Association of behavioural and social-communicative profiles in children with 16p11.2 copy number variants: a multi-site study.

BACKGROUND: Despite the established knowledge that recurrent copy number variants (CNVs) at the 16p11.2 locus BP4-BP5 confer risk for behavioural and language difficulties, limited research has been conducted on the association between behavioural and social-communicative profiles. The current study aims to further delineate the prevalence, nature and severity of, and the association between, behavioural and social-communicative features of school-aged children with 16p11.2 deletion syndrome (16p11.2DS) and 16p11.2 duplication (16p11.2Dup). METHODS: A total of 68 individuals (n = 47 16p11.2DS and n = 21 16p11.2Dup) aged 6-17 years participated. Standardised intelligence tests were administered, and behavioural and social-communicative skills were assessed by standardised questionnaires. Scores of both groups were compared with population norms and across CNVs. The influence of confounding factors was investigated, and correlation analyses were performed. RESULTS: Compared with the normative sample, children with 16p11.2DS showed high rates of social responsiveness (67%) and communicative problems (69%), while approximately half (52%) of the patients displayed behavioural problems. Children with 16p11.2Dup demonstrated even higher rates of social-communicative problems (80-90%) with statistically significantly more externalising and overall behavioural challenges (89%). In both CNV groups, there was a strong positive correlation between behavioural and social-communicative skills. CONCLUSIONS: School-aged children with 16p11.2 CNVs show high rates of behavioural, social responsiveness and communicative problems compared with the normative sample. These findings point to the high prevalence of autistic traits and diagnoses in these CNV populations. Moreover, there is a high comorbidity between behavioural and social-communicative problems. Patients with difficulties in both domains are vulnerable and need closer clinical follow-up and care.

The COVID-19 pandemic's impact on worry and medical disruptions reported by individuals with chromosome 22q11.2 copy number variants and their caregivers.

BACKGROUND: The world has suffered immeasurably during the COVID-19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic. METHODS: The University of Pennsylvania COVID-19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages. RESULTS: A total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID-19 had the highest average endorsed worry, whilst currently having COVID-19 had the lowest rated worry. Total COVID-19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID-19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID-19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged. CONCLUSIONS: Widespread medical care disruptions and pandemic-related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long-term effects of COVID-19 worries, interruptions to care and hospital avoidance require further study.

Strategies to defeat ketamine-induced neonatal brain injury.

Studies using animal models have shown that general anesthetics such as ketamine trigger widespread and robust apoptosis in the infant rodent brain. Recent clinical evidence suggests that the use of general anesthetics on young children (at ages equivalent to those used in rodent studies) can promote learning deficits as they mature. Thus, there is a growing need to develop strategies to prevent this injury. In this study, we describe a number of independent approaches to address therapeutic intervention. Postnatal day 7 (P7) rats were injected with vehicle (sterile PBS) or the NMDAR antagonist ketamine (20 mg/kg). After 8 h, we prepared brains for immunohistochemical detection of the pro-apoptotic enzyme activated caspase-3 (AC3). Focusing on the somatosensory cortex, AC3-positive cells were then counted in a non-biased stereological manner. We found AC3 levels were markedly increased in ketamine-treated animals. In one study, microarray analysis of the somatosensory cortex from ketamine-treated P7 pups revealed that expression of activity dependent neuroprotective protein (ADNP) was enhanced. Thus, we injected P7 animals with the ADNP peptide fragment NAPVSIPQ (NAP) 15 min before ketamine administration and found we could dose-dependently reverse the injury. In separate studies, pretreatment of P6 animals with 20 mg/kg vitamin D(3) or a nontoxic dose of ketamine (5 mg/kg) also prevented ketamine-induced apoptosis at P7. In contrast, pretreatment of P7 animals with aspirin (30 mg/kg) 15 min before ketamine administration actually increased AC3 counts in some regions. These data show that a number of unique approaches can be taken to address anesthesia-induced neurotoxicity in the infant brain, thus providing MDs with a variety of alternative strategies that enhance therapeutic flexibility.

