Bickerstaff's brainstem encephalitis (BBE) in childhood: rapid resolution after intravenous immunoglobulins treatment.

Three young patients with Bickerstaff's brainstem encephalitis (BBE) are reported. Some weeks following an upper tract infection, the children after a short period of recovery, showed acute onset of symmetric weakness of the lower limbs with difficulty in standing by and walking. The distal muscle weakness had a rapid progression with involvement of the cranial nerve, and then with severe impairment of the consciousness till to coma in one of the three children. BBE is a rare and often underdiagnosed affection in childhood. Common neuro-immune pathogenesis, overlap of clinical signs and strict correlation among BBE with Fisher syndrome and Guillain-Barrè syndrome lead to think that these affections represent an unique spectrum with different central and peripheral involvement. In these children, treatment with intravenous immunoglobulins resulted in a progressive and rapid resolution of the clinical features.

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.

HyperCKemia as a biomarker for muscular diseases.

An increased level of serum creatine kinase has been considered as an indirect sign of muscular disorders but it may be an indicator of other diseases (malignant hyperthermia, tumors or endocrinopathy). Some patients present with a stationary clinical condition and absence of muscular symptoms, in whom the unique abnormality is hyperCKemia that is not associated with any biological or genetic diagnosis of MD. In others asymptomatic patients, an increase in CK may be a hematological marker that can predict muscular disease. In this article, we review the causes that can lead to transitory or persistent HC.

Acute disseminated encephalomyelitis: a long-term prospective study and meta-analysis.

BACKGROUND: There are only a few series in the literature on acute disseminated encephalomyelitis (ADEM) in children. OBJECTIVES AND METHODS: the aims of this study were to perform (i) a prospective clinical/imaging study (1992-2009) on ADEM in children consecutively referred to our institution in Catania, Italy, and (ii) to undertake a systematic review and meta-analysis of published ADEM pediatric cohorts (>10 cases). RESULTS: We identified 17 patients with ADEM (incidence <10 years of age=1.1 per 100 000 person-years). 15 previously published cohorts were compared with our cohort: (i) systematically reviewed (750 cases); and (ii) meta-analyzed (492/750 cases). The 17 patients had the following characteristics: (a) male-to-female ratio, 1.4 (vs. 1.2-1.3 in previous cohorts); (b) mean age at presentation, 3.6 years (vs. 7.1 years in previous cohorts); (c) specific preceding triggering factor, 88% (vs. 69-79% in previous cohorts); (d) the most common initial signs were ataxia, seizures, headache, and thalamic syndrome; (e) brain imaging revealed >3 lesions in 100% (vs. 92% in previous cohorts); (f) the outcome was good in 94% (vs. 70-75% in previous cohorts); and (g) 12% relapsed once (vs. 18% in previous cohorts). CONCLUSIONS: ADEM is generally a benign condition that mosly affects boys more than girls and rarely recurs.

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.

Congenital insensitivity to pain with Anhidrosis (NTRK1 mutation) and early onset renal disease: clinical report on three sibs with a 25-year follow-up in one of them.

Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF). We report the clinical course in three sibs with CIPA and proven NTRK1 gene mutations with a follow-up over a 25-year period in one of them. They had the characteristic clinical features of an abnormally high pain threshold, and mental retardation; in addition their clinical course was marked by the occurrence of early onset renal disease with recurrent microhematuria and proteinuria and frequent observations of increased serum creatinine and blood urea levels. Light microscopy study of a renal biopsy performed in one of them at age of 20 months showed focal glomerulosclerosis, interstitial fibrosis and tubular atrophy. This patient and his younger brother died because of renal failure at the age of 25 years and 14 years, respectively. The sister still alive showed renal impairment and deep venous thrombosis associated with lupus anticoagulant activity, decrease of circulating autoreactive CD5 (+) B lymphocytes and increased urinary levels of IgG and kappa and lambda light chains, suggesting a possible defect in regulation of B-lymphocyte function. In the light of the NGF-related molecular defect, the extraneurological tissue involvement in CIPA might in part reflect dysregulation of immune mechanisms which possibly brings about a chronic inflammatory response. This, in turn, could result in renal disease which should be mentioned among the life-threatening complications associated with this disorder.

