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Pediatric acute onset neuropsychiatric syndrome (PANS) is viewed as an autoimmune/autoinflammatory condition characterized by the abrupt onset of severe neurological and psychiatric symptoms, in particular obsessive-compulsive disorder (OCD), tics, anxiety, mood swings, irritability, and restricted eating, often triggered by infections. However, direct evidence of autoimmunity, infections, or a proinflammatory state is often lacking, and there is no unifying pathogenic pathway. This could be due to underlying genetic heterogeneity, which could lead to the development of PANS through different cellular and molecular pathways. Unfortunately, little is known about the genetic basis of PANS. Consequently, we carried out whole exome sequencing (WES) on a U.S. cohort of 386 cases who met diagnostic criteria for PANS, including 133 family triads, and whole genome sequencing (WGS) on ten cases from the European Union, who were selected for WGS because of severe PANS symptoms. We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency (MAF) < 0.001. Candidate mutations were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 20 cases, which included two sets of siblings, and two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4, RAG1, and SHANK3. The PANS candidate genes we identified separate into two broad functional categories. One group regulates peripheral innate and adaptive immune responses (e.g., PPM1D, CHK2, NLRC4, RAG1, PLCG2), some of which also influence microglia function. Another is expressed primarily at neuronal synapses or directly modulates synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). These neuronal PANS candidate genes are often mutated in autism spectrum disorder, developmental disorders, and myoclonus-dystonia. In fact, eight out of 20 cases in this study developed PANS superimposed on a preexisting neurodevelopmental disorder. There is, however, clinical overlap between these two groups and some crossover expression (e.g., some neuronal genes are expressed in immune cells and vice versa) that diminishes the neuronal/immune dichotomy. Genes in both categories are also highly expressed in the enteric nervous system, and in the choroid plexus and brain vasculature, suggesting they might contribute to a breach in the blood-CSF barrier and blood-brain barrier (BBB) that would permit the entry of autoantibodies, inflammatory cytokines, chemokines, prostaglandins, and autoantibodies into the brain. Thus, PANS is a genetically heterogeneous condition that can occur as a stand-alone neuropsychiatric condition or co-morbid with neurodevelopmental disorders, with candidate genes functioning at several levels of the neuroinflammatory axis.

Objectives: To report a case series of children presenting with episodes of abrupt onset psychotic symptoms presumably linked to pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS). Methods: Children/adolescents were selected among the group of individuals affected by clinical diagnosis of PANDAS/PANS. One group was selected by affected individuals coming from the Center UMDNJ--New Jersey Medical School, New Jersey, USA and the other from the Department of Pediatrics Catania University, Italy. Child health Questionnaire Parent form 50 was given to parents to describe children's quality of life. Results: Among the group of individuals with PANDAS/PANS disorders, eight children/adolescents were selected, six coming from the UMDNJ--New Jersey and two from Catania, University centers showing among the other typical manifestations severe episodes of abrupt onset of psychotic symptoms. Conclusions: Severe psychotic symptoms may be considered one among the other neuropsychiatric clinical manifestations presenting in individuals with PANDAS/PANS syndromes.

We report four children with Down Syndrome (DS) without evidence of congenital heart disease who sustained cerebral infarction in the context of an infectious disease. In one child, stroke occurred in the context of acute infection with Mycoplasma pneumonia. In another child, stroke occurred in the context of Streptococcus oralis (viridans subgroup) infection. In two other children, stroke occurred in the context of a bibasilar pneumonia for which an etiologic agent was not found. All patients had evidence of selective IgG4 subclass deficiency. We followed 8 other children with down syndrome with infectious diseases, but without stroke and a control group of healthy children, and measured the value of IgG4 for each group. We found a statistical significant difference of levels of IgG4 subclass deficiency in the group of stroke, in comparison with the other two groups (P values

Streptococcal infection in children is usually benign and self-limited. In a small percentage of children, prominent neurologic and/or psychiatric sequelae can occur. Sydenham chorea is the best defined and best recognized. PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive-compulsive disorder consistently exacerbate in temporal correlation to a group A β-hemolytic streptococcal infection. PANDAS constitutes a subset of children with tics, Tourette syndrome, and obsessive-compulsive disorder. In addition to strictly defined PANDAS, we and others have recognized several PANDAS variants, including adult-onset variant, a dystonic variant, a myoclonic variant, and a ``chronic'' PANDAS variant. The nosology and classification of these entities are rapidly evolving. The recognition that some pediatric neurobehavioral syndromes have infectious and/or immunologic triggers points to important new avenues of disease treatment. In this review, we summarize this complex and rapidly evolving area of clinical research. (J Child Neurol 2006;21:727—736; DOI 10.2310/7010.2006.00182).

This report describes a proband and his family consisting of 14 patients affected with simple congenital ptosis. Pedigree suggests an autosomal dominant pattern with 70-90% penetrance. The family includes patients with both unilateral and bilateral involvement, and cases with and/or without complex synkinesia. Left unilateral preponderance is striking, and pedigree analysis suggests the possibility of a modifier gene determining laterality. This study represents the first report of a large family with congenital autosomal dominant simple ptosis which demonstrates the full clinical spectrum of this condition. (c) 2005 by Elsevier Inc. All rights reserved.

