Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome.

OBJECTIVE: The aim of this study is to describe the long-term neurological, neuropsychological and neuroradiological sequelae and to determine prognostic factors for neurological outcome in children with neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome. METHODS: Data on medical history were collected for the study patients. Examinations with grading of neurological signs, neuropsychological tests and brain magnetic resonance imaging with spectroscopy were performed during a follow-up clinic. RESULTS: Fourteen subjects entered the study. All had localized neuroblastoma and they were evaluated after a median of 7.8 years. Patients with a chronic/multiphasic neurological course received steroids combined with intravenous immunoglobulins in the majority of cases. 71% presented neurological sequelae and 62% had a full-scale IQ below the normal range. All patients showed at least some deficit in the neuropsychological functions assessed (language, visual-motor integration, memory, attention and motor ability). Long-term deficits were more frequently detected in patients with an interval of more than 2 months between OMA onset and its diagnosis, even if in most comparisons statistical significance was not reached. Cerebellar atrophy, observed in 36% of patients, was not associated with the neurological outcome. CONCLUSIONS: Persisting disability is present in most children with neuroblastoma-associated OMA. However, our results support the role of an early diagnosis of OMA in reducing sequelae and encourage the use of new immunosuppressive therapies.

Lorazepam in childhood status epilepticus and serial seizures: effectiveness and tachyphylaxis.

We report our experience with 300 consecutive parenteral doses of lorazepam (LOR) for status epilepticus (SE) or serial seizures in 77 children and young adults. The median dose for SE in children less than 12 years old was 0.10 mg/kg. LOR stopped the SE in 79% and diminished the intensity of SE in an additional 4%. Prior acute or chronic anticonvulsant use (excepting chronic benzodiazepines) did not alter effectiveness or increase side effects. Duration of freedom from seizures following acute therapy was independent of LOR dosage. In patients requiring sequential doses, LOR becomes progressively less effective. Side effects were few and, when present, always associated with a single or first dose in a series. LOR is a safe and effective acute anticonvulsant agent for in-hospital control of SE in the pediatric age group. Tachyphylaxis of anticonvulsant action occurs when serial doses are used.

Very-high-dose phenobarbital for refractory status epilepticus in children.

Status epilepticus refractory to initial anticonvulsant therapy is a serious condition with a high morbidity and mortality. We present 50 cases with refractory status epilepticus (RSE) treated with very-high-dose phenobarbital (VHDPB) without reference to a predetermined maximum level or dose. Maximum serum levels ranged from 70 to 344 micrograms/ml (median, 114 micrograms/ml). VHDPB controlled seizures in all cases where no limits were imposed upon maximum dose (47/50). We found no maximum dose beyond which further doses are likely to be ineffective. Forty patients were intubated prior to VHDPB, but recovered respiratory drive and could be removed from the ventilator despite very high serum levels. This is explained by acute drug tolerance. Hypotension was unusual, related to the highest levels, and easily controlled. VHDPB has many relative advantages over other therapies presently used for RSE.

Encephalitis lethargica-like illness in a girl with mycoplasma infection.

We describe a patient with mycoplasma infection and clinical manifestations of encephalitis lethargica. The patient was brought to our attention after acute neurologic deterioration followed by a prolonged sleep-like state and the emergence of extrapyramidal features. MRI of the brain disclosed a striking pattern of subcortical involvement by the inflammatory process, corroborating the clinical picture.

Brain-adrenal axis hormones are altered in the CSF of infants with massive infantile spasms.

Massive infantile spasms (MIS), a seizure disorder unique to infants, is considered an age-dependent response of the immature brain to various insults and stressors. The seizures improve with ACTH and glucocorticoids, both major components of the brain-adrenal axis. We hypothesized that CNS levels of these hormones are abnormal in infants with MIS and studied CSF from 14 infants with MIS and 13 age-matched controls by analysis for corticotropin-releasing hormone (CRH), ACTH, cortisol, and interleukin-1-beta. ACTH levels in CSF of patients were significantly lower than those of controls, but differences in cortisol levels between patients and controls were not statistically significant. CRH levels in both groups were similar and fluctuated diurnally. These results indicate an alteration of specific CNS components of the brain-adrenal axis in MIS.

Treating repetitive seizures with a rectal diazepam formulation: a randomized study. The North American Diastat Study Group.

