Prophylactic Radiotherapy Of MInimally Symptomatic Spinal Disease (PROMISSeD): study protocol for a randomized controlled trial.

BACKGROUND: Early palliative/pre-emptive intervention improves clinical outcomes and quality of life for patients with metastatic cancer. A previous signal-seeking randomized controlled trial (RCT) demonstrated that early upfront radiotherapy to asymptomatic or minimally symptomatic high-risk osseous metastases led to reduction in skeletal-related events (SREs), a benefit driven primarily by subgroup of high-risk spine metastasis. The current RCT aims to determine whether early palliative/pre-emptive radiotherapy in patients with high-risk, asymptomatic or minimally symptomatic spine metastases will lead to fewer SREs within 1 year. METHODS: This is a single-center, parallel-arm, in-progress RCT in adults (≥ 18 years) with ECOG performance status 0-2 and asymptomatic or minimally symptomatic (not requiring opioids) high-risk spine metastases from histologically confirmed solid tumor malignancies with > 5 sites of metastatic disease on cross-sectional imaging. High-risk spine metastases are defined by the following: (a) bulkiest disease sites ≥ 2 cm; (b) junctional disease (occiput to C2, C7-T1, T12-L2, L5-S1); (c) posterior element involvement; or (d) vertebral body compression deformity > 50%. Patients are randomized 1:1 to receive either standard-of-care systemic therapy (arm 1) or upfront, early radiotherapy to ≤ 5 high-risk spine lesions plus standard-of-care systemic therapy (arm 2), in the form of 20-30 Gy of radiation in 2-10 fractions. The primary endpoint is SRE, a composite outcome including spinal fracture, spinal cord compression, need for palliative radiotherapy, interventional procedures, or spinal surgery. Secondary endpoints include (1) surrogates of health care cost, including the number and duration of SRE-related hospitalizations; (2) overall survival; (3) pain-free survival; and (4) quality of life. Study instruments will be captured pre-treatment, at baseline, during treatment, and at 1, 3, 6, 12, and 24 months post-treatment. The trial aims to accrue 74 patients over 2 years to achieve > 80% power in detecting difference using two-sample proportion test with alpha < 0.05. DISCUSSION: The results of this RCT will demonstrate the value, if any, of early radiotherapy for high-risk spine metastases. The trial has received IRB approval, funding, and prospective registration (NCT05534321) and has been open to accrual since August 19, 2022. If positive, the trial will expand the scope and utility of spine radiotherapy. TRIAL REGISTRATION: ClinicalTrials.Gov NCT05534321 . Registered September 9, 2022. TRIAL STATUS: Version 2.0 of the protocol (2021-KOT-002), revised last on September 2, 2022, was approved by the WCG institutional review board (Study Number 1337188, IRB tracking number 20223735). The trial was first posted on ClinicalTrials.Gov on September 9, 2022 (NCT05534321). Patient enrollment commenced on August 19, 2022, and is expected to be completed in 2 years, likely by August 2024.

The Vagus Nerve Somatosensory-evoked Potential in Neural Disorders: Systematic Review and Illustrative Vignettes.

Objective. To review the scientific publications reporting vagal nerve somatosensory-evoked potential (VSEP) findings from individuals with brain disorders, and present novel physiological explanations on the VSEP origin. Methods. We did a systematic review on the papers reporting VSEP findings from individuals with brain disorders and their controls. We evaluated papers published from 2003 to date indexed in PubMed, Web of Science, and Scielo databases. We extracted the following information: number of patients and controls, type of neural disorder, age, gender, stimulating/recording and grounding electrodes as well as stimulus side, intensity, duration, frequency, and polarity. Information about physiological parameters, neurobiological variables, and correlation studies was also reviewed. Representative vignettes were included to add support to our conclusions. Results. The VSEP was studied in 297 patients with neural disorders such as Parkinson's disease (PD), Alzheimer's disease, vascular dementia, mild cognitive impairment, subjective memory impairment, major depression, and multiple sclerosis. Scalp responses marked as the VSEP showed high variability, low validity, and poor reproducibility. VSEP latencies and amplitudes did not correlate with disease duration, unified PD rating scale score, or heart function in PD patients nor with cerebrospinal fluid ß amyloid, phosphor-τ, and cognitive tests from patients with mental disorders. Vignettes demonstrated that the VSEP was volume conduction propagating from muscles surrounding the scalp recording electrodes. Conclusion. The VSEP is not a brain-evoked potential of neural origin but muscle activity induced by electrical stimulation of the tragus region of the ear. This review and illustrative vignettes argue against assessing the parasympathetic system using the so-called VSEP.

