Impact and management of drooling in children with neurological disorders: an Italian Delphi consensus.

BACKGROUND: The rate of chronic drooling in children older than 4 years is 0.5%, but it rises to 60% in those with neurological disorders. Physical and psychosocial consequences lead to a reduction in the quality of Life (QoL) of affected patients; however, the problem remains under-recognized and under-treated. We conducted an Italian consensus through a modified Delphi survey to discuss the current treatment paradigm of drooling in pediatric patients with neurological disorders. METHODS: After reviewing the literature, a board of 10 experts defined some statements to be administered to a multidisciplinary panel through an online encrypted platform. The answers to the questions were based on a 1-5 Likert scale (1 = strongly disagree; 5 = strongly agree). The scores were grouped into 1-2 (disagreement) and 4-5 (agreement), while 3 was discarded. The consensus was reached when the sum of the disagreement or agreement was ≥75%. RESULTS: Fifteen statements covered three main topics, namely clinical manifestations and QoL, quantification of drooling, and treatment strategies. All statements reached consensus (≥75% agreement). The 55 Italian experts agreed that drooling should be assessed in all children with complex needs, having a major impact on the QoL. Attention should be paid to investigating posterior hypersalivation, which is often neglected but may lead to important clinical consequences. Given that the severity of drooling fluctuates over time, its management should be guided by the patients' current needs. Furthermore, the relative lack of validated and universal scales for drooling quantification limits the evaluation of the response to treatment. Finally, the shared therapeutic paradigm is progressive, with conservative treatments preceding the pharmacological ones and reserving surgery only for selected cases. CONCLUSION: This study demonstrates the pivotal importance of a multidisciplinary approach to the management of drooling. National experts agree that progressive treatment can reduce the incidence of complications, improve the QoL of patients and caregivers, and save healthcare resources. Finally, this study highlights how the therapeutic strategy should be reconsidered over time according to the available drugs on the market, the progression of symptoms, and the patients' needs.

Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort.

Background: Moyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs). Methods: We conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country. Results: A total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively). Conclusions: Moyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

Oxidative stress and gut-derived lipopolysaccharides in children affected by paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

BACKGROUND: Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections syndrome (PANDAS) identifies patients with acute onset of obsessive-compulsive and tic disorders. The objective of this study was to evaluate serum NOX2 levels, as well as 8-iso-prostaglandin F2α (8-iso-PGF2α) and lipopolysaccharide (LPS) of PANDAS patients. METHODS: In this study we wanted to compare serum levels of soluble NOX2-dp (sNOX-2-dp), iso-PGF2α and LPS in 60 consecutive subjects, including 30 children affected by PANDAS and 30 controls (CT) matched for age and gender. Serum zonulin was used as intestinal permeability assay. RESULTS: Compared with CT, PANDAS children had increased serum levels of sNOX-2-dp, 8-iso-PGF2α and LPS. Bivariate analysis showed that serum sNOX2-dp was significantly correlated with LPS (Rs = 0.359; p = 0.005), zonulin (Rs = 0.444; p < 0.001) and 8-iso-PGF2α (Rs = 0.704; p < 0.001). Serum LPS significantly correlated with zonulin (Rs = 0.610; p < 0.001), and 8-iso-PGF2α (Rs = 0.591; p = 0.001). Finally, a multiple linear regression analysis showed that serum 8-iso-PGF2α and zonulin were the only independent variables associated with sNOX2-dp (R2 = 68%). CONCLUSION: This study shows that children affected by PANDAS have high circulating levels of sNOX2-dp, isoprostanes and of LPS that could be involved in the process of neuroinflammation.

Oxidative Stress and Gut-Derived Lipopolysaccharides in Neurodegenerative Disease: Role of NOX2.

BACKGROUND: Neurodegenerative diseases (ND) as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis represent a growing cause of disability in the developed countries. The underlying physiopathology is still unclear. Several lines of evidence suggest a role for oxidative stress and NADPH oxidase 2 (NOX2) in the neuropathological pathways that lead to ND. Furthermore, recent studies hypothesized a role for gut microbiota in the neuroinflammation; in particular, lipopolysaccharide (LPS) derived from Gram-negative bacteria in the gut is believed to play a role in causing ND by increase of oxidative stress and inflammation. The aim of this study was to assess NOX2 activity as well as serum 8-iso-prostaglandin F2α (8-iso-PGF2α (8-iso-PGF2. METHODS: One hundred and twenty-eight consecutive subjects, including 64 ND patients and 64 controls (CT) matched for age and gender, were recruited. A cross-sectional study was performed to compare serum activity of soluble NOX2-dp (sNOX2-dp), blood levels of isoprostanes, serum H2O2, and LPS in these two groups. Serum zonulin was used to assess gut permeability. RESULTS: Compared with CT, ND patients had higher values of sNOX2-dp, 8-iso-PGF2α (8-iso-PGF2p < 0.001), zonulin (Rs = 0.411; p < 0.001), zonulin (Rs = 0.411; p < 0.001), zonulin (Rs = 0.411; α (8-iso-PGF2p < 0.001), zonulin (Rs = 0.411; p < 0.001), zonulin (Rs = 0.411; α (8-iso-PGF2p < 0.001), zonulin (Rs = 0.411; ß, 0.459; p < 0.001), zonulin (Rs = 0.411; α (8-iso-PGF2ß, 0.459; p < 0.001), zonulin (Rs = 0.411; R 2 = 57%). CONCLUSION: This study provides the first report attesting that patients with ND have high NOX2 activation that could be potentially implicated in the process of neuroinflammation.

