Autosomal dominant acute necrotizing encephalopathy.

OBJECTIVE: To define the clinical and biochemical abnormalities of an autosomal dominant form of acute encephalopathy. METHODS: The clinical details of 11 affected family members in comparison with 63 unaffected relatives were analyzed. RESULTS: Affected children become comatose after onset of a febrile illness. Outcomes include full recovery, permanent neurologic impairment, and death. Recurrences produce more severe impairments. Lesions of necrotizing encephalopathy of the thalamus and brainstem are present on autopsy and MRI. Oxidative phosphorylation of intact mitochondria from a muscle biopsy shows loose coupling. Unaffected family members, including obligate carriers, share no clinical characteristics, demonstrating incomplete penetrance. CONCLUSIONS: Characteristic pathology and MRI findings define this disorder of autosomal dominant acute encephalopathy. Leigh syndrome and sporadic acute necrotizing encephalopathy share similarities but are distinct.

Feasibility and potential gains of enhancing the subacute rat study protocol (OECD test guideline no. 407) by additional parameters selected to determine endocrine modulation. A pre-validation study to determine endocrine-mediated effects of the antiandrogenic drug flutamide.

Groups of five male and five female Wistar rats were treated by gavage with 0, 1, 10, and 100 mg flutamide/kg body weight for at least 28 days to investigate whether proposed enhancements to the current subacute rodent OECD test guideline no. 407 could be included into the testing routine, which of the current and/or additional parameters would detect endocrine-mediated effects of flutamide reliably and sensitively, and to provide information on intra-laboratory variability. Two identical studies were performed concurrently. The enhanced protocol requests the additional determination of the specific hormones triiodothyronine, thyroxine, thyroid stimulating hormone, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin, testosterone, corticosterone; of oestrus cyclicity and necropsy of all females in the dioestrus stage; of the number of homogenization-resistant testicular spermatids and the number, motility, viability, and morphology of cauda epididymal spermatozoa; of additional organ weights (pituitary, ovaries, uterus, thyroid, male accessory reproductive organs); and of the histopathology of additional organs (pituitary, epididymides, coagulation glands, pancreas, vagina). From a technical standpoint, it was possible to conduct a study according to the enhanced protocol, however, with substantial additional effort, an increase in costs by some 67%, and logistic problems. In line with the specific pharmacological effect of flutamide, treatment-related changes were mainly found in male rats, while females were hardly affected by 100 mg/kg. In male rats, 100 mg/kg was the maximal tolerated dose resulting in reduced body weight gain, but no or little other effects on clinical, haematological, clinico-chemical, or behavioral parameters, and 1 mg/kg was the no-observed-adverse-effect level. Antagonism of peripheral androgen receptors by flutamide resulted in decreased relative organ weights of male accessory reproductive organs, changes that were reliably detected in both studies at 100 mg/kg, but only in one of both studies at 10 mg/kg. Corresponding histopathological changes were also detected reliably at 100 mg/kg. Antagonism of central androgen receptors by flutamide increased LH and FSH levels. LH stimulation of testicular Leydig cells in turn increased testosterone and estradiol levels. Again, all these changes were detected reliably at 100 mg/kg, but only in one of both studies at 10 mg/kg. Corresponding histopathological alterations (increase of LH- and FSH-secreting cells, Leydig cell hypertrophy) were detected reliably and sensitively at 10 mg/kg. Studies on liver enzymes performed outside the scope of the enhanced protocol showed that flutamide at 100 mg/kg generally induced hepatic enzyme activities, but decreased the activity of the sex-specific testosterone-dependent liver enzyme CYP2C11 in male rats. The laboratory methods employed yielded reliable results, i.e., 93.6% of the quantitative measurements obtained in both studies were in agreement. Doubling the animal number from five to ten per sex and dose does not increase the sensitivity of detection of endocrine-mediated effects above the level already provided by histopathological examination of groups of five animals. Some of the proposed enhancements evaluated (additional organgravimetry and histopathology) were helpful in detecting the endocrine-mediated effects of flutamide reliably, while others did not contribute towards this aim (spermatology resulted in doubtful effects, female cyclicity was not affected, hormone determinations provided mechanistic information). Ongoing testing according to the revised version of the enhanced OECD test guideline no. 407 protocol and using ten compounds interfering with the endocrine system by different mechanisms will result in the identification of the most appropriate enhancements.

