Subtypes of type I IFN differentially enhance cytokine expression by suboptimally stimulated CD4(+) T cells.

Human type I interferons (IFNs) include IFN-ß and 12 subtypes of IFN-α. During viral infection, infiltrating memory CD4(+) T cells are exposed to IFNs, but their impact on memory T-cell function is poorly understood. To address this, we pretreated PBMCs with different IFNs for 16 h before stimulation with Staphylococcus aureus enterotoxin B and measured cytokine expression by flow cytometry. IFN-α8 and -α10 most potently enhanced expression of IFN-γ, IL-2, and IL-4. Potency among the subtypes differed most at doses between 10 and 100 U/mL. While enhancement of IL-2 and IL-4 correlated with the time of preincubation with type I IFN, IFN-γ production was enhanced best when IFN-α was added immediately preceding or simultaneously with T-cell stimulation. Comparison of T-cell responses to multiple doses of Staphylococcus aureus enterotoxin B and to peptide libraries from RSV or CMV demonstrated that IFN-α best enhanced cytokine expression when CD4(+) T cells were suboptimally stimulated. We conclude that type I IFNs enhance Th1 and Th2 function with dose dependency and subtype specificity, and best when T-cell stimulation is suboptimal. While type I IFNs may beneficially enhance CD4(+) T-cell memory responses to vaccines or viral pathogens, they may also enhance the function of resident Th2 cells and exacerbate allergic inflammation.

Cerebral sinus thrombosis as an initial symptom of acute promyelocytic leukemia: Case report and literature review.

Background: Cerebral sinus thrombosis as presentation of acute promyelocytic leukemia (AMPL) is exceptional, with only three cases registered in the literature. Case Description: A 24-year-old female patient was transferred to our center after a car accident. The patient had a witnessed generalized seizure while driving. Computerized tomography (CT) demonstrated a temporal intraparenchymal hemorrhage and CT venogram diagnosed a cerebral sinus thrombosis on the left transverse and sigmoid sinus. The patient underwent surgical evacuation of the hematoma and was treated with anticoagulation 48 h after surgery. Pancytopenia alerted of a possible hematological disorder. The patient was subsequently diagnosed with AMPL and treated with arsenic trioxide. The patient had a complete neurological recovery with no postoperative complications. Conclusion: The management of cerebral sinus thrombosis in patients with AMPL remains controversial. The previous reported cases of cerebral sinus thrombosis preceding the diagnosis of AMPL are reviewed and treatment of cerebral sinus thrombosis with anticoagulation in the setting of intraparenchymal hemorrhage and bleeding disorders is also discussed.

Automated intraoperative central sulcus localization and somatotopic mapping using median nerve stimulation.

Objective. Accurate identification of functional cortical regions is essential in neurological resection. The central sulcus (CS) is an important landmark that delineates functional cortical regions. Median nerve stimulation (MNS) is a standard procedure to identify the position of the CS intraoperatively. In this paper, we introduce an automated procedure that uses MNS to rapidly localize the CS and create functional somatotopic maps.Approach. We recorded electrocorticographic signals from 13 patients who underwent MNS in the course of an awake craniotomy. We analyzed these signals to develop an automated procedure that determines the location of the CS and that also produces functional somatotopic maps.Main results. The comparison between our automated method and visual inspection performed by the neurosurgeon shows that our procedure has a high sensitivity (89%) in identifying the CS. Further, we found substantial concordance between the functional somatotopic maps generated by our method and passive functional mapping (92% sensitivity).Significance. Our automated MNS-based method can rapidly localize the CS and create functional somatotopic maps without imposing additional burden on the clinical procedure. With additional development and validation, our method may lead to a diagnostic tool that guides neurosurgeons and reduces postoperative morbidity in patients undergoing resective brain surgery.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Deep Brain Stimulations for Obsessive-Compulsive Disorder: Update of the 2014 Guidelines.