Gelastic seizures not associated with hypothalamic hamartoma: A long-term follow-up study.

OBJECTIVE: The objective of the study was to describe the electroclinical features, seizure semiology, and the long-term evolution of gelastic seizures (GS) not associated with hypothalamic hamartoma (HH). METHODS: We reviewed video-electroencephalogram (video-EEG) recordings from pediatric patients with GS without HH admitted to 14 Italian epilepsy centers from 1994 to 2013. We collected information about age at onset, seizures semiology, EEG and magnetic resonance imaging (MRI) findings, treatment, and clinical outcome in terms of seizure control after a long-term follow-up. RESULTS: A total of 30 pediatric patients were stratified into two groups according to neuroimaging findings: group 1 including 19 children (63.3%) with unremarkable neuroimaging and group 2 including 11 children with structural brain abnormalities (36.7%). At the follow-up, patients of group 1 showed better clinical outcome both in terms of seizure control and use of AED polytherapy. Our patients showed remarkable clinical heterogeneity, including seizure semiology and epilepsy severity. Electroencephalogram recordings showed abnormalities mainly in the frontal, temporal, and frontotemporal regions without relevant differences between the two groups. Overall, carbamazepine showed good efficacy to control GS. CONCLUSIONS: Patients with nonlesional GS have a more favorable outcome with better drug response, less need of polytherapy, and good long-term prognosis, both in terms of seizure control and EEG findings.

Unusual association of SCN2A epileptic encephalopathy with severe cortical dysplasia detected by prenatal MRI.

We present an atypical association of SCN2A epileptic encephalopathy with severe cortical dysplasia. SCN2A mutations are associated with epileptic syndromes from benign to extremely severe in absence of such macroscopic brain findings. Prenatal MRI (Magnetic Resonance Imaging) in a 32 weeks fetus, with US (Ultrasonography) diagnosis of isolated ventriculomegaly showed CNS (Central Nervous System) dysplasia characterized by lack of differentiation between cortical and subcortical layers, pachygyria and corpus callosum dysgenesis. Postnatal MRI confirmed the prenatal findings. On day 6 the baby presented a focal status epilepticus, partially controlled by phenobarbital, phenytoin, and levetiracetam. After three weeks a moderate improvement in seizure control has been achieved with carbamazepine. Exome sequencing detected a de novo heterozygous mutation in the SCN2A gene, encoding the αII-subunit of a sodium channel. The patient findings expand the phenotype spectrum of SCN2A mutations to epileptic encephalopathies with macroscopic brain developmental features.

Sudden benzodiazepine-induced resolution of post-operative pediatric cerebellar mutism syndrome: a clinical-SPECT study.

Post-operative pediatric cerebellar mutism syndrome (PPCMS) is a clinical syndrome arising from cerebellar injury and characterized by absence of speech and other possible symptoms and signs. Rare reports described some benefit after administration of dopamine agonist therapy, but no treatment has proven efficacy. In this paper, we report on the dramatic, sudden resolution of PPCMS induced by midazolam administration in a boy who underwent posterior fossa surgery for choroid plexus papilloma of the fourth ventricle. In addition to clinical improvement, post-midazolam single-photon emission computed tomography also demonstrated amelioration of brain perfusion.

Epilepsy is a possible feature in Williams-Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region.

Seizures are rarely reported in Williams-Beuren syndrome (WBS)--a contiguous-gene-deletion disorder caused by a 7q11.23 heterozygous deletion of 1.5-1.8 Mb--and no previous study evaluated electro-clinical features of epilepsy in this syndrome. Furthermore, it has been hypothesized that atypical deletion (e.g., larger than 1.8 Mb) may be responsible for a more pronounced neurological phenotypes, especially including seizures. Our objectives are to describe the electro-clinical features in WBS and to correlate the epileptic phenotype with deletion of the 7q11.23 critical region. We evaluate the electro-clinical features in one case of distal 7q11.23 deletion syndrome and in eight epileptic WBS (eWBS) patients. Additionally, we compare the deletion size-and deleted genes-of four epileptic WBS (eWBS) with that of four non-epileptic WBS (neWBS) patients. Infantile spasms, focal (e.g., motor and dyscognitive with autonomic features) and generalized (e.g., tonic-clonic, tonic, clonic, myoclonic) seizures were encountered. Drug-resistance was observed in one patient. Neuroimaging discovered one case of focal cortical dysplasia, one case of fronto-temporal cortical atrophy and one case of periventricular nodular heterotopia. Comparison of deletion size between eWBS and neWBS patients did not reveal candidate genes potentially underlying epilepsy. This is the largest series describing electro-clinical features of epilepsy in WBS. In WBS, epilepsy should be considered both in case of typical and atypical deletions, which do not involve HIP1, YWHAG or MAGI2.