Nitration of protein tyrosine residues by nitric oxide (NO)-derived reactive species results in the production of stable nitrotyrosine (NT) moieties that are immunochemically detectable in many regions of normal brain and enriched in those areas containing constitutive nitric oxide synthase (cNOS). These include the caudate-putamen nucleus (CPN) and the globus pallidus, which receives major inhibitory input from the CPN. To determine the functional sites for NT production in these critical motor nuclei, we examined the electron microscopic immunocytochemical localization of NT and cNOS in rat brain. In the CPN, NT was localized to the somata and dendrites of cNOS-containing interneurons and spiny neurons, some of which received input from cNOS-labeled terminals. The NT immunoreactivity was most prevalent on outer mitochondrial membranes and nearby segments of the plasma membranes in dendrites and within asymmetric synapses on dendritic spines. In the CPN and globus pallidus, there was also a prominent labeling of NT in astrocytic processes, small axons, and tubulovesicles and/or synaptic vesicles in axon terminals. These terminals formed mainly asymmetric synapses in the CPN and inhibitory-type synapses in the globus pallidus where they often apposed cNOS-containing terminals that also formed asymmetric, excitatory-type synapses. Our results suggest that NT is generated by mechanisms requiring the dual actions of excitatory transmitters and NO derived either from interneurons in the CPN or from excitatory afferents in the globus pallidus. The findings also implicate NT in the physiological actions of NO within the striatal circuitry and, particularly, in striatopallidal neurons severely affected in Huntington's disease.

Abnormal oxidative processes including a reduction in thiamine-dependent enzymes accompany many neurodegenerative diseases. Thiamine deficiency (TD) models the cellular and molecular mechanisms by which chronic oxidative aberrations associated with thiamine-dependent enzyme deficits cause selective neurodegeneration. The mechanisms underlying selective cell death in TD are unknown. In rodent TD, the earliest region-specific pathological change is breakdown of the blood-brain barrier (BBB). The current studies tested whether nitric oxide and microglia are important in the initial events that couple BBB breakdown to selective neuronal loss. Enhanced expression of endothelial nitric oxide synthase and nicotinamide adenine dinucleotide phosphate diaphorase reactivity in microvessels, as well as the presence of numerous inducible nitric oxide synthase-immunoreactive microglia, accompanied the increases in BBB permeability. Nitric oxide synthase induction appears critical to TD pathology, because immunoreactivity for nitrotyrosine, a specific nitration product of peroxynitrite, also increased in axons of susceptible regions. In addition, TD elevated iron and the antioxidant protein ferritin in microvessels and in activated microglia, suggesting that these cells are responding to an oxidative challenge. All of these changes occurred in selectively vulnerable regions, preceding neuronal death. These findings are consistent with the hypothesis that the free radical-mediated BBB alterations permit entry of iron and extraneuronal proteins that set in motion a cascade of inflammatory responses culminating in selective neuronal loss. Thus, the TD model should help elucidate the relationship between oxidative deficits, BBB abnormalities, the inflammatory response, ferritin and iron elevation, and selective neurodegeneration.

Background. The relation between aortic atheroma severity and stroke after coronary artery bypass grafting is established. The relation between atheroma severity and other outcome measures or numbers of emboli has not been determined. Methods. Using transesophageal echocardiography, we determined the severity of atheroma in the ascending, arch, and descending aortic segments in 84 patients undergoing operations. Seventy patients were monitored using transcranial Doppler ultrasonography. Results. The incidence of stroke was 33.3% among 9 patients with mobile plaque of the arch and 2.7% among 74 patients with nonmobile plaque ( p = 0.011). Cardiac complications were not significantly related to atheroma severity in any aortic segment. Length of stay was significantly related to atheroma severity in the aortic arch ( p = 0.025) and descending segment ( p = 0.024). The presence of severe atheroma in both the arch and descending segments was associated with significantly longer hospital stays as compared with patients with severe atheroma in neither segment ( p = 0.05). Numbers of emboli were greater in patients with severe atheroma at clamp placement, although the differences did not achieve statistical significance. Conclusions. Aortic atheroma severity is related to stroke and to the duration of hospitalization after coronary artery bypass grafting. The lack of correlation between numbers of emboli and atheroma severity suggests that many emboli may be nonatheromatous in nature.

