Successful Pneumocystis carinii pneumonia prophylaxis using aerosolized pentamidine in children with acute leukemia.

PURPOSE: We report our experience replacing trimethoprim-sulfamethoxazole (TMP/SMX) with aerosolized pentamidine (AP) in 22 children with acute leukemia who could not tolerate TMP/SMX. PATIENTS AND METHODS: Children (age 1 to 15 years) with acute leukemia during maintenance chemotherapy or post-bone marrow transplantation (BMT) receiving prophylaxis for Pneumocystis carinii pneumonia (PCP) with TMP/SMX received AP following prolonged neutropenia or allergy to TMP/SMX. Patients received 300 mg of AP monthly (children < 4 years received 150 mg) dissolved in 5 mL of distilled water over 20 to 30 minutes. RESULTS: Over a 3-year period, 358 courses of AP were administered over 10,124 observable days. AP was adequately tolerated on a monthly basis for prophylaxis against PCP in 22 children with acute leukemia. AP was demonstrated to be effective in preventing PCP. There were minimal side effects observed during this trial. The majority of children with acute lymphoblastic leukemia (ALL; 12 of 14 [86%]) undergoing maintenance chemotherapy were able to resume full-dose therapy. CONCLUSION: AP in children is well tolerated and shows high efficacy for PCP prophylaxis in children with leukemia. We conclude that AP should be considered as second-line PCP prophylactic therapy for children with acute leukemia in instances in which TMP/SMX cannot be tolerated. Phase III trials are required to determine its effect on dose intensification and event-free survival.

Clinical research techniques in tardive dyskinesia.

The authors have developed standardized assessment and control techniques designed to provide objective measures of tardive dyskinesia in patients progressing through an experimental treatment program. Standardized videotaping is carried out and blind ratings on the Abnormal Involuntary Movement Scale are made by a team of psychiatrists and neurologists. Other assessments include several measurements of vocal function and a quantitative acceleration profile standardized on normal subjects. Such measures allow quantifiable determination of response to drug treatment and may provide clues to the etiology and definition of the dyskinetic syndrome.

Rett's syndrome. Correlation of electroencephalographic characteristics with clinical staging.

Rett's syndrome is a progressive disorder in female patients, characterized by autistic behavior, dementia, ataxia, loss of purposeful use of the hands, and seizures. The electroencephalographic (EEG) characteristics of 17 patients with Rett's syndrome, studied between the ages of 1 and 16 years, are reported and correlated with a recently proposed system of clinical staging. Although a specific diagnostic EEG pattern was not seen in these patients, we did observe a progressive deterioration in the EEG, characterized by a slowing of EEG activity, a loss of normal sleep EEG characteristics, and the appearance of multifocal epileptiform abnormalities, followed by a pattern of generalized slow spike-wave activity. These characteristics appear to be typically seen in patients with Rett's syndrome and can be correlated with clinical staging. The EEG may be of benefit in identifying variations or subgroups in patients with Rett's syndrome as a complement to the clinical examination.

Quantitative assessment of parkinsonian and essential tremor: clinical application of triaxial accelerometry.

Triaxial accelerometry was used to study various motion characteristics in 10 patients with Parkinson disease and 11 patients with essential tremor. The smoothness of motion factor (SPMEF) and the acceleration waveform factor (TIPAR) were frequently and consistently abnormal. When both factors were analyzed together and compared with a control population, 100% of the left arm and 88% of the right arm values were abnormal in the Parkinson disease group, and 82% of the left arm and 91% of the right arm values were abnormal in the essential tremor patients. Repeat evaluation revealed consistent intrapatient results. Therefore, this technique may provide an objective assessment of movement disorders.

Effect of tetrabenazine on tics and sleep of Gilles de la Tourette's syndrome.

Supersensitivity of dopaminergic receptors may be responsible for the tics of Tourette's syndrome. Symptoms improve after treatment with dopamine blockers, but side effects limit use of these drugs. We evaluated tetrabenazine (which has both presynaptic monoamine-depleting effects and postsynaptic blocking action) in nine patients. Marked and lasting (more than 6 months) improvement occurred in four patients (ages 10 to 14 years), mild or transient (less than 6 months) improvement occurred in three patients (ages 11 to 20 years), and two patients (age 48 years) had minimal or no response. Side effects included drowsiness in six, "nervousness" in two, depression in two, parkinsonism in one, and oculogyric crises in one, but all undesirable effects cleared with maintenance or reduction of the dosage.

Sleep in Gilles de la Tourette's syndrome: disorder of arousal.