Combined Presigmoid-Subtemporal Approach in a Semi-Sitting Position for Petroclival Meningiomas: A Technical Report.

The removal of petroclival meningiomas (PMs) is considered a neurosurgical challenge due to the critical mobilization of key neurovascular structures. Limited knowledge about the benefits of operating on patients with PMs using the combined presigmoid-subtemporal approach (CPSA) in a semi-sitting position has precluded its generalizability. We report on ten patients with PMs operated in a semi-sitting position using CPSA. We remark that before the surgical approach was accomplished in our group of patients, the CPSA via semi-sitting position was conducted and standardized in six adult cadaveric heads. The neuroanatomic dissections made in cadavers allowed us to confidently use CPSA in our set of patients. There were no comorbidities, perioperative complications, or deaths associated with the surgical procedure. CPSA via a semi-sitting position can be considered a safe approach to remove PMs.

The vagus nerve somatosensory evoked potential in the intact brain: state-of-evidence and some representative vignettes.

OBJECTIVE: Scalp-recorded evoked potentials elicited by applying afferent electrical stimulation at the tragus region of the human external ear have shown inconsistent results. We aim to disentangle discrepant findings and interpretations, and put forward novel physiological explanations on the origin of the vagus nerve somatosensory evoked potentials (VSEP). METHODS: We systematically search and critically appraise in PubMed, Web of Science, and Scielo databases the scientific reports publishing VSEP findings elicited by afferent electrical stimulation at the tragus region from individuals without brain disorders. Eligible studies published from January 2000 to April 2020 were extracted. The following information was identified from each article: number of participants; age; gender; stimulating/recording and grounding electrodes as well as stimulus side, intensity, duration, frequency, and polarity. Information about physiological parameters and neurobiological variables was also extracted. Representative vignettes with novel scalp responses induced by stimulating the tragus were also included to add support to our conclusions. RESULTS: 140 healthy participants were identified from six selected reports. Mean age ranged from 24.3 to 61.5 years. Stimulating and recording aspects were miscellaneous among studies. Scalp responses marked as the VSEP were recorded in 76% of participants, and showed high variability, low validity and poor reproducibility. Age correlated with response latencies. There were not gender differences in scalp response parameters. Cardiovascular function was unaltered by tragus stimulation. Vignettes showed that the VSEP was scalp muscle responses. CONCLUSION: VSEP did not fulfil evoked potential guidelines. VSEP corresponded to volume conduction propagating from muscles surrounding scalp recording sites.

Territorial and Extraterritorial Trigeminocardiac Reflex: A Review for the Neurosurgeon and a Type IV Reflex Vignette.

The trigeminocardiac reflex (TCR) is a complex and, sometimes, fatal event triggered by overstimulation of the trigeminal nerve (TN) and its territorial and spinal cord branches. We reviewed and compiled for the neurosurgeon key aspects of the TCR that include a novel and straightforward classification, as well as morphophysiology, pathophysiology, neuromonitoring and neuromodulation features. Further, we present intraoperative data from a patient who developed extraterritorial, or type IV, TCR while undergoing a cervical surgery. TCR complexity, severity and unwanted outcomes indicate that this event should not be underestimated or overlooked in the surgical room. Timely TCR recognition in surgical settings is valuable for applying effective intraoperative management to prevent catastrophic outcomes.

Neurophysics Assessment of the Muscle Bioenergy Generated by Transcranial Magnetic Stimulation.

The content of the rectified motor evoked potential (MEP) induced by transcranial magnetic stimulation (TMS) has ambiguously been assessed without the precision that energy calculation deserves. This fact has misled data interpretation and misguided biomedical interventions. To definitively fill the gap that exits in the neurophysics processing of these signals, we computed, in Walls ( W ^ ), the bioenergy within the rectified MEP recorded from the human first digitorum index (FDI) muscle at rest and under isometric contraction. We also gauged the biowork exerted by this muscle. Here we show that bioenergy and biowork can accurately and successfully be assessed, validated, and determined in W ^ from MEP signals induced by TMS, regardless of knowing the mathematical expression of the function of the signal. Our novel neurophysics approach represents a dramatic paradigm shift in analysis and interpretation of the content of the MEP and will give a true meaning to the content of rectified signals. Importantly, this innovative approach allowed unveiling that women exerted more bioenergy than men at the magnetic stimulations used in this study. Revisitation of conclusions drawn from studies published elsewhere assessing rectified EMG signals that have used ambiguous units is strongly recommended.