OBJECTIVE: To evaluate the effectiveness and safety of a single-dose treatment for acute repetitive seizure (ARS) episodes (e.g., clusters) administered in a nonmedical setting by caregivers. BACKGROUND: Patients with epilepsy may experience ARS episodes despite optimal anticonvulsant treatment. Such episodes require rapid treatment as medical emergencies. Typically, the patient is treated in an emergency medical setting with i.v. medication by trained medical personnel. METHODS: The authors undertook a multicenter, randomized, parallel, double-blind study of a single administration of Diastat (diazepam rectal gel) for treating episodes of ARS. ARS episodes and treatment criteria were defined for each patient at the start of the study. Caregivers were taught to determine ARS episode onset, administer a predetermined dose of study medication, monitor outcome, count respirations, and record seizures and adverse events. RESULTS: A total of 29 centers enrolled 158 patients, of whom 114 patients had a treated ARS episode (Diastat, n = 56; placebo, n = 58). Diastat treatment reduced median seizure frequency (p = 0.029). More Diastat patients were seizure free post-treatment (Diastat, 55%; placebo, 34%; p = 0.031). Kaplan-Meier analysis of the time to the next seizure favored Diastat treatment (p < 0.007). The most common adverse event was somnolence. CONCLUSION: Administration of a single rectal dose of Diastat was significantly more effective than placebo in reducing the number of seizures following an episode of ARS. Caregivers could administer treatment safely and effectively in a nonmedical setting.

Intraparenchymal cerebral cysticercosis in children: diagnosis and treatment.

Cerebral cysticercosis is being diagnosed with increasing frequency in children in the United States. A total of 52 patients with intraparenchymal cerebral cysticercosis, 21 months to 20 years of age, were observed for 2 to 72 months. Actively inflamed acute lesions, with or without coexisting chronic calcified lesions, were seen in 42 patients. Solitary lesions were seen in 39 patients, multiple lesions in 13. Chronic inactive calcified lesions were seen in ten children. A total of 51 patients had seizures that were either partial or partial with secondary generalization. Patients were treated with anticonvulsants. Praziquantel was not used. All active lesions resolved completely or with punctate calcification in 2 to 9 months, according to radiographic findings. Seizures were easily controlled. Patients were gradually weaned from anticonvulsants and in 60% no seizures recurred. Prognosis was generally good. Characteristics of the CT scans are detailed.

Psychosocial, behavioral, and medical outcomes in children with epilepsy: a developmental risk factor model using longitudinal data.

OBJECTIVE: We studied factors predicting the risk of adverse long-term psychosocial, behavioral, and medical outcomes in children with epilepsy. METHODS: Children (N = 157, 4.5 to 13 years) were enrolled in a prospective longitudinal study when first seen. Potential subjects were excluded if they were moderately or severely mentally retarded, had motor or sensory handicaps interfering with testing, or did not speak either English or Spanish. MEASURES: To develop risk predictors, we collected information regarding the child's medical and seizure history, cognitive functioning, and behavior problems, and family functioning. Children and their families were followed for a minimum of 18 months, then underwent reassessment of medical status, parent's attitudes toward epilepsy, and the child's behavioral and cognitive functioning. Data were analyzed by confirmatory factor analysis to develop baseline factors (Sociocultural Risk, Seizure Risk, and Behavior Problems) and outcome factors (Medical/Seizure Problems, Parent's Negative Attitudes Toward Epilepsy, and Behavior Problems), followed by structural equation modeling to determine across-time causal effects. Eighty-eight subjects completed all baseline and outcome measures. RESULTS: Among significant across-time effects, Medical Outcome was predicted by Seizure Risk. An increased number of stressful life events predicted better Medical Outcome. Low acculturation increased Parent's Negative Attitudes and was associated with increased Behavior Problems at baseline. Behavior Problems were stable across time. It is interesting that IQ did not affect any of the outcomes, although its effect may have been mediated through other baseline measures. CONCLUSIONS: Seizure history was the best predictor of ongoing medical difficulties, whereas the most important causes of ongoing parental anxiety and negative attitudes toward epilepsy were sociocultural. Variation in medical or attitudinal outcomes was not influenced by either the child's IQ or reported behavioral problems. These findings suggest that to alter attitudes toward epilepsy, programs should be tailored to the sociocultural background of the family. Studies of quality of life of children with epilepsy should include appropriate sociocultural measures.

Failure-to-thrive: a study in a primary care setting. Epidemiology and follow-up.

A cohort of 312 children followed in three rural primary care centers was studied. All cases of failure-to-thrive were identified (30) and compared to the remainder of the group. With the use of data from medical records, children with history of failure-to-thrive were found to be significantly lighter and shorter than the remainder of the population in each of the first five years of life. More cases had family problems. No differences were found in demographic characteristics or chronic illnesses. In the second phase of the study, cases and an equal-sized control group, from the same social setting, matched for age, sex, mother's marital status, and family problems, were examined at 3 to 6 years of age to assess outcome. This included physical examination, the McCarthy Scale of Children's Abilities, a behavior questionnaire, and an interview to assess life events. Cases were lighter but not shorter than controls. No instances of occult organic disease causing failure-to-thrive were identified. No behavioral or developmental deficits could be attributed to the failure-to-thrive.