Spinal neurofibromatosis in a family with classical neurofibromatosis type 1 and a novel NF1 gene mutation.

Familial spinal neurofibromatosis (FSNF) is a rare form of neurofibromatosis type 1 (NF1) characterized by multiple, histologically proven neurofibromas of the spinal roots leaving no intact segments and associated neurofibromas of major peripheral nerves. It is sometimes associated with other NF1 stigmata. Most patients have NF1 gene mutations. We describe a patient who fulfilled the diagnostic criteria for spinal neurofibromatosis and belonged to a family in which other affected members exhibited classical NF1 stigmata. A novel missense (c.7109 T>A; p.Val2370Asp) mutation in exon 39 of the NF1 gene was present in the affected family members. The family displayed extreme phenotypic variability in the spectrum of NF1. To our knowledge, this is the first patient with spinal neurofibromatosis in the context of classical NF1 with an NF1 gene mutation. The term FSNF is inaccurate as this condition simply reflects the typical autosomal dominant pattern of NF1 inheritance with phenotypoc variability and does not encompass patients with sporadic disease or those in the context of a classical NF1 phenotype as reported in the present family. The term could be replaced by "spinal neurofibromatosis".

Evaluation of the basal ganglia in neurofibromatosis type 1.

PURPOSE: Alterations of the brain microstructure and metabolism have been identified in patients with neurofibromatosis type 1 (NF1). In this study, we analyzed the basal ganglia of NF1 subjects without cognitive delay throughout a combined approach with magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in order to better define the metabolic and microstructural characteristics of these regions and, furthermore, to verify if metabolic and microstructural abnormalities may be present in normally developed NF1 patients. METHODS: A 3-T MRI with multivoxel MRS and DTI was performed in 14 NF1 patients and eight controls. N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr) values and ratios, fractional anisotropy, and apparent diffusion coefficient (ADC) were calculated, for a total of four regions of interest (ROI) for each hemisphere. RESULTS: NF1 patients, compared to healthy controls, showed (a) decreased NAA in all the four ROI, (b) increased Cho and decreased Cr in three of the four ROI, (c) decreased NAA/Cho ratio in three ROI, and (d) increased ADC in all the four ROI. A trend of increased ADC was present in three of the four ROI of NF1 patients with unidentified bright objects (UBOs) and younger than 18 years. CONCLUSION: These data confirm the presence of neuroaxonal damage with myelin disturbances in NF1 patients. We showed that metabolic and microstructural anomalies can be present in the same time in NF1 patients without developmental delay or cognitive deficits. Relations between brain anomalies, UBOs, and cognitive functions need further studies.

Surgical timing of craniosynostosis: what to do and when.

Craniosynostosis, both isolated and syndromic, are challenging malformations for the craniofacial team. They present the team with an articulated cascade of choices, which need to be addressed early in life and in the growing age to intercept, remove, or correct the direct and indirect consequences of the malformation. Timing of treatment is thus critical and it stands on the experience of a multi-specialty trained craniofacial team. In this paper the authors discuss the timing of treatment of the major craniosynostosis, isolated and syndromic, reviewing the options for treatment and their experience in this complex field.

Posterior fossa malformations and sex chromosomes anomalies. Report of a case with XYY syndrome and overview of known associations.

UNLABELLED: Sex chromosome anomalies have been previously associated with several brain malformations including posterior fossa anomalies, such as cerebellar dysplasia or hypoplasia, cerebellar cysts, vermis dysgenesis or hypoplasia, and mega cistern magna. XYY syndrome is a sex chromosome aneuploidy characterized by an extra copy of the Y chromosome. Although it has been proposed that the presence of such extra chromosome may have an adverse effect on brain development, to date few reports on brain abnormalities in patients with XYY syndrome have been published. In a male child with 47, XYY karyotype we describe a particular brain malformation which consisted of enlarged posterior fossa and hypoplasia of posterior and inferior regions of left cerebellar hemisphere and vermis. In addition we revised other sex chromosome anomalies which have been previously associated with posterior fossa malformations in humans. CONCLUSION: Our finding suggests that having an extra Y chromosome may affect brain development. Brain radiological imaging in patients with XYY syndrome would be useful to determine whether such brain abnormalities are an incidental finding or part of the spectrum of XYY syndrome. A deeper investigation of the extra chromosome effects may help to better comprehend the pathophysiology of functional disorders in affected individuals.