Is age-dependent, ketamine-induced apoptosis in the rat somatosensory cortex influenced by temperature?

General anesthetics have long been thought to be relatively safe but recent clinical studies have revealed that exposure of very young children (4 years or less) to agents that act by blocking the N-methyl-D-aspartate receptor (NMDAR) can lead to cognitive deficits as they mature. In rodent and non-human primate studies, blockade of this receptor during the perinatal period leads to a number of molecular, cellular and behavioral pathologies. Despite the overwhelming evidence from such studies, doubt remains as to their clinical relevance. A key issue is whether the primary injury (apoptotic cell death) is specific to receptor blockade or due to non-specific, patho-physiological changes. Principal to this argument is that loss of core body temperature following NMDAR blockade could explain why injury is observed hours later. We therefore examined the neurotoxicity of the general anesthetic ketamine in P7, P14 and P21 rats while monitoring core body temperature. We found that, at P7, ketamine induced the pro-apoptotic enzyme activated caspase-3 in a dose-dependent manner. As expected, injury was greatly diminished by P14 and absent by P21. However, contrary to expectations, we found that core body temperature was not a factor in determining injury. Our data imply that injury is directly related to receptor blockade and is unlikely to be overcome by artificially changing core body temperature.

View of the larynx obtained using the Miller blade and paraglossal approach, compared to that with the Macintosh blade.

The purpose of this study was to determine if laryngoscopy using a Miller blade with a paraglossal approach would yield an improved view of the larynx compared to that obtained with a Macintosh blade using the standard approach. One-hundred and sixty-one patients, scheduled for elective surgery requiring tracheal intubation, voluntarily participated in this study. Patients were randomly assigned to one of the two groups (Miller vs. Macintosh). A standard general anaesthetic was administered. Comparisons were made of the percentage of the vocal cords visible at laryngoscopy. The view of the airway was also graded using the Cormack and Lehane scale. Statistical analysis using Fisher's exact test was performed. A P value < 0.05 was considered statistically significant. The time required to complete intubation and complications if any, were also recorded. Laryngoscopy using the Miller blade allowed 100% of the vocal cords to be viewed in 78% of cases, whereas this was achievable in only 53% with the Macintosh blade (P = 0.0014). The Miller blade enabled greater than 25% of the vocal cords to be seen in 95% of the cases, whereas this was achievable in only 80% with the Macintosh laryngoscope (P = 0.003). A grade 1 Cormack and Lehane view of the larynx was obtained in 96.5% of cases in the Miller group compared with 85% in the Macintosh group (P = 0.02). Direct laryngoscopy using the Miller blade and paraglossal approach, afforded a much-improved view of the larynx in the majority of cases. For this reason trainees should learn laryngoscopy using both blades.

Gender, genotype, and phenotype differences in Smith-Magenis syndrome: a meta-analysis of 105 cases.

Smith-Magenis syndrome (SMS) is a multisystem disorder characterized by developmental delay and mental retardation, a distinctive behavioral phenotype, and sleep disturbance. We undertook a comprehensive meta-analysis to identify genotype-phenotype relationships to further understand the clinical variability and genetic factors involved in SMS. Clinical and molecular information on 105 patients with SMS was obtained through research protocols and a review of the literature and analyzed using Fisher's exact test with two-tailed p values. Several differences in these groups of patients were identified based on genotype and gender. Patients with RAI1 mutation were more likely to exhibit overeating, obesity, polyembolokoilamania, self-hugging, muscle cramping, and dry skin and less likely to have short stature, hearing loss, frequent ear infections, and heart defects when compared with patients with deletion, while a subset of small deletion cases with deletions spanning from TNFRSF13B to MFAP4 was less likely to exhibit brachycephaly, dental anomalies, iris abnormalities, head-banging, and hyperactivity. Significant differences between genders were also identified, with females more likely to have myopia, eating/appetite problems, cold hands and feet, and frustration with communication when compared with males. These results confirm previous findings and identify new genotype-phenotype associations including differences in the frequency of short stature, hearing loss, ear infections, obesity, overeating, heart defects, self-injury, self-hugging, dry skin, seizures, and hyperactivity among others based on genotype. Additional studies are required to further explore the relationships between genotype and phenotype and any potential discrepancies in health care and parental attitudes toward males and females with SMS.

