Structural Connectivity Analysis in Children with Segmental Callosal Agenesis.

BACKGROUND AND PURPOSE: Segmental callosal agenesis is characterized by the absence of the intermediate callosal portion. We aimed to evaluate the structural connectivity of segmental callosal agenesis by using constrained spherical deconvolution tractography and connectome analysis. MATERIALS AND METHODS: We reviewed the clinical-radiologic features of 8 patients (5 males; mean age, 3.9 years). Spherical deconvolution and probabilistic tractography were performed on diffusion data. Structural connectivity analysis, including summary network metrics, modularity analysis, and network consistency measures, was applied in 5 patients and 10 age-/sex-matched controls. RESULTS: We identified 3 subtypes based on the position of the hippocampal commissure: beneath the anterior callosal remnant in 3 patients (type I), beneath the posterior callosal remnant in 3 patients (type II), and between the anterior and posterior callosal remnants in 2 patients (type III). In all patients, the agenetic segment corresponded to fibers projecting to the parietal lobe, and segmental Probst bundles were found at that level. Ectopic callosal bundles were identified in 3 patients. Topology analysis revealed reduced global connectivity in patients compared with controls. The network topology of segmental callosal agenesis was more variable across patients than that of the control connectomes. Modularity analysis revealed disruption of the structural core organization in the patients. CONCLUSIONS: Three malformative subtypes of segmental callosal agenesis were identified. Even the absence of a small callosal segment may impact global brain connectivity and modularity organization. The presence of ectopic callosal bundles may explain the greater interindividual variation in the connectomes of patients with segmental callosal agenesis.

Anti-NMDAR encephalitis misdiagnosed as Hashimoto's encephalopathy.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a well-defined autoimmune disorder. Hashimoto's encephalopathy (HE) is a still controversial entity, lacking definite diagnostic criteria. We described a 14-year-old-girl presenting with a clinical picture consistent with the diagnosis of anti-NMDAR encephalitis, confirmed by NMDAR antibody testing. Four years earlier, she had presented a similar episode of acute encephalopathy diagnosed as HE. Anti-NMDAR encephalitis and HE share similar clinical features so that the differential diagnosis can be difficult if specific antibodies are not tested. The correct diagnosis of anti-NMDAR encephalitis is crucial to plan the appropriate management and follow-up, namely in term of oncological screening, since it can be paraneoplastic in origin. We suggest to re-evaluate the clinical history of all subjects with previous HE diagnosis in order to evaluate the possible diagnosis of anti-NMDAR encephalitis and plan the appropriate management of these patients.

Chronic inflammatory demyelinating polyneuropathy of childhood: clinical and neuroradiological findings.

INTRODUCTION: This study aims to report on serial magnetic resonance imaging (MRI) studies and clinical features in a cohort of children with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Clinical, neuroradiological, and statistical investigations performed on nine children with CIDP were retrospectively reviewed. Pathological nerve root enhancement was categorized according to severity, extension, and morphology. A MRI score was thus obtained, and correlations with the clinical picture and disease course were explored. RESULTS: Intrathecal nerve root enhancement (NRE) of varying degrees was seen in a high percentage of patients. There was no significant correlation between the total MRI score at the first MRI study and either severity or course of the disease. However, we found a significant difference (p = 0.002) in NRE of patients with improving CIDP with respect to those with stable or progressing disease at the time of follow-up MRI. CONCLUSION: Contrast-enhanced MRI plays a pivotal role in children with CIDP, both for the initial diagnosis as well as a biomarker of clinical evolution, and should be performed in all children with suspected CIDP both at initial presentation and during follow-up. Further multicenter studies on larger cohorts are awaited to determine the ideal timing for follow-up MRI.

Cognitive profile in spastic paraplegia with thin corpus callosum and mutations in SPG11.

Autosomal recessive hereditary spastic paraplegia with thinning of the anterior corpus callosum (ARHSP-TCC) due to mutations in SPG11 on chromosome 15q (MIM610844) is the single most common cause of ARHSP. It is characterized by slowly progressive paraparesis and peripheral neuropathy. Although cognitive impairment, sometimes diagnosed as mental retardation, is an almost invariable feature, the extent and specific neuropsychological features are not fully understood. We report a comprehensive neuropsychological assessment in two ARHSP-TCC patients harbouring mutations in SPG11. A specific impairment in executive functions occurring even before cognitive decline, may be considered the core of the neuropsychological profile of patients harbouring mutations in SPG11.

Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome.

