Commentary : The value of intraoperative neurophysiological monitoring: evidence, equipoise and outcomes.

The use of intraoperative neurophysiological monitoring (IONM) has grown despite an absence of randomized controlled trials that might unequivocally demonstrate improved outcomes. At issue is how to demonstrate value when other evidence indicates patient harms (opportunity cost) if IONM is withheld for the sake of randomization. In this article we review other non-randomized methods to assess the effects of IONM on post-operative outcomes. We also examine how clinical equipoise may resolve whether (or not) an anticipated controlled study is ethical. We conclude that the value of IONM in a particular surgical setting should be determined by a benefits/harms analysis based on all the available evidence.

Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

11p14.1 microdeletions associated with ADHD, autism, developmental delay, and obesity.

Genomic copy number imbalances are being increasingly identified as an important cause of intellectual disability and behavioral abnormalities. The typical deletion in WAGR syndrome encompasses the PAX6 and WT1 genes, but larger deletions have been associated with neurobehavioral abnormalities and obesity. We identified four patients with overlapping interstitial deletions on 11p14.1 and extending telomeric to the WAGR critical domain. The minimal overlapping critical chromosomal region was 2.3 Mb at 11p14.1. The deletions encompass the BDNF and LIN7C genes that are implicated in the regulation of development and differentiation of neurons and synaptic transmission. All patients with this deletion exhibit variable degrees of developmental delay, behavioral problems, and obesity. Our data show that ADHD, autism, developmental delay, and obesity are highly associated with deletion involving 11p14.1 and provide additional support for a significant role of BDNF in obesity and neurobehavioral problems.

Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders.

BACKGROUND: Microdeletions within chromosome 15q13.3 are associated both with a recently recognised syndrome of mental retardation, seizures, and dysmorphic features, and with schizophrenia. METHODS AND RESULTS: Based on routine diagnostic testing of approximately 8200 samples using array comparative genomic hybridisation, we identified 20 individuals (14 children and six parents in 12 families) with microdeletions of 15q13.3. Phenotypes in the children included developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems. Both parents were available in seven families, and the deletion was de novo in one, inherited from an apparently normal parent in four, and inherited from a parent with learning disability and bipolar disorder in two families. Of the 14 children, six in five families were adopted, and DNA was available for only one of these 10 biological parents; the deletion was very likely inherited for one of these families with two affected children. Among the unavailable parents, two mothers were described as having mental retardation, another mother as having "mental illness", and one father as having schizophrenia. We hypothesise that some of the unavailable parents have the deletion. CONCLUSIONS: The occurrence of increased adoption, frequent autism, bipolar disorder, and lack of penetrance are noteworthy findings in individuals with deletion 15q13.3. A high rate of adoption may be related to the presence of the deletion in biological parents. Unconfirmed histories of antisocial behaviours in unavailable biological parents raise the concern that future research may show that deletion 15q13.3 is associated with such behaviours.

Motor evoked potential recovery with surgeon interventions and neurologic outcomes: A meta-analysis and structural causal model for spine deformity surgeries.

OBJECTIVE: To improve estimates of motor evoked potential (MEP) performance during spine deformity surgeries by accounting for potential confounders. METHODS: A meta-analysis of MEPs for spine deformity surgeries determined the probability of a MEP deterioration which recovered by the end of surgery, P(RSC), and the conditional probability of no new post-operative deficit given an RSC, P(NND|RSC), stratified by category of intraoperative adverse event associated with the MEP deterioration. A structural causal model (SCM) and propensity score matching accounted for intraoperative adverse events and patient diagnosis as potential confounders. RESULTS: MEPs changes (either reversible, RSC or irreversible, IRREV) were reported for 295 of 5055 cases (6%) in 21 studies. The probability of no new motor deficit, P(NND), plotted against the probability of a RSC, P(RSC), for studies in the meta-analysis was highly significant (r = 0.71, p < 0.001). P(RSC) was 0.76 for an alert associated with correction, less for osteotomies (0.48, p = 0.0008), and tended to be higher for hypotension (0.92, p = 0.06). P(NND|RSC) was 0.94 for correction, less for positioning (0.82), and osteotomies (0.86), and greater for hypotension (1.0). In the SCM, a RSC after an alert was a highly significant and independent predictor of no new motor deficits (odds 25.2, p < 0.001). CONCLUSION: There are significant differences in P(RSC) for hypotension and osteotomies, and in P(NND) for osteotomies and instrumentation, compared to correction. P(RSC) is a significant and independent predictor of outcomes. SIGNIFICANCE: When MEPs are used for spine deformity surgeries, accounting for adverse events associated with an alert and patient diagnosis as potential confounders is expected to improve RSC prediction of post-operative outcomes and estimates of RSC efficacy in improving outcomes.

Microvascular architecture of experimental colon tumors in the rat.

Tumor cell proliferation is dependent upon concurrent growth of a supporting vasculature. This study aims to characterize the structural features of the microvasculature within a primary tumor model. There were 22 colon tumors induced in 16 rats by repeated administration of dimethylhydrazine. A cast of the microvessels was prepared by intraarterial administration of acrylic resin (Mercox). After corrosion of the tissue, the cast was examined by scanning electron microscopy. Tumors 2.6 to 12.0 mm in diameter were examined. Within polypoid carcinomas up to 5.7 mm in diameter, there were two distinct vascular zones, a luminal vascular zone continuous with the vasculature of normal mucosa and a central zone continuous with the normal submucosa and muscularis propria vessels. Within both vascular zones, the organization of microvessels had the same general pattern as in normal mucosa. However, in tumors with diameters greater than 5.7 mm, the vasculature was seen to be disorganized and of a greater density than normal. In the smallest tumors, few morphological changes were seen in the individual microvessels when compared to normal. However, with tumor growth, there was elongation and increased diameters of the microvessels within the tumor. Microvessels within the luminal zone of the tumors which could definitely be traced to veins had diameters of 50 to 100 microns (compared to 12 to 30 microns for normal venules). Individual microvessels varied in diameter along their course forming saccular dilations in places. Networks of frequently anastomosing microvessels were formed. Extravasation of resin occurred from some microvessels. Elongated vessels of uniform diameter which travel distances up to 2 mm without branching were seen and were probably arterioles. These appearances indicate that there are two distinct stages of development of the vasculature within primary tumors, an early phase where the tumor is supplied by the preexisting host microvessels, followed by a phase of proliferation of new vessels with abnormal morphological characteristics.

An evaluation of motor evoked potential surrogate endpoints during intracranial vascular procedures.

OBJECTIVE: MEPs are used as surrogate endpoints to predict the effectiveness of interventions, made in response to MEP deterioration, in avoiding new postoperative deficits. MEP performance in capturing intervention effects on these outcomes was investigated. METHODS: A meta-analysis of studies using MEPs during intracranial vascular surgeries between 2003 and 2014 was performed. MEP diagnostic performance and relative risk of new postoperative deficits for reversible compared with irreversible MEP changes were determined. Intervention efficacy in reversing MEP deterioration and postoperative outcomes was compared across studies. RESULTS: MEP diagnostic performance compared favorably with that of other tests used in medicine, with all likelihood ratios >10. The summary relative risk comparing reversible and irreversible changes was 0.40, indicating a 60% decrease in new deficits for reversible MEP changes. The proportion of MEP deteriorations which recovered was negatively correlated with the proportion of new postoperative deficits (r=-0.81, p<.005). CONCLUSIONS: The effectiveness of interventions in recovering an MEP decline was predictive of preserved neurologic status. MEPs are provisionally qualified as surrogate endpoints given potentially major harms to the patient if they are not used, compared to the minimal harms and costs associated with their use. SIGNIFICANCE: The performance of MEPs as substitute, or surrogate, endpoints during intracranial vascular surgeries for new deficits in motor strength in the immediate postoperative period was directly assessed for ten recent studies.