Effects of antiepileptic drugs on reaction time, attention, and impulsivity in children.

Simple, choice, and complex reaction times, attention (variability of responses and omission errors), and impulsivity (commission and wrong-hand errors on choice and complex reaction time) were repeatedly measured in 111 epileptic children, aged 5 to 13 years, tested a total of 232 times. Antiepileptic drugs (AEDs) were started, stopped, and adjusted throughout the study period, for a variety of clinical indications, and AED serum levels were monitored. The relationship of performance to AED serum level was examined. Overall the nonspecific effect of AEDs was minimal: higher total serum levels of AEDs correlated with more impulsive errors on complex reaction time testing only. In contrast, in 54 children receiving carbamazepine monotherapy, we found a dose-related beneficial effect upon reaction time, with higher serum levels associated with faster responses and fewer omission errors, particularly on complex reaction time. Phenobarbital caused minimal dose-related effects: only variability and impulsive errors increased with increasing serum levels, and only on one segment of the test (73 subjects).

Effects of human immunodeficiency virus and immune status on magnetic resonance imaging of the brain in hemophilic subjects: results from the hemophilia growth and development study.

To determine the effects of hemophilia and human immunodeficiency virus (HIV) infection on the nervous system, the authors examined the relationship of brain magnetic resonance imaging (MRI) findings to immunologic function and neurologic examination findings. Baseline examinations included physical and neurologic examination, immunologic and virologic testing, and MRI of the brain. On neurologic examination, muscle atrophy was considered to be related to hemophilia if adjacent joints had arthropathy due to bleeding. Muscle atrophy was considered non-hemophilia-related if unrelated to arthropathy or if muscle atrophy was diffuse. Subjects were boys aged 6 to 19 years, enrolled in a multicenter study of the effects of hemophilia and HIV infection on growth and development, all with congenital coagulopathies requiring factor infusions. Three hundred ten subjects had complete data including neurologic examination, T-cell subsets, HIV antibodies, and MRI. Subjects with HIV infection whose CD4+ counts were < 200/microL were compared with subjects with HIV infection and CD4+ counts > or = 200/microL and with HIV-negative subjects, all of whom had CD4+ counts > 200/microL. MRI studies were normal in 230. Abnormal MRI studies were more frequent in HIV-positive subjects with CD4+ counts < 200 (29.4% abnormal compared with 17% in HIV-positive subjects with CD4+ counts > or = 200 and 15.3% in HIV-negative subjects). Diffuse atrophy accounted for most of the excess abnormalities in HIV-positive subjects with CD4+ counts < 200 (77.3% of abnormal scans). Diffuse atrophy on MRI was associated with decreased muscle bulk on neurologic examination, but not with abnormal tendon reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study.

OBJECTIVE: To compare the efficacy of corticotropin (ACTH) (150 U/m2/day) and prednosone (2 mg/kg/day) given for 2 weeks, in suppressing clinical spasms and hypsarrhythmic electroencephalogram (EEG) in infantile spasms (IS). AACTH and prednisone are standard treatments for IS. ACTH at high doses causes severe dose- and duration-dependent side effects, but may be superior to prednisone, based on retrospective or uncontrolled studies. Blinded prospecive studies have shown equal efficacy of prednisone and low-dose ACTH, and low versus high-dose ACTH. DESIGN: A prospective, randomized, single-blinded study. SUBJECTS AND METHODS: Patient population consisted of consecutive infants fulfilling entry criteria, including the presence of clinical spasms, hypsarrhythmia (or variants) during a full sleep cycle video-EEG, and no prior steroid/ACTH treatment. Response required both cessation of spasms and elimination of hypsarrhythmia by the end of the 2-week treatment period, as determined by an investigator "blinded" to treatment. Treatment of responders was tapered off over 12 days; those failing one hormone were crossed-over to the other. RESULTS: OF 34 eligible infants, 29 were enrolled. Median age of patients was 6 months. Twenty-two infants were "symptomatic" with known or suspected cause, and seven were cryptogenic (two normal). Of 15 infants randomized to ACTH, 13 responded by EEG and clinical criteria (86.6%); Seizures stopped in an additional infant, but EEG remained hypsarrhythmic (considered a failure). Four of the 14 patients given prednisone responded (28.6%,, with complete clinical-EEG correlation), significantly less than with ACTH, (chi2 test). CONCLUSIONS: Using a prospective, randomized approach, a 2-week course of high-dose ACTH is superior to 2 weeks of prednsone for treatment of IS, as assessed by both clinical and EEG criteria.