BACKGROUND: In 2020, the Guidelines Task Force conducted another systematic review of the relevant literature on deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) to update the original 2014 guidelines to ensure timeliness and accuracy for clinical practice. OBJECTIVE: To conduct a systematic review of the literature and update the evidence-based guidelines on DBS for OCD. METHODS: The Guidelines Task Force conducted another systematic review of the relevant literature, using the same search terms and strategies as used to search PubMed and Embase for relevant literature. The updated search included studies published between 1966 and December 2019. The same inclusion/exclusion criteria as the original guideline were also applied. Abstracts were reviewed and relevant full-text articles were retrieved and graded. Of 864 articles, 10 were retrieved for full-text review and analysis. Recommendations were updated according to new evidence yielded by this update. RESULTS: Seven studies were included in the original guideline, reporting the use of bilateral DBS as more effective in improving OCD symptoms than sham treatment. An additional 10 studies were included in this update: 1 class II and 9 class III. CONCLUSION: Based on the data published in the literature, the following recommendations can be made: (1) It is recommended that clinicians utilize bilateral subthalamic nucleus DBS over best medical management for the treatment of patients with medically refractory OCD (level I). (2) Clinicians may use bilateral nucleus accumbens or bed nucleus of stria terminalis DBS for the treatment of patients with medically refractory OCD (level II). There is insufficient evidence to make a recommendation for the identification of the most effective target.The full guidelines can be accessed at https://www.cns.org/guidelines/browse-guidelines-detail/deep-brain-stimulation-obsessive-compulsive-disord.

Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain.

OBJECTIVE: The authors' laboratory has previously demonstrated beneficial effects of noninvasive low intensity focused ultrasound (liFUS), targeted at the dorsal root ganglion (DRG), for reducing allodynia in rodent neuropathic pain models. However, in rats the DRG is 5 mm below the skin when approached laterally, while in humans the DRG is typically 5-8 cm deep. Here, using a modified liFUS probe, the authors demonstrated the feasibility of using external liFUS for modulation of antinociceptive responses in neuropathic swine. METHODS: Two cohorts of swine underwent a common peroneal nerve injury (CPNI) to induce neuropathic pain. In the first cohort, pigs (14 kg) were iteratively tested to determine treatment parameters. liFUS penetration to the L5 DRG was verified by using a thermocouple to monitor tissue temperature changes and by measuring nerve conduction velocity (NCV) at the corresponding common peroneal nerve (CPN). Pain behaviors were monitored before and after treatment. DRG was evaluated for tissue damage postmortem. Based on data from the first cohort, a treatment algorithm was developed, parameter predictions were verified, and neuropathic pain was significantly modified in a second cohort of larger swine (20 kg). RESULTS: The authors performed a dose-response curve analysis in 14-kg CPNI swine. Specifically, after confirming that the liFUS probe could reach 5 cm in ex vivo tissue experiments, the authors tested liFUS in 14-kg CPNI swine. The mean ± SEM DRG depth was 3.79 ± 0.09 cm in this initial cohort. The parameters were determined and then extrapolated to larger animals (20 kg), and predictions were verified. Tissue temperature elevations at the treatment site did not exceed 2°C, and the expected increases in the CPN NCV were observed. liFUS treatment eliminated pain guarding in all animals for the duration of follow-up (up to 1 month) and improved allodynia for 5 days postprocedure. No evidence of histological damage was seen using Fluoro-Jade and H&E staining. CONCLUSIONS: The results demonstrate that a 5-cm depth can be reached with external liFUS and alters pain behavior and allodynia in a large-animal model of neuropathic pain.

Development of a common peroneal nerve injury model in domestic swine for the study of translational neuropathic pain treatments.

