologic findings of previously reported cases of pentasomy X are reviewed.

Treatment for fixation complications: Femoral neck fractures.

Of 102 hips with femoral neck fracture complications, 75 required major secondary procedures such as total hip replacement, femoral prosthesis, cup arthroplasty, tibial bone grafting, and head and neck resection. The method chosen depended on the specific problem: nonunion, aseptic necrosis, infection, degenerative arthritis, or a failed primary prosthesis. Other factors influencing treatment were the patient's chronological and physiological age, his general health, his life pattern, and the familiarity of the surgeon with the technique and the advantages and disadvantages of the various salvage procedures.

The effects of contact pressure elevations and aseptic necrosis on the long-term outcome of congenital hip dislocation.

The relationship between excessive articular contact pressure, aseptic necrosis, and the long-term outcome with unilateral congenital dislocation of the hip (CDH) was studied in a series of 84 patients treated by closed reduction and followed for an average of 29.2 years. Contact stress was estimated from archived radiographs taken at the time of maturity and at several follow-up visits. At a recent review, each patient was rated both clinically for pain and function and radiographically for deformity, degeneration, and aseptic necrosis. For each of 431 archived films, articular contact stress (force/area) was estimated mathematically, based upon a frontal plane equilibrium (force) analysis and a landmark-based inference of three-dimensional head surface (area). Good correlation with final deformity (Spearman rho = 0.78) was obtained when the hips were ranked in terms of a new cumulative overpressure index Pc, defined as a time-pressure product involving years of pressure exposure beyond a 2 MPa pressure damage level. An unsatisfactory outcome occurred in 90.4% of the hips experiencing Pc greater than 10 MPa-years (most of which had aseptic necrosis involvement), whereas the outcome was satisfactory in 80.9% of hips with Pc less than 10 MPa-years.

Early seizure detection.

For patients with medically intractable epilepsy, there have been few effective alternatives to resective surgery, a destructive, irreversible treatment. A strategy receiving increased attention is using interictal spike patterns and continuous EEG measurements from epileptic patients to predict and ultimately control seizure activity via chemical or electrical control systems. This work compares results of seven linear and nonlinear methods (analysis of power spectra, cross-correlation, principal components, phase, wavelets, correlation integral, and mutual prediction) in detecting the earliest dynamical changes preceding 12 intracranially-recorded seizures from 4 patients. A method of counting standard deviations was used to compare across methods, and the earliest departures from thresholds determined from non-seizure EEG were compared to a neurologist's judgement. For these data, the nonlinear methods offered no predictive advantage over the linear methods. All the methods described here were successful in detecting changes leading to a seizure between one and two minutes before the first changes noted by the neurologist, although analysis of phase correlation proved the most robust. The success of phase analysis may be due in part to its complete insensitivity to amplitude, which may provide a significant source of error.

Use of recombinant human erythropoietin to avoid blood transfusion in a Jehovah's Witness requiring hemispherectomy. Case report.

The use of perioperative human recombinant erythropoietin is described in a Jehovah's Witness patient. Despite significant anemia, the child's hematocrit was sufficiently increased by the use of erythropoietin so that a two-stage hemispherectomy could be performed without blood transfusion.

Scoliosis in pediatric Chiari malformations without myelodysplasia.

A prospective study was undertaken in 1985 to better understand how the surgical manipulation of hindbrain herniation affected abnormal spinal curvature. Eleven patients under 16 years of age with Chiari malformation (not associated with myelodysplasia) and scoliosis of at least 15 degrees were studied. The mean curve angle at the time of original treatment was 29 degrees, with the convexity to the right in seven patients. The curvature was rapidly progressing in four patients. The most common presenting signs were myelopathy and weakness. Investigative procedures included spine radiographs with the patient standing and magnetic resonance (MR) imaging of the brain, spinal cord, and craniovertebral junction. Eight children had associated hydrosyringomyelia. Surgical intervention consisted of a dorsal posterior fossa decompression in all patients and a transoral ventral decompression of the cervicomedullary junction in five. All patients were followed at 3, 6, and 12 months, and at yearly intervals thereafter with clinical evaluations, spine radiographs in the standing position, and postoperative MR imaging. The mean follow-up period was 35 months. The scoliosis improved in eight patients, stabilized in one, and progressed in two. Only one child required postoperative spinal fusion and instrumentation for progression of scoliosis. Hematomyelia or hematobulbia was associated with persistent scoliosis in two patients. The presence of hydrosyringomyelia and bone erosion did not preclude curve improvement. All patients under 10 years of age had resolution of their scoliosis, despite preoperative curves of more than 40 degrees. These findings emphasize the importance of early surgical intervention, with the restoration of normal cerebrospinal fluid dynamics at the craniovertebral junction in children with symptomatic Chiari malformations.

