Use of Thalamus L-Sign to Differentiate Periventricular Leukomalacia From Neurometabolic Disorders.

PURPOSE: To assess the diagnostic value of the thalamus L-sign on magnetic resonance imaging (MRI) in distinguishing between periventricular leukomalacia and neurometabolic disorders in pediatric patients. METHODS: In this retrospective study, clinical and imaging information was collected from 50 children with periventricular leukomalacia and 52 children with neurometabolic disorders. MRI was used to evaluate the L-sign of the thalamus (ie, injury to the posterolateral thalamus) and the lobar distribution of signal intensity changes. Age, sex, gestational age, and level of Gross Motor Function Classification System (only for periventricular leukomalacia) constituted the clinical parameters. Statistical evaluation of group differences for imaging and clinical variables were conducted using univariable statistical methods. The intra- and inter-observer agreement was evaluated using Cohen's kappa. Univariable or multivariable logistic regression was employed for selection of variables, determining independent predictors, and modeling. RESULTS: The thalamus L-sign was observed in 70% (35/50) of patients in the periventricular leukomalacia group, but in none of the patients with neurometabolic disorder (P < .001). The gestational age between groups varied significantly (P < .001). Involvement of frontal, parietal, and occipital lobes differed significantly between groups (P < .001). In the logistic regression, the best model included negative thalamus L-sign and gestational age, yielding an area under the curve, accuracy, sensitivity, specificity, and precision values of 0.995, 96.1%, 96%, 96.2%, and 96%, respectively. Both the lack of thalamus L-sign and gestational age were independent predictors (P < .001). CONCLUSIONS: The thalamus L-sign and gestational age may be useful in distinguishing between periventricular leukomalacia and neurometabolic disorders.

l-Carnitine prevents oxidative stress in striatum of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload.

The deficiency of the enzyme glutaryl-CoA dehydrogenase leads to predominant accumulation of glutaric acid (GA) in the organism and is known as glutaric acidemia type I (GA1). Despite the mechanisms of brain damage involved in GA1 are not fully understood, oxidative stress may be involved in this process. Treatment is based on protein/lysine (Lys) restriction and l-carnitine (L-car) supplementation. L-car was recently shown to have an important antioxidant role. A knockout mice model (Gcdh-/-) submitted to a dietary overload of Lys was developed to better understand the GA1 pathogenesis. In this study, we evaluated L-car and glutarylcarnitine levels, the lipid and protein damage, reactive oxygen species (ROS) production and antioxidant enzymes activities in striatum of Gcdh-/- and wild-type (WT) mice. We also determined the effect of the L-car treatment on these parameters. Thirty-day-old Gcdh-/- and WT mice were fed a normal chow (0.9% Lys) or submitted to a high Lys diet (4.7%) for 72 h. Additionally, these animals were administered with three intraperitoneal injections of saline or L-car in different times. Gcdh-/- mice were deficient in L-car and presented a higher glutarylcarnitine levels. They also presented lipid and protein damage, an increased ROS production and altered antioxidant enzymes compared to WT mice. Additionally, mice exposed to Lys overload presented higher alterations in these parameters than mice under normal diet, which were significantly decreased or normalized in those receiving L-car. Thus, we demonstrated a new beneficial effect of the L-car treatment attenuating or abolishing the oxidative stress process in Gcdh-/- mice.

Addressing the Unintentional Consequences of Cancer Therapy With Novel Integrative Therapeutics.

There are 15.5 million cancer survivors in the United States because of, in part, improvements in therapy. As a result, there will be an increased burden of long- and late-term complications of cancer care, such as metabolic alterations. These metabolic changes will include alterations in bone resorption, obesity, hypercholesterolemia, and diabetes mellitus. The majority of cancer treatment-related toxicities have focused on endocrine therapy; however, chemotherapy and supportive medications, such as steroids, contribute to the development of these disorders. Because of the chronicity of these metabolic changes and their impact on morbidity, cancer risk, and outcomes as well other negative effects, including musculoskeletal pain and vasomotor symptoms, alternative strategies must be developed. These strategies should include nonpharmacologic approaches. Here, we summarize metabolic changes secondary to cancer care and integrative approaches to help alleviate therapy-associated toxicities.