Frequency and time trends of spontaneous tumors found in B6C3F1 mice oncogenicity studies over 10 years.

Historical data from 2883 B6C3F1 mice used as controls in 29 two-year oncogenicity studies terminated between 1988 and 1998 were analyzed for possible time trends in mortality, terminal body weight and tumor incidences. There was no time trend in terminal body weights. Concerning mortality data a slight decreasing trend (p > 0.05) was evident in males, whereas in females mortality rates increased significantly (p = 0.0009). The overall tumor spectrum of the collectives used was roughly in line with the tumor profile known for B6C3F1 mice. Most tumor types occurred in the hematopoietic tissue, liver, lungs, Harderian glands, vascular system, endocrinium (pituitary, adrenals and thyroids) or female reproductive organs. In comparison to literature data mice used in our lab exhibited less hepatocellular tumors and lung adenomas. Hepatocellular adenomas (females only) and carcinomas (both sexes) as well as adenomas in the Harderian glands decreased significantly over the time examined. For ovarian cystadenomas as well as uterine polyps and uterine stromal sarcomas significantly positive time trends were calculated. A positive time trend was also found for adrenal adenomas in males (p < 0.05) and histiocytic sarcomas in females (p > 0.05). Lymphomas occurred with increasing incidences over time in males (p < 0.05) and females (p < 0.05). Other factors such as genetic drifts might be responsible for these trends rather than changes in the body weights, which remained stable over 10 years.

Management of the respiratory complications of neuromuscular diseases in the pediatric intensive care unit.

Pediatric neuromuscular diseases such as Duchenne muscular dystrophy and spinal muscular atrophy cause pulmonary compromise. In severely affected patients, upper respiratory tract infections exacerbate lower respiratory tract secretion retention, with the potential for pneumonia, pulmonary atelectasis, and respiratory failure. In the pediatric intensive care unit, effective treatment includes noninvasive positive pressure ventilation and manual and mechanical mucus clearance techniques. A practical approach to commonly encountered respiratory complications in pediatric neuromuscular diseases is presented in this review.

Trends in mortality, body weights and tumor incidences of Wistar rats over 20 years.

Historical data of more than 8,000 Wistar rats (designation: WISW SPF Cpb) used as controls in seventy 2-year studies terminated between 1975 and 1994 were analyzed for time trends in food consumption, terminal body weight, mortality, and tumor incidences. In males there was a significant (p < 0.01) time trend towards higher terminal body weight and a tendency (p > 0.05) to lower incidences of pituitary tumors and adrenal pheochromocytomas, while mortality remained stable. Leydig cell tumors showed a significant (p = 0.0005) positive trend. In females, terminal body weight did not increase over time but pituitary and mammary tumors showed a marked and highly significant (p = 0.0001) increase, which explains a significant (p = 0.0045) positive trend in mortality. There was a significant (p = 0.0001) negative time trend for uterine adenomas/carcinomas and a slight tendency (p = 0.4135) towards a decreased incidence of endo-metrial stromal polyps. Since the average food intake data do not indicate a time trend the changes observed might probably not be related to higher caloric intake. In contrast to other authors we could not find a positive correlation between either body weight and incidences of pituitary tumors or body weight and mortality. Certain selection measures at breeding and/or a genetic drift over time might explain the time trends observed. This data does not yet indicate a need for a change in ad-libitum feeding of these animals.

Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding.

