Phantom limb pain, traumatic neuroma, or nerve sheath tumor? Illustrative case.

BACKGROUND: Phantom limb pain and traumatic neuromas are not commonly seen in neurosurgical practice. These conditions can present with similar symptoms; however, management of traumatic neuroma is often surgical, whereas phantom limb pain is treated with conservative measures. OBSERVATIONS: A 77-year-old female patient with a long-standing history of an above-the-knee amputation experienced severe pain in her right posterior buttocks area for several years' duration, attributed to phantom limb pain, which radiated down the stump of her leg and was treated with a variety of conservative measures. A recent exacerbation of her pain led to a prolonged hospitalization with magnetic resonance imaging of her leg stump, revealing a mass in the sciatic notch, at a relative distance from the stump. The anatomical location of the mass on the sciatic nerve in the notch led to a presumed radiological diagnosis of nerve sheath tumor, for which she underwent excision. At surgery, a neuroma of the proximal portion of the transected sciatic nerve that had retracted from the amputated stump to the notch was diagnosed. LESSONS: Traumatic neuromas of transected major nerves after limb amputation should be considered in the differential diagnosis of phantom limb pain.

Anticoagulation for the treatment of septic cerebral venous sinus thrombosis in the setting of pediatric sinogenic and otogenic intracranial infections.

OBJECTIVE: Septic cerebral venous sinus thrombosis (CVST) is a recognized complication of pediatric sinogenic and otogenic intracranial infections. The optimal treatment paradigm remains controversial. Proponents of anticoagulation highlight its role in preventing thrombus propagation and promoting recanalization, while others cite the risk of hemorrhagic complications, especially after a neurosurgical procedure for an epidural abscess or subdural empyema. Here, the authors investigated the diagnosis, management, and outcomes of pediatric patients with sinogenic or otogenic intracranial infections and a septic CVST. METHODS: All patients 21 years of age or younger, who presented with an intracranial infection in the setting of sinusitis or otitis media and who underwent neurosurgical treatment at Connecticut Children's, Rady Children's Hospital-San Diego, or Ann and Robert H. Lurie Children's Hospital of Chicago from March 2015 to March 2023, were retrospectively reviewed. Demographic, clinical, and radiological data were systematically collated. RESULTS: Ninety-six patients were treated for sinusitis-related and/or otitis media-related intracranial infections during the study period, 15 (15.6%) of whom were diagnosed with a CVST. Of the 60 patients who presented prior to the COVID-19 pandemic, 6 (10.0%) were diagnosed with a septic CVST, whereas of the 36 who presented during the COVID-19 pandemic, 9 (25.0%) had a septic CVST (p = 0.050). The superior sagittal sinus was involved in 12 (80.0%) patients and the transverse and/or sigmoid sinuses in 4 (26.7%). Only 1 (6.7%) patient had a fully occlusive thrombus. Of the 15 patients with a septic CVST, 11 (73.3%) were initiated on anticoagulation at a median interval of 4 (IQR 3-5) days from the most recent neurosurgical procedure. Five (45.5%) patients who underwent anticoagulation demonstrated complete recanalization on follow-up imaging, and 4 (36.4%) had partial recanalization. Three (75.0%) patients who did not undergo anticoagulation demonstrated complete recanalization, and 1 (25.0%) had partial recanalization. None of the patients treated with anticoagulation experienced hemorrhagic complications. CONCLUSIONS: Septic CVST is frequently identified among pediatric patients undergoing neurosurgical intervention for sinogenic and/or otogenic intracranial infections and may have become more prevalent during the COVID-19 pandemic. Anticoagulation can be used safely in the acute postoperative period if administered cautiously, in a monitored setting, and with interval cross-sectional imaging. However, some patients exhibit excellent outcomes without anticoagulation, and further studies are needed to identify those who may benefit the most from anticoagulation.

Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep-wake Disturbances in AD Mice.

