Pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection: the role of surgical treatment.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive compulsive disorders (OCD) consistently exacerbate in temporal correlation to a Group A beta-haemolytic streptococcal infection. In children with PANDAS, there is speculation about whether tonsillectomy or adenotonsillectomy might improve the neuropsychiatric course. Our objective was to examine whether such surgery impacted remission or, in patients without remission, modified clinical course of the disease, streptococcal antibody titers, neuronal antibodies or clinical severity of Obsessive-Compulsive Disorder (OCD) and/or tics. Study participants (n = 120) with positive PANDAS criteria were recruited, examined, and divided into surgical or non-surgery groups. The surgical group consisted of children with tonsillectomy or adenotonsillectomy (n=56). The remaining children were categorized as non-surgery (n=64). Clinical follow-up was made every 2 months for more than 2 years. Surgery did not affect symptomatology progression, streptococcal and neuronal antibodies, or the clinical severity of neuropsychiatric symptoms in these children. In conclusion, in our series clinical progression, antibody production, and neuropsychiatric symptom severity did not differ on the basis of surgical status. We cannot uphold surgical management as likely to impact positive remission rates, course of OCD/tics, or antibody concentrations in children with PANDAS.

Blepharoptosis in children: our experience at the light of literature.

AIMS: We herein report a 5 years experience of management and care of children presenting blepharoptosis at the light of the literature regarding this uncommon pathology. This report aims to display the most common causes of blepharoptosis and its possible treatment. PATIENTS AND METHODS: Clinical and epidemiological data collected from our institution, over a fi ve year period, on 60 patients, 37 males and 23 females with a mean age of 5.4 years (range 0.6 to 15.6 years) affected by blepharoptosis were analyzed. RESULTS: Ptosis was unilateral in 39/60 patients (65%) and bilateral in 21/60 (35%). The causes of ptosis were myogenic (40%), and neurogenic (35%), most commonly congenital. Among the neurogenic ptosis, the most frequent causes were PTOS type 1 and Marcus-Gunn syndrome. All the cases of acquired neurogenic ptosis were associated with paralysis of the oculomotor nerve. Ptosis plus was found in 23.3% of the patients, mechanical origin was present in 1.7% of patients. Family history was positive in the 10% of the patients. CONCLUSIONS: Our series reflect the range of ptosis of the general pediatric population. This study highlights the high degree of heterogeneity in patients with ptosis; only with an accurate analysis of the family and patient history and of the clinical features it is possible to perform an accurate diagnosis, finding the genetic causes and an adequate treatment.

A syndrome with coarse face, mental retardation and unusual stereotyped movements*.

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.

Epilepsy is not a prominent feature of primary autism.

The authors report on a series of 72 patients (57 male, 15 female; aged from 4 to 21 years) affected by autism with the aim of evaluate their experience regarding the prevalence of seizure and/or epilepsy. Patients were divided into two groups: the first includes individuals (n = 54) affected by so-called idiopathic or primary autism which was further subdivided according to the grade of mental retardation (MR) and the second (n = 18) in which a known pathological event was associated to the autism (secondary autism). According to these results in the first group 12 % of autistic patients with moderate MR (i.e., IQ > 55) suffered from seizures but in three patients (9 %) they were occasional and only in one recurrent (i.e., epileptic) (3 %). Autistic patients with severe MR (i.e., IQ < 55) suffered from seizures in 20 % of the cases: in three the episodes were recurrent (15 %) and in one occasional (5 %). In the second group in which autism was associated to other morbidities 61 % (n = 11/18) had seizures, being recurrent in 10 (55 %). According to this series, in autism the risk of epilepsy is higher compared to the general population but it does not seem to be correlated to the autism itself, but rather to the associated co-morbidities and underlying brain dysfunction (overall prevalence of epilepsy in primary autism [4/54 or 7.4 %] vs. secondary autism [10/18 or 55 %]).

Fetal cells in maternal blood: a six-fold increase in women who have undergone amniocentesis and carry a fetus with Down syndrome: a multicenter study.

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.

Fetal nucleated red blood cell counts in peripheral blood of mothers bearing Down syndrome fetus.

Currently, prenatal detection of Down syndrome and other most common aneuploidies relies on invasive procedures such as amniocentesis and villocentesis, and on non-invasive screening tests such as second trimester maternal serum screening (Triple test), and first trimester screening (ULTRA-screen). However, it well known that invasive techniques carry a small risk of fetal loss, while both Triple test and ULTRA-screen are not diagnostic, may miss from 15 - 40 % of cases of Down syndrome, in addition to having a 5 - 8 % rate of false-positives. We now report clear evidence that the number of fetal nucleated red blood cells (FNRBCs) in the maternal circulation is remarkably higher in pregnant women carrying aneuploid fetuses, especially in cases of Down syndrome. These results are in agreement with the findings of other investigators using different methods, and suggest that the number of FNRBCs present in the maternal blood sample could be used as additional marker, in concert with existing screening tests, to improve non-invasive detection of Down syndrome, and other most common aneuploidies.

Noninvasive prenatal diagnosis of chromosomal aneuploidies by isolation and analysis of fetal cells from maternal blood.

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 <72 hrs, produced complete concordance with the results of amniocentesis. We also confirm findings of prior studies suggesting that the number of FNRBCs in maternal circulation is remarkably higher in abnormal pregnancies than in normal pregnancies, especially in women carrying a fetus with trisomy 21.