OBJECTIVE: To date, muscular and bone pain have been studied in domestic swine models, but the only neuropathic pain model described in swine is a mixed neuritis model. Common peroneal nerve injury (CPNI) neuropathic pain models have been utilized in both mice and rats. METHODS: The authors developed a swine surgical CPNI model of neuropathic pain. Behavioral outcomes were validated with von Frey filament testing, thermal sensitivity assessments, and social and motor scoring. Demyelination of the nerve was confirmed through standard histological assessment. The contralateral nerve served as the control. RESULTS: CPNI induced mechanical and thermal allodynia (p < 0.001 [n = 10] and p < 0.05 [n = 4], respectively) and increased pain behavior, i.e., guarding of the painful leg (n = 12). Myelin protein zero (P0) staining revealed demyelination of the ligated nerve upstream of the ligation site. CONCLUSIONS: In a neuropathic pain model in domestic swine, the authors demonstrated that CPNI induces demyelination of the common peroneal nerve, which the authors hypothesize is responsible for the resulting allodynic pain behavior. As the anatomical features of domestic swine resemble those of humans more closely than previously used rat and mouse models, utilizing this swine model, which is to the authors' knowledge the first of its kind, will aid in the translation of experimental treatments to clinical trials.

Postoperative fever workup in pediatric neurosurgery patients.

OBJECTIVE: Fevers are common in the postoperative period, and adult data indicate that workup for an isolated fever is not warranted in the first 4 postoperative days (PODs). Pediatric literature on the subject similarly questions the value of further investigation during the first 2 PODs. The purpose of this study was to determine the incidence of acute fever in the postoperative pediatric neurosurgical population, as well as to assess the utility of performing further workup on these patients. METHODS: A single-institution retrospective study was performed to assess pediatric neurosurgery patients following surgical intervention for the diagnoses of craniosynostosis, Chiari malformation, and brain tumors from 2009 to 2018. Fevers were identified during the first 4 PODs and were defined as a temperature ≥ 38.0°C. The patient charts were queried for urinalysis and urine culture (UA/Ucx), chest radiographs, blood cultures, CSF culture, respiratory viral panel, white blood cell (WBC) count, transfusion history, development of wound infection, and placement of external ventricular drains (EVDs) or lumbar drains. Thirty-day postoperative microbiology results and readmissions were reviewed. Descriptive statistics were performed using logistic regression analysis. RESULTS: Two hundred thirty-five patients were evaluated, and 61% had developed fevers within the first 4 PODs. Thirty-eight (26.6%) of the 143 febrile patients underwent further workup, and those with high fevers (> 39.0°C) were more likely to undergo further evaluation, which most commonly included UA/Ucx (21.7%). Approximately 1% (2/235) of the patients were found to have an infection during the first 4 days, and 8 additional patients developed a complication following the initial 4 days and within the first 30 PODs. The development of infectious complications within the first 4 PODs did not correlate with acute postoperative fevers (p = 0.997), nor did the development of complications within the 30 days following surgery (p = 0.776); however, multiple days of acute postoperative fevers (p = 0.034) and the presence of an EVD (p = 0.001) were associated with the development of infectious complications within 30 days. Acute postoperative fevers were associated with EVD placement (p = 0.038), as well as blood product transfusions and an increased WBC count (p < 0.001). CONCLUSIONS: Isolated fevers manifesting within the first 4 PODs are rarely associated with an infectious etiology. Additional factors should be taken into consideration when deciding to pursue further investigation.

Functional Use of Directional Local Field Potentials in the Subthalamic Nucleus Deep Brain Stimulation.