Dextrose 5% in water: fluid medium for maintaining electrical stimulation of peripheral nerves during stimulating catheter placement.

It is well documented that a higher electrical current is required to elicit a motor response following a normal saline (NS) injection during the placement of stimulating catheters for peripheral nerve block. We present three cases of continuous brachial plexus catheter placement in which Dextrose 5% in water (D5W) was used to dilate the perineural space instead of NS. Three brachial plexus blocks (two interscalene and one axillary) were performed in three different patients for pain relief. In each case, an insulated needle was advanced towards the brachial plexus. A corresponding motor response was elicited with a current less than 0.5 mA after needle repositioning. A stimulating catheter was advanced with ease after 3-5 ml of D5W was injected to dilate the perineural space. A corresponding motor response was maintained when the current applied to the stimulating catheter was less than 0.5 mA. Local anesthetic was then injected and the motor response immediately ceased. All blocks were successful and provided excellent pain relief with the continuous infusion of local anesthetics.

Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net!

PURPOSE: The chromosome 22q11.2 deletion has been identified in the majority of patients with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome and in some patients with the autosomal dominant Opitz G/BBB syndrome and Cayler cardiofacial syndrome. In addition, 22q11.2 deletion studies are becoming part of a standardized diagnostic workup for some isolated defects such as conotruncal cardiac anomalies and velopharyngeal incompetence. However, there is little information available on the clinical findings of unselected patients. For example, those individuals identified during prenatal diagnosis, as part of a generalized screening protocol, or following the diagnosis in a relative. This information will be invaluable in defining the variability of the disorder and in observing long-term outcome in the absence of targeted remediations. This study allows one to examine the first unselected cohort of patients and serves to highlight the importance of deletion testing in parents of affected probands. METHODS: Thirty individuals with a 22q11.2 deletion were identified following the diagnosis in a relative. Nineteen were adults ascertained only following the diagnosis in their child, 10 were children identified following the diagnosis in their sibling, and one was a child diagnosed prenatally following the diagnosis in her parent. RESULTS: Sixty percent of patients had no visceral anomalies. In fact, only 6 of the 19 adults (32%) and 6 of the 11 children (55%) had major findings which would have brought them to medical attention. Deletion sizing demonstrated the same large 3-4 MB deletion in most families despite wide inter and intrafamilial variability and there was no difference in clinical findings based on the parent of origin. Thus, no genotype-phenotype correlations could be made. CONCLUSION: We report the first unselected cohort of patients with the 22q11.2 deletion identified through an affected relative. Analysis of this series of 30 patients, many with very mild manifestations of the deletion, allows one to examine the outcome in individuals who lacked specific remediations for this disorder. It emphasizes the importance of broadening the index of suspicion in order to provide appropriate recurrence risk counseling, cognitive remediation, and medical management. Further, it underscores the lack of familial concordance and the current lack of genotype-phenotype correlations in this disorder, and it raises the possibility that the deletion is more common than previously reported.

The attitude of the general public towards preoperative assessment and risks associated with general anesthesia.