OBJECTIVE: The aim of this study is to describe the long-term neurological, neuropsychological and neuroradiological sequelae and to determine prognostic factors for neurological outcome in children with neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome. METHODS: Data on medical history were collected for the study patients. Examinations with grading of neurological signs, neuropsychological tests and brain magnetic resonance imaging with spectroscopy were performed during a follow-up clinic. RESULTS: Fourteen subjects entered the study. All had localized neuroblastoma and they were evaluated after a median of 7.8 years. Patients with a chronic/multiphasic neurological course received steroids combined with intravenous immunoglobulins in the majority of cases. 71% presented neurological sequelae and 62% had a full-scale IQ below the normal range. All patients showed at least some deficit in the neuropsychological functions assessed (language, visual-motor integration, memory, attention and motor ability). Long-term deficits were more frequently detected in patients with an interval of more than 2 months between OMA onset and its diagnosis, even if in most comparisons statistical significance was not reached. Cerebellar atrophy, observed in 36% of patients, was not associated with the neurological outcome. CONCLUSIONS: Persisting disability is present in most children with neuroblastoma-associated OMA. However, our results support the role of an early diagnosis of OMA in reducing sequelae and encourage the use of new immunosuppressive therapies.

MR imaging findings in 2 cases of late infantile GM1 gangliosidosis.

SUMMARY: Late infantile GM1 gangliosidosis is a rare lysosomal disorder characterized by mental deterioration and progressive spastic, cerebellar, and extrapyramidal signs, without facial dysmorphisms and organomegaly. Neuroimaging findings have been reported in only a few cases. Here we report on predominant globus pallidus MR signal-intensity abnormalities in 2 patients with the late infantile form of GM1 gangliosidosis.

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes.

It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T > C p.Ile72Thr and c.380A > G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145 + 2 T > C and c.2376 + 5G > A, the c.1648C > T p.Arg550X and the MPLA-identified c.162_99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162_99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.

Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy.

Aicardi-Goutières syndrome is an autosomal recessive encephalopathy characterised by acquired microcephaly, basal ganglia calcifications, leukodystrophy, cerebral atrophy, chronic cerebrospinal lymphocytosis, and raised titres of interferon alpha in the cerebrospinal fluid. The disease onset is generally within the first months of life. We here report a case of Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy following satisfactory psychomotor development up to the age of 16 months. This case highlights the importance of considering Aicardi-Goutières syndrome in the differential diagnosis of an unexplained leukoencephalopathy and the possibility of later onset of the disease.

Five-year follow-up of a cognitive-behavioural lifestyle multidisciplinary programme for childhood obesity outpatient treatment.

OBJECTIVE: Aim of this study is to examine the 5-year follow-up results of MI PIACE PIACERMI (I like to like and please myself), a cognitive-behavioural programme intended to obtain a weight growth regulation over an extended period. DESIGN: Longitudinal observational clinical study. SETTING: Hospital-based programme, through outpatient activities. SUBJECTS: Thirty-one simple obese children, 13 boys and 18 girls, 6-12 years of age on admission. INTERVENTION: The intervention was carried out by a multidisciplinary team (paediatrician, cognitive-behavioural psychologist, physical therapist). It employed cognitive-behavioural techniques, nutrition education, promotion of physical activity, setting a high value on free play in motion. The programme actively involves parents. The following measurements were taken on admission and at 5-year follow-up: height, weight, waist circumference, body mass index (BMI), BMI standardized (BMI-SDS), and adjusted BMI (a-BMI) as actual BMI/BMI (50th percentile)*100. Dietary habits were investigated by interview and 24-h recall. Parents completed the Family Habit Inventory and the Child Behaviour Checklist (CBCL). Motor skills were assessed by using Frostig's test. RESULTS: The dropout rate was 35.5%. In subjects who completed the 5-year follow-up, the mean and s.d. of BMI-SDS and a-BMI were, respectively, 4.23+/-0.71 and 54.7%+/-9.0 at baseline and 2.74+/-0.85 and 43.2%+/-17.3 at the last visit. Waist circumference decreased. Family habits improved significantly. Total energy intake was significantly reduced. Emotional and social aspects of obesity-related behaviours showed positive changes. Motor skills globally improved. CONCLUSIONS: The study provides further evidence that positive persistent results may be obtained in obese children with treatment programmes combining a lifestyle centred approach, parental involvement, nutrition education and cognitive-behavioural strategies.

Metabolic and genetic risk factors for migraine in children.

Migraine can induce ischaemic stroke, and is considered an independent risk factor for stroke in the young. To date, the nature of the link between migraine and stroke is essentially unknown. Forty-five children were studied. Homocysteine levels (fasting and post methionine load), vitamin B12 and plasma folate levels, factor V Leiden, factor II G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations were examined. Compared with controls, patients with migraine had higher levels of post-methionine load homocysteine values (19.5 +/- 4.9 vs. 16.9 +/- 1.9; P = 0.025) and significantly lower folate levels (5.8 +/- 2.6 vs. 7.5 +/- 2.1; P = 0.002). We found a trend toward an increased risk of migraine in subjects carrying a homozygous mutant genotype for MTHFR C677T and MTHFR A1298C polymorphisms. Genetic prothrombotic conditions do not seem to be related to migraine in the young, whereas the biochemical differences between migrainous patients and controls are an appealing topic for further investigation.