Hemihydranencephaly: case report and literature review.

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.

Neuropsychological assessment in children with absence epilepsy.

OBJECTIVE: To define cognitive deficits in children with absence epilepsy. BACKGROUND: Cognitive deficits have often been reported in children with epilepsy, but have rarely been characterized in patients with a specific epileptic syndrome. METHODS: Detailed neuropsychological testing was carried out on 16 right-handed children with absence epilepsy with similar clinical and EEG findings, and the findings were compared to 16 well-matched right-handed children without absence epilepsy. RESULTS: The authors found lower scores of measures of general cognitive functioning and visuospatial skills in patients with absence epilepsy, as compared to controls. Memory disturbances were also detected in absence epilepsy patients, with selective involvement of nonverbal memory and delayed recall. In contrast, verbal memory and language skills were relatively preserved. Patients whose seizures began at an earlier age seemed to have more severe cognitive deficits. CONCLUSION: Language skills tend to be relatively well preserved in children with generalized epilepsy, with more dysfunction seen in global terms rather than specific lateralizing deficits. Patients with absence epilepsy seem to show a similar neurocognitive profile that may be a reflection of the underlying epilepsy syndrome.

Diabetes insipidus in neurobrucellosis.

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.

Autoimmune mechanisms in movement disorders.

A number of disorders, including childhood-onset obsessive compulsive disorder (OCD) and Gilles de la Tourette's syndrome (TS), are 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.

Ultrastructural localization of nitrotyrosine within the caudate-putamen nucleus and the globus pallidus of normal rat brain.

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.

Colobomatous microphthalmia, microcephaly with cerebellar hypoplasia: association or new syndrome?

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.

Arthrogryposis multiplex congenita and pituitary ectopia. A case report.

We report a patient with a form of arthrogryposis multiplex congenita who developed seizures at 4 months of age that proved to be hypoglycemic. Further evaluation of the etiology of hypoglycemia led to the discovery of partial anterior hypopituitarism, with normal posterior pituitary function. Neuroimaging revealed an ectopic neurohypophysis with very small anterior pituitary, the presumed anatomic basis for his endocrine dysfunction. A chance association between the pituitary ectopia and the arthrogryposis cannot be ruled out. However, it is more likely that in the present patient a common genetic mechanism may be the basis for both the arthrogryposis and the pituitary dysfunction.

Immune mechanisms in pediatric neuropsychiatric disorders. Tourette's syndrome, OCD, and PANDAS.

The authors have reviewed recent data supporting the presence of immune abnormalities in several neuropsychiatric disorders (TS, OCD, and PANDAS). Several groups agree that there is a subset of patients with TS and OCD (perhaps about 10%) for whom there is a clear streptococcal trigger, validating the PANDAS concept. Also, evidence of biochemical markers for TS and OCD have begun to emerge, namely D8/17 and antibrain antibodies, which suggest the presence of similar immune abnormalities, even in idiopathic cases. If this line of research reveals definable, and relatively specific, immune abnormalities in at least some cases of TS and OCD, it will likely have important implications for the diagnosis and treatment of these common neuropsychiatric disorders, particularly in children who respond poorly to conventional therapies. Child psychiatrists are encouraged to stay tuned.

Metabolic disorders presenting with behavioral symptoms in the school-aged child.

This article presented some principles useful in identifying children with neuropsychiatric symptoms who will prove to have metabolic disease. In general, any organic condition that produces cortical dysfunction could present with psychiatric symptomatology. The full range and incidence of neuropsychiatric manifestations are poorly studied for most of these diseases. In most instances, rarity of these conditions precludes any one clinic from collecting a large enough patient base to assess the full range of manifestations. A good deal of the information is based on small series and case reports. At present, because it is not possible to associate a specific cognitive and behavioral profile with a specific metabolic disease, a staged metabolic assessment is indicated in children displaying any of the specific historical features or clinical signs previously noted. It is important to note that the genetic basis, and consequently the fundamental biochemical defect, for most of these disorders has been known for less than a decade. Definitive (gene or enzyme replacement therapy) is therefore at a very early stage for these conditions. It is anticipated that continuing advances in genetics and gene therapy will soon lead to more specific and effective diagnostic and treatment strategies for many, if not all, of these conditions. The child psychiatrist, who may first encounter these patients at an early (and thus more readily treatable) point in the course of illness, will serve an increasingly important role in establishing a correct diagnosis and directing patients to specific therapies as quickly as possible.

Extraordinary intrathecal bone reaction in beta-thalassaemia intermedia.

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.

Focal neurological deficits in children with beta-thalassemia major.

The hematologic disorder beta-thalassemia major is relatively common in Southern Italy. Stroke is a well described, though infrequently reported, complication of this disorder. We now report our experience regarding 300 children with beta-thalassemia major examined at the University of Catania, Italy, over a 20-year period. We encountered 9 patients (3%; 3 males, 6 females) with beta-thalassemia major who had hemorrhagic stroke. Two groups of patients can be identified: group 1 (2 patients 22%) with early-onset post-transfusion hemorrhage and group 2 (7 patients 77%) with delayed post-transfusion hemorrhage. In the first group, the hemorrhage occurred within 48 hours following blood transfusion. In the second group, hemorrhage occurred 7-15 days from last transfusion. In 5 patients out of 7 of this second group the first transfusion and ictal event both occurred after age five, suggesting prolonged chronic anemia might play a role in the hemorrhage.