Animals with one deletedjerkyallele are more susceptible to chemically induced seizures than wild-type mice and display recurrent behavioral seizures. The phenotype of these hemizygotes is characterized by no apparent neurological symptoms other than recurrent seizures reminiscent of human idiopathic epilepsy. Thejerkygene encodes a 60 kDa protein resembling a number of DNA-binding proteins. Here, we show that thejerkygene is expressed in all tissues examined, including brain, liver, lung, spleen, testis, and ovary, and study an apparent paradox of how an allelic deletion of the ubiquitously expressedjerkygene can lead to hyperexcitability and seizures but not to other symptoms. We demonstrate that jerky has a dosage-sensitive function (haploinsufficiency) in brain and that this sensitivity to reduced jerky dosage could explain the occurrence of seizures in hemizygotes. However, jerky has a nondosage-sensitive function as well, because the total absence of jerky in homozygotes results in abnormalities of somatic and sexual development. A number of idiopathic epilepsies are dominantly inherited, such as benign familial neonatal convulsions, juvenile myoclonic epilepsy, as well as benign epilepsy with centrotemporal spikes, and the pathomechanism of these epilepsies may be based on haploinsufficiency in the brain.

Background. Embolic signals have been detected within both the aortic lumen and the intracranial vasculature during coronary artery bypass grafting. Total numbers of these emboli have been reported. The present study examined the size of individual emboli and the total volume of embolization. Methods. Using transesophageal echocardiography, we continuously monitored the aortic lumen of 10 patients undergoing isolated coronary artery bypass grafting. We manually analyzed 720,000 individual echo frames over a 4-minute period after the release of aortic clamps to track and to calculate the volume of 657 individual particles. The embolic load for the entire procedure was calculated from mean volume based on analysis of 1,508 particles. We simultaneously monitored the middle cerebral artery using transcranial Doppler ultrasonography and compared numbers of emboli detected by the two techniques. Results. Particle diameter ranged from 0.3 to 2.9 mm (mean, 0.8 mm), and particle volume from 0.01 to 12.5 mm 3 (mean, 0.8 mm 3 ). Twenty-eight percent of particles measured 1 mm or more, 44% measured 0.6 to 1.0 mm, and only 27% measured 0.6 mm or less in diameter. Aortic embolic load for the procedure ranged from 0.6 cm 3 to 11.2 cm 3 (mean, 3.7 cm 3 ). Estimated cerebral embolic load for the procedure ranged from 60 to 510 mm 3 (mean, 276 mm 3 ). The fraction of aortic emboli entering the cerebral circulation was very variable (3.9% to 18.1%). Seventy-six percent of the embolic volume after the release of clamps occurred over a 20-second period. Only 1 patient was encephalopathic perioperatively. This patient had the largest estimated cerebral embolic load (510 mm 3 ) and the second largest aortic embolic load (8.4 cm 3 ). Conclusions. We determined the size of individual intraaortic embolic particles and the total volume of embolization during coronary artery bypass grafting, and found the proportion entering the cerebral circulation to be very variable. The constitution of these particles and the neurologic impairment resulting from such embolization remains to be determined.

Background . Transcranial Doppler ultrasonography detects emboli in most patients during coronary artery bypass grafting. However, the significance of these emboli has not yet been established. Methods . We monitored 82 patients during coronary artery bypass grafting with this technique and related the numbers of emboli to the outcomes and length of hospital stay. Results . We detected cerebral emboli in all patients. Patients with stroke (n = 4; 4.9%) had a mean of 449 emboli, as compared with 169 emboli in patients without stroke (n = 78) ( p = 0.005). Patients with major cardiac complications (n = 7) had a mean of 392 emboli, as compared with 163 in patients without such complications (n = 75) ( p = 0.003). The mean hospital stay of survivors was 8.6 days in patients with fewer than 100 emboli (n = 40), 13.5 days in patients with 101 to 300 emboli (n = 23), 16.3 days in those with 301 to 500 emboli (n = 16), and 55.8 days in patients with more than 500 emboli (n = 6) ( p = 0.0007). This relation was unchanged when patients with complications were excluded. The correlation between embolization and outcome was independent of the extent of aortic atheroma or age. Conclusions . Emboli detected during coronary artery bypass grafting are significantly related to major cardiac and neurologic complications and affect length of stay in all patients, even in the absence of such specific complications. (Ann Thorac Surg 1997;63:998–1002)

The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3–5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.

Three hundred forty patients were diagnosed with pertussis infection at the Pediatric Clinic of the University of Catania, Sicily during the period 1979-1994. None of these patients had been previously vaccinated. Fourteen developed neurological complications at some point in their course, which took the form of seizures (both febrile and afebrile) and, in some cases, encephalopathy. Serious permanent neurological sequelae were not observed in this series of patients though they had pertussis severe enough to require hospitalization.

The usefulness of felbamate (FBM) levels in managing epilepsy patients has not been determined. The purpose of the present study was to determine if FBM levels obtained at routine office visits correlated with side effects reported by patients. We determined FBM levels by high-pressure liquid chromatography (HPLC) of 46 epilepsy patient plasma specimens (41 patients) and assessed medication toxicity and seizure frequency by a questionnaire. Thirty-six patients were treated with other antiepileptic drugs (AEDs); concomitant AED levels not in ranges believed to cause toxicity. FBM levels ranged from 9 to 134 microgram/ml, and were divided into three groups for analysis, resulting in low-range (9-36 microgram/ml), midrange (37-54 microgram/ml), and high-level (44-134 microgram/ml) groups. Anorexia and complaints of severe side effects were reported significantly more often in the high-level group as compared with the low- and midrange groups. Significantly more patients in the high-level group (10/13) reported decreased seizure frequency, as compared with 12 of 30 patients in the low- and midrange groups combined. FBM levels correlated linearly with doses overall, but most closely in FBM monotherapy patients.

Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening disorder of neonates manifested by vasoconstriction of the pulmonary arteries. Recently, the gas nitric oxide (NO) has been used with some success in the management of infants with PPHN. Exogenous administration of NO selectively dilates the pulmonary vascular bed. NO is naturally synthesized in the body from the amino acid L-arginine. Here we report our findings that infants with PPHN are deficient in arginine and achieve normal or elevated plasma arginine concentrations with intravenous hyperalimentation. We prospectively identified and studied 10 infants with PPHN who were not receiving protein or amino acids for at least 24 h and compared their plasma arginine concentrations to 8 control infants without PPHN given similar nutrition. Plasma arginine concentrations were 32 ± 14 and 52 ± 20 µmol/l in infants with PPHN and control infants, respectively (p = 0.02). There were no other statistically significant differences in plasma amino acid concentration for any of the 22 other amino acids determined. Infants with PPHN who were subsequently treated with amino acid infusions had plasma arginine concentrations of 115 ± 48 µmol/l (mean often determinations at 86 ± 27 h after initiation of intravenous amino acids in five PPHN infants).

Nitric oxide has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures. A number of indicators of brain nitric oxide production (nitric and cyclic guanosine monophosphate [cGMP] concentrations and nitric oxide synthase activity) were examined after bilateral carotid ligation and right middle cerebral artery occlusion in adult rats. Brain nitrite was significantly increased in the right versus left cortex 5, 10, and 20 minutes after middle cerebral artery occlusion (P < .05), with a return to baseline at 60 minutes. There were no significant changes in cerebellar concentrations. Cortical levels of cGMP were increased at 10, 20, and 60 minutes after occlusion, with significant right-to-left differences (P < .05). Cerebellar concentrations of cGMP were also increased but without significant side-to-side differences. Nitric oxide synthase activity increased approximately 10-fold from baseline 10 minutes after occlusion in the right cortex but decreased markedly by 60 minutes from its peak at 10 minutes. The right-to-left difference in nitric oxide synthase activity was significant at 20 minutes (P < .05). Pretreatment of rats with NG-nitro-L-arginine, a nitric oxide synthase inhibitor, abolished the rise in nitrite and cGMP. These results suggest that a sharp transient increase in the activity of nitric oxide synthase occurs during the first hour of cerebral ischemia, which leads to a burst in nitric oxide production and activation of guanylate cyclase.

The mitochondrial benzodiazepine receptor (mBzR) has been solubilized with retention of reversible ligand binding, and the associated subunits were characterized. mBzR comprises immunologically distinct protein subunits of 18-, 30-, and 32-kDa. The 18-kDa protein is labeled by the isoquinoline carboxamide mBzR ligand [3H]PK14105, whereas the 30- and 32-kDa subunits are labeled by the benzodiazepine (Bz) ligands [3H]flunitrazepam and [3H]AHN-086. Selective antibodies and reagents identify the 32- and 30-kDa proteins as the voltage-dependent anion channel (VDAC) and the adenine nucleotide carrier (ADC), respectively. While isoquinoline carboxamide and Bz ligands target different subunits, they interact allosterically, as the binding of Bz and isoquinoline carboxamide ligands is mutually competitive at low nanomolar concentrations. Moreover, eosin-5-maleimide and mercuric chloride inhibit [3H]PK11195 binding to the intact receptor via sulfhydryl groups that are present in ADC. VDAC and ADC, outer and inner mitochondrial membrane channel proteins, respectively, together with the 18-kDa subunit, may comprise mBzR at functionally important transport sites at the junction of two mitochondrial membranes.

Brucellosis is an infection due to Brucella species and is characterized by acute febrile illness, chilly sensations, sweats, weakness, generalized malaise, body aches and headache. The involvement of the nervous system is rare. A few cases have been reported with symptoms and sign of optic neuritis, meningoencephalitis, meningomyelitis and cranial nerve palsy. We report a case with culture proven neurobrucellosis who presented with diabetes insipidus along with systemic signs. Neuroimaging revealed multiple lesions in brain parenchyma, including the suprasellar region. Both diabetes and suprasellar lesions improved markedly with specific antibiotic therapy. (C) 2000 Elsevier Science B.V.

We report on a 3.5-year-old girl with microcephaly, microphthalmia, coloboma of the iris, mild developmental delay, and other minor anomalies. Neuroimaging showed marked cerebellar and vermian hypoplasia. This condition has not been described previously and is discussed in the context of the 'micro syndrome,' together with other similar syndromes. Our case highlights the heterogeneity of the 'microphthalmia plus brain malformations' group of patients. (C) 2000 Wiley-Liss, Inc.