The hypothalamus as the primary brain region of metabolic abnormalities in APP/PS1 transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is an amyloid-related neurodegenerative disorder and is also considered to be a metabolic disease. Thus, investigation of metabolic mechanisms of amyloid pathology progression is of substantial importance for the diagnosis, prevention and treatment of AD. In the present study, cognitive function and brain metabolism were explored in the transgenic APP/PS1 mouse model of amyloid pathology at different ages. Using an NMR-based metabolomic approach, we examined metabolic changes in six different brain regions of wild-type and APP/PS1 mice at 1, 5 and 10months of age. Learning and memory performance in mice was evaluated using the Morris water maze test. Furthermore, a generalized linear mixed model was employed to analyze the interaction effect between the mouse-type and brain region (or age) on metabolic alterations. Brain region-specific changes in energy metabolism occurred prior to a very early-stage of amyloid pathology (1month of age) in APP/PS1 mice. A hypermetabolic state was identified in the brains of APP/PS1 mice at 5months of age, and the hypothalamus was identified as the main brain region that underwent significant metabolic alterations. The cognitive function of APP/PS1 mice was impaired at 10months of age; moreover, the hypermetabolic state identified in various brain regions at 5months of age was also significantly decreased. In conclusion, our results suggest that a hypothalamic metabolism abnormality may comprise a potential indicator for the early-diagnosis and monitoring of amyloid pathology progression.

Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment.

The neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, which is suggestive of a still unexplained selective topography of bilirubin-induced damage. By applying the organotypic brain culture (OBC: preserving in vitro the cellular complexity, connection and architecture of the in vivo brain) technique to study hyperbilirubinemia, we mapped the regional target of bilirubin-induced damage, demonstrated a multifactorial toxic action of bilirubin, and used this information to evaluate the efficacy of drugs applicable to newborns to protect the brain. OBCs from 8-day-old rat pups showed a 2-13 fold higher sensitivity to bilirubin damage than 2-day-old preparations. The hippocampus, inferior colliculus and cerebral cortex were the only brain regions affected, presenting a mixed inflammatory-oxidative mechanism. Glutamate excitotoxicity was appreciable in only the hippocampus and inferior colliculus. Single drug treatment (indomethacin, curcumin, MgCl2) significantly improved cell viability in all regions, while the combined (cocktail) administration of the three drugs almost completely prevented damage in the most affected area (hippocampus). Our data may supports an innovative (complementary to phototherapy) approach for directly protecting the newborn brain from bilirubin neurotoxicity.

Lead encephalopathy in an infant mimicking a neurometabolic disorder.

We report the case of a 7-month-old child who presented with regression of milestones, seizures, altered sensorium, and vomiting. An elder sibling had died of similar complaints. Lead encephalopathy was considered because of presence of microcytic hypochromic anemia and dense metaphyseal bands on wrist radiogram. Magnetic resonance imaging (MRI) of the brain revealed diffuse dysmyelination involving both periventricular and subcortical white matter. Such diffuse changes have not been described previously. The child's father was operating an illicit lead-acid battery manufacturing unit at home. The child was subjected to chelation therapy, which was accompanied by environmental exposure source modification. He showed significant improvement. Our case highlights the importance of taking a detailed occupational history and considering lead poisoning in the differential diagnosis of encephalopathy of unidentifiable cause.

Neurologic complications of gastric bypass surgery for morbid obesity.

BACKGROUND: The number of bariatric procedures is rapidly growing as the prevalence of obesity in the USA is increasing. Such procedures are not without complications, and those affecting the nervous system are often disabling and irreversible. We now describe our experience with these complications and review the pertinent literature. METHODS: We describe 26 patients with major neurologic conditions that seemed causally related to bariatric surgery encountered in the neurology service of a tertiary referral university medical center over a decade. RESULTS: The neurologic complications affected most regions of the nervous system: encephalopathy, optic neuropathy, myelopathy, polyradiculoneuropathy, and polyneuropathy. Myelopathy was the most frequent and disabling problem; symptoms began about a decade after surgery. Encephalopathy and polyradiculoneuropathy were acute and early complications. Except for vitamin B(12) and copper deficiencies in patients with myelopathy, we could not correlate specific nutritional deficiencies to the neurologic complications. All patients had multiple nutritional deficiencies, but their correction did not often yield dramatic results. The best result was achieved in one patient after surgical revision to reduce the bypassed jejunum. CONCLUSIONS: A wide spectrum of serious neurologic conditions may follow bariatric surgery. These complications may occur acutely or decades later.