Alzheimer's disease (AD) increases the risk for seizures and sleep disorders. We show here that germline deletion of ß-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) in neurons, but not in astrocytes, increased epileptiform activity. However, Bace1 deletion at adult ages did not alter the normal EEG waveform, indicating less concern for BACE1 inhibition in patients. Moreover, we showed that deletion of Bace1 in the adult was able to reverse epileptiform activity in 5xFAD mice. Intriguingly, treating 5xFAD and APPNL-G-F/NL-G-F (APP KI) mice of either sex with one BACE1 inhibitor Lanabecestat (AZD3293) dramatically increased epileptiform spiking, likely resulting from an off-target effect. We also monitored sleep-wake pathologies in these mice and showed increased wakefulness, decreased non-rapid eye movement sleep, and rapid eye movement sleep in both 5xFAD and APP KI mice; BACE1 inhibition in the adult 5xFAD mice reversed plaque load and sleep disturbances, but this was not seen in APP KI mice. Further studies with and without BACE1 inhibitor treatment showed different levels of plaque-associated microgliosis and activated microglial proteins in 5xFAD mice compared with APP KI mice. Together, BACE1 inhibition should be developed to avoid off-target effect for achieving benefits in reducing epileptic activity and sleep disturbance in Alzheimer's patients.SIGNIFICANCE STATEMENT BACE1 is widely recognized as a therapeutic target for treating Alzheimer's disease patients. However, BACE1 inhibitors failed in clinical trials because of inability to show cognitive improvement in patients. Here we show that BACE1 inhibition actually reduces sleep disturbances and epileptic seizures; both are seen in AD patients. We further showed that one of clinically tested BACE1 inhibitors does have off-target effects, and development of safer BACE1 inhibitors will be beneficial to AD patients. Results from this study will provide useful guidance for additional drug development.

Beyond acute concussion assessment to office management: a systematic review informing the development of a Sport Concussion Office Assessment Tool (SCOAT6) for adults and children.

OBJECTIVES: To systematically review the scientific literature regarding the assessment of sport-related concussion (SRC) in the subacute phase (3-30 days) and provide recommendations for developing a Sport Concussion Office Assessment Tool (SCOAT6). DATA SOURCES: MEDLINE, Embase, PsycINFO, Cochrane CENTRAL, CINAHL, SPORTDiscus and Web of Science searched from 2001 to 2022. Data extracted included study design, population, definition of SRC diagnosis, outcome measure(s) and results. ELIGIBILITY CRITERIA: (1) Original research, cohort studies, case-control studies, diagnostic accuracy and case series with samples >10; (2) SRC; (3) screening/technology that assessed SRC in the subacute period and (4) low risk of bias (ROB). ROB was performed using adapted Scottish Intercollegiate Guidelines Network criteria. Quality of evidence was evaluated using the Strength of Recommendation Taxonomy classification. RESULTS: Of 9913 studies screened, 127 met inclusion, assessing 12 overlapping domains. Results were summarised narratively. Studies of acceptable (81) or high (2) quality were used to inform the SCOAT6, finding sufficient evidence for including the assessment of autonomic function, dual gait, vestibular ocular motor screening (VOMS) and mental health screening. CONCLUSION: Current SRC tools have limited utility beyond 72 hours. Incorporation of a multimodal clinical assessment in the subacute phase of SRC may include symptom evaluation, orthostatic hypotension screen, verbal neurocognitive tests, cervical spine evaluation, neurological screen, Modified Balance Error Scoring System, single/dual task tandem gait, modified VOMS and provocative exercise tests. Screens for sleep disturbance, anxiety and depression are recommended. Studies to evaluate the psychometric properties, clinical feasibility in different environments and time frames are needed. PROSPERO REGISTRATION NUMBER: CRD42020154787.

Changes in the epidemiology of pediatric sinogenic and otogenic intracranial infections during the COVID-19 pandemic: a single-institution study.

OBJECTIVE: Focal intracranial infections (epidural abscesses, subdural empyemas, and intraparenchymal abscesses) are uncommon complications of sinusitis and otitis media but can be associated with significant morbidity. Treatment typically requires neurosurgical and otolaryngological interventions in combination with antibiotic treatment. Historically, children have presented to the authors' pediatric referral center with sinusitis- or otitis media-related intracranial infections in low numbers. However, since the onset of the COVID-19 pandemic, the incidence of intracranial pyogenic complications has increased at this center. The objective of this study was to compare the epidemiology, severity, microbial causes, and management of pediatric sinusitis- and otitis-related intracranial infections in the periods before and during the COVID-19 pandemic. METHODS: All patients 21 years of age or younger who presented with an intracranial infection in the setting of sinusitis or otitis media and who underwent neurosurgical treatment at Connecticut Children's from January 2012 to December 2022 were retrospectively reviewed. Demographic, clinical, laboratory, and radiological data were systematically collated, and variables before and during COVID-19 were compared statistically. RESULTS: Overall, 18 patients were treated for sinusitis-related (n = 16) or otitis media-related (n = 2) intracranial infections during the study period. Ten patients (56%) presented from January 2012 to February 2020, none from March 2020 to June 2021, and 8 (44%) from July 2021 to December 2022. There were no significant demographic differences between the pre-COVID-19 and COVID-19 cohorts. The 10 patients in the pre-COVID-19 cohort underwent a total of 15 neurosurgical and 10 otolaryngological procedures, while the 8 patients in the COVID-19 cohort underwent a total of 12 neurosurgical and 10 otolaryngological procedures. Surgically obtained wound cultures yielded a variety of organisms; Streptococcus constellatus/S. anginosus/S. intermedius were more prevalent in the COVID-19 cohort (87.5% vs 0%, p < 0.001) as was Parvimonas micra (62.5% vs 0%, p = 0.007). CONCLUSIONS: At an institutional level, there has been an approximately threefold increase in cases of sinusitis- and otitis media-related intracranial infections during the COVID-19 pandemic. Multicenter studies are needed to confirm this observation and to investigate whether the mechanisms of infection are related directly to SARS-CoV-2, changes in the respiratory flora, or delayed care. The next steps will include expansion of this study to other pediatric centers throughout the United States and Canada.