Type I spinal muscular atrophy (SMA) is a rapidly progressive, degenerative neuromuscular disease of infancy. In severe SMA, weakness, hypotonia, and bulbar involvement lead to progressive respiratory insufficiency and swallowing dysfunction, which are frequently complicated by aspirations. There are few studies reported in the literature that address the respiratory management of type I SMA. This article reports the results of treating four patients with infantile SMA with noninvasive positive pressure ventilation and gastrostomy feeding. All patients had gastroesophageal reflux disease, which was managed medically. Despite these therapies, survival was only 1 to 3.5 months after presenting with severe aspirations. The treatment strategy, which can be effective in less rapidly progressive neuromuscular diseases, did not alter the very poor prognosis of type I SMA. The treatment options are reviewed, and a strategy designed to optimize quality of life for infants with this fatal disease is presented.

Pediatric noninvasive nasal ventilation.

Noninvasive nasal ventilation is an effective but underutilized method of chronic respiratory support for patients with respiratory insufficiency due to neuromuscular disease. Noninvasive nasal ventilation corrects nocturnal hypoxia and hypercapnia, resolving symptoms of chronic alveolar hypoventilation. Noninvasive nasal ventilation can allow selected patients with acute respiratory failure to avoid intubation and it can facilitate endotracheal extubation. Practical guidelines and the rationale for pediatric noninvasive nasal ventilation therapy will be discussed in this review.

School-age outcomes in children with birth weights under 750 g.

BACKGROUND: Since the mid-1980s, increasing numbers of children with birth weights under 750 g have survived to school age. METHODS: We matched a regional cohort of 68 surviving children born from 1982 through 1986 with birth weights under 750 g (mean, 670 g; gestational age, 25.7 weeks) with 65 children weighting 750 to 1499 g at birth and 61 children born at term. Growth, neurosensory status, and functioning at school age in the three groups were compared. Associations of biologic and social risk factors with major developmental outcomes were examined by means of logistic-regression analyses. RESULTS: Children with birth weights under 750 g were inferior to both comparison groups in cognitive ability, psychomotor skills, and academic achievement. They had poorer social skills and adaptive behavior and more behavioral and attention problems. The mean (+/- SD) Mental Processing Composite score for the cohort was 87 +/- 15, as compared with 93 +/- 14 for children with birth weights of 750 to 1499 g and 100 +/- 13 for children born at term (P < 0.001). The rates of mental retardation (IQ < 70) in the three groups were 21, 8, and 2 percent, respectively; the rates of cerebral palsy were 9, 6, and 0 percent; and the rates of severe visual disability were 25, 5, and 2 percent. Major cerebral ultrasonographic abnormalities were associated with mental retardation (odds ratio, 5.4; 95 percent confidence interval, 1.8 to 15.8) and cerebral palsy (odds ratio, 15.2; 95 percent confidence interval, 3.0 to 77.4). Oxygen dependence at 36 weeks was associated with mental retardation (odds ratio, 4.5; 95 percent confidence interval, 1.2 to 10.7) and severe visual disability (odds ratio, 4.3; 95 percent confidence interval, 1.3 to 14.2). Social disadvantage, though associated with several neuropsychological outcomes, was not associated with major developmental impairment. CONCLUSIONS: Children with birth weights under 750 g who survive represent a subgroup of very-low-birth-weight children who are at high risk for neurobehavioral dysfunction and poor school performance.

The persistent vegetative state in children: report of the Child Neurology Society Ethics Committee.

Increasing concern about children in a persistent vegetative state (PVS) prompted a survey of members of the Child Neurology Society regarding aspects of the diagnosis and management of this disorder. Major findings of those responding to this survey (26% response rate) were as follows: (1) 93% believed that a diagnosis of PVS can be made in children, but only 16% believed that this applied to infants younger than 2 months and 70% in the 2-month to 2-year group; (2) a period of 3 to 6 months was believed to be the minimum observation period required before a diagnosis of PVS could be made; (3) 86% believed that the age of the patient would affect the duration of time needed to make the diagnosis of PVS; (4) 78% thought a diagnosis of PVS could be made in children with severe congenital brain malformations; (5) 75% believed that neurodiagnostic studies would be of value and supportive of the clinical diagnosis of PVS; (6) members' opinions as to the average life expectancy (in years) for the following age groups after the patients were considered vegetative were: newborn to 2 months, 4.1; 2 months to 2 years, 5.5; 2 to 7 years, 7.3; and more than 7 years, 7.4; (7) 20% believed that infants and children in a PVS experience pain and suffering; and (8) 75% "never" withhold fluid and nutrition from infants and children in a PVS and 28% "always" give medication for pain and suffering.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative investigations on the cataractogenic effect of a triazin-derivative in albino and pigmented rats: II. Effects documented by Scheimpflug photography.