BACKGROUND: Directional deep brain stimulation (DBS) technology aims to address the limitations, such as stimulation-induced side effects, by delivering selective, focal modulation via segmented contacts. However, DBS programming becomes more complex and time-consuming for clinical feasibility. Local field potentials (LFPs) might serve a functional role in guiding clinical programming. OBJECTIVE: In this pilot study, we investigated the spectral dynamics of directional LFPs in subthalamic nucleus (STN) and their relationship to motor symptoms of Parkinson's disease (PD). METHODS: We recorded intraoperative STN-LFPs from 8-contact leads (Infinity-6172, Abbott Laboratories, Illinois, United States) in 8 PD patients at rest. Directional LFPs were referenced to their common average and time-frequency analysis was computed using a modified Welch periodogram method. The beta band (13-35 Hz) features were extracted and their correlation to preoperative UPDRS-III scores were assessed. RESULTS: Normalized beta power (13-20 Hz) and normalized peak power (13-35 Hz) were found to be higher in anterior direction despite lack of statistical significance (p > 0.05). Results of the Spearman correlation analysis demonstrated positive trends with bradykinesia/rigidity in dorsoanterior direction (r = 0.659, p = 0.087) and with axial scores in the dorsomedial direction (r = 0.812, p = 0.072). CONCLUSION: Given that testing all possible combinations of contact pairs and stimulation parameters is not feasible in a single clinic visit, spatio-spectral LFP dynamics obtained from intraoperative recordings might be used as an initial marker to select optimal contact(s).

Differences in EEG patterns between tonic and high frequency spinal cord stimulation in chronic pain patients.

OBJECTIVE: To investigate the differences in neural patterns between spinal cord stimulation (SCS) waveforms (60-Hz tonic vs 10-KHz high frequency stimulation, HFS) and their correlation to stimulation-induced pain relief. METHODS: We recorded 10-channel electroencephalogram (EEG) in response to stimulation ON and OFF in 9 chronic pain patients (4 women, 5 men) during SCS surgery and examined the intraoperative spatio-spectral EEG features. RESULTS: We discovered stronger relative alpha power in the somatosensory region and higher trend in alpha/theta peak power ratio in frontal cortex with HFS. We also observed a shift in peak frequency from theta to alpha rhythms in HFS as compared to baseline and tonic stimulation, where slower theta activity was maintained. Further, a positive correlation was found between changes in Oswestry disability index (ODI) scores (from preoperative to postoperative) and HFS-induced alpha/theta peak power ratio in frontal and somatosensory regions. CONCLUSIONS: Altogether, our findings suggest that dynamic spectral interactions in theta-alpha band and their spatial distributions might be the first intraoperative neural signatures of pain relief induced by HFS in chronic pain. SIGNIFICANCE: Examining electrophysiological changes intraoperatively has a potential to elucidate response to SCS therapy prior to device selection, reducing the healthcare expenditures associated with failed implants.

A Systematic Review of Deep Brain Stimulation Targets for Obsessive Compulsive Disorder.

BACKGROUND: Obsessive compulsive disorder (OCD) is a complex neuropsychiatric disease characterized by obsessions and compulsions. Deep brain stimulation (DBS) has demonstrated efficacy in improving symptoms in medically refractory patients. Multiple targets have been investigated. OBJECTIVE: To systematically review the current level and quality of evidence supporting OCD-DBS by target region with the goal of establishing a common nomenclature. METHODS: A systematic literature review was performed using the PubMed database and a patient/problem, intervention, comparison, outcome search with the terms "DBS" and "OCD." Of 86 eligible articles that underwent full-text review, 28 were included for review. Articles were excluded if the target was not specified, the focus on nonclinical outcomes, the follow-up period shorter than 3 mo, or the sample size smaller than 3 subjects. Level of evidence was assigned according to the American Association of Neurological Surgeons/Congress of Neurological Surgeons joint guideline committee recommendations. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Selected publications included 9 randomized controlled trials, 1 cohort study, 1 case-control study, 1 cross-sectional study, and 16 case series. Striatal region targets such as the anterior limb of the internal capsule, ventral capsule/ventral striatum, and nucleus accumbens were identified, but stereotactic coordinates were similar despite differing structural names. Only 15 of 28 articles included coordinates. CONCLUSION: The striatal area is the most commonly targeted region for OCD-DBS. We recommend a common nomenclature based on this review. To move the field forward to individualized therapy, active contact location relative to stereotactic coordinates and patient specific anatomical and clinical variances need to be reported.

Pituitary hyperplasia causing complete bitemporal hemianopia with resolution following surgical decompression: case report.