We describe a mentally retarded 24-year-old man followed by our group since age 18 months who exhibited nearly continuous stereotypic movements while awake. These movements, which have persisted over many years, consist of synchronous lateral flexion at the neck and waist. Movements could be partially voluntarily suppressed and disappeared in sleep. The patient has drug-resistant seizures and a constellation of dysmorphic features, including coarse face, large nose, large thin lips, brachicephaly, marked hirsutism on the face, and limbs proportionally smaller than the trunk, which suggests that the unusual stereotypic movements described may be part of a syndrome. Routine and full metabolic serum and urine analyses, full ophthalmological examination, internal organs ultrasound examination, full skeletal survey, standard karyotype and array-CGH analysis yielded normal results.

GLUCOSE (D-glucose) is an essential fuel for the brain and many other tissues. Five glucose-transporter proteins facilitate the diffusion of glucose across lipophilic plasma membranes.1 2 3 This pr...

Fetal nucleated red blood cells (FNRBCs) circulate in the maternal blood throughout pregnancy. Even if the frequency of fetal cells in the maternal circulation remains to be ascertained, complications of pregnancy such as fetal cells aneuploidies, preeclampsia, abnormal Doppler of the uterine artery without symptoms of preeclampsia, fetal growth restriction and polyhydramnios are associated with an increased feto-maternal trafficking. Based on these observations, previous studies have suggested that determination of the fetal nucleated red blood cell count (FNRBCC) might be a useful non-invasive screening test, either alone or in combination with existing maternal tests, for the non-invasive assessment of aneuploidies, in particular Down syndrome (DS). In this paper we have evaluated the distribution of FNRBCC in a set of 18 normal pregnancies and 18 pregnancies with a trisomy 21-affected fetus, matching for gestational age, maternal age, and, when possible, fetal gender, in order to quantify the difference in the number of fetal cells between the two populations. Maternal blood was collected from each pregnant woman two to three weeks after amniocentesis after knowing the cytogenetic results. Correlation of FNRBCC with the gestational week and clinical status (affected vs. non affected) by multiple regression analysis provided significant results (p < 0.001). Adjusted values of FNRBCC were 48 +/- 10.2 in controls and 301 +/- 17.01 in DS cases, corresponding to a 6.27 fold increase. These retrospective results prompt a prospective evaluation of the use of FNRBCC for screening purposes.

The objective of this study was to assess brain involvement through the presence of antineuronal antibodies in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) and in uncomplicated active Group A streptococcal infection. We compared serum antibrain antibody to human basal ganglia sections assessed by indirect tissue immunofluorescence in two groups: a PANDAS group, comprised of 22 patients (mean age 10.1 years; 20 male, 2 female) who met strict National Institutes of Mental Health diagnostic criteria for PANDAS and had clinically active tics or obsessive-compulsive disorder, or both; and a GABHS control group consisting of 22 patients (mean age 9.1 years; 15 mol/L, 7 female) with clinical evidence of active Group A beta-hemolytic streptococcal (GABHS) infection confirmed by throat culture and elevated antistreptolysin O titers but without history or clinical evidence of tics or obsessive-compulsive disorder. We observed positive anti-basal ganglia staining (defined as detectable staining at 1:10 serum dilution) in 14/22 patients in the PANDAS group (64%) but only 2/22 (9%) in the GABHS control group (P < 0.001, Fisher's exact test). These results suggest that antibrain antibodies are present in children with PANDAS that cannot be explained merely by a history of GABHS infection. (C) 2004 by Elsevier Inc. All rights reserved.

Mucopolysaccharidosis (MPS) type I (?-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome).The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment. Copyright © 2002 Elsevier Science B.V.

Until today there is a large debate about the existence of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) or PANS (pediatric acute onset neuropsychiatric syndrome). These children usually have dramatic, “overnight” onset of symptoms, including motor or vocal tics, obsessions, and/or compulsions. In addition to these symptoms, children may also have comorbid features of associated disorders. Herein, we report a family with an early onset of tics, with exclusively dystonic and guttural tics. All patients had a particularly strong excitement trigger. Two of the patients were shown to have signs suggestive of PANDAS and all family members were Group A beta-hemolytic Streptococcus (GABHS) carriers. The PANDAS spectrum is probably a group of disorders. We have described a PANDAS variant, in which the family seems to share common autoimmune pattern and may be viewed in the large spectrum of PANDAS.

The isolation and analysis of nucleated fetal cells (NFCs) from maternal blood may represent a new approach to noninvasive prenatal diagnosis. Although promising, these techniques require highly accurate separation of NFCs from nucleated cells of maternal origin; the two major problems limiting these techniques are the relative rarity of fetal cells in maternal blood and the need to establish their fetal origin. We now report a novel procedure that has allowed accurate separation of NFCs from maternal cells. The technique reported involves direct micromanipulator isolation of histochemically identified hemoglobin F-positive nucleated cells to obtain fetal nucleated red blood cells (FNRBCs) of high yield and purity. Using this technique, followed by cell-by-cell multicolor fluorescence in situ hybridization (FISH) analysis of purified FNRBCs, we were able to detect some of the most common human aneuploidies (including Down syndrome, Klinefelter syndrome, and trisomy 13) in 33 pregnant women referred for amniocentesis. The procedure used, which can be completed in