Temporal relationship of generalized epileptiform discharges to spindle frequency activity in childhood absence epilepsy.

OBJECTIVE: The hypothesis that the two main synchronizing mechanisms (spindle and delta oscillations) acting during non-rapid eye movement sleep show opposite relationship with the distribution of generalized epileptiform discharges (GEDs) during sleep was evaluated. METHODS: We studied the temporal relationship between the distribution of sleep GEDs and the dynamics of Sigma Activity (SA, 12-16 Hz) and Delta Activity (DA, 0.5-4.5 Hz) in 5 children affected by childhood absence epilepsy. RESULTS: Using correlation techniques, we found a high and positive correlation between GEDs and SA, while DA resulted negatively correlated with GEDs. CONCLUSION: Sleep generalized spike-and-slow-waves seems to be produced when spindle synchronizing mechanisms are active while DA production seem to exert an inhibiting role. Such a feature seems to be common to other childhood partial and undetermined epileptic syndromes.

Clinical and EEG findings in 18 cases of late infantile neuronal ceroid lipofuscinosis.

The objective of this study was to present clinical and electroencephalographic findings in 18 cases with late infantile neuronal ceroid lipofuscinoses, focusing on features that assist early diagnosis. Clinical and EEG findings have been described in the past for classic types, but several variants have recently been reported. The authors reviewed the clinical and EEG findings of 18 childhood onset neuronal ceroid lipofuscinoses cases. In the late infantile neuronal ceroid lipofuscinoses type, both typical and variant cases have been observed. In this type, the presence of a particular pseudoperiodic EEG pattern that we found in 15/18 patients and observed in the first stages of the disease could be useful in early diagnosis, especially if associated with the absence of sleep spindles. A precise nosological classification, based both on clinical and instrumental findings is the prerequisite for a correct genotype-phenotype correlation that could greatly improve our knowledge of this disease, providing a better understanding of pathogenesis and increasing our ability to treat it.

Long-lasting myopathy as a major clinical feature of sarcoidosis in a child: case report with a 7-year follow-up.

Muscle involvement in sarcoidosis is rarely described as the predominant feature and muscular symptoms are seldom observed. In recent pediatric series, sarcoid myopathy was no longer considered a typical aspect of sarcoidosis. The authors report a case of sarcoidosis in a patient presenting predominant muscular symptoms since childhood, due to biopsy-proven muscle localization. A seven-year follow-up has demonstrated a slow improvement of symptoms with persistency of electromyography (EMG) and biochemical abnormalities. Mild and transient pulmonary involvement was demonstrated only after diagnosis. Clinical improvement associated with a decrease in serum muscular enzyme levels with no changes in EMG was observed after a six-month course of systemic corticosteroid therapy. In childhood, skeletal muscle symptoms may be the presenting feature of sarcoidosis.

Malignant migrating partial seizures in infancy.

A previously unreported epileptic condition characterised by onset before 6 months of age, nearly continuous electroencephalographic seizures involving multiple independent areas originating in both hemispheres, no identifiable cause, and poor outcome has been described by Coppola et al. We report three cases presenting the same clinical and EEG pictures. They show a peculiar epileptic condition unlike the other early epileptogenic encephalopathies, so they may represent a new infantile epileptic syndrome.

Neuropsychological disorders related to interictal epileptic discharges during sleep in benign epilepsy of childhood with centrotemporal or Rolandic spikes.

Nine children (five males, four females; age range 6 years 1 month to 11 years 1 month) affected by benign epilepsy of childhood with centrotemporal or Rolandic spikes (BECRS) with EEG evidence of marked activation of interictal epileptic discharges (IEDs) during sleep, and nine unaffected control children matched for age, sex, and socioeconomic status, were enrolled in a prospective study. At the time of detection of IED activation during sleep, patients showed a mean Full-Scale IQ score within the normal range, but significantly below that of control participants; neuropsychological assessment revealed disorders in visuospatial short-term memory (Corsi's Block Tapping Test), attention, and cognitive flexibility (Trail Making Test and Stroop Color-Word Test), picture naming, and fluency (Benton's Naming Test and Word Fluency), visuoperceptual skill (Ghent-Poppelreuter and Street Gestalt Completion Tests) and visuomotor coordination (Bender Test). After detection of IED activation during sleep, children were followed up for 2 years. At the time of IED remission (T1), neuropsychological re-evaluation showed a notable increase in IQ score and a significant improvement (t-test: p<0.007) in visuomotor coordination, non-verbal short-term memory, sustained attention and mental flexibility, picture naming, and visual-perceptual performance. At T1, patients' performance did not differ from the controls (Mann-Whitney U test).

