Trigeminal Research Articles

Management of cutaneous head and neck squamous cell carcinoma with trigeminal nerve involvement: a systematic review

Cutaneous head and neck squamous cell carcinoma (cHNSCC) is the second most common cancer worldwide, carrying a favorable prognosis. Perineural invasion/spread dramatically reduces survival outcomes. The trigeminal nerve (CNV) is most commonly affected, providing abundant opportunities for skull base and intracranial cavity invasion. Standard treatment includes surgery and radiotherapy (SRT). We intended to systematically review the literature on cHNSCC with CNV involvement and evaluate the effects of treatment modalities and pattern of CNV invasion/spread on outcomes. We performed a systematic review according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Kaplan-Meier curves were utilized to determine the impact of treatment and pattern of invasion/spread on disease-free survival (DFS) and overall survival (OS). Fifty-one studies were identified, generating a sample size of 172 patients with cHNSCC and CNV involvement. The most common treatment modality was SRT (n=90, 52.9%), and all three major CNV branches were affected with similar frequency (V1 33.7%, V2 33.7%, V3 32.6%). Cox proportional hazards regression models revealed significant differences in OS for V1 vs V2 involvement (HR 2.84 95% CI 1.02-7.89), skull base invasion (HR 3.90 95%CI 1.30-11.65), SRT vs RT alone (HR 5.77 95% CI 2.13-15.6), SRT vs other treatment (HR 6.21 95 CI 2.24-17.20). Only SRT and RT had a significant difference in DFS (HR of 3.90, 95%CI 1.30-11.65). In cHNSCC with CNV involvement, treatment modality and the pattern of CNV are crucial for locoregional control and mortality. V1 involvement and definitive RT are associated with significantly lower survival curves.

Management of treatment-naïve Koos grade IV vestibular schwannomas using hypofractionated Gamma Knife radiosurgery: a retrospective single-institution study.

While single-fraction Gamma Knife radiosurgery (GKRS) has shown efficacy in managing vestibular schwannomas (VSs), some concerns have been raised regarding its safety profile, particularly in the context of hearing preservation. Hypofractionation has emerged as a promising approach to improving the safety profile. This retrospective, single-institution study evaluated patient outcomes following hypofractionated GKRS (hf-GKRS) for treatment-naïve Koos grade IV VSs. This study involved all patients with treatment-naïve Koos grade IV VSs who underwent hf-GKRS (3 or 5 fractions) between January 2018 and June 2021, with a follow-up period of ≥ 36 months. The outcomes assessed included local control (LC), the preservation of serviceable hearing as determined by the Gardner-Robertson hearing scale, and procedure-related adverse events. Twenty-nine patients (14 females, median age 49 years) were treated with three different dose regimens: 21 patients received 18Gy in 3 fractions, 6 patients received 20Gy in 5 fractions, and 2 patients received 25Gy in 5 fractions. Prior to treatment, 13 patients (44.8%) had serviceable hearing, one (3.4%) presented with facial palsy, and four (13.8%) had trigeminal nerve dysfunction. The median tumor volume was 10.8 cm3. During a median radiological follow-up period of 60 months (range, 36-78 months), LC was achieved in all patients. All 13 patients retained serviceable hearing at the last follow-up. Trigeminal nerve dysfunction occurred in one patient (3.4%), while another patient (3.4%) needed a ventriculoperitoneal shunt insertion due to new-onset hydrocephalus. No new-onset facial palsy was observed. hf-GKRS shows promise as an effective and safe primary or adjuvant treatment for Koos grade IV VSs with non-life-threatening or debilitating symptoms. Future studies with larger cohorts and extended follow-up periods are needed to validate these findings and to refine fractionation schemes.

A Case of Supraorbital Hypoesthesia Following Double Orbital Sphere Volume Implant.

The patient is a 63-year-old female with past ocular history of end-stage glaucoma in her OD. To maintain symmetry and achieve cosmesis with her right orbit, she chose to proceed with enucleation of the eye with a donor sclera-wrapped 20-mm silicone sphere implant. After 1 year, she developed right enophthalmos due to volume loss. The patient opted for an additional sphere to be placed posterior to the original sphere. A 14-mm silicone sphere was placed through a lateral orbitotomy into the intraconal space. On postoperative day 1, the patient developed numbness along the V1 trigeminal nerve in the supraorbital region, extending past her hairline. The implant was removed 1 week later, and the authors are currently waiting for nerve recovery. This is a rare and challenging postoperative complication, possibly explained by nerve compression, demyelination, or nerve ischemia.

Immediate consecutive microvascular decompression for bilateral classical trigeminal neuralgia

BackgroundClassical trigeminal neuralgia (TN) is characterized by sudden, severe facial pain, typically resulting from a neurovascular conflict affecting the trigeminal nerve. In rare cases, both nerves are affected simultaneously causing bilateral TN (BTN), increasing the complexity of the treatment. Microvascular decompression (MVD) is a well-established treatment for TN; however, the experience with immediate consecutive bilateral MVD procedures is limited and requires further evaluation.ObjectiveTo evaluate the safety and efficacy of immediate consecutive bilateral MVD in patients with severe BTN compared to non-consecutive bilateral MVD procedures.MethodsA retrospective analysis was conducted on 15 patients with BTN who underwent bilateral MVD. The data on clinical presentation, surgical technique, perioperative findings, complications, and follow-up outcomes of three cases of BTN treated with consecutive bilateral MVD surgeries were analyzed and compared to 12 who received separated procedures. Moreover, a detailed presentation of the three cases of consecutive MVD is provided to illustrate clinical decision-making, surgical nuances, and individual outcomes.ResultsBoth groups achieved significant pain relief (p < 0.001) without notable differences in Barrow Neurological Institute (BNI) pain intensity score (p = 0.305), indicating that both approaches were equally effective. The consecutