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.

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.

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."

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.

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.

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.

Inhibition of beta-catenin translocation in rodent colorectal tumors: a novel explanation for the protective effect of nonsteroidal antiinflammatory drugs in colorectal cancer.

In a rodent colorectal cancer model, nonsteroidal antiinflammatory drugs reduce tumor mass by increasing the rate of tumor cell apoptosis and decreasing proliferation. We have examined beta-catenin as a potential target for these agents in colorectal cancer. Carcinogen-treated rats were treated for 23 weeks with a range of nonsteroidal antiinflammatory drugs. Control animals received vehicle alone. Intracellular beta-catenin was examined using immunohistochemistry. In tumors from untreated animals, staining was seen in the cytoplasm and nucleus (median 24% of nuclei). The frequency of nuclear beta-catenin staining correlated directly with the volume of tumor and inversely with the rate of apoptosis. In tumors from treatment groups, the cytoplasmic staining for beta-catenin was unchanged; however, nuclear staining was absent except in the celecoxib group, where it was reduced to a median of 14%. Colorectal tumors from animals treated with NSAIDs show reduced levels of nuclear beta-catenin immunoreactivity.

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.

Non-steroidal anti-inflammatory drugs with activity against either cyclooxygenase 1 or cyclooxygenase 2 inhibit colorectal cancer in a DMH rodent model by inducing apoptosis and inhibiting cell proliferation.

BACKGROUND: Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer by 40-60% but the mechanism by which this occurs is uncertain. Selective cyclooxygenase 2 inhibitors are potentially ideal chemopreventive agents as they are less toxic than standard NSAIDs. No study has compared the efficacy of these drugs at clinically relevant doses in a tumour model. AIMS: To assess the efficacy of a range of NSAIDs with varying activity against the two cyclooxygenase isoforms in a rodent colorectal carcinogen model at anti-inflammatory doses and to explore the effect of NSAIDs on the rate of tumour apoptosis and proliferation. METHODS: Colorectal tumours were induced in six week old Sprague-Dawley rats with five weekly doses of 1,2 dimethylhydrazine. Test agents were: indomethacin 2 mg/kg/day, meloxicam 0.6 mg/kg/day, celecoxib 6 mg/kg/day, and sulindac sulphone 40 mg/kg/day. Sulindac was tested at its chemoprotective dose of 20 mg/kg/day. After 23 weeks the number and volume of tumours per animal were recorded. Histology was performed. Tumour apoptosis was quantified on haematoxylin-eosin sections. Tumour proliferation was quantified using an immunohistochemical stain for bromodexoyuridine incorporation. RESULTS: Test agents effectively reduced the number and volume of tumours developing in the treatment period. In all groups there was an increase in the rate of tumour apoptosis and a reduced rate of proliferation. CONCLUSIONS: These data suggest that the chemopreventive effect of NSAIDs is independent of their cyclooxygenase inhibitory profile. One potential mechanism for their action may be through induction of apoptosis and inhibition of proliferation.

5-aminosalicyclic acid and olsalazine inhibit tumor growth in a rodent model of colorectal cancer.

The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.

Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation.

Nonsteroidal anti-inflammatory drug (NSAID) use reduces the risk of colorectal cancer by 40-50%. Previous studies suggest that effective inhibition of colorectal cancer by NSAIDs may be dependent on the presence or absence of a K-ras mutation. This study was aimed at determining the relationship between inhibition of colorectal cancer by sulindac and sulindac sulfone and the presence of activating K-ras mutations in the 1,2-dimethylhydrazine dihydrochloride rat model. Sulindac (20 mg x kg(-1) x day(-1)), sulindac sulfone (40 mg x kg(-1) x day(-1)), or vehicle was administered orally to male Sprague-Dawley rats for a 4-wk period beginning 20 wk after tumor induction. Tumor number and volume were measured before treatment by laparotomy and colonoscopy and again after treatment. Sulindac and sulindac sulfone treatment significantly reduced the number and volume of colorectal tumors compared with control rats. For K-ras (codon 12) mutation detection, frozen tumor tissue was collected at the endpoint. We found K-ras codon 12 mutations in 11 of 21 (52%) control tumors. The proportion of tumors with K-ras mutations in the sulindac-treated group [5 of 8 (62%); odds ratio = 1.51 (95% confidence interval = 0.29, 8.33)] and the proportion of sulindac sulfone-treated tumors [9 of 14 (64%); odds ratio = 1.63 (95% confidence interval = 0.41, 6.66)] were not significantly different from controls. Tumor inhibition did not correlate with K-ras (codon 12) mutation status, which suggests that the mechanism of inhibition of rat colorectal cancer by sulindac and sulindac sulfone is independent of K-ras mutation.