FDG-PET findings in the Wernicke-Korsakoff syndrome.

This study reports FDG-PET findings in Wernicke-Korsakoff patients. Twelve patients suffering amnesia arising from the Korsakoff syndrome were compared with 10 control subjects without alcohol-related disability. Subjects received [18F]-fluorodeoxyglucose (FDG-PET) imaging as well as neuropsychological assessment and high-resolution MR imaging with volumetric analysis. Volumetric MRI analysis had revealed thalamic and mamillary body atrophy in the patient group as well as frontal lobe atrophy with relative sparing of medial temporal lobe structures. Differences in regional metabolism were identified using complementary region of interest (ROI) and statistical parametric mapping (SPM) approaches employing either absolute methods or a reference region approach to increase statistical power. In general, we found relative hypermetabolism in white matter and hypometabolism in subcortical grey matter in Korsakoff patients. When FDG uptake ratios were examined with occipital lobe metabolism as covariate reference region, Korsakoff patients showed widespread bilateral white matter hypermetabolism on both SPM and ROI analysis. When white matter metabolism was the reference covariate; Korsakoff patients showed relative hypometabolism in the diencephalic grey matter, consistent with their known underlying neuropathology, and medial temporal and retrosplenial hypometabolism, interpreted as secondary metabolic effects within the diencephalic-limbic memory circuits. There was also evidence of a variable degree of more general frontotemporal neocortical hypometabolism on some, but not all, analyses.

Neuropathological study of the role of mast cells and histamine-positive neurons in selective vulnerability of the thalamus and inferior colliculus in thiamine-deficient encephalopathy.

The purpose of the present study was to examine the role of histamine in the pathogenesis of experimental thiamine-deficient encephalopathy. By studying sagittal serial sections the authors were able to examine the topographical relationship between histamine-positive neurons and fibers, the number of mast cells, and localized lesions in the thalamus (TH) and inferior colliculus (IC). Adult rats were given a thiamine-deficient diet and pyrithiamine was given intraperitoneally (30 microg/100 g bodyweight per day), and the distribution of vulnerable regions and petechial bleeding was histologically examined by reconstruction of the sagittal serial sections. The distribution of mast cells and histamine-positive neurons and fibers was examined immunohistochemically in control rats, and compared between the vulnerable and non-vulnerable regions of the TH and tectum. Changes in the aforementioned measures during the thiamine-deficient state were also examined. The blood-brain barrier was examined using antibodies against rat endothelial barrier antigen (EBA) and albumin. The density of histamine-positive fibers in the vulnerable regions of the TH and IC was very low and not different from the non-vulnerable regions, and the number of mast cells was significantly higher in the lateral portion of the TH than the medial portion of the TH. The numbers of mast cells increased on days 7-10 after the start of the experiment, and significantly decreased on days 14-21. Histamine-positive neurons and fibers in the TH and IC also had the same changes. Bleeding of the IC occurred exclusively around arteries, and perivenous bleeding was absent. Albumin exudation and suppression of EBA expression of capillaries were found in the spongy lesions of the TH and IC. The role of histamine in selective vulnerability of the TH and IC in experimental thiamine-deficient encephalopathy was not supported. Findings in the present study suggest that the spongy change is a primary event, and vascular changes are secondary.

Whipple's disease and the central nervous system. A case report and a review of the literature.