Closed reduction for congenital dysplasia of the hip. Functional and radiographic results after an average of thirty years.

The functional and radiographic results of closed reduction in 152 congenitally dislocated hips of 119 patients who had been managed between 1938 and 1969 were reviewed retrospectively. The average age of the patients at the time of the reduction was twenty-one months (range, one to ninety-six months). At the time of the latest follow-up evaluation, the average age was thirty-one years (range, sixteen to fifty-six years). The average duration of follow-up was thirty years (range, fifteen to fifty-three years). At the latest follow-up evaluation, the Iowa hip rating averaged 91 points (range, 38 to 100 points) and the Harris hip score averaged 90 points (range, 33 to 100 points). Thirty-five hips were rated Severin Class I; thirty-five, Class II; twenty-eight, Class III; fifty-three, Class IV; and one, Class VI. Disturbance of growth in the proximal end of the femur occurred in ninety-one hips (60 per cent). Eight contralateral hips that had appeared normal also demonstrated disturbance of proximal femoral growth. In many hips, partial physeal arrest could not be determined for ten to twelve years after the reduction. Seventeen hips (twelve patients) had a total replacement when the patients were an average age of thirty-six years (range, nineteen to fifty-three years). Sixty-five hips (43 per cent) had radiographic evidence of degenerative joint disease. Patients who did not have a growth disturbance of the proximal end of the femur or evidence of subluxation tended to function extremely well for many years despite a radiographic result that was less than anatomical. Function tended to deteriorate with time, even in the absence of disturbance of growth in the proximal end of the femur. Despite generally good function at the latest follow-up evaluation, the prognosis for these patients remained guarded.

Spike osteotomy for angular deformities of the long bones in children.

We reviewed the results of fifty consecutive spike osteotomies that were performed in thirty-five children for the treatment of angular deformity of a long bone. After forty-three of the procedures, the radiographs were adequate to assess the stability of the fragments. At the time of healing, the average loss of correction from the position that had been accepted at operation was 2 degrees in the anterior-posterior plane and 1.2 degrees in the lateral plane. In four limbs, more than 5 degrees of correction had been lost. No patient lost more than 10 degrees of correction. The rates of complications and of recurrence were similar to those of other reported series. We concluded that the spike osteotomy is safe and effective.

Long-term follow-up of patients with grade-III and IV spondylolisthesis. Treatment with and without posterior fusion.

The outcome in eleven patients in whom Grade-III and IV spondylolisthesis was treated non-operatively (Group I) was compared with that in twenty-one patients in whom the same degrees of spondylolisthesis were treated by posterior interlaminar fusion (Group II). At an average eighteen-year follow-up of the eleven patients in Group I, four (36 per cent) were asymptomatic, six (55 per cent) had mild symptoms, and only one had significant symptoms. Five (45 per cent) had one or more neurological findings, but none were incontinent. All of the patients in this group led an active life, and all had required only minor adjustments in their life-style. At an average twenty-four-year follow-up of the twenty-one patients in Group II, twelve (57 per cent) were asymptomatic, eight (38 per cent) had mild symptoms, and only one had significant symptoms. Nine (50 per cent) of the eighteen patients who had a physical examination had one or more neurological findings. Roentgenographically demonstrated failure of fusion did not adversely affect the results, and the patients remained asymptomatic despite the development of pseudarthrosis in one patient and bending of the fusion mass in three (14 per cent). In situ arthrodesis provides acceptable results for the patient who has Grade-III or IV spondylolisthesis and pain that interferes with life-style and that is unresponsive to non-operative treatment. In the skeletally immature patient, in situ fusion is recommended for disturbances of gait secondary to tight hamstrings and when the spondylolisthesis progresses.

Curve progression in idiopathic scoliosis.

One hundred and thirty-three curves in 102 patients who were followed for an average of 40.5 years were evaluated to quantitate curve progression after skeletal maturity and for prognostic factors leading to curve progression. Sixty-eight per cent of the curves progressed after skeletal maturity. In general, curves that were less than 30 degrees at skeletal maturity tended not to progress regardless of curve pattern. In thoracic curves the Cobb angle, apical vertebral rotation, and the Mehta angle were important prognostic factors. In lumbar curves the degree of apical vertebral rotation, the Cobb angle, the direction of the curve, and the relationship of the fifth lumbar vertebra to the intercrest line were of prognostic value. Translatory shifts played an important role in curve progression. Curves that measured between 50 and 75 degrees at skeletal maturity, particularly thoracic curves, progressed the most.