Somatosensory and motor evoked potentials as biomarkers for post-operative neurological status.

SEPs and MEPs (EPs) are often used as surrogates for postoperative clinical endpoints of muscle strength and sensory status, as these true endpoints are not available during surgery. EPs as surrogate endpoints were evaluated using a three step framework (Analytical Validation, Qualification, Utilization) recently proposed by the Institute of Medicine (USA). EP performance on Analytical Validation may surpass that of some other biomarkers used in medicine (tumor size, cardiac troponin). Qualification of EP surrogates was evaluated with guidelines for causation proposed by A.B. Hill, which supported causal links between surgical events and EP changes and revised estimates of EP diagnostic test performance for three illustrative studies. Qualification was also addressed with a 3×2 contingency analysis which demonstrated decreased deficit proportions for EP declines which recovered after surgeon intervention. Utilization of EP surrogates will depend on surgical procedure and alert criteria. EPs are often used as surrogate endpoints to avoid new postoperative deficits. Although not fully validated, their continued use as surrogates during surgical procedures with the potential for significant morbidity is justified by their potential to help avoid injury and the absence of "second best options."

Intersitial deletion of 20p: new candidate region for Hirschsprung disease and autism?

We describe a patient with Hirschsprung disease and autism. High-resolution karyotyping indicated that the patient has an interstitial deletion of 20p11.22-p11.23. Microsatellite analysis showed a deletion involving a 5-6 cM region from the maternally derived chromosome 20. The deleted region is proximal to, and does not overlap, the recently characterized Alagille syndrome region. This region of 20p has not yet been implicated in Hirschsprung disease or autism. However, this region contains several genes that could plausibly contribute to any phenotype that includes abnormal neural development.

Deletion involving D15S113 in a mother and son without Angelman syndrome: refinement of the Angelman syndrome critical deletion region.

Deletions of 15q11-q13 typically result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and the D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients.

Autism and maternally derived aberrations of chromosome 15q.

Of the chronic mental disabilities of childhood, autism is causally least well understood. The former view that autism was rooted in exposure to humorless and perfectionistic parenting has given way to the notion that genetic influences are dominant underlying factors. Still, identification of specific heritable factors has been slow with causes identified in only a few cases in unselected series. A broad search for genetic and environmental influences that cause or predispose to autism is the major thrust of the South Carolina Autism Project. Among the first 100 cases enrolled in the project, abnormalities of chromosome 15 have emerged as the single most common cause. The four abnormalities identified include deletions and duplications of proximal 15q. Other chromosome aberrations seen in single cases include a balanced 13;16 translocation, a pericentric inversion 12, a deletion of 20p, and a ring 7. Candidate genes involved in the 15q region affected by duplication and deletion include the ubiquitin-protein ligase (UBE3A) gene responsible for Angelman syndrome and genes for three GABA(A) receptor subunits. In all cases, the deletions or duplications occurred on the chromosome inherited from the mother.

Sulindac inhibits the rate of growth and appearance of colon tumors in the rat.

Sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene] indene-3-acetic acid), an inhibitor of prostaglandin synthesis, has been reported to cause regression of colon polyps in patients with familial polyposis coli and Gardner's syndrome. We examined the effect of sulindac on the growth of primary colon carcinomas in rats. Colon tumors were induced in 18 rats by repeated subcutaneous administration of dimethylhydrazine. The site and diameter of each tumor were measured via laparotomy and colonoscopy. Rats were randomized to receive either sulindac (10 mg/kg) twice daily or vehicle (0.5% methylcellulose). After 4 weeks of treatment, the site and size of tumors in the colon were again recorded. In eight rats receiving sulindac, no new tumors were identified, while in 10 control rats, 13 additional tumors were found after treatment. There was a significantly greater increase in size of the tumors in the control group (56.4 mm for 26 tumors) compared with the rats receiving sulindac (9.3 mm for 14 tumors). We report that sulindac inhibits the rate of development and the rate of growth of colon tumors in the rat.

