Posterior drooling in children with cerebral palsy and other neurodevelopmental disorders.

AIM: To evaluate the effect of botulinum neurotoxin A (BoNT-A) injections, submandibular gland excision (SMGE), and bilateral submandibular duct ligation (2DL) for the control of posterior drooling in children with neurological impairment. METHOD: In a retrospective cohort, children with neurological impairment (e.g. cerebral palsy) treated between 2000 and 2016 were identified. Mean age at time of surgery was 9 years (range 1-21y). The primary outcome was posterior drooling severity by a visual analogue scale (VAS; 0-10) at baseline, 8-weeks, and 32-weeks follow-up. The secondary outcome was lower respiratory tract infections during the follow-up period. RESULTS: Ninety-two patients (out of 475; 47 males, 45 females) were identified. They were undergoing three different treatments: BoNT-A (n=63), SMGE (n=16), and 2DL (n=13). A significant reduction in VAS over time was observed in the total group of 92 patients. After SMGE, VAS decreased significantly from 6.82 (SD 3.40) at baseline to 2.29 (SD 1.93) at 8 weeks, and 2.17 (SD 2.58) at 32 weeks (F[2.34]=11.618, p<0.001). There was no significant decrease after both BoNT-A and 2-DL. INTERPRETATION: Posterior drooling is an unfamiliar, potentially life-threatening condition that is treatable with medication, BoNT-A injections, or surgery. Although all treatments reduced signs and symptoms of posterior drooling, there is a greater effect after SMGE compared to BoNT-A and 2-DL. What this paper adds Submandibular gland excision has better results for posterior drooling than botulinum toxin A or submandibular duct ligation.

Neurodevelopmental Aspects and Cortical Auditory Maturation in Children with Cochlear Implants.

Background and objectives: The cochlear implant is not only meant to restore auditory function, but it also has a series of benefits on the psychomotor development and on the maturation of central auditory pathways. In this study, with the help of neuropsychological tests and cortical auditory potentials (CAEPs), we intend to identify a series of instruments that allow us to monitor children with a cochlear implant, and later on, to admit them into an individualized rehabilitation program. Materials and methods: This is a longitudinal study containing 17 subjects (6 boys and 11 girls) diagnosed with congenital sensorineural hearing loss. The average age for cochlear implantation in our cohort is 22 months old. Each child was tested before the cochlear implantation, tested again 3 months after the implant, and then 6 months after the implant. To test the general development, we used the Denver Developmental Screening Test (DDST II). CAEPs were recorded to assess the maturation of central auditory pathways. Results: The results showed there was progress in both general development and language development, with a significant statistical difference between the overall DQ (developmental quotient) and language DQ before the cochlear implantation and three and six months later, respectively. Similarly, CAEP measurements revealed a decrease of positive-going component (P1) latency after cochlear implantation. Conclusion: CAEPs and neuropsychological tests prove to be useful instruments for monitoring the progress in patients with cochlear implants during the rehabilitation process.

Pilot Study of Neurodevelopmental Impact of Early Epilepsy Surgery in Tuberous Sclerosis Complex.

BACKGROUND: To determine if early epilepsy surgery mitigates detrimental effects of refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex who underwent surgery before age two years. METHODS: Prospective multicenter observational study of 160 children with tuberous sclerosis complex. Surgical outcome was determined for the seizure type targeted by surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II); Mullen Scales of Early Learning; and Preschool Language Scales, Fifth Edition, at age three, six, nine, 12, 18, 24, and 36 months. Surgical cases were compared with children without seizures, with controlled seizures, and with medically refractory seizures. RESULTS: Nineteen children underwent surgery (median age 17 months, range 3.7 to 21.3), and mean follow-up was 22.8 months (range 12 to 48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in seven (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from those surgically targeted. All children with seizures demonstrated longitudinal decline or attenuated gains in neurodevelopment, the surgical group scoring the lowest. Favorable surgical outcome was associated with increased Mullen Scales of Early Learning receptive and expressive language subscores compared with the medically refractory seizure group. A nonsignificant but consistent pattern of improvement with surgery was seen in all tested domains. CONCLUSIONS: These pilot data show neurodevelopmental gains in some domains following epilepsy surgery. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics.