Observable player behaviours and playing performance following helmet strikes in elite cricket.

OBJECTIVES: Investigate the observable player behaviours and features of both concussive (HS-C) and non-concussive (HS-NC) helmet strikes and describe their impact on playing performance. METHODS: Elite male cricketers sustaining helmet strikes between the 2016 and 2018 seasons were identified by the England and Wales Cricket Board. Medical records identified players sustaining a concussion and those in whom concussion was excluded. Retrospective cohort analysis was performed on batting and bowling performance data available for these players in the 2 years prior to and 3 months post helmet strike. Video analysis of available incidents was conducted to describe the characteristics of the helmet strike and subsequent observable player behaviours. The HS-C and HS-NC cohorts were compared. RESULTS: Data were available for 194 helmet strikes. 56 (29%) resulted in concussion. No significant differences were seen in playing performance in the 3 months post concussive helmet strike. However, a significant decline in batting performance was seen in this period in the HS-NC group (p<0.001).Video features signifying motor incoordination were most useful in identifying concussion post helmet strike, however, typical features suggesting transient loss of consciousness were not seen. Features such as a longer duration pause prior to the batsman resuming play and the level of concern shown by other players were also useful features. CONCLUSION: HS-NC may be more significant for player performance than previously thought. Guidance for using video replay to identify concussion in cricket may need to be modified when compared with other field sports.

Unique diagnostic signatures of concussion in the saliva of male athletes: the Study of Concussion in Rugby Union through MicroRNAs (SCRUM).

OBJECTIVE: To investigate the role of salivary small non-coding RNAs (sncRNAs) in the diagnosis of sport-related concussion. METHODS: Saliva was obtained from male professional players in the top two tiers of England's elite rugby union competition across two seasons (2017-2019). Samples were collected preseason from 1028 players, and during standardised head injury assessments (HIAs) at three time points (in-game, post-game, and 36-48 hours post-game) from 156 of these. Samples were also collected from controls (102 uninjured players and 66 players sustaining a musculoskeletal injury). Diagnostic sncRNAs were identified with next generation sequencing and validated using quantitative PCR in 702 samples. A predictive logistic regression model was built on 2017-2018 data (training dataset) and prospectively validated the following season (test dataset). RESULTS: The HIA process confirmed concussion in 106 players (HIA+) and excluded this in 50 (HIA-). 32 sncRNAs were significantly differentially expressed across these two groups, with let-7f-5p showing the highest area under the curve (AUC) at 36-48 hours. Additionally, a combined panel of 14 sncRNAs (let-7a-5p, miR-143-3p, miR-103a-3p, miR-34b-3p, RNU6-7, RNU6-45, Snora57, snoU13.120, tRNA18Arg-CCT, U6-168, U6-428, U6-1249, Uco22cjg1,YRNA_255) could differentiate concussed subjects from all other groups, including players who were HIA- and controls, immediately after the game (AUC 0.91, 95% CI 0.81 to 1) and 36-48 hours later (AUC 0.94, 95% CI 0.86 to 1). When prospectively tested, the panel confirmed high predictive accuracy (AUC 0.96, 95% CI 0.92 to 1 post-game and AUC 0.93, 95% CI 0.86 to 1 at 36-48 hours). CONCLUSIONS: SCRUM, a large prospective observational study of non-invasive concussion biomarkers, has identified unique signatures of concussion in saliva of male athletes diagnosed with concussion.

Tomographic Task-Related Functional Near-Infrared Spectroscopy in Acute Sport-Related Concussion: An Observational Case Study.

Making decisions regarding return-to-play after sport-related concussion (SRC) based on resolution of symptoms alone can expose contact-sport athletes to further injury before their recovery is complete. Task-related functional near-infrared spectroscopy (fNIRS) could be used to scan for abnormalities in the brain activation patterns of SRC athletes and help clinicians to manage their return-to-play. This study aims to show a proof of concept of mapping brain activation, using tomographic task-related fNIRS, as part of the clinical assessment of acute SRC patients. A high-density frequency-domain optical device was used to scan 2 SRC patients, within 72 h from injury, during the execution of 3 neurocognitive tests used in clinical practice. The optical data were resolved into a tomographic reconstruction of the brain functional activation pattern, using diffuse optical tomography. Moreover, brain activity was inferred using single-subject statistical analyses. The advantages and limitations of the introduction of this optical technique into the clinical assessment of acute SRC patients are discussed.

Machine Learning Classifiers for Twitter Surveillance of Vaping: Comparative Machine Learning Study.

BACKGROUND: Twitter presents a valuable and relevant social media platform to study the prevalence of information and sentiment on vaping that may be useful for public health surveillance. Machine learning classifiers that identify vaping-relevant tweets and characterize sentiments in them can underpin a Twitter-based vaping surveillance system. Compared with traditional machine learning classifiers that are reliant on annotations that are expensive to obtain, deep learning classifiers offer the advantage of requiring fewer annotated tweets by leveraging the large numbers of readily available unannotated tweets. OBJECTIVE: This study aims to derive and evaluate traditional and deep learning classifiers that can identify tweets relevant to vaping, tweets of a commercial nature, and tweets with provape sentiments. METHODS: We continuously collected tweets that matched vaping-related keywords over 2 months from August 2018 to October 2018. From this data set of tweets, a set of 4000 tweets was selected, and each tweet was manually annotated for relevance (vape relevant or not), commercial nature (commercial or not), and sentiment (provape or not). Using the annotated data, we derived traditional classifiers that included logistic regression, random forest, linear support vector machine, and multinomial naive Bayes. In addition, using the annotated data set and a larger unannotated data set of tweets, we derived deep learning classifiers that included a convolutional neural network (CNN), long short-term memory (LSTM) network, LSTM-CNN network, and bidirectional LSTM (BiLSTM) network. The unannotated tweet data were used to derive word vectors that deep learning classifiers can leverage to improve performance. RESULTS: LSTM-CNN performed the best with the highest area under the receiver operating characteristic curve (AUC) of 0.96 (95% CI 0.93-0.98) for relevance, all deep learning classifiers including LSTM-CNN performed better than the traditional classifiers with an AUC of 0.99 (95% CI 0.98-0.99) for distinguishing commercial from noncommercial tweets, and BiLSTM performed the best with an AUC of 0.83 (95% CI 0.78-0.89) for provape sentiment. Overall, LSTM-CNN performed the best across all 3 classification tasks. CONCLUSIONS: We derived and evaluated traditional machine learning and deep learning classifiers to identify vaping-related relevant, commercial, and provape tweets. Overall, deep learning classifiers such as LSTM-CNN had superior performance and had the added advantage of requiring no preprocessing. The performance of these classifiers supports the development of a vaping surveillance system.

Integrating physical activity promotion into UK medical school curricula: testing the feasibility of an educational tool developed by the Faculty of Sports and Exercise Medicine.

BACKGROUND: At present education on exercise medicine and physical activity (PA) promotion does not feature heavily within the medical curriculum. OBJECTIVES: The purpose of this study was to test the feasibility of a self-directed educational tool (Faculty of Sports and Exercise Medicine (FSEM) exercise prescription booklet) on medical students' understanding of PA in disease management. METHODS: Students from 22 UK medical schools were invited to complete a brief online questionnaire before and after being provided access to the FSEM exercise prescription booklet. RESULTS: A total of 205 students responded to the open invitation to participate. At baseline 59% of students agreed that PA promotion was an important part of a doctor's job with 86% agreeing that PA was important in the prevention of disease. However, confidence to prescribe PA and knowledge of chief medical officer's adult PA guidelines was low. Following use of the FSEM booklet students' (n=53) knowledge of PA guidelines and confidence to advise patients about PA significantly improved (p<0.05). Correct response answers to case scenarios covering PA in disease management (specifically osteoarthritis and cancer) also improved (32% and 44% increase, respectively, p<0.01). CONCLUSION: Self-guided educational tools have the potential to improve the exercise prescription skills of undergraduate medical students. Future research should compare different methods of delivering education on PA within medical schools to determine the most effective means of integrating PA into the curriculum.

Study of Concussion in Rugby Union through MicroRNAs (SCRUM): a study protocol of a prospective, observational cohort study.