Hypersomnia in the Prader Willi syndrome: clinical-electrophysiological features and underlying factors.

OBJECTIVE: Excessive daytime sleepiness is a common symptom in Prader Willi syndrome (PWs). Sleep disordered breathing (SDB) and narcoleptic traits such as REM sleep onsets (SOREMPs) have been reported in these subjects. We evaluated nighttime and daytime sleep patterns in patients with PWs in order to clarify the nature of their hypersomnia. DESIGN AND METHODS: We performed overnight continuous EEG-polysomnographic studies (with breathing monitoring included) in 14 subjects (6 M,8 F; mean age 17 years, range 8-37) affected by PWs unselected for sleep disturbances. Ten patients underwent a Multiple Sleep Latency Test (MSLT) the day following the nocturnal sleep studies. Patients assessment was completed by means of immunogenetic characterization. RESULTS: Nocturnal polysomnographic investigation documented sleep related breathing abnormalities such as central apneas, hypopneas or hypoventilation which mainly occurred during REM sleep in 8 subjects and did not cause sleep disruption. Only 4 subjects presented an increase in the Respiratory Disorder Index (RDI) slightly above the normal limits. In 8 subjects out of 10, with and without SDB, the mean daytime sleep latency could be considered abnormal according to the Tanner staging of pubertal development. Five patients showed at least two SOREMPs at MSLT. Subjects with and without SOREMPs had, respectively, a mean age of 18.6 SD 7.9 (4 M, 1 F) and 14.5 SD 2.9 (4 F, 1 M). The paternal deletion:uniparental dysomy ratio at genotypic characterization was 4:1 and 3.5:1 in subjects with and without SOREMPs, respectively. No patient presented DR-15 nor Dq-6. CONCLUSIONS: Excessive sleepiness is a frequent disturbance in PWs. Subgroups of PW patients show hypersomnolence and SOREMPs. Sleep disordered breathing appears to have a limited role in the genesis of hypersomnia which not seems on the other hand attributable to the coexistence of narcolepsy phenotype. Hypersomnia in PW syndrome is likely to mainly be attributable to a primary hypothalamic dysfunction. The potential interacting role of other factors such as subjects age, sex and genetic pattern is suggested and deserve further investigation.

Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases.

The early onset type of cobalamin (Cbl) C/D deficiency is characterised by feeding difficulties, failure to thrive, hypotonia, seizures, microcephaly and developmental delay. It has an unfavourable outcome, often with early death and significant neurological impairment in survivors. While clinical and biochemical features of Cbl C/D deficiency are well known, only a few isolated case reports are available concerning neurophysiological and neuroimaging findings. We carried out clinical, biochemical, neurophysiological and neuroradiologic investigations in 14 cases with early-onset of the Cbl CID defect. Mental retardation was identified in most of the cases. A variable degree of supratentorial white matter atrophy was detected in 11 cases by MR imaging and tetraventricular hydrocephalus was present in the remaining 3 patients. Waking EEG showed a clear prevalence of epileptiform abnormalities, possibly related to the high incidence of seizures in these cases. Increased latency of evoked responses and/or prolongation of central conduction time were the most significant neurophysiological abnormalities. The selective white matter involvement, shown both by neuroradiologic and neurophysiological studies, seems to be the most consistent finding of Cbl C/D deficiency and may be related to a reduced supply of methyl groups, possibly caused by the dysfunction in the methyl-transfer pathway.

Distribution of epileptiform discharges during nREM sleep in the CSWSS syndrome: relationship with sigma and delta activities.

PURPOSE: The EEG pattern of epilepsy with continuous spike-waves during slow wave sleep (CSWSS) is characterized by an almost continuous activation of spike-and-slow-wave complexes during nREM sleep with a marked reduction of EEG abnormalities during REM sleep and the awake state. Experimental studies indicate that normal sleep oscillations that during nREM sleep lead to the appearance of spindles and delta waves on scalp EEG might develop into paroxysmal synchronization. Spectral analysis enables the quantitative description of the dynamics of delta (Delta Activity, DA, 0.5-4.5 Hz) and sigma activity (SA, 12-16 Hz) and can be used to assess the relationship between SA, DA and epileptiform discharges (EDs) during sleep. METHODS: We analyzed the EDs distribution during sleep in five children affected by CSWSS. We used a model of the evolution of power of DA and SA to which the time series of EDs could be fitted. RESULTS: We found a high and positive correlation between EDs and SA. DA resulted negatively correlated with EDs. CONCLUSION: Our data suggest that neural mechanisms involved in the generation of sleep spindles facilitate EDs production in the CSWSS syndrome. Such a mechanism seems to be an age related phenomenon shared by other epileptic syndromes of childhood.