A number of disorders, including childhood-onset obsessive compulsive disorder (OCD) and Gilles de la Tourette's syndrome (TS), are now known to be neurobiological in nature. Both TS and OCD are neuropsychiatric diagnoses that involve congitive and perceptual dysfunction in addition to motor and psychiatric manifestations. The association of the B-cell marker with both Sydenham's chorea and a group of neuropsychiatric disorders, such as OCD, tics, and TS, has been useful as a marker in these diseases. This evidence, coupled with the recent finding of anti-brain antibodies in the sera of these patients, raises a number of interesting questions concerning the pathological mechanisms involved in these diseases. Thus, further molecular characterization of the brain and streptococcal antigens will be crucial to our understanding of the neurophysiological processes involved in these disorders.

The decrement in dopamine levels exceeds the loss of dopaminergic neurons in Parkinson’s disease (PD) patients and experimental models of PD. This discrepancy is poorly understood and may represent an important event in the pathogenesis of PD. Herein, we report that the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is a selective target for nitration following exposure of PC12 cells to either peroxynitrite or 1-methyl-4-phenylpyridiniun ion (MPP + ). Nitration of TH also occurs in mouse striatum after MPTP administration. Nitration of tyrosine residues in TH results in loss of enzymatic activity. In the mouse striatum, tyrosine nitration-mediated loss in TH activity parallels the decline in dopamine levels whereas the levels of TH protein remain unchanged for the first 6 hr post MPTP injection. Striatal TH was not nitrated in mice overexpressing copper/zinc superoxide dismutase after MPTP administration, supporting a critical role for superoxide in TH tyrosine nitration. These results indicate that tyrosine nitration-induced TH inactivation and consequently dopamine synthesis failure, represents an early and thus far unidentified biochemical event in MPTP neurotoxic process. The resemblance of the MPTP model with PD suggests that a similar phenomenon may occur in PD, influencing the severity of parkisonian symptoms.

Reflex sympathetic dystrophy (RSD or causalgia) has been rarely reported in children. We now report a 10-year-old boy with RSD in whom we performed extensive ancillary investigations including thermography, bone scintigraphy and dermo-echography. The clinical, laboratory and ancillary studies reported here highlight the profound focal acquired autonomic disturbance in this disorder. The patient presented a compression of the deep peroneal nerve at the inferior extensor retinaculum in the affected limb. Surgical decompression lead to rapid improvement of the patient's condition. Peripheral nerve decompression should be considered as a possible treatment of RSD in children, particularly those that are refractory to conservative maneuvers.

Objective: The purpose of this study was to determine whether emboli can be detected within the aortic lumen in patients undergoing coronary artery bypass surgery (CABG) and to relate the appearance of emboli to specific operative events. Design: Twenty patients were prospectively studied intra-operatively. Setting: Subjects were inpatients in an academic medical center. Participants: All participants were scheduled for elective, isolated CABG. Interventions: Patients were continuously monitored using transesophageal echocardiography (TEE) from aortic cannulation to bypass discontinuation. After completion of the aortic examination, the probe was focused at the level of the aortic arch, just before the takeoff of the left subclavian artery. Emboli were defined as echogenic intraluminal signals not present in the same position on consecutive cross-sectional frames. Results: Intraluminal emboli were detected in all subjects, with a mean number of 535 and range of 8 to 1,885. Embolization was unevenly distributed through the procedure. A mean of 224 (42%) of 535 were detected within 4 minutes of aortic cross-clamp release and another 140 (24%) appeared after partial occlusion clamp release. Together, clamp placement and release represented 84% of all emboli. Emboli detected after clamp release were large, echodense particles easily distinguishable from the small, indistinct, poorly echogenic signals observed at bypass initiation. Conclusions: Emboli can be visualized within the aortic lumen during CABG. Confirming previous reports, the majority of emboli detected are related to manipulation of aortic clamps. The composition and clinical significance of embolic material are unclear. The value of intraoperative TEE monitoring in predicting neurologic outcome remains to be determined.

Background and Purpose Transcranial Doppler ultrasonography (TCD) is the standard technique for monitoring emboli in the cerebral circulation. Embolic signals have been detected with the use of this technique in most patients undergoing coronary artery bypass surgery. We previously reported that the majority of emboli are detected after release of aortic cross-clamps and partial occlusion clamps. In this study we compare the intraoperative use of TCD with transesophageal echocardiography (TEE) to monitor cerebral emboli. Methods We simultaneously monitored 20 patients undergoing coronary bypass surgery with TCD and TEE. All patients also underwent routine TEE examination of the aorta. Results Embolic signals were detected in all patients by both techniques. Mean total number of emboli was 535±109 by TEE compared with 133±28 by TCD. We found correlation between numbers of emboli detected by the two techniques at clamp placement and release ( r =.65, P =.002). Clamp placement and release accounted for 84% of all emboli by TEE and 83% by TCD. By TEE, large, highly echogenic particles were detected after clamp release compared with small, barely echo-dense particles at the onset of bypass. No such distinction was apparent by TCD. We found correlation between severity of aortic atheroma and both TEE- ( P =.003) and TCD-detected ( P =.009) emboli. Conclusions TEE and TCD can both be used to continuously monitor emboli during coronary artery bypass surgery. However, TEE is invasive and justified only if it is being performed for intraoperative assessment of aortic atheromatosis or cardiac function.