A Triazin-derivative from a group of industrial chemicals was found to cause cataracts in albino rats during a subchronic toxicity study. To get more insight into this effect, a study was designed with 20 albino (Wistar) and 40 pigmented (black-hooded FB 30) rats using different dosages of the test compound. In a 3 months study period, all rats were photographed with a Scheimpflug camera TOPCON SL-45 3 times, at a baseline examination, prior to any treatment, in the middle and at the end of the study period, prior to sacrifice. The black-and-white film (Kodak T-Max 400R) was standardly developed and evaluated with a Joyce-Loebl microdensitometer in 3 regions of the lens, the capsule, the cortex and the nucleus. The density data from the second and third examination clearly demonstrate that cataract development in the albino rats takes place in the cortical region, whereas in the pigmented rats it takes place in the cortical and partly in the nuclear region. In addition, one albino and two pigmented animals of the groups investigated developed bilateral mature cataracts. Differences in cataract morphology between albino and pigmented rats are presented by Eiben and Wegener (1). The results underline the importance of toxicity testings in pigmented rats, they evidence that the data derived solely from albino animals can be misleading.

Detection and evaluation of lesions in the retina, optic nerve and ciliary muscle of old rats using a electron microscope.

Spontaneous eye alteration found in retina, ciliary muscle and optic nerve of old female Wistar rats were studied using an electron microscope. Normal ultrastructures and severity of age-dependent changes were defined in all three locations using a qualitative scoring system or morphometric measurements. Degenerative changes of various severity such as vacuolization or loss of receptor membranes in the retina, and fragmentation or swelling of myelin sheaths in the optic nerve were detected in eyes of untreated animals. Only very slight changes e.g. detachment of sarcoplasma and fragmentation or reduction of myofibrils were found in the ciliary muscle. These evaluation methods have been applied to quantify a chemically-induced exacerbation of spontaneous lesions in the retina and the optic nerve.

A new CT pattern in adrenoleukodystrophy.

A new CT pattern was observed in 2 patients with adrenoleukodystrophy (ALD). This pattern, which the authors call Type II, is characterized by the absence of posterior periventricular areas of decreased attenuation around the trigone on non-contrast scans: after contrast infusion, however, there is striking enhancement of various white-matter structures (tracts or fiber systems) such as the internal capsules, corpus callosum, corona radiata, forceps major, and cerebral peduncles. This is different from numerous previous descriptions of the CT pattern in ALD. Type II ALD does not appear to have been seen in any other leukoencephalopathy and is probably specific for a phenotypic variant or an evolving stage of ALD.

New phenotypic variant of adrenoleukodystrophy. Pathologic, ultrastructural, and biochemical study in two brothers.

