Faculty Bibliography

OBJECTIVES/OBJECTIVE:This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis. METHODS:Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis. RESULTS:R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice. CONCLUSIONS:Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.

BACKGROUND AND PURPOSE:Transcranial Doppler (TCD) criteria for cerebrovascular stenosis are only based on velocity with unsatisfactory positive predictive value (PPV) in previous studies. We refined a published scoring system that integrates several characteristics of TCD data in diagnosing middle cerebral artery (MCA) stenosis. METHODS:Using the TCD-digital subtraction angiography (DSA) database from Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial, velocity, spectrum pattern, diffuse ratio, and asymmetry ratio were assessed. The cutpoints were defined for each parameter and a point value was assigned to each category within that parameter. A summed score was calculated for each MCA. The accuracy was assessed for different cutpoints in predicting ≥50% MCA stenosis measured by DSA. Logistic regression and C-statistics were used for analysis. RESULTS:A total of 114 MCAs were included in vessel-based and 87 patients were included in patient-based analysis. Compared to the velocity-only cutpoints in SONIA, the score results in much improved PPV while negative predictive value (NPV) remains unchanged. The score based on mean velocity (score 0: <140 cm/s, score 3: ≥140 cm/s), spectrum pattern (score 0: no turbulence; score 1: mild turbulence; 2: significant turbulence), and asymmetry ratio (score 0: ratio <1.5, score 1: ratio 1.5-2; score 2: ratio ≥2.1) has the highest NPV while PPV remains favorable (PPV: 72% [95% CI 54-90%]; NPV: 84% [95% CI: 75-93%], area under curve [AUC]: .76 [95% CI: .66-.86]). CONCLUSIONS:The multiparameter scoring system incorporating several characteristics of TCD measures yielded higher PPV while maintaining high NPV compared with the single-parameter velocity criteria in diagnosing MCA ≥50% stenosis.

OBJECTIVE:Generalized epileptiform discharges (GEDs) can occur during seizures or without obvious clinical accompaniment. Motor vehicle driving risk during apparently subclinical GEDs is uncertain. Our goals were to develop a feasible, realistic test to evaluate driving safety during GEDs, and to begin evaluating electroencephalographic (EEG) features in relation to driving safety. METHODS:Subjects were aged ≥15 years with generalized epilepsy, GEDs on EEG, and no clinical seizures. Using a high-fidelity driving simulator (miniSim) with simultaneous EEG, a red oval visual stimulus was presented every 5 minutes for baseline testing, and with each GED. Participants were instructed to pull over as quickly and safely as possible with each stimulus. We analyzed driving and EEG signals during GEDs. RESULTS:Nine subjects were tested, and five experienced 88 GEDs total with mean duration 2.31 ± 1.89 (SD) seconds. Of these five subjects, three responded appropriately to all stimuli, one failed to respond to 75% of stimuli, and one stopped driving immediately during GEDs. GEDs with no response to stimuli were significantly longer than those with appropriate responses (8.47 ± 3.10 vs 1.85 ± 0.69 seconds, P < .001). Reaction times to stimuli during GEDs were significantly correlated with GED duration (r = 0.30, P = .04). In addition, EEG amplitude was greater for GEDs with no response to stimuli than GEDs with responses, both for overall root mean square voltage amplitude (66.14 μV vs 52.99 μV, P = .02) and for fractional power changes in the frequency range of waves (P < .05) and spikes (P < .001). SIGNIFICANCE:High-fidelity driving simulation is feasible for investigating driving behavior during GEDs. GEDs with longer duration and greater EEG amplitude showed more driving impairment. Future work with a large sample size may ultimately enable classification of GED EEG features to predict individual driving risk.

Background/UNASSIGNED:Pediatric intracranial aneurysms tend to differ in etiology, size, and location from their adult counterparts, and they are often less amenable to microsurgical clip reconstruction techniques. Endovascular treatment with detachable coils is an accepted treatment technique for pediatric patients, though high recurrence rates have been reported with coil embolization of large and giant aneurysms in this population. While the Pipeline Embolization Device (PED) is FDA-approved for adult intracranial aneurysms, the use of PEDs in pediatric patients is considered off-label. Case Descriptions/UNASSIGNED:We present 3 cases of pediatric intracranial aneurysms in a 5-year-old male, a 12-year-old male, and a 12-year-old female who presented with symptoms including seizure, headache, and blurred vision. The 2 male patients were found to have intradural vertebral artery saccular aneurysms, while the female patient had a paraophthalmic right internal carotid complex aneurysm. After endovascular reconstruction of the aneurysms with PEDs, follow-up angiography showed complete occlusion of the previous aneurysms with no residual aneurysm filling in all 3 cases. Conclusion/UNASSIGNED:While further investigation is needed, the evidence presented here supports the conclusion that the PED can be an effective and viable treatment strategy in the pediatric population.