Overnight polygraphic sleep studies, which included accelerometry and video monitoring, were performed on 14 Tourette patients before therapy and on 11 age-matched controls. Tourette patients less than 23 years old had a significantly increased percentage of stage 3/4 sleep, had an increased number of awakenings, had a decreased percentage of REM sleep, experienced paroxysmal events during stage 4 sleep, and had motor tics during all stages of sleep. Three patients were treated with tetrabenazine and subsequently showed significant decreases in percentage of total sleep, number of awakenings, and number of tics during sleep. These findings suggest a disorder of arousal in Tourette patients.

Sleep characteristics in infantile spasms.

Sleep staging was performed on 32 patients with infantile spasms. All patients demonstrated significantly less total sleep time and lower percentage of REM time than the expected normal values for age. Seventeen were treated with ACTH or prednisone. There was no increase in total sleep time in those who received hormone therapy, whether or not it was successful. However, the percentage of REM time increased significantly in patients who responded to therapy; this increase occurred concurrently with clinical and electroencephalographic improvement. There was no significant change in REM-sleep values in patients who did not respond.

Infant apnea: polygraphic studies and follow-up monitoring.

Twenty-six infants with unexplained and apparently life-threatening apnea were evaluated clinically, underwent eight- or 12-hour polygraphic recordings during sleep, and were then observed on home monitors. The one exception was an infant who was treated with theophylline and not monitored at home. Clinical evaluation revealed a history of vomiting in 19 infants, gastroesophageal reflux (GER) on esophagram in 19, and subtle neurologic abnormalities in ten. Polygraphic studies revealed questionable EEG abnormalities in nine infants, abnormal rapid eye movement (REM) time in four, prolonged apnea in one, and increased frequency of brief mixed (central and obstructive) and obstructive apneas in five. Of the 11 infants who underwent pH monitoring during their polygraphic sleep studies, seven had at least one recorded episode of GER, but the episodes were not accompanied by apnea or bradycardia. Thirteen infants had a subsequent episode of apnea that required stimulation, and in eight infants, cardiopulmonary resuscitation was given. There was two deaths. Two infants subsequently developed seizure disorders. Three of the five infants who underwent surgical fundoplication had recurrent apneic episodes. GER commonly occurred in these infant apnea patients but did not correlate with the clinical outcome. Although subtle abnormalities may be detected by sophisticated polygraphic monitoring studies, they are not predictive of recurrent apnea or death. Home monitoring may be useful in detecting the infant at risk for recurrent life-threatening apnea and in providing some safeguard for that infant.

Two siblings with recurrent cardiorespiratory arrest: Munchausen syndrome by proxy or child abuse?

The terms "Munchausen syndrome by proxy" or "Polle syndrome" have been used to describe children who are victims of parentally induced or fabricated illness. This report gives case histories of two siblings (a 7-month-old girl and a 4-year-old boy) with recurrent episodes of cardiorespiratory arrest that were induced by a mother who skillfully resuscitated the children and who demonstrated model parental behavior. Polygraphic monitoring with hidden camera was used to determine that the episodes of cardiorespiratory arrest were parentally induced in the infant. The 4-year-old sibling had previously undergone multiple diagnostic and surgical procedures. After the diagnosis was made in the infant, and the mother was no longer permitted to be alone with the children, neither child had further episodes. A psychologic profile of the mother is presented, and special features of these two and other cases in the literature are reviewed. These cases represent a form of child abuse. A parentally induced illness should be considered in the differential diagnosis of unusual illnesses with bizarre features, even when the parent's behavior appears exemplary.

An IL-2/Ig fusion protein influences CD4+ T lymphocytes in naive and simian immunodeficiency virus-infected Rhesus monkeys.

The T cell-stimulatory cytokine interleukin 2 (IL-2) is being evaluated as a therapeutic in the clinical settings of HIV infection and cancer. However, the clinical utility of IL-2 may be mitigated by its short in vivo half-life, toxic effects, and high production costs. We show here that an IL-2/Ig fusion protein possesses IL-2 immunostimulatory activity in vitro and a long in vivo half-life. IL-2/Ig treatment of healthy rhesus monkeys induced significant increases in CD4(+) T lymphocyte counts and expression of CD25 by these cells. Short courses of IL-2/Ig treatment of simian immunodeficiency virus (SIV)-infected rhesus monkeys in conjunction with antiretroviral drugs resulted in increased CD25 expression on T lymphocytes, and transient increases in CD4(+) T lymphocyte counts. Plasma viremia did not increase in these treated animals. Treatment of healthy or SIV-infected rhesus monkeys with a plasmid encoding the IL-2/Ig protein did not affect CD4(+) T lymphocytes. These results demonstrate that IL-2/Ig has potential utility as an immunostimulatory therapeutic.