A 65-year-old man was suffering from recurrent manic psychosis accompanied by weight loss. He also had a history of pleural effusion, aspecific migratory non-deforming seronegative polyarthritis, sensorineural hearing loss and semicircular canal paresis. Whipple's disease (WD) had been diagnosed at the age of 63 years. On admission to hospital) he had weight loss, diarrhoea in combination with an organic brain syndrome, hemiparesis and ophthalmoplegia, including internuclear ophthalmoplegia (INO). A clinical diagnosis of central nervous system (CNS) WD was made. MRI revealed a thalamus lesion that halved in size during sulfamethoxazole-trimethoprim treatment. The organic brain syndrome and ophthalmoplegia diminished also, as did the cerebrospinal fluid (CSF) IgG level. A review of CNS WD is presented and implications for treatment are discussed.

N-acetylaspartic aciduria in Canavan disease: another proof in two infants.

Increased amounts of urinary N-acetyl-aspartic acid was found in two infants with biopsy proven Canavan disease. The aspartoacylase assay is a new tool for determining both the prenatal and antenatal diagnosis of Canavan disease. This assay should be screened in patients with early onset of psychomotor deterioration, macrocephaly, spasticity/hypotonia and white matter hyperleucency at CT scan.

[Glycine encephalopathy: a non-ketotic disorder of glycine catabolism]. / Glyzinenzephalopathie: eine nicht-ketotische Glyzinabbaustörung.

We report on a newborn with peracute glycine encephalopathy. The child exhibited poor feeding, incipient respiratory failure and increasing muscular hypotonia from the first few days of life onwards and was admitted to hospital at six weeks due to regression of the symptoms. Following respiratory arrest the child had to be placed on controlled ventilation and died at the age of four months in spite of therapeutic measures. Previous papers on this rare disease have described elevated CSF glycine levels, EEG patterns, CT scan and acoustic and visual evoked potentials. We have supplemented these for the first time by somatosensory evoked potentials. The following is an account of the clinical course and the therapy given.

The effect of copper supplementation on the brindled mouse: a clinico-pathological study.

Brindled mottled is a neurological mutant mouse. Hemizygous males have many clinical and biochemical features in common with kinky hair syndrome (KHS) in humans, and usually die around postnatal day 15, after severe emaciation. Neuronal mitochondrial abnormalities and neuronal degeneration in the cerebrum and cerebellum were constant neuropathological findings in this mutant. A single intraperitoneal injection of cupric chloride, 10 micrograms/g body weight, resulted in an improvement of clinical symptoms and prevention of neuronal degeneration. The degree of improvement was dependent on the date of injection, and day 7 to 10 postnatal appeared to the most effective date. The male hemizygotes which received cupric chloride injections at day 7 or 10 overcame the lethality, and no neuronal degeneration was detected in these mice, although neuronal mitochondrial changes were still persistent. However, following two injections at days 7 and 10, no abnormalities were detected in the cerebral cortical neurons. Even at the ultrastructural level, abnormal mitochondria were very scarce. In the cerebellum, however, mitochondrial changes in the Purkinje cells, particularly in the rostral portion, and generation of white matter were noted in these mice, which were clinically perfectly healthy, judging from the growth rate and behavior. However, cerebellar changes were far less in those which received additional injections later on. These observations indicate that, at least in brindled mutant mice, supplementation of copper is quite beneficial for clinical improvement and the prevention of neuropathological lesions, but the date of administration appears to have crucial importance.

Brindled mottled mouse: morphological changes of brain and visceral organs in hemizygous males following copper supplementation.

Intraperitoneal injections of cupric chloride prevent neuronal degeneration in the hemizygous brindled mottle mouse, MO br/Y, a murine model of kinky hair syndrome (KHS) in humans. At 6-9 months after two i.p. injections, the brain of MO br/Y revealed slightly increased amounts of lipofuscin pigments in the cerebral cortical neurons, cytoplasmic inclusions in the thalamic neurons, and axonal spheroid formation in the tuber cinereum, cerebellum and brain stem. Increased numbers of mitoses, bizarre hyperchromatic giant nuclei, and numerous clear vacuoles were frequently seen in the proximal renal tubular epithelium. Numerous myelin figures were conspicuous features in these epithelial cells at ultrastructural level. Such changes were not found in the littermate controls but in the heterozygous brindled mottled mouse, MO br/ +, identical changes were noted in equal or even higher frequency. These observations suggest that cupric chloride injections effectively modify the expression of the genetic defect in MO br/ Y.