Neurodevelopmental and Psychiatric Symptoms in Patients with a Cyst Compressing the Cerebellum: an Ongoing Enigma.

A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap-namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?

Application of Human-Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders.

Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human-induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC-derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl-CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease-related synaptopathy.

Neurodevelopmental outcomes in children with large temporal arachnoid cysts.

OBJECTIVE Management of children with large temporal arachnoid cysts (TACs) remains controversial, with limited data available on their neurodevelopmental outcome. The aim of this study was to examine neurodevelopmental outcomes in children with large TACs. METHODS In this medical center-based cohort study, 25 patients (19 males) who were diagnosed in childhood with large TACs (9 patients [36%] with a Galassi type II and 16 patients [64%] with a Galassi type III TAC) were examined. The mean ± SD age at assessment was 11.1 ± 5.6 years (range 2.7-22 years). Twelve patients (48%) had right-sided, 12 (48%) had left-sided, and 1 (4%) had bilateral cysts. Nine patients (36%) underwent surgery for the cyst. The siblings of 21 patients (84%) served as control participants. Neurodevelopmental function was assessed using the Adaptive Behavior Assessment System (ABAS), Vanderbilt Behavioral Rating Scale (VBRS), and Developmental Coordination Disorder Questionnaire (DCDQ), and quality of life was measured using the treatment-oriented screening questionnaire (TOSQ). The results of all instruments except for TOSQ were compared with those of the sibling control participants. RESULTS The mean ± SD ABAS score of the patients was 93.3 ± 20.09 compared with 98.3 ± 18.04 of the sibling control participants (p = 0.251). Regarding the incidence of poor outcome (ABAS score < 80), there was a trend for more patients with TAC to have poor outcome than the sibling controls (p = 0.058). Patients who underwent surgery scored significantly worse with regard to the VBRS total score compared with those who did not (p = 0.020), but not on ABAS, DCD, or TOSQ. The mean score of the cognitive and psychological items on TOSQ was lower than that for the physical items (p < 0.001). CONCLUSIONS Children with a large TAC performed similarly to their sibling control participants in neurodevelopmental function. However, a subgroup of those with cysts did have an increased risk for poor outcomes in general function. Neurodevelopmental assessment should be part of the management of all patients with TAC.

The promise of induced pluripotent stem cells for neurodevelopmental disorders.

A major challenge in clinical genetics and medicine is represented by genetically and phenotypically highly diverse neurodevelopmental disorders, like for example intellectual disability and autism. Intellectual disability is characterized by substantial limitations in cognitive function and adaptive behaviour. At the cellular level, this is reflected by deficits in synaptic structure and plasticity and therefore has been coined as a synaptic disorder or "synaptopathy". In this review, we summarize the findings from recent studies in which iPSCs have been used to model specific neurodevelopmental syndromes, including Fragile X syndrome, Rett syndrome, Williams-Beuren syndrome and Phelan-McDermid syndrome. We discuss what we have learned from these studies and what key issues need to be addressed to move the field forward.

Understanding neurodevelopmental disorders using human pluripotent stem cell-derived neurons.

Research into psychiatric disorders has long been hindered by the lack of appropriate models. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient-specific cells, which in principle can be differentiated into all disease-relevant somatic cell types to create in vitro models of the disorder of interest. Here, neuronal differentiation protocols available for this purpose and the current progress on iPSCs-based models of schizophrenia, autism spectrum disorders and bipolar disorder were reviewed. We also discuss the impact of the recently developed CRISPR/Cas9 genome editing tool in the disease modeling field. Genetically engineered mutation of disease risk alleles in well characterized reference "control" hPSCs or correction of disease risk variants in patient iPSCs has been used as a powerful means to establish causality of the identified cellular pathology. Together, iPSC reprogramming and CRISPR/CAS9 genome editing technology have already significantly contributed to our understanding of the developmental origin of some major psychiatric disorders. The challenge ahead is the identification of shared mechanisms in their etiology, which will ultimately be relevant to the development of new treatments.