In this report, the authors demonstrated that idiopathic pituitary hyperplasia (PH) can cause complete bitemporal hemianopia and amenorrhea, even in the setting of mild anatomical compression of the optic chiasm and normal pituitary function. Furthermore, complete resolution of symptoms can be achieved with surgical decompression. PH can occur in the setting of pregnancy or end-organ insufficiency, as well as with medications such as oral contraceptives and antipsychotics, or it can be idiopathic. It is often found incidentally, and surgical intervention is usually unnecessary, as the disorder rarely progresses and can be managed by treating the underlying etiology. Here, the authors present the case of a 24-year-old woman with no significant prior medical history, who presented with bitemporal hemianopia and amenorrhea. Imaging revealed an enlarged pituitary gland that was contacting, but not compressing, the optic chiasm, and pituitary hormone tests were all within normal limits. The patient underwent surgical decompression of the sella turcica and exploration of the gland through an endoscopic endonasal transsphenoidal approach. Pathology results demonstrated PH. A postoperative visual field examination revealed complete resolution of the bitemporal hemianopia, and menstruation resumed 3 days later. The patient remains asymptomatic with no hormonal deficits.

Utility of Postoperative Fever Workup After Craniosynostosis Repair.

BACKGROUND: Craniosynostosis is the premature fusion of ≥1 cranial sutures. Surgical management involves early cranial vault reconstruction. Postoperative management of these patients is often complicated by fever of unknown origin and results in additional laboratory studies, extended hospital intensive care unit stays, and increased cost to the patient. METHODS: A retrospective analysis of 70 consecutive patients who underwent cranial vault reconstruction were included. Postoperative fever (Tmax), length of stay, transfusions, estimated blood loss, and white blood cell counts were obtained, as well as blood, urine, and other culture data. RESULTS: Mean age at surgery was 1.1 years. Sixty (86%) patients had idiopathic postoperative fevers >38°C. Of those, 20% underwent fever workups, none of which returned a positive culture or concern for pneumonia. Length of stay was significantly increased in patients who had fever workups (6.1 days vs. 4.7, P < 0.001). There was no significant difference in age, estimated blood loss, Tmax, white blood cell count, and day of postoperative fever between groups. The average estimated cost of a fever workup at our institution is $1288 (U.S. dollars). CONCLUSIONS: Fever of unknown origin is a common finding after craniosynostosis repair. Workup for fever of unknown did not result in the identification of an infection and added significantly to the cost and patient's length of stay.

The shh signaling pathway is upregulated in multiple cell types in cortical ischemia and influences the outcome of stroke in an animal model.

Recently the sonic hedgehog (shh) signaling pathway has been shown to play an important role in regulating repair and regenerative responses after brain injury, including ischemia. However, the precise cellular components that express and upregulate the shh gene and the cellular components that respond to shh signaling remain to be identified. In this study, using a distal MCA occlusion model, our data show that the shh signal is upregulated both at the cortical area near the injury site and in the adjacent striatum. Multiple cell types upregulate shh signaling in ischemic brain, including neurons, reactive astrocytes and nestin-expressing cells. The shh signaling pathway genes are also expressed in the neural stem cells (NSCs) niche in the subventricular zone (SVZ). Conditional deletion of the shh gene in nestin-expressing cells both at the SVZ niche and at the ischemic site lead to significantly more severe behavioral deficits in these shh iKO mice after cortical stroke, measured using an automated open field locomotion apparatus (Student's t-test, p<0.05). In contrast, animals given post-stroke treatment with the shh signaling agonist (SAG) demonstrated less deficits in behavioral function, compared to vehicle-treated mice. At 7 days after stroke, SAG-treated mice showed higher values in multiple horizontal movement parameters compared to vehicle treated mice (Student's t-test, p<0.05) whereas there were no differences in pre-stroke measurements, (Student's t-test, p>0.05). In summary, our data demonstrate that shh signaling plays critical and ongoing roles in response to ischemic injury and modulation of shh signaling in vivo alters the functional outcome after cortical ischemic injury.