Insomnia in the elderly: treatment with flurazepam hydrochloride.

Under sleep-laboratory control, the efficacy of flurazepam hydrochloride (15 mg) was evaluated in 6 women (age range, 67-82 years) with objectively verified insomnia. A 15-night, single-blind, crossover procedure was followed. Sleep records obtained during 3 placebo-baseline nights, 7 consecutive flurazepam nights, and 3 placebo-withdrawal nights were evaluated by means of electroencephalographic, electro-oculographic, and electromyographic criteria. A statistically significant reduction in sleep latency and total awake time and a corresponding increase in total sleep time (P less than 0.05) were demonstrated during the active drug period. No evidence of diminishing effectiveness was observed during the 7 days of drug administration. For the rapid-eye-movement (REM) stage, a significant decrease (P less than 0.05) in mean REM percent was noted during the drug period despite an increase in mean absolute REM time. No REM rebound occurred upon drug withdrawal. There were no significant changes in mean percentages for stages 3 and 4 during the drug period and the withdrawal period. Adverse reactions were rare (chiefly some daytime drowsiness in 2 subjects).

The presence of CD34+ cell clusters predicts impending relapse in children with acute lymphoblastic leukemia receiving maintenance chemotherapy.

Early detection of relapse in children with acute lymphoblastic leukemia (ALL), as well as distinction of leukemic blasts from hematogones, can be difficult by morphologic examination alone. Using CD34 and terminal deoxynucleotidyl transferase (TdT) immunoperoxidase stains, we studied specimens from 25 children with ALL in morphologic remission to determine if we could identify children at risk of relapse. We studied morphologic remission bone marrow specimens from 9 patients who experienced relapse during the subsequent 6 months and 16 children who remained in complete remission, including 10 specimens with increased numbers of hematogones. Despite morphologic remission, clusters of more than 5 CD34+ and/or TdT-positive cells were identified before overt relapse in 6 of 9 cases of relapse, but were noted in only 1 of 10 specimens from children in continuous complete remission and none of 10 specimens with increased numbers of hematogones. Clusters of CD34+ or TdT-positive cells can identify individual patients at risk for imminent relapse. Hematogones may be differentiated from lymphoblasts by this method.

Tetanus toxin-induced seizures in infant rats and their effects on hippocampal excitability in adulthood.

A new experimental model of developmental epilepsy is reported. Behavioral and EEG features of seizures produced by unilateral intrahippocampal injection of tetanus toxin in postnatal day 9-11 rats, are described. Within 24-72 h of tetanus toxin injection, rat pups developed frequent and often prolonged seizures which included combinations of repetitive wet dog shakes, and wild running-jumping seizures. Intrahippocampal and cortical surface EEG recordings showed that coincident with these behaviors, electrographic seizures occurred not only in the injected hippocampus, but also in the contralateral hippocampus and bilaterally in the neocortex. Analysis of the interictal EEG revealed multiple independent spike foci. One week following tetanus toxin injection, the number of seizures markedly decreased; however, interictal spiking persisted. After injection rats were allowed to mature some were observed to have unprovoked behavioral seizures and/or epileptiform EEG activity. Mature animals were also studied using in vitro slice techniques. Recordings from hippocampal slices demonstrated spontaneous epileptiform burst discharges in the majority of rats which had tetanus toxin induced seizures as infants. These events occurred in area CA3 and consisted of interictal spikes and intracellularly recorded paroxysmal depolarization shifts (PDSs). On rarer occasions, electrographic seizures were recorded. The use of the tetanus toxin model in developing rats may facilitate a better understanding of the unique features of epileptogenesis in the developing brain and the consequences early-life seizures have on brain maturation and the genesis of epileptic conditions in later life.

Automatic recognition and characterization of epileptiform discharges in the human EEG.

Methods proposed for the automatic identification and quantification of epileptiform EEG activity are reviewed, and the potential role of this technology in clinical electroencephalography is assessed. Techniques developed for the detection of spikes, sharp waves, and spike and wave complexes are described. Emphasis is placed on the problems associated with artifact rejection and the need for establishing context-based decision-making processes.

Coupling of focal electrical seizure discharges with infantile spasms: incidence during long-term monitoring in newly diagnosed patients.

To investigate the coupling of focal electrical seizure discharges (FS) and infantile spasms, we analyzed the video/polygraphic monitoring studies performed on 96 consecutive patients newly diagnosed with infantile spasms and hypsarrhythmic EEGs. A FS was considered to be coupled with infantile spasms if it occurred during a cluster of spasms (a series of individual spasms separated by < 1 min) or within 10 s of spasm onset or cessation. Ten patients demonstrated FS. In five patients (5% of the entire population) an apparent coupling of some FS with infantile spasms was observed during the baseline monitoring study. However, in three patients (only 3% of the entire population) was the observed coupling of FS and infantile spasms significant (p < 0.05). These results indicate that coupling of FS and infantile spasms occurs rarely, and that, in some instances, apparent couplings of FS and infantile spasms are best explained by chance coincidence. These findings do not support the hypothesis that the generation of infantile spasms at a subcortical level is dependent on a focal cortical discharge.

An automated system for epileptogenic focus localization in the electroencephalogram.

This paper describes an automated system for the detection and localization of foci of epileptiform activity in the EEG. The system detects sharp EEG transients (STs) in the process, but the emphasis is on epileptic focus localization. A combination of techniques involving signal processing, pattern recognition, and the expert rules of an experienced electroencephalographer, involving considerable spatiotemporal context information, is applied to multichannel EEG data. An overall emphasis on minimizing the number of false-positive sharp transient detections drives the system design. Tested on data from 13 subjects with epileptiform activity and 5 controls, all areas of focal epileptiform activity were detected by the system, although not all of the contributing foci were reported separately. Two false-positive foci were detected as well due to nonfocal spike activity and normal spike-like activity not present in the training set. The system detected 95.7% of the epileptiform events constituting the correctly detected foci, with a false detection rate of 11.1%.

Alpha rhythm slowing during initiation of carbamazepine therapy: implications for future cognitive performance.

A prospective study comparing the immediate changes in occipital electroencephalographic (EEG) frequency following institution of carbamazepine therapy to long-term alterations of neuropsychological performance is reported. The patient group consisted of 16 previously untreated children in the 5-14-year age range who had recent onset partial seizures and were managed for at least 1 year with carbamazepine monotherapy. EEG changes following initiation of carbamazepine therapy, as compared to baseline, were determined by a computer-based quantitative method. Neuropsychological factors were assessed at baseline and after 1 year of therapy. While the alpha frequency decreased following institution of carbamazepine in most subjects, a greater decline (typically > 0.5 Hz) was observed in the subset who subsequently demonstrated decreased neuropsychological performance at 1 year. The major effects could be attributed to the Arithmetic and Picture Completion subtests of the Wechsler Intelligence Scale for Children-Revised (WISC-R). The findings suggest that quantitative EEG analysis may be useful for identifying individuals at increased risk for developing anticonvulsant-related long-term cognitive changes.

Extraction of motion strength and motor activity signals from video recordings of neonatal seizures.

This paper presents two methods developed to extract quantitative information from video recordings of neonatal seizures in the form of temporal motion strength and motor activity signals. Motion strength signals are extracted by measuring the area of the body parts that move during the seizure and the relative speed of motion using a combination of spatiotemporal subband decomposition of video, nonlinear filtering, and segmentation. Motor activity signals are extracted by tracking selected anatomical sites during the seizure using a modified version of a feature-tracking procedure developed for video, known as the Kanade-Lucas-Tomasi (KLT) algorithm. The experiments indicate that the temporal signals produced by the proposed methods provide the basis for differentiating myoclonic from focal clonic seizures and distinguishing these types of neonatal seizures from normal infant behaviors.

Context-based automated detection of epileptogenic sharp transients in the EEG: elimination of false positives.

This paper describes a knowledge-based system for the elimination of false positives in the automated detection of epileptogenic sharp transients in the EEG. The system makes comprehensive use of spatial and temporal context information available on 16 channels of EEG, EKG, EMG, and EOG. A knowledge-based implementation is used because of the ease with which it allows the contextual rules to be expressed and refined. The resulting system is shown to be capable of rejecting a wide variety of artifacts commonly found in EEG recordings, artifacts that cause numerous false positive detections in systems making less comprehensive use of context.

Computed tomography in infantile spasms: effects of hormonal therapy.

During a prospective double-blind, crossover study of ACTH versus prednisone therapy, serial computed tomography (CT) scans were performed on 16 children with infantile spasms. Pre-treatment scans revealed four findings: normal (6 patients), generalized atrophy (bilaterally enlarged ventricles and/or subarachnoid space) (2 patients), predominantly focal atrophy (3 patients), and congenital anomalies (5 patients). Within 2 weeks of initiating relatively low therapeutic dosages of ACTH or prednisone, a significant number of the infants (63%) had CT findings consistent with decreased cortical volume; in many cases (44%), these findings had not reversed 4 to 6 weeks after discontinuing therapy. Duration of therapy did not correlate significantly with the persistence of CT changes.