Treatment of anal fissure with glyceryl trinitrate in patients referred for surgical management.

BACKGROUND: A number of recent studies indicate that anal fissure may be treated by applying glyceryl trinitrate (GTN) ointment. The present study aims to determine the effectiveness and patient acceptability of GTN treatment for patients referred to a consultant surgeon. METHODS: A prospective study of 65 consecutive patients referred to one surgeon (ALP) over a 12-month period was undertaken. All patients were offered 0.2% GTN ointment to be applied intra-anally four times daily for 4 weeks. Informed consent was obtained and review planned for 4 weeks. RESULTS: Fourteen patients declined treatment and nine of the 14 (64%) subsequently underwent lateral sphincterotomy. Twelve of the 51 patients (18.5%) who accepted treatment could not complete it due to headache or persisting severe anal pain. Thirty-nine of the 51 patients (77%) were able to complete 4 weeks of treatment. Twenty-two of the 39 reported an improvement in symptoms. A total of 22 patients (43%) who started GTN treatment subsequently underwent lateral sphincterotomy. CONCLUSIONS: Evidence from the present study suggests that GTN ointment has a place in the management of referred patients with severe and/or chronic anal fissure, but sphincterotomy remains an important treatment option for the majority.

Clinical severity and quality of life in children and adolescents with Rett syndrome.

OBJECTIVE: The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. METHODS: Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. RESULTS: Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. CONCLUSIONS: Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures.

Laparoscopic assisted right hemicolectomy with Valtrac BAR (Biofragmentable Anastomotic Ring) ileotransverse anastomosis.

Laparoscopic techniques have been employed in a group of medically compromised patients requiring right hemicolectomy, permitting a shorter and lower placed abdominal incision than may have been expected with a conventional surgical approach. In eight patients requiring right hemicolectomy, full mobilization of the right colon from the caecum to the proximal transverse colon was performed laparoscopically. Resection and anastomosis then proceeded through a small right-sided transverse abdominal incision. End to end ileotransverse anastomosis was performed in each instance employing the Valtrac BAR (Biofragmentable Anastomotic Ring) compressive anastomotic technique. The average operating time was 133 min. There was no mortality, but one patient developed pulmonary complications and three developed minor wound infections. An additional three patients developed urinary tract infections. There were no anastomotic complications. The average postoperative stay was 10 days. This study has indicated that laparoscopic techniques can be successfully applied to large bowel surgery, and may be of benefit to high risk patients.

Acampomelic campomelic dysplasia.

Two newborn infants with respiratory distress showed all the clinical and radiologic stigmata of the campomelic dysplasia except campomelia itself.

Sulindac inhibits colorectal tumour growth, but not prostaglandin synthesis in the rat.

We have determined the dose-response relationship between sulindac administration and inhibition of tumour growth in the rat. The effect of tumour-inhibiting doses of sulindac on the production of prostaglandin E in tumours and macroscopically normal colon was then examined. Growth of pre-existing tumours was significantly reduced following administration of sulindac at 0.1 (P=0.004), 1 (P=0.01), 3 (P<0.001) and 10 mg/kg b.d. (P=0.002) for 4 weeks. There was no significant difference in prostaglandin E synthesis between tumours from control rats and those treated with sulindac at either 3 or 10 mg/kg b.d. (P=0.09 and 0.4, respectively). Prostaglandin E synthesis was reduced by 33 and 32% in macroscopically normal tissue from these treatment groups. These data show that sulindac inhibits tumour growth at low doses and do not support a role for the inhibition of prostaglandin synthesis, by sulindac, in the inhibition of tumour growth.