Smell status in functional movement disorders: New clues for diagnosis and underlying mechanisms.

OBJECTIVE: Functional movement disorders (FMDs) mimic a range of movements, neuropsychiatric and neurodegenerative disorders known to have smell dysfunction, which has been neglected in terms of its application to FMD. We aim to determine the smell status in FMD patients tested by a non-invasive, reliable and validated olfactory test. PATIENTS AND METHODS: We quantitatively assessed in thirty-five FMD patients their smell status and compared it to that of healthy age- and sex-matched controls, and of patients with Parkinson's disease (PD). All participants were administered the Brief Smell Identification Test (B-SIT), a standardized short version of the University of Pennsylvania Smell Identification Test (UPSIT). The Picture Identification Test (PIT), a visual test analogous in content and form to the UPSIT designed to control for non-olfactory cognitive confounds, was also administered. RESULTS: The B-SIT scores of the FMD patients were higher than those from PD patients [respective means (standard deviations: SDs) = FMD, 9.54 (1.57); PD, 4.64 (1.05), p < 0.01)] but similar to the smell scores from healthy controls [9.97 (1.77), p = 0.35]. Gender, age, time of disease onset, smoking status, and phenotypic expression did not influence the test scores. Fourteen FMD patients who mentioned having olfactory dysfunction before smell testing have their test results within normal range. PIT scores from patients and healthy controls were within normal range. CONCLUSIONS: These findings indicate that FMD patients have normal olfactory function. Olfactory testing may be helpful in identifying and differentiating FMD from other movement, neurodegenerative and neuropsychiatric diseases for which smell function is altered.

The Three Nociceptive Responses of the Orbicularis Oculi Reflex in Alzheimer's Disease: State of the Evidence and Meta-analysis.

There is an emerging belief that electrically elicited blink reflexes (BR) may distinguish Alzheimer's disease (AD) from other disorders characterized by memory dysfunction. To qualitatively and quantitatively distinguish the effects that electrical stimulation has over the blink reflex (eBR) recorded from patients with AD and healthy controls (HCs), we did a systematic review of the literature, and conducted a meta-analysis. Following our selected criteria, 94 AD patients and 97 HCs were identified from articles published in English between 1950 and 2017. Although the 3 responses (R1, R2 and R3) of the eBR were studied in a number of patients, only the R2 response was quantified in all studies. Thresholds and stimulation intensities parameters were found to be used in a miscellaneous form, and the majority of times, such parameters deviated from validated guidelines. The stimulation frequencies used to elicit the BR responses ranged between 0.14 and 0.2 Hz. These frequencies favored HCs compared with AD patients (odds ratio = 1.08; 95% CI = 0.30-1.85), I2 = 0% [P = .99]; Q = 271.89 [df = 7, P < .000]). Egger's regression test suggested publication bias (intercept = 32.38; 95% CI = -8.98 to -3.2; P = .001). Our results unveiled key shortcomings in the data reported; such shortcomings need to be corrected in future AD research looking for obtaining more reliable and reproducible eBR studies; otherwise, interventions may be misleading.

Evidences in Neurological Surgery and a Cutting Edge Classification of the Trigeminocardiac Reflex: A Systematic Review.

BACKGROUND: The trigeminocardiac reflex (TCR) is characterized by bradycardia, decrease of mean arterial blood pressure, and sometimes, asystole during surgery. We critically reviewed TCR studies and devised a novel classification scheme for assessing the reflex. METHODS: A comprehensive systematic literature review was performed using PubMed, MEDLINE, Web of Science, EMBASE, and Scielo databases. Eligible studies were extracted based on stringent inclusion and exclusion criteria. Statistical analyses were used to assess cardiovascular variables. TCR was classified according to morphophysiologic aspects involved with reflex elicitation. RESULTS: A total of 575 patients were included in this study. TCR was found in 8.9% of patients. The reflex was more often triggered by interventions made within the anterior cranial fossa. The maxillary branch (type II in the new classification) was the most prevalent nerve branch found to trigger the TCR. Heart rate and mean arterial blood pressure were similarly altered (P = 0.06; F = 0.3912809), covaried with age (P = 0.012; F = 9.302), and inversely correlated to each other (r = -0.27). CONCLUSIONS: TCR is a critical cardiovascular phenomenon that must be quickly identified and efficiently classified and should trigger vigilance. Prompt therapeutic measures during neurosurgical procedures should be carefully addressed to avoid unwanted complications. Accurate categorization using the new classification scheme will help to improve understanding and guide the management of TCR in the perioperative period.