The clinical spectrum of the congenital muscular dystrophies is reviewed using as a sample population 10 Sicilian patients with various clinical subtypes. A comprehensive classification scheme for the muscular dystrophies is presented based on recent advances in our understanding of this heterogeneous group of syndromes. © 1995.

A large Sicilian kinship in which myotonic dystrophy (DM) affected spanning four generations is presented. The pedigree clearly illustrates the phenomenon of anticipation, and illustrates that this phenomenon is more marked when transmission occurs through an affected female rather than an affected male. The pedigree is interpreted in light of recent genetic advances in DM. Neurosurgeons and neurologists should consider a diagnosis of DM when asked to evaluate a floppy infant with enlarged lateral ventricles, and should be aware of special features regarding its inheritance pattern. © 1995 Springer-Verlag.

Six patients with congenital muscular dystrophy examined from January, 1990 to January, 1993 are presented. Vastus lateralis muscle biopsies were performed on all patients. Five of 6 patients had "pure" congenital muscular dystrophy without evidence of central nervous system disease. Of these 5 patients, 2 had mild courses, 2 moderate, and 1 severe. Possible correlation between severity of muscle pathology and severity of clinical course in "pure" congenital muscular dystrophy patients is discussed.

The molecular mechanism of the clinical antiepileptic/antimyoclonic action of adrenocorticotrophic hormone (ACTH) is unknown. To explore the possible role of excitatory amino acid receptors, we studied the influence of ACTH and ACTH fragments in vitro on the binding of [3H]MK-801 to rat hippocampus, a region relevant to epilepsy. ACTH-(1-39), ACTH-(1-24), and ACTH-(1-17) displayed micromolar affinities compared to the nanomolar affinity of MK-801, whereas ACTH-(4-10) and four clinically used anticonvulsants were inactive. These findings are not specific for NMDA receptors but conform to the rank order of potency of ACTH fragments at other receptor binding sites.

Recent evidence in primary neuronal cell culture implicates nitric oxide (NO) as a mediator of glutamatergic neurotoxicity acting via N-methyl-D-aspartate (NMDA) receptors. We find that administration of the potent nitric oxide synthetase (NOS) inhibitor NG-nitro-L-arginine (NO-Arg) at 50 mg/kg to 100 mg/kg i.p. to 6-day old Sprague-Dawley rat pups results in prompt and long-lasting in vivo inhibition of NOS. Fifteen hours after administration, NO-Arg produces essentially complete neuroprotection against hypoxic-ischemic in a standard (Rice-Vanucci) model. These results support the hypothesis that NO may play a key mediatory role in brain damage attending focal ischemic stroke.

Marco Sciuto1, Gaetano Bertino2, Mariangela Zocco3, Ignazio Vecchio4, Rocco Raffaele4, Rosario R Trifiletti5, Piero Pavone3,61Neonatal Care Section, Valsalva Hospital, Catania, Italy; 2Department of Internal Medicine, Hospital S Marta University of Catania, Italy; 3Pediatric Unit, Department of Pediatric Hospital Civile, Ragusa, Italy; 4Department of Neurology, University of Catania, Italy; 5Department of Neurology, Morristown Memorial Hospital, New Jersey, USA; 6Pediatric Unit, Department of Pediatric and Pediatric Neurology, University of Catania, Italy Aim and scope: We conducted this study to estimate the incidence of hyperbilirubinemia in a small neonatal care unit in Catania, Italy, and to determine the underlying causes, which would be of value in identifying and implementing strategies to prevent morbidity from this condition.Background: Management of hyperbilirubinemia remains a challenge for neonatal medicine because of the risk for serious neurological complications related to the toxicity of bilirubin. Methods: From January 2006 to January 2007, we screened 525 newborns born at the Neonatal Care Unit of Valsalva Hospital in Catania, Italy. Infants aged 3–5 days and with unconjugated hyperbilirubinemia were included for assessment if they had a peak serum total bilirubin level exceeding 6 mg/dl (102 μmol/L). Sex, birth weight, gestational age, breast feeding, type of birth, presence of facial bruising (including cephalohematoma) and ABO group were noted. Patients with Toxoplasma or Cytomegalovirus infection, hepatic insufficiency, or suspected drug-induced hyperbilirubinemia were excluded from more detailed analysis.Results: Our year-long nursery sample examined otherwise healthy-appearing term infants for the prevalence of hyperbilirubinemia (defined as bilirubin levels exceeding 6 mg/dL [11mol/L]). We found hyperbilirubinemia in 19% (100/525). Among the patients with hyperbilirubinemia, almost all (99%) had peak levels of bilirubin < 20 mg/dL, levels which are generally considered to be potentially neurotoxic.Conclusions: In our clinic experience, hyperbilirubinemia was generally a serious medical issue and one whose etiology can usually be well defined. Keywords: hyperbilirubinemia, newborns, incidence, breastfeeding

We report a 7-year-old boy with serologic evidence of active Epstein-Barr virus (EBV) infection who developed transient unilateral hypoglossal nerve palsy, with complete recovery within 21 days. This is, to our knowledge, the youngest reported patient with isolated hypoglossal nerve palsy in the context of EBV infection. Acute EBV infection should be considered early in the evaluation of children with twelfth nerve palsy in order to avoid extensive ancillary testing.