Recent understanding on diagnosis and management of central nervous system vasculitis in children.

Central nervous system vasculitides in children may develop as a primary condition or secondary to an underlying systemic disease. Many vasculitides affect both adults and children, while some others occur almost exclusively in childhood. Patients usually present with systemic symptoms with single or multiorgan dysfunction. The involvement of central nervous system in childhood is not frequent and it occurs more often as a feature of subtypes like childhood polyarteritis nodosa, Kawasaki disease, Henoch Schönlein purpura, and Bechet disease. Primary angiitis of the central nervous system of childhood is a reversible cause of severe neurological impairment, including acute ischemic stroke, intractable seizures, and cognitive decline. The first line therapy of CNS vasculitides is mainly based on corticosteroids and immunosuppressor drugs. Other strategies include plasmapheresis, immunoglobulins, and biologic drugs. This paper discusses on current understanding of most frequent primary and secondary central nervous system vasculitides in children including a tailored-diagnostic approach and new evidence regarding treatment.

WTX R353X mutation in a family with osteopathia striata and cranial sclerosis (OS-CS): case report and literature review of the disease clinical, genetic and radiological features.

Osteopathia striata with cranial sclerosis (OS-CS) or Horan-Beighton syndrome is a rare X-linked dominant inherited bone dysplasia, characterized by longitudinal striations of long bones and cranial sclerosis. Patients can be asymptomatic or present with typical facial dysmorphism, sensory defects, internal organs anomalies, growth and mental retardation, depending on the severity of the disease. WTX gene (Xq11) has been recently identified as the disease causing gene. Aim of this article is to present the case of a 6 year old girl initially evaluated for bilateral hearing loss. Patient's head CT scan pointed out sclerosis of skull base and mastoid cells, and abnormal middle-ear ossification. Clinical examination of the patient and her mother were suspicious for OS-CS. The diagnosis was confirmed by X-rays examination showing typical longitudinal striation. Genetic analysis allowed the identification of maternally transmitted heterozygous nonsense c.1057C>T (p.R353X) WTX gene mutation. We also provide a systematic review of currently available knowledge about clinical, radiologic and genetic features typical of the OS-CS.

Complex malformation (Ruggieri-Happle) phenotype with "cutis tricolor" in a 10-year-old girl.

The term cutis tricolor describes the combination of congenital hyper- and hypo-pigmented skin lesions in close proximity to each other in a background of normal complexion. It is currently regarded as a twin-spotting phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far: (a) as an isolated skin manifestation; (b) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome - RHS); (c) as a distinct phenotype [cutis tricolor parvimaculata]; (d) in association with other (e.g., vascular) skin disturbances. We report a novel case of cutis tricolor in a 10-year-old girl who had dysmorphic facial features [alike those seen in cases with syndromic (RHS) cutis tricolor], overall overgrowth [weight, length, and head circumference were >90th percentile; there was increased bone age], mild cognitive delay (current IQ=55), behavioural disturbances, febrile seizures and (later) partial complex epilepsy (currently under good control), and skeletal defects [i.e., posterior scalloping of the lumbar vertebrae]. We discuss the main similarities and differences between the various phenotypes in the spectrum of cutis tricolor and with other conditions sharing features with the present case.

Long-term outcome of epilepsy in Kabuki syndrome.

UNLABELLED: PURPOSES AND METHODS: Kabuki syndrome (KS) is a rare dysmorphic disorder characterized by multiple congenital anomalies and mental retardation. Although epilepsy is one of the most common clinical complications associated with KS, few studies have evaluated its electroclinical aspects and long-term outcome. Therefore, we describe here a clinical series of 10 Caucasian KS patients who developed epilepsy in childhood. We followed all children for at least 5 years. RESULTS: All patients presented partial seizures and interictal EEGs revealed focal epileptic paroxysms with prevalent involvement of temporo-occipital areas. Seven children had no central nervous system abnormalities, but enlargement of lateral ventricles, corpus callosum hypoplasia, and adenohypophysis hypoplasia were revealed in three. Although antiepileptic drug (AED) treatment was effective in controlling seizures and normalizing EEG abnormalities in 8 patients, the other 2 cases were resistant to multiple AEDs. In one of these two patients, withdrawal of AED resulted in status epilepticus and death. CONCLUSIONS: Partial seizures and temporo-occipital abnormalities on interictal EEG are common features of KS patients who suffer from epilepsy. Prognosis of this epilepsy is favourable in the majority of cases with complete disappearance of seizures and EEG abnormalities.