Key Aspects in Foramen Magnum Meningiomas: From Old Neuroanatomical Conceptions to Current Far Lateral Neurosurgical Intervention.

Foramen magnum meningiomas represent a challenge for neurosurgeons. These tumors require careful surgical manipulation as they are often located in proximity to critical neurovascular structures and the cranial nerves. The far lateral approach is considered the safest neurosurgical approach for excising foramen magnum lesions. It facilitates the access to the anterior foramen magnum and reduces the retraction of vital structures. We describe key historical, epidemiological, genetic, epigenetic, clinical, and neurosurgical aspects of foramen magnum meningiomas. We emphasize the far lateral approach for lesions arising in the foramen magnum, as well as the most appropriate patient positioning for such approach. Caring for these aspects will be rewarded with the best perioperative neurosurgical outcomes.

Sensory aspects in myasthenia gravis: A translational approach.

Myasthenia gravis is a paradigmatic muscle disorder characterized by abnormal fatigue and muscle weakness that worsens with activities and improves with rest. Clinical and research studies done on nicotinic acetylcholine receptors have advanced our knowledge of the muscle involvement in myasthenia. Current views still state that sensory deficits are not "features of myasthenia gravis". This article discusses the gap that exists on sensory neural transmission in myasthenia that has remained after >300years of research in this neurological disorder. We outline the neurobiological characteristics of sensory and motor synapses, reinterpret the nanocholinergic commonalities that exist in both sensory and motor pathways, discuss the clinical findings on altered sensory pathways in myasthenia, and propose a novel way to score anomalies resulting from multineuronal inability associated sensory troubles due to eugenic nanocholinergic instability and autoimmunity. This medicine-based evidence could serve as a template to further identify novel targets for studying new medications that may offer a better therapeutic benefit in both sensory and motor dysfunction for patients. Importantly, this review may help to re-orient current practices in myasthenia.

"Unclassical" Combination of Smell Dysfunction, Altered Abdominal Nociception and Human Hypertension Associated "Classical" Adrenal-Augmentation.

We report a 33-year-old female patient, who arrived to the emergency ward with an abdominal pain that suddenly started 10 days before admission. Simultaneously, the patient developed sudden arterial hypertension and smell disturbances. Conventional medical treatment for pain and arterial hypertension was effortless. Laboratory tests ruled out pancreatitis. Metanephrines in her urine were also normal. A dual-phase intravenous contrast computed tomography of the abdomen showed a large mass within left adrenal gland. Adrenocortical adenoma was diagnosed. The mass was not hypervascularized but positive for synaptophysin and chromogranin A. Importantly, these proteins are heavily involved with acetylcholine metabolism. The triad of olfactory disorders, pain and arterial hypertension normalized after surgically extracting the adrenal mass. To our knowledge, this medical case is the first reported patient exhibiting immediate recovery of such unclassical triad of local and remote findings. The function and dysfunction of key nanocholinergic pathways involved with smell, blood pressure and nociception would explain the pathophysiology of this unique medical case.

Auditory and Lower Limb Tactile Prepulse Inhibition in Primary Restless Legs Syndrome: Clues to Its Pathophysiology.

The resting sensory discomfort transiently relieved upon movement of the affected area in restless legs syndrome suggests that sensorimotor integration mechanisms, specifically gating, may be altered in the disease. The authors sought to determine the effects of prepulse auditory and tactile stimulation applied to lower limbs on the blink reflex of patients with restless legs syndrome and healthy subjects. Seventeen patients with restless legs syndrome and 17 age- and sex-matched healthy controls were investigated. Auditory stimuli and tactile lower limb stimulation were applied as prepulses. The R2 response of the blink reflex induced by electrical stimulation applied to the right supraorbital nerve was selected as the test stimulus. Time intervals between prepulses and response-eliciting stimuli were 40, 70, 90, 110, and 200 milliseconds. There were no differences in either the auditory or tactile prepulse conditions between patients and controls and no differences between these measures within subject groups. We concluded that the tactile lower limb and the auditory prepulse effects on the brainstem interneurons mediating the blink reflex share common neural pathways. Because forebrain interneurons mediate these prepulse effects, they are likely not involved in the disordered sensorimotor interaction of restless legs syndrome.