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.

Congenital muscular dystrophy with adducted thumbs, ptosis, external ophthalmoplegia, mental retardation and cerebellar hypoplasia: a novel form of CMD.

At least six different forms of congenital muscular dystrophy are associated with structural changes of the central nervous system, and three of these have been mapped: merosin-deficient congenital muscular dystrophy on chromosome 6q2, Fukuyama congenital muscular dystrophy on chromosome 9q31, and muscle eye brain disease on chromosome 1p32. Walker-Warburg syndrome, congenital muscular dystrophy with calf hypertrophy, pontocerebellar hypoplasia, and normal eyes, and congenital muscular dystrophy with severe mental retardation and cerebellar cysts are nosologically distinct and have been excluded from the known congenital muscular dystrophy loci with structural changes of the central nervous system. Here, we describe a novel congenital muscular dystrophy syndrome which is phenotypically distinct from the recognized forms of congenital muscular dystrophy with brain involvement. Two siblings, a boy and a girl, were born to consanguineous parents from Sicily. Both children were born with adducted thumbs and toe contractures. They were floppy from birth, walked late, showed profound generalized muscle weakness including facial muscles, elevated creatine kinase levels of 200-700U/l, and histological changes compatible with muscular dystrophy. In addition, both showed ptosis, external ophthalmoplegia, mild mental retardation, and mild cerebellar hypoplasia on MRI. Immunocytochemistry showed normal expression of muscle membrane proteins including laminin alpha 2, laminin beta 2, and alpha-dystroglycan. Linkage analysis excluded the candidate loci on chromosomes 6q2, 9q31, and 1q32. The gene locus for congenital muscular dystrophy 1B, MDC 1B, on chromosome 1q42 was also excluded. Adducted thumbs are a distinct clinical sign that has not been reported in congenital muscular dystrophy before and should facilitate recognition of further patients with this disorder.

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.

A genomewide screen for autism susceptibility loci.

We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19.

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.

Lack of progression of brain atrophy in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome is a severe and progressive familial encephalopathy that is characterized by acquired microcephaly, intracranial calcification (mainly of the basal ganglia), signs of white matter disease, and chronic lymphocytosis with elevated levels of interferon-alpha in the cerebrospinal fluid in the absence of other evidence of infection. Although the degree of calcification and the severity of brain atrophy are variable, typically the brain lesions appear to progress on successive examinations. In this article a 4-year-old male patient with Aicardi-Goutières syndrome who manifested the typical neurologic signs of the disease was re-evaluated. The evaluation revealed, on successive cranial computed tomography and magnetic resonance imaging scans, increasing calcification with remarkable reduction of brain atrophy. To the best of our knowledge, there is only one previously mentioned study of a 4-year-old female patient with progressive features of Aicardi-Goutières syndrome, including intracranial calcification, who displayed a lack of progression of brain atrophy at MRI scan.

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.

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.

Holoprosencephaly (lobar form) associated with bilateral vocal cord palsy.

There have been many causes associated with bilateral vocal cord palsy, both congenital and perinatal. Until now, the main congenital causes of bilateral vocal cord palsy have been associated with meningomyelocele, Arnold-Chiari malformation, and hydrocephalus. We report a patient with bilateral vocal cord palsy associated with the lobar form of holoprosencephaly. In this case, bilateral vocal cord palsy was caused by the disruption of the cortical laryngeal motoneurons. Neonatal stridor must be carefully evaluated by the neonatologist to exclude severe cerebral anomalies.

Long-term survival in a child with arthrogryposis multiplex congenita and spinal muscular atrophy.

Spinal muscular atrophy type 0 is a severe form of spinal muscular atrophy that is usually fatal in the first months of life. These children present with arthrogryposis multiplex congenita and respiratory compromise. We describe a child with spinal muscular atrophy and arthrogryposis multiplex congenita who has had a much better course and is alive without ventilator support at age 6 years. This case illustrates that the prognosis for spinal muscular atrophy and arthrogryposis multiplex congenita cannot always be predicted with certainty.