Congenital dislocation of the hip.

From January 1970 to December 1976, seventeen patients with twenty-two congenital hip dislocations were treated by open reduction through a medial approach. The average follow-up was 42.2 months. The patients were evaluated for acetabular development, aseptic necrosis, and intraoperative findings. The incidence of aseptic necrosis was 10 per cent. The acetabular index improved rapidly during the first year after reduction. After the first year the rate of development was decreased, but the acetabular index continued to improve throughout the period of study. The medial approach provides a safe, effective way to reduce a dislocated hip in infancy. This procedure is advocated when closed reduction cannot be obtained by gentle manipulation or maintained by positioning once reduction is done.

A long-term follow-up of Legg-Calvé-Perthes disease.

In an effort to define the impairment in hips affected by Legg-Calvé-Perthes disease, we attempted to contact 112 patients whose disease had been diagnosed between 1920 and 1940. Data were available on thirty-five patients with thirty-seven affected hips. The average period of follow-up was 47.7 years. Statistically significant correlations were found between clinical outcome (as measured by the Iowa hip rating and by the incidence of arthroplasty) and Catterall head-at-risk signs, femoral head-size ratio, and age at onset of the disease. The measurements of deformity, both femoral and acetabular, and the congruity of the articular surfaces did not change significantly with time. The Catterall classification alone did not correlate well with the clinical outcome. Fifteen affected hips in fourteen patients had undergone hip arthroplasty because of pain and dysfunction. Eleven arthroplasties had been done in the fifth or sixth decade of life and four (three patients), in the third or fourth decade.

The long-term functional and radiographic outcomes of untreated and non-operatively treated metatarsus adductus.

Thirty-one patients (forty-five feet) who had metatarsus adductus were evaluated at our institution and were followed for an average of thirty-two years and six months. Of these thirty-one patients, twenty-one (thirty-one feet) were examined clinically and radiographically. Information on the remaining ten patients (fourteen feet) was obtained by letter or telephone, or both. Twelve patients (sixteen feet) who had a passively correctable deformity (mild or moderate) at the time of the initial presentation had no treatment. Twenty patients (twenty-nine feet) who had a partly flexible or rigid deformity (moderate or severe) at the time of the initial presentation were managed with serial manipulation and application of plaster holding casts. (One patient who had a bilateral deformity had no treatment on one side and conservative management on the other). The results were good in all sixteen of the untreated feet and in twenty-six (90 per cent) of the twenty-nine feet that had been conservatively treated. There were no poor results. The passively correctable deformities resolved spontaneously. Radiographs showed an obliquity of the medial cuneiform-metatarsal joint in twenty-one (68 per cent) of the thirty-one feet that were examined clinically and radiographically. Similar findings were observed in four of eleven contralateral, normal feet. Hallux valgus was not a common outcome. No patient had operative correction.

Long-term follow-up of slipped capital femoral epiphysis.

The data on 155 hips in 124 patients who had slipped capital femoral epiphysis were retrospectively reviewed at a mean follow-up of forty-one years after the onset of symptoms. The slips were classified, by the duration of symptoms, as acute, chronic, or acute on chronic. As determined by the head-shaft angle, 42 per cent of the slips were mild; 32 per cent, moderate; and 26 per cent, severe. Reduction was performed in thirty-nine hips, and realignment was done in sixty-five hips. Treatment of chronic slips included symptomatic only in 25 per cent of the hips, a spica cast in 30 per cent, pinning in 24 per cent, and osteotomy in 20 per cent. The Iowa hip-rating and the radiographic classification of degenerative joint disease were determined at follow-up; both worsened with increasing severity of the slip and when reduction or realignment had been done. Osteonecrosis (12 per cent) and chondrolysis (16 per cent) also were more common with increasing severity of the slip and when reduction or realignment had been performed; both led to a poor result. Deterioration over time was most marked with increasing severity of the slip. The natural history of the malunited slip is mild deterioration related to the severity of the slip and complications. Techniques of realignment are associated with a risk of appreciable complications and adversely affect the natural history of the disease. Regardless of the severity of the slip, pinning in situ provided the best long-term function and delay of degenerative arthritis, with a low risk of complications.