A new neurometric dissection of the area-under-curve-associated jiggle of the motor evoked potential induced by transcranial magnetic stimulation.

OBJECTIVE: The jiggle of the motor evoked potential (MEP) induced by transcranial magnetic stimulation (TMS) depends on a number of factors including the assessment of this stochastic signal by the method known as area under curve (AUC). We aim to ascertain the MEP findings assessed by the AUC method obtained from individuals affected by lesions at different levels of the neuroaxis. METHODS: We systematically search and critically appraise the scientific reports publishing on the MEP obtained from individuals with hypo- or hyperkinetic disorders of the neural system, and dissect the neurophysical assessment of the obtained data. To accomplish this, we used the instruments named to as U-Pen Instrument for Neurometric Evaluation Uncommonly and Rarely Obtained from NeuroSignals 1.0 (UPINEURON 1.0), and the Quality of Assessment Statistics Index (QuASI). RESULTS: The MEP differences found by the classical peak-to-peak method decreased or disappeared when the AUC was used. The opposite was also true (Kappa=<0.00). The internal consistency of the UPINEURON was 0.88. The mean of the UPINEURON 1.0 indicator was 34.8 (range=16-50), and the mean of the QuASI scores was 56.5 (range 30-80). Spearman correlation between UPINEURON 1.0 and QuASI was 0.513. CONCLUSIONS: The MEP jiggle found in individuals with disordered neural function is not a "minor" factor; it is beyond the underlying neural condition, sample size, type of coils, and number of trials, among other variables. The use of the novel indicators introduced in this investigation will help to improve the analysis of the AUC of neural signals. They may also lead to the reconsideration of current practices.

The lateralized smell test for detecting Alzheimer's disease: failure to replicate.

OBJECTIVES: A widely publicized study by Stamps, Bartoshuk and Heilman (2013) reported that a simple measure of left:right naris differences in the ability to detect the odor of peanut butter is a sensitive marker of Alzheimer's disease (AD). AD patients were said to have abnormal smell function on the left side of the nose and normal function on right side of the nose. In light of its implications for medical practice and the world-wide publicity that it engendered, we sought to replicate and expand this work. METHODS: Two studies were performed. In the first, 15 AD patients were tested according to the procedures described by Stamps et al. in which the nostril contralateral to the tested side was occluded by the patient using lateral pressure from the index finger. Since this can potentially distort the contralateral naris, we repeated the testing using tape for naris occlusion. In the second, 20 AD patients were administered 20 odors of the University of Pennsylvania Smell Identification Test (UPSIT) to each side of the nose, with the contralateral naris being closed with tape. In both studies, the order of the side of testing was systematically counterbalanced. RESULTS: No evidence of a left:right asymmetry on any test measure was observed. CONCLUSION: Although hyposmia is well-established in AD, no meaningful asymmetry in smell perception is apparent. If olfactory function on the right side of the nose was normal as claimed, then AD patients should exhibit normal function when tested bilaterally, a phenomenon not seen in dozens of AD-related olfactory studies.

Dysfunctional chemosensation in myasthenia gravis: a systematic review.

OBJECTIVES: Myasthenia gravis has traditionally been viewed as a disorder that solely affects the neuromuscular junction within the peripheral nervous system. However, there is now evidence that the cholinergic dysfunction of this disorder may be more widespread than previously believed. This article provides a systematic review of the studies that examined smell and taste function in myasthenia gravis. METHODS: We analyzed studies that reported chemosensory function alterations in patients with myasthenia gravis. PubMed, MEDLINE, Web of Science, EMBASE, and SciELO, searched to identify articles published from January 1950 through December 2012, were supplemented by relevant articles. The following information was identified from each article: the number of patients, number of controls (if any), clinical stage of patients, neurological involvement, serological state, taste or smell involvement, chemosensory test used, and country of publication. RESULTS: Ten studies reporting smell and taste function and dysfunction in patients with myasthenia gravis were identified, most of which were case reports commenting on apparent abnormalities in the taste system. The sole empirical study that investigated taste function, however, was negative, suggesting that some reports of taste loss may reflect olfactory loss. One study clearly documented olfactory dysfunction in patients with myasthenia gravis, dysfunction most likely attributable to altered central nervous system cholinergic function. CONCLUSIONS: Chemosensory dysfunction has been reported in a number of patients with myasthenia gravis. Given the close association between complaints of taste dysfunction and loss of flavor sensations secondary to olfactory system damage, quantitative testing should be used to accurately assess the nature and degree of the dysfunction present in this debilitating disorder.