PURPOSE: To survey the general public's attitude towards preoperative assessment and commonly perceived fears about general anesthesia. METHODS: A province wide telephone survey was conducted in Alberta. General and regional anesthesia were defined, a scenario involving major knee surgery was described, and participants were asked to choose between regional and general anesthesia. Respondents used a seven-point scale to rate the importance of seeing an anesthesiologist preoperatively and were questioned about the timing of such a visit. Attitudes towards commonly perceived fears associated with anesthesia were also assessed. RESULTS: A total of 1,216 people were surveyed. Over 30% of respondents felt that it was very important to see an anesthesiologist preoperatively, with a total of over 60% attributing a high degree of importance to this. Fifty percent felt that this assessment should occur on the day prior to surgery. A preference for regional or general anesthesia was not expressed in the situation. Approximately 20% of respondents were very concerned about brain damage, waking up intraoperatively and memory loss. Twelve percent were concerned about dying intraoperatively. Nine percent expressed concern about postoperative pain, with 12% reporting being concerned about nausea and vomiting. CONCLUSIONS: The general public considers anesthetic assessment on the day prior to surgery an important part of preoperative preparation. Fears of brain damage, death and intraoperative awareness associated with general anesthesia remain prevalent, suggesting that preoperative education of patients should address these concerns. The general population was less concerned about realistic fears such as nausea, vomiting and postoperative discomfort.

Complications of regional anaesthesia Incidence and prevention.

The complications of failure, neural injury and local anaesthetic toxicity are common to all regional anaesthesia techniques, and individual techniques are associated with specific complications. All potential candidates for regional anaesthesia should be thoroughly evaluated and informed of potential complications. If there is significant risk of injury, then these techniques should be avoided. Central neural blockade (CNB) still accounts for more than 70% of regional anaesthesia procedures. Permanent neurological injury is rare (0.02 to 0.07%); however, transient injuries do occur and are more common (0.01 to 0.8%). Pain on injection and paraesthesiae while performing regional anaesthesia are danger signals of potential injury and must not be ignored. The incidence of systemic toxicity to local anaesthetics has significantly reduced in the past 30 years, from 0.2 to 0.01%. Peripheral nerve blocks are associated with the highest incidence of systemic toxicity (7.5 per 10000) and the lowest incidence of serious neural injury (1.9 per 10000). Intravenous regional anaesthesia is one of the safest and most reliable forms of regional anaesthesia for short procedures on the upper extremity. Brachial plexus anaesthesia is one of the most challenging procedures. Axillary blocks are performed most frequently and are safer than supraclavicular approaches. Ophthalmic surgery is particularly suited to regional anaesthesia. Serious risks include retrobulbar haemorrhage, brain stem anaesthesia and globe perforation, but are uncommon with skilled practitioners. Postdural puncture headache remains a common complication of epidural and spinal anaesthesia; however, the incidence has decreased significantly in the past 2 to 3 decades from 37 to approximately 1%, largely because of advances in needle design. Backache is frequently linked with CNB; however, other causes should also be considered. Duration of surgery, irrespective of the anaesthetic technique, seems to be the most important factor. The syndrome of transient neurological symptoms is a form of backache that is associated with patient position and use of lidocaine (lignocaine). Disturbances of micturition are a common accompaniment of CNB, especially in elderly males. Hypotension is the most common cardiovascular disturbance associated with CNB. Severe bradycardia and even cardiac arrest have been reported in healthy patients following neuraxial anaesthesia, with a reported incidence of cardiac arrest of 6.4 per 10 000 associated with spinal anaesthesia. Prompt diagnosis, immediate cardiopulmonary resuscitation and aggressive vasopressor therapy with epinephrine (adrenaline) are required. New complications of regional anaesthesia emerge occasionally, e.g. cauda equina syndrome with chloroprocaine, microspinal catheters and 5% hyperbaric lidocaine, and epidural haematoma formation in association with low molecular weight heparin. Even so, after 100 years of experience, most discerning physicians appreciate the benefits of regional anaesthesia.

Prolonged epidural infusions of ropivacaine (2 mg/mL) after colonic surgery: the impact of adding fentanyl.