Hydranencephaly is a severe brain condition characterized by complete or almost complete absence of cerebral cortex with preservation of meninges, basal ganglia, pons, medulla, cerebellum, and falx. It has been ascribed to different causes (infections, irradiations, fetal anoxia, medications, twin-twin transfusion), all leading to vascular disruption. Hemihydranencephaly is an extremely rare condition in which the vascular anomaly is unilateral. We report on a patient who was suspected to have hydrocephalus in utero; a brain magnetic resonance imaging scan showed left-sided hydranencephaly with preservation of basal ganglia. The patient developed signs of right hemiparesis but notably has only mild language delay. The available literature on hemihydranencephaly is reviewed. ( J Child Neurol 2001;16:218-221).

We report on a patient with thalassaemia which was refractory to blood transfusions. The clinical picture was striking, and highlights the potential severity of intrathecal bone reactions after chronic intractable haemolytic anaemia.

Nitric oxide (NO) has been identified as a neurotransmitter, which regulates cerebral blood flow and exhibits a neurotoxic effect during cerebral ischemia. The objective of this study was to determine the levels of nitrite(NO2-)/ nitrate (NO3-) as markers of NO production in the CSF of neonates and to correlate their concentrations with the extent of brain damage, as demonstrated by cranial ultrasonography (CUSG). CSF was obtained by lumbar puncture during the first 24 hrs of life in 42 preterm(EGA: 24-34 wks) and 5 full term babies.CUSG was done as part of clinical care. NO2- and NO3- levels were measured by fluorometric method and spectroscopy, respectively. In neonates without intracranial hemorrhage (ICH), we found total concentrations(mean±S.D.) of NO2-/ NO3- (29.6±2.7μM,n=30), which were 5-6 times higher than levels reported in adults (4-5μM), and changed nonlinearly with GA, with peak concentration at 30-31 weeks (p=.04, ANOVA). In babies with grade I-II ICH the NO2-/ NO3- levels (31±7.6 μM, n=15) were not different from those without ICH; while two babies with grade III-IV ICH had very high levels(225±152μM, p=.0001 vs no ICH). We conclude that NO production is higher in the CSF of neonates than in adults and is related to GA. Further studies are needed to elucidate the role of NO in neonatal brain damage.

The cerebroprotective effects of mild hypothermia have been extensively studied in various animal models of ischemia, but the mechanism by which mild hypothermia diminishes ischemic injury is not well understood. Nitric oxide (NO) has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures, and its synthesis is acutely increased during focal ischemia in vivo. To evaluate possible mechanisms of hypothermic neuroprotection, we measured markers of NO synthesis--nitrite and cyclic guanosine monophosphate (cGMP) levels and NO synthase activity--during right middle cerebral artery occlusion (MCAO) in the rat under normothermic (36.5 degrees C) and mild hypothermic (33 degrees C) conditions. There was a significant increase in nitrite concentration in the right hemisphere versus the left under normothermic conditions at 10 and 20 minutes after MCAO (P < 0.01), with a return to baseline levels by 60 minutes. The increase in cortical nitrite levels in the right hemisphere versus the left was not observed with mild hypothermia. There was a threefold increase in cGMP synthesis in the normothermic right cortex 10 minutes after MCAO (P < 0.05). This rise in cGMP did not occur in hypothermic animals, and the right to left cortical disparity in cGMP production was abolished. Finally, the significant increase in NO synthase activity seen in the normothermic ischemic cortex was absent in hypothermic rats (P < 0.05). These results suggest that mild hypothermia (33 degrees C) modulates the burst of nitric oxide synthesis during cerebral ischemia and may account, at least partially, for its cerebroprotective effects.

The cage convulsant [ 35 S]tert-butylbicyclophosphorothionate ([ 35 S]TBPS) labels a presumed sedative-convulsant receptor complex. The relative potencies of barbiturates in competing for [ 35 S]TBPS binding parallels their potencies in enhancing benzodiazepine receptor binding. Barbiturates inhibit [ 35 S]TBPS binding in a complex, mixed competitive fashion, leading to a decrease in both the apparent affinity of TBPS for its sites and the apparent number of TBPS sites. All of the barbiturates examined markedly accelerate the dissociation of [ 35 S]TBPS from its recognition sites, while picrotoxinin does not affect the dissociation. These results suggest that the barbiturate and picrotoxinin/TBPS recognition sites are distinct but allosterically linked.