Background/UNASSIGNED:Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. Methods/UNASSIGNED:/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI. Results/UNASSIGNED:Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment. Conclusions/UNASSIGNED:This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.

Background and Purpose/UNASSIGNED:Many studies supporting the association between specific surgical procedure categories and postoperative stroke (POS) do not account for differences in patient-level characteristics between and within surgical categories. The risk of POS after high-risk procedure categories remains unknown after adjusting for such differences in patient-level characteristics. Methods/UNASSIGNED:Using inpatients in the American College of Surgeons National Surgical Quality Initiative Program database, we conducted a retrospective cohort study between January 1, 2000, and December 31, 2010. Our primary outcome was POS within 30 days of surgery. We characterized the relationship between surgical- and individual patient-level factors and POS by using multivariable, multilevel logistic regression that accounted for clustering of patient-level factors with surgical categories. Results/UNASSIGNED:We identified 729 886 patients, 2703 (0.3%) of whom developed POS. Dependent functional status (odds ratio [OR]: 4.11, 95% confidence interval [95% CI]: 3.60-4.69), history of stroke (OR: 2.35, 95%CI: 2.06-2.69) or transient ischemic attack (OR: 2.49 95%CI: 2.19-2.83), active smoking (OR: 1.20, 95%CI: 1.08-1.32), hypertension (OR: 2.11, 95%CI: 2.19-2.82), chronic obstructive pulmonary disease (OR: 1.39 95%CI: 1.21-1.59), and acute renal failure (OR: 2.35, 95%CI: 1.85-2.99) were significantly associated with POS. After adjusting for clustering, patients who underwent cardiac (OR: 11.25, 95%CI: 8.52-14.87), vascular (OR: 4.75, 95%CI: 3.88-5.82), neurological (OR: 4.60, 95%CI: 3.48-6.08), and general surgery (OR: 1.40, 95%CI: 1.15-1.70) had significantly greater odds of POS compared to patients undergoing other types of surgical procedures. Conclusions/UNASSIGNED:Vascular, cardiac, and neurological surgery remained strongly associated with POS in an analysis accounting for the association between patient-level factors and surgical categories.

OBJECTIVE:To assay EEG signal quality recorded with tripolar concentric ring electrodes (TCREs) compared to regular EEG electrodes. METHODS:EEG segments were recorded simultaneously by TCREs and regular electrodes, low-pass filtered at 35 Hz (REG35) and 70 Hz (REG70). Clips were rated blindly by nine electroencephalographers for presence or absence of key EEG features, relative to the "gold-standard" of the clinical report. RESULTS:TCRE showed less EMG artifact (F = 15.4, p < 0.0001). Overall quality rankings were not significantly different. Focal slowing was better detected by TCRE and spikes were better detected by regular electrodes. Seizures (n = 85) were detected by TCRE in 64 cases (75.3%), by REG70 in 75 (88.2%) and REG35 in 69 (81.2%) electrodes. TCRE detected 9 (10.6%) seizures not detected by one of the other 2 methods. In contrast, 14 seizures (16.5%) were not detected by TCRE, but were by REG35 electrodes. Each electrode detected interictal spikes when the other did not. CONCLUSIONS:TCRE produced similar overall quality and confidence ratings versus regular electrodes, but less muscle artifact. TCRE recordings detected seizures in 7% of instances where regular electrodes did not. SIGNIFICANCE/CONCLUSIONS:The combination of the two types increased detection of epileptiform events compared to either alone.

OBJECTIVE:Surgical resection of seizure-producing brain tissue is a gold standard treatment for drug-resistant focal epilepsy. However, several patient-specific factors can preclude resective surgery, including a spatially extensive ("regional") seizure-onset zone (SOZ). For such patients, responsive neurostimulation (RNS) represents a potential treatment, but its efficacy has not been investigated in this population. METHODS:We performed a multicenter retrospective cohort study of patients (N = 30) with drug-resistant focal epilepsy and a regional neocortical SOZ delineated by intracranial monitoring who were treated with the RNS System for at least 6 months. RNS System leads were placed at least 1-cm apart over the SOZ, and most patients were treated with a lead-to-lead stimulation pathway. Five patients underwent partial resection of the SOZ concurrent with RNS System implantation. We assessed change in seizure frequency relative to preimplant baseline and evaluated correlation between clinical outcome and stimulation parameters. RESULTS:), but charge density, interlead distance, and duration of treatment were not significantly correlated with outcome. SIGNIFICANCE/CONCLUSIONS:RNS is a feasible and effective treatment in patients with drug-resistant regional neocortical seizures. Prospective studies in larger cohorts are necessary to determine optimal lead configuration and stimulation parameters, although our results suggest that lead-to-lead stimulation and low charge density may be effective in some patients.