Adrenoleukodystrophy is not usually considered in the differential diagnosis of the infantile onset of failure to thrive with motor and intellectual retardation. Rather, symptoms have started in childhood and have progressed over some years; not all patients have had overt adrenocortical insufficiency. The two brothers reported here developed symptoms in the neonatal period. In each the nature of the primary cerebral disorder was not recognized, because other etiologic factors clouded the diagnostic studies. In the younger brother, Case 1, a high titer (1:256) for cytomegalovirus (CMV) led to the suspicion that CMV infection accounted for the neurologic and ophthalmologic findings. Progressive neurologic deterioration at the age of 6 years prompted brain biopsy to confirm the diagnosis of progressive CMV encephalitis. In the older brother, Case 2, hemogenic hydrocephalus due to traumatic birth injury was held responsible for the psychomotor retardation and cerebral palsy. At necropsy, the adrenal glands in both cases were severly atrophic. In Case 1, a markedly inflammatory leukodystrophic process affected chiefly the frontal centra semiovalia and internal capsules, with relative sparing of parieto-occipital white matter and subcortical U-fibers. Heavy lymphocyte and monocyte cuffs surrounded many blood vessels in the white matter, and oil-red-O and PAS-positive macrophages were scattered in the zones of myelin disintegration and loss. Focally, the leukodystrophic process was so intense that cavitation necrosis was present, especially in the internal capsules. Further, PAS-positive, striated macrophages were aggregated in large clusters in liver, spleen, and lymph nodes. At the ultrastructural level, linear and gently arced, parallel, coapted or widely separated leaflets measuring 3-4 nm in width were identified in macrophages of the brain biopsy and in autopsy liver and lymph node. Biochemical analysis of fresh, frozen autopsy brain demonstrated cholesterol esters with long-chain fatty acids by thin-layer and gas-liquid chromatography. In Case 2, the leukodystrophic process could be readily identified in the brainstem and cerebellum but was masked in the cerebral hemispheres by the extensive hydrocephalus. The adrenal glands were atrophic and at light microscopy revealed adenomatoid nodules, many ballooned coritcal cells and very rare cells with striated cytoplasm. Masses of PAS-positive macrophages were encountered in liver and lymph nodes. In both cases, only old Wallerian degeneration of the corticospinal tracts was found in the spinal cord.

Reincarnation in cultured muscle of mitochondrial abnormalities. Two patients with epilepsy and lactic acidosis.

Two unrelated 9-year-old boys failed to thrive from ages 5 and 4 years, and had focal cerebral seizures followed by transcent hemipareses. Histochemistry of their muscle biopsies showed "ragged-red" fibers, which ultrastructurally contained clusters of mitochondria having loss of crisp delineation of crista membranes and contained amorphous inclusion material and parallel-packed cristae and sometimes paracrystalline inclusions. In the patients' cultured muscles, similar mitochondrial abnormalities were present. 2,4-Dinitrophenol, introduced to the medium of cultures of normal human muscle, produced mitochondrial abnormalities similar to those of the patients', and the medium of the patients' muscle cultures worsened the mitochondrial abnormalities. This study, in demonstrating a mitochondrial defect reproducible in the cultured muscle fibers and, therefore, intrinsic to the ragged-red muscle fibers themselves, raises the possibility of a collateral mitochondrial defect in CNS cells as part of a multicellular mitochondriopathy.

Computer assisted tomography in adrenoleukodystrophy.

Our findings on computer assisted tomography of the brain in four cases of adrenoleukodystrophy are sufficiently consistent to warrant delineation. Early changes, which may predate obvious clinical findings, are represented by areas of decreased attenuation coefficient in the posterior (parieto-occipital) white matter around the trigonum of each lateral ventricle. Subsequently the temporal, parietal, and frontal lobes are involved, and the extensive areas of decreased attenuation coefficient in the white matter become almost indistinguishable from the conspicuously enlarged ventricles. Only a thin ependymal wall separates the ventricular cavities from the leukomalacia lesions. Contrast medium enhancement at the periphery of the affected regions is an important, although inconsistent, feature.

Carnitine deficiency: clinical, morphological, and biochemical observations in a fatal case.

A fatal case of carnitine deficiency is described. The patient had intermittent metabolic acidosis, fluctuating hepatomegaly, and progressive muscle weakness since 22 months of age. One of two liver biopsies revealed lipid accumulation in the hepatocytes, and a muscle biopsy at age 5 years showed a lipid storage myopathy. Type 1 fibres were the most severely affected. Satellite and vascular endothelial cells also contained abnormal lipid deposits. Quantitative electron microscopy demonstrated an approximately 50-fold increase in lipid material, and a twofold increase in mitochondria in myofibres. The muscle carnitine level was less than one-seventh of the lowest value encountered in 74 biopsies from non-weak or neuromuscular disease controls. The basic abnormality in this patient is assumed to be a defect in carnitine biosynthesis.