UNLABELLED: We evaluated the safety and efficacy of a 72-h epidural infusion of ropivacaine and measured the impact of adding fentanyl 2 microg/mL to the required infusion rate, on the quality of postoperative pain relief and the incidence of side effects, after colonic surgery. One hundred fifty-five patients scheduled for elective colonic surgery were randomized in this trial. Epidural infusions of ropivacaine 2 mg/mL with fentanyl 2 microg/mL (R + F) and without fentanyl (R) were commenced during surgery and continued for 72 h postoperatively. This was a prospective, randomized, double-blinded, multi-center trial. The median infusion rate required was less in the R + F group (9.3 vs 11.5 mL/h, P < 0.001). Median pain scores at rest and on coughing were lower in the R + F group (P < 0.0001). The incidence of hypotension was more in the R + F group (P = 0.01). Time to readiness for discharge was delayed in the R + F group (median 6.6 vs 5.5 days, P = 0.012). The addition of fentanyl to ropivacaine resulted in decreased infusion rates and enhanced pain control; however, adverse effects were increased and readiness to discharge was delayed. IMPLICATIONS: Epidural infusions of ropivacaine with and without fentanyl were administered to patients to control pain after colonic surgery. Patients who received ropivacaine with fentanyl had better pain control, increased side effects, and delayed readiness to discharge. This study questions the value of adding opioids to epidural infusions of local anesthetics.

Characterization of self-injurious behaviors in children and adults with Smith-Magenis syndrome.

A characteristic pattern of stereotypic and self-injurious behavior (SIB) distinguishes Smith-Magenis syndrome from many other genetic disorders. We examined the prevalence and severity of 11 specific types of SIB in 29 children and adults with Smith-Magenis syndrome. We confirmed the near universal presence of SIB in people with this disorder. The overall prevalence of SIB was found to increase with age as was the number of different types of SIB demonstrated by individuals with Smith-Magenis syndrome. The number of different types of SIB exhibited was also directly correlated with level of intellectual functioning. Our data suggest that with increasing age and ability levels, people with Smith-Magenis syndrome add to their repertoire of SIB from among a small number of specific behaviors.

Thoracic epidural anesthesia for bilateral reduction mammoplasty in a patient with Klippel-Feil syndrome.

General anesthesia is best avoided in cases of Klippel-Feil syndrome where tracheal intubation is potentially difficult. The syndrome features severe abnormalities of the neck and upper thoracic spine, which may also lead to difficulties with neuraxial blockade. We describe the use of epidural anesthesia for bilateral reduction mammoplasty in a patient with this condition.

Detection of subdural placement of epidural catheter using nerve stimulation.

PURPOSE: To report the detection of a subdural catheter placement using nerve stimulation through an epidural catheter. CLINICAL FEATURES: An 85-yr-old gentleman was scheduled for radical cystectomy and creation of an ileal conduit. Combined general anesthesia and regional technqiue was selected. An epidural catheter (19 G Arrow Flextip Plus) was inserted prior to induction of general anesthesia. Intra-operatively, the patient received 5 mg morphine and 10 ml bupivacane 0.5% via the epidural catheter. The patient remained hemodynamically stable throughout the operation and did not require intravenous opioids. The patient was discharged to the ward with an order for epidural morphine for pain control. The next day, the patient remained comfortable. As an ongoing quality assessment to survey the success rate of epidural catheters at our institution, all patients are invited to have their catheter assessed using an electrical epidural stimulation test. Electrical stimulation (1-10 mA) with a segmental motor response (truncal or extremities movement) indicates that the catheter is in the epidural space. No motor response indicates that it is not. In this case, subdural catheter placement was suspected because a diffuse motor response including right anterior chest wall, back muscle, and bilateral lower extremities was observed using only 0.3 mA. Subdural catheter placement was subsequently confirmed by a radiograph showing a very thin film of dye spreading cephalad and caudad over many segments. CONCLUSION: This new electrical test helps to detect subdural placement objectively.

Determining epidural catheter location using nerve stimulation with radiological confirmation.