The computer as an unbiased medical investigator. Experience on an active surgical service.

An adaptable on-line computer system for entry, retrieval, and analysis of medical discharge summaries has been developed and applied in the Trauma Service of a busy city hospital. Each summary occupied 5 to 10 minutes of the physician's time and compared favorably in cost to the standard dictated summary. While the average dictated summary contained 15 +/- 7 relevant facts, the machine-generated summaries were found to have 53 +/- 20 relevant facts. The summaries are well organized, easily comprehensible, and a duplicate copy can be obtained at any time by using the patient's name or number for identification. To date, 495 discharge summaries have been entered and reside in the memory of the computer. Statistical analysis from the data base is done by the computer, thus eliminating human prejudice. It provides facility for rapid and accurate retrospective studies as well as pattern-of-care and individual case review.

Opsoclonus-ataxia due to childhood neural crest tumors: a chronic neurologic syndrome.

Five children with subacute or acute onset of cerebellar ataxia and opsoclonus are described. Two had cerebrospinal fluid pleocytosis at the onset of ataxia and were initially thought to have acute parainfectious cerebellar ataxia of childhood. All were found to have tumors of neural crest origin (two neuroblastomas, three ganglioneuroblastomas). Tumors were small and only found by computed tomographic techniques. Urinary catecholamine metabolites were elevated in only two of the patients. Four of the five failed to improve neurologically with resection of the tumor. All four have had a steroid-sensitive chronic ataxic syndrome that worsens with acute nonspecific illnesses and has resulted in long-term deficits, particularly in speech and gross motor function. This is a metabolic encephalopathy associated with permanent residual neurologic deficits but without visible lesions on neuroimaging studies. We stress the frequency of cerebrospinal fluid pleocytosis in patients with tumor-associated opsoclonus and the clinical difficulty in separating tumor-associated cases from those due to other causes [corrected].

Cognitive and behavioral effects of carbamazepine in children: data from benign rolandic epilepsy.

The effects of antiepileptic drugs on cognition are difficult to delineate, yet of critical importance for children with epilepsy. We investigated the cognitive and behavioral effects of carbamazepine in children with benign rolandic epilepsy. Ten subjects with benign rolandic epilepsy were evaluated with and without carbamazepine treatment. Fourteen unmedicated subjects with migraine headache evaluated twice served as a control group. Subjects were 6 to 12 years of age, fluent in English, and not mentally retarded. We found that children with benign rolandic epilepsy were quicker on a visual-search task and recalled stories better when not treated than when treated with carbamazepine. After correction for multiple comparisons only the memory finding remained significant. Higher carbamazepine serum level was associated with slower performance on the same visual-search task. This latter finding did not meet multiple comparison criteria. Numerous significant practice effects were found within the control group. Comparisons with reliable change indices identified two subjects with benign rolandic epilepsy with particularly poor scores while receiving carbamazepine. These findings suggest some effects on memory from carbamazepine; however, they do not support meaningful dosage-related effects, within the recommended range. Significant practice effects confirmed the need to control for such effects when evaluating treatments. Finally, identification of two subjects who performed more poorly while on carbamazepine suggests that some children might experience particular difficulties while receiving this medication and highlights the need to investigate individual subject responses to treatment.

Academic underachievement in children with epilepsy.

Academic achievement was studied in 78 children with epilepsy, ages 5 to 13 years, to determine how seizures, treatment of seizures, and sociocultural factors influence academic achievement. Cognitive abilities were assessed with either the McCarthy Scales of Children's Abilities or the Wechsler Intelligence Scale for Children--Revised. Achievement was measured with the Peabody Individual Achievement Tests. Achievement scores were corrected for cognitive ability (IQ), and underachievement was defined as achievement score 1/2 standard deviation or more below IQ. Information regarding seizure history (severity, duration) and treatment with anticonvulsant drugs was obtained. In addition, the family was extensively interviewed regarding the child's environment, behavior, and demographic background. The Home Observation for Measurement of the Environment (HOME) scale was completed on a home visit. Underachievement was frequent, ranging from 16% (Reading Recognition) to 50% (General Knowledge), but there was no relationship between severity or duration of seizure disorder or total exposure to anticonvulsant medications and achievement. Major determinants of achievement included subscales of the HOME scale, age (older children more likely to be underachieving), and parental education. An equal proportion of newly diagnosed and/or untreated subjects were underachieving compared to those with longstanding epilepsy and anticonvulsant drug treatment.