All-cause mortality and obstructive sleep apnea severity revisited.

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is a pervasive problem that affects millions worldwide. It is strongly linked to hypertension, coronary artery disease, and stroke. However, its association with mortality is not clearly quantified. A large database of patients who underwent sleep testing was explored for associations with all-cause mortality. STUDY DESIGN: Database study. SETTING: Community-based use of a portable sleep study device. SUBJECTS AND METHODS: More than 77,000 patients who underwent a validated, portable sleep study were matched to the Social Security Death File to establish mortality. Measures of OSAS severity and other confounding factors were correlated to all-cause mortality using survival analysis with multivariate Cox proportional hazards regression. RESULTS: As expected, increasing age (adjusted hazard ratio [HR], 1.080; 95% confidence interval [CI], 1.074-1.086; P < .0001), body mass index (HR, 1.042; 95% CI, 1.033-1.051; P < .0001), and male sex (HR, 1.378; 95% CI, 1.190-1.595; P < .001) were associated with increased all-cause mortality. Epworth sleepiness score was also associated with mortality (HR, 1.015; 95% CI, 1.005-1.025; P = .002). Apnea-hypopnea index (AHI) was not associated with mortality after adjustment for age (HR, 1.001; 95% CI, 0.998-1.004; P = .416). However, within 10-year age subgroups, desaturation index (ages 41-50 years; adjusted HR, 1.217; 95% CI, 1.014-1.461; P = .035), apnea index (ages 21-30 years; HR, 1.632; 95% CI, 1.053-2.532; P = .028), and AHI (ages 31-40 years; HR, 1.222; 95% CI, 1.010-1.478; P = .039) were significantly associated with all-cause mortality in younger patients. In patients older than 50 years, age, sex, and body mass index were dominantly associated with mortality. CONCLUSION: Increasing OSAS severity, measured by a validated home sleep test and quantified by AHI, the apnea index, and the desaturation index, is independently associated with modestly increased all-cause mortality in patients younger than 50 years after adjustment for major confounding factors.

An epidemiologic study of snoring and all-cause mortality.

OBJECTIVE: Snoring is a common problem that is often associated with obstructive sleep apnea syndrome (OSAS). However, it is suggested that snoring may itself be harmful. Patients with objectively measured snoring were matched against a mortality database and associations were explored. STUDY DESIGN: Database study. SETTING: Community-based use of a portable sleep study device. SUBJECTS AND METHODS: More than 77,000 patients who underwent a portable sleep study (SNAP Test, SNAP Labs Inc, Wheeling, Illinois) with a detailed, acoustical snoring analysis were matched to the Social Security Death Master File to establish mortality (1653 deaths matched). Snoring indices to include amount (snoring events per hour), volume (dB), and palatal versus nonpalatal snoring were correlated to mortality using stepwise multivariate logistic regression and survival analysis. RESULTS: As expected, increasing age (odds ratio [OR] = 1.84; 95% confidence interval [CI], 1.76-1.93; P < .001), body mass index (BMI) (OR = 1.23; 95% CI, 1.18-1.28; P < .001), and male sex (OR = 1.38; 95% CI, 1.2-1.56; P < .001) were associated with increased all-cause mortality. The presence of increasing OSAS confounded the relationship between snoring and mortality. For patients without OSAS (apnea­hypopnea index [AHI] < 5) and with a BMI < 30 (n = 5955), increasing snoring was associated with an age- and sex-adjusted increase in mortality (OR = 1.16; 95% CI, 1.01-1.32; P = .034). For all patients, increasing nonpalatal snoring was associated with an increase in mortality (OR = 1.21; 95% CI, 1.09-1.35; P < .001) after adjustment for age, sex, BMI, and AHI. Survival analysis produced identical results to logistic regression. CONCLUSION: In patients without OSAS and with a BMI less than 30, increasing snoring was associated with a significant increase in all-cause mortality. Nonpalatal snoring is associated with an increase in observed all-cause mortality controlling for age, sex, BMI, and AHI.