BACKGROUND AND OBJECTIVES: The use of epidural stimulation to confirm epidural catheter placement has been shown. This case report describes the benefits and problems of using the epidural stimulation test to confirm epidural catheter placement and provides supporting evidence for these observations using radiological imaging. METHODS: A nerve stimulator was connected to the proximal end of an epidural catheter via an adapter. The cathode lead was connected to the adapter. The anode lead was connected to an electrode placed on the upper extremity as a grounding site. Using 1 to 10 mA current, a segmental motor response indicated that the catheter was in the epidural space. The absence of a motor response indicated that it was not. CASES: In the first patient, the new test predicted subcutaneous epidural catheter placement, which was subsequently confirmed radiologically. In the second patient, the catheter tip was found to be lying near a nerve root, which was again confirmed radiologically. In the third case, a negative test was initially observed with only local muscle movement over the biceps area (T2). After relocation of the grounding electrode to the lower extremity, segmental intercostal muscle movement (T4-5 level) was observed. The catheter placement was radiologically shown to be in the T4-5 region. CONCLUSION: This report illustrates some of the potential benefits and problems of using the nerve stimulation test to confirm epidural catheter placement, with radiological verification.

Recent Advances in Brachial Plexus Anesthesia: a Review

Avances recientes en la anestesia del Plexo Braquial. La anestesia del plexo braquial a estado en boga por más de 80 años. De todas las técnicas regionales que se han realizado, la anestesia del plexo braquial (APB) es la que representa mayores retos al anestesiólogo alrededor del mundo. Parece ser que el riesgo y la incidencia de complicaciones es mayor con abordaje supraclavicular. El pneumotórax casi ha desaparecido como complicación y se ha puesto mayor atención a la alteración respiratoria secundaria a la paresia unilateral del frénico. La incidencia de toxicidad por anestésicos locales es mayor con APB que con otros bloqueos y cuando se compara la incidencia de toxicidad sistémica comparando varios abordajes al plexo braquial, esta es cuatro veces mayor con el método supraclavicular, es por eso que se continua buscando nuevos métodos que sean más satisfactorios. La presente revisión describe los diferentes métodos y técnicas así como los beneficios y/o complicaciones derivadas de la APB

Detection of subarachnoid and intravascular epidural catheter placement.

PURPOSE: To report the detection of subarachnoid and intravascular catheter placement using nerve stimulation through an epidural catheter. CLINICAL FEATURES: Electrical stimulation (1-10 mA) was applied through the catheter. A positive motor response (truncal or limb movement) indicated that the catheter was in the epidural space. Absence of a motor response indicated that it was not. A low milliamperage (<1 mA) with bilateral response indicated subarachnoid placement. Intravascular catheter placement was indicated by a positive response to the test, which remains at or returns to the baseline levels (i.e. prior to any local anesthetic injection), despite the administration of local anesthetics. In the first patient, the test confirmed subarachnoid catheter placement during attempts at continuous spinal anaesthesia even though CSF could not be aspirated. Bilateral motor response in the legs was observed at 0.2 mA. In the second patient, inadvertent subarachnoid placement was detected during attempted lumbar epidural block by observing bilateral motor response in the legs at 0.3 mA. In the third patient, intravascular placement was suspected and confirmed by failure to obliterate the motor response despite repeated local anesthetic injection. CONCLUSION: The new test provides objective information in managing epidural catheters when their position is uncertain.

In vivo brain myo-inositol levels in children with Down syndrome.

The Na+/myo-inositol cotransporter (SLC5A3) gene, located on the long arm of human chromosome 21, may play a key role in osmoregulation including the regulation of levels of the "idiogenic osmole," myo-inositol, in brain cells. To determine whether the levels of myo-inositol are increased in the basal ganglia of children with Down syndrome, we performed in vivo brain hydrogen 1-nuclear magnetic resonance or 1H-magnetic resonance spectroscopy and measured plasma osmolality in a cohort of children with trisomy 21. Myo-inositol is elevated in the corpus striatum of infants and children with Down syndrome, even in the absence of hypertonic stress.