INTRODUCTION: The diagnosis of mild traumatic brain injury or sports-related concussion is a challenge for all clinicians, players, coaches and parents involved in contact sports. Currently, there is no validated objective biomarker available to assess the presence or severity of concussion in sport, and so it is necessary to rely on subjective measures like self-reporting of symptoms which depend on the cooperation of the athlete. There is a significant health risk associated with repetitive injury if the diagnosis is missed, and so there is great value in an objective biomarker to assist diagnostic and prognostic decisions. OBJECTIVE: To establish a panel of non-invasive MicroRNA biomarkers in urine and saliva for the rapid diagnosis of sports-related concussion and investigate the kinetics and clinical utility of these biomarkers in assisting diagnostic, prognostic and return-to-play decisions. METHODS AND ANALYSIS: Observational, prospective, multicentre cohort study recruiting between the 2017-2018 and 2018-2019 Rugby Union seasons. Professional rugby players in the two highest tiers of senior professional domestic rugby competition in England will be recruited prospectively to the study. During the season, three groups will be identified: athletes entering the World Rugby Head Injury Assessment (HIA) protocol, uninjured control athletes and control athletes with musculoskeletal injuries. Saliva and urine will be collected from these athletes at multiple timepoints, coinciding with key times in the HIA protocol and return-to-play process. ETHICS AND DISSEMINATION: Ethics approval has been obtained. The compiled and analysed results will be presented at national and international conferences concerning the care of patients with traumatic brain injury. Results will also be submitted for peer review and publication in the subject journals/literature.

Runners with patellofemoral pain have altered biomechanics which targeted interventions can modify: A systematic review and meta-analysis.

Patellofemoral pain (PFP) is the most prevalent running pathology and associated with multi-level biomechanical factors. This systematic review aims to guide treatment and prevention of PFP by synthesising prospective, observational and intervention studies that measure clinical and biomechanical outcomes in symptomatic running populations. Medline, Web of Science and CINAHL were searched from inception to April 2015 for prospective, case-control or intervention studies in running-related PFP cohorts. Study methodological quality was scored by two independent raters using the modified Downs and Black or PEDro scales, with meta-analysis performed where appropriate. 28 studies were included. Very limited evidence indicates that increased peak hip adduction is a risk factor for PFP in female runners, supported by moderate evidence of a relationship between PFP and increased peak hip adduction, internal rotation and contralateral pelvic drop, as well as reduced peak hip flexion. Limited evidence was also identified that altered peak force and time to peak at foot level is a risk factor for PFP development. Limited evidence from intervention studies indicates that both running retraining and proximal strengthening exercise lead to favourable outcomes in both pain and function, but only running retraining significantly reduces peak hip adduction, suggesting a possible kinematic mechanism. Put together, these findings highlight limited but coherent evidence of altered biomechanics which interventions can alter with resultant symptom change in females with PFP. There is a clear need for high quality prospective studies of intervention efficacy with measurement of explanatory mechanisms.

Extra-corporeal pulsed-activated therapy ("EPAT" sound wave) for Achilles tendinopathy: a prospective study.

Achilles tendinopathy is common and extracorporeal shockwaves have become a popular treatment for this condition, even though previous research has not provided conclusive results regarding its efficacy in cases of Achilles tendinopathy. Our aim was to evaluate 3 weekly shockwave treatments in patients with Achilles tendinopathy, as quantified by the Roles and Maudsley score. A total of 74 tendons in 60 patients were assessed at baseline and at least 1 year posttreatment, including 32 (43.24%) paratendinoses, 23 (31.08%) proximal tendinoses, and 19 (25.68%) insertional tendinoses. The mean age of the participants was 48.6 ± 12.94 years, and patients with paratendinosis (41.44 ± 14.01 years) were statistically significantly younger than those with proximal (53 ± 8.9 years) and insertional (54.26 ± 9.74 years) tendinopathy, and these differences were statistically significant (P = .0012 and P = .0063, respectively). Overall, 58 (78.38%) tendons improved by at least 1 year posttreatment, including 75% in the paratendinosis, 78.26% in the proximal tendinosis, and 84.21% in the insertional tendinosis groups, and no adverse effects were observed. The Roles and Maudsley score improved from 3.22 ± 0.55 to 1.84 ± 1.05 (P < .0001) in the paratendinosis group, 3.39 ± 0.5 to 1.57 ± 0.66 (P < .0001) in the proximal tendinopathy group, and 3.32 ± 0.58 to 1.47 ± 0.7 (P = .0001) in the insertional tendinopathy group. Based on these results, we believe that shockwave therapy serves as a safe, viable, and effective option for the treatment of Achilles tendinopathy.