Reaction time, impulsivity, and attention in hyperactive children and controls: a video game technique.

Maturation of sustained attention was studied in a group of 52 hyperactive elementary school children and 152 controls using a microcomputer-based test formatted to resemble a video game. In nonhyperactive children, both simple and complex reaction time decreased with age, as did variability of response time. Omission errors were extremely infrequent on simple reaction time and decreased with age on the more complex tasks. Commission errors had an inconsistent relationship with age. Hyperactive children were slower, more variable, and made more errors on all segments of the game than did controls. Both motor speed and calculated mental speed were slower in hyperactive children, with greater discrepancy for responses directed to the nondominant hand, suggesting that a selective right hemisphere deficit may be present in hyperactives. A summary score (number of individual game scores above the 95th percentile) of 4 or more detected 60% of hyperactive subjects with a false positive rate of 5%. Agreement with the Matching Familiar Figures Test was 75% in the hyperactive group.

Stroke as a late sequela of cranial irradiation for childhood brain tumors.

Cerebrovascular disease involving large and medium-size vessels is thought to be an uncommon sequela of treatment of childhood brain tumors. We reviewed 11 children who developed cerebrovascular disease manifested by strokes or transient ischemic attacks 6 months to 4 years after treatment of brain tumors, while their tumors were in remission. All had received radiation therapy, and seven had received chemotherapy. One child died of acute bilateral cerebral infarctions due to carotid occlusion on one side and marked stenosis on the other 2 years after receiving radiation therapy for an incompletely resected craniopharyngioma. Pathologically, there was marked subendothelial fibrosis of the vessels of the circle of Willis, with inflammatory changes surrounding some of the vessels. In addition to the widely recognized small-vessel damage caused by radiation and chemotherapy in children (mineralizing microangiopathy), damage to medium and large intracranial vessels may result in late sequelae, manifested by stroke or transient ischemic attacks.

Neurocysticercosis and acquired cerebral toxoplasmosis in children.

Neurocysticercosis, prevalent wherever pigs are raised in the presence of poor sanitation, is the most common identifiable cause of new-onset epilepsy throughout the developing world. As immigration patterns have changed, children with neurocysticercosis are seen throughout the United States. Acute cysticercosis, the most common manifestation in children, reflects the host response to the dying parasite. Children typically present with seizures and have an excellent prognosis. Neuroimaging demonstrates a single ring or nodular enhancing lesion surrounded by edema. Short-term anticonvulsant therapy is indicated, but treatment with antiparasitic agents is not required. Other forms, such as active cysts (intact organism), intraventricular or subarachnoid racemous cysticercosis, and cysticercal meningoencephalitis, are less common manifestations of parasitic infection. Toxoplasmosis, caused by the parasite Toxoplasma gondii, can be acquired by ingestion of infected undercooked meat or from oocytes shed in cat feces. Acquired cerebral toxoplasmosis, due to primary or reactivated infections, rarely occurs in immunocompetent children. In children who are immunodeficient as the result of AIDS, chemotherapy, tissue transplantation, or congenital immunodeficiency, toxoplasmosis may be difficult to distinguish from cerebral lymphoma. A variety of techniques, including neuroimaging, Thallium-201 SPECT, polymerase chain reaction analysis of CSF, and special histological methods, may be used to diagnose acquired toxoplasmosis. Antiparasitic therapy, using pyrimethamine and sulfadiazine, and serial neuroimaging often enable clinicians to differentiate toxoplasmosis from other central nervous system lesions. Toxoplasmosis may respond to other antimicrobials, including macrolide antibiotics, dapsone, clinidamycin, and atovaquone. Suppressive treatment is generally required for life in immunodeficient patients. Immunodeficient children with acquired toxoplasmosis have high rates of mortality and neurological sequelae.

Intraparenchymal cerebral cysticercosis in children: a benign prognosis.

This paper reports 26 consecutive cases of cerebral cysticercosis in children, 21 presenting with intraparenchymal mass lesions, two with encephalitic disease, and three with intraventricular (racemous) cysticercosis. The intraparenchymal and encephalitic forms of the disease were benign. Regression of the lesions occurred within four months of diagnosis in all children treated conservatively with antiepileptic drugs, but no antiparasitic drugs. Major morbidity was limited to those patients who were subjected to operative intervention. Intraventricular disease was most malignant; all three patients manifested acute, severely increased intracranial pressure, all required immediate surgical decompression, and one patient died. The apparent overall benign course of intraparenchymal cerebral cysticercosis in children appears not to warrant antiparasitic drug therapy.