Non-steroidal anti-inflammatory drugs with different cyclooxygenase inhibitory profiles that prevent aberrant crypt foci formation but vary in acute gastrotoxicity in a rat model.

BACKGROUND: Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer; however, their use as preventive agents is limited by their inherent toxicity. Drugs that selectively inhibit cyclooxygenase-2 (COX-2) may be useful in this setting as they are supposedly less toxic. No study has directly compared the ability of standard NSAIDs and selective COX-2 inhibitors to inhibit colorectal cancer at clinically relevant doses. METHODS: Aberrant crypt foci (ACF) were induced in Sprague-Dawley rats by using 1,2-dimethylhydrazine (DMH). Test agents or vehicle were then administered for 3 weeks, twice daily through orogastric gavage. At the end of this period, the number and multiplicity of ACF were determined. The agents tested at equivalent anti-inflammatory doses were: sulindac and indomethacin (standard NSAIDs), meloxicam (selective COX-2 inhibitor), celecoxib (specific COX-2 inhibitor) and sulindac sulfone (no known COX activity). Acute gastrotoxicity of NSAID in rats was compared by using quantitative histology. RESULTS: All test agents reduced the number of ACF. There was a 42% reduction with indomethacin, 46% with sulindac, 46% with meloxicam, 22% with celecoxib and 36% with sulindac sulfone. Only the COX-2 inhibitors caused no significant gastrotoxicity in rats. CONCLUSIONS: Cyclooxygenase-2 inhibitors are potentially ideal chemopreventive agents as they inhibit ACF and are not gastrotoxic.

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 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.

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.

The microvascular structure of the normal colon in rats and humans.

The colonic microcirculation may be expected to have a central role in the absorptive, secretory, and protective functions of the colon. To characterize the microvascular structure of the colon in rats and humans, microvascular casts were prepared and examined by scanning electron microscopy. Quantitative measures of the microvasculature were obtained from histological sections. The overall organization of microvessels was found to be similar in the rat and human colon. Capillaries in the colonic mucosa formed a honeycomb-like network around each of the mucosal glands. This capillary plexus was supplied by arterioles which divide into their capillary branches at the level of the submucosa. Mucosal capillaries drain into venules at the luminal surface of the mucosa. Venules then pass to submucosal veins without receiving further capillary branches. Examination of vascular casts also showed that in both the rat and the human colon, there was an increased density of subluminal capillaries in the cecum and proximal colon compared to that of the rest of the colon. This was supported by quantitative measures which indicated a significantly greater microvascular surface area in the rat cecum (24.1 mm2/mm3) compared to that of the midcolon (19.8 mm2/mm3) (P = 0.04) and the distal colon (19.1 mm2/mm3) (P = 0.03). Similarly in the human colon there was a significantly greater total microvascular volume in the proximal colon (13.4%) compared to that of the distal colon (7.7%) (P < 0.0005) and there was a significantly greater total microvascular surface area in the proximal colon (22.4 mm2/mm3) compared to that of the distal colon (17.5 mm2/mm3)(P=0.032). This study details quantitative vascular data for the colon in rats and humans which has not previously been documented, despite its important role in the absorptive function of the colon and in many disease processes affecting the colon. These data provide the normal values with which pathological conditions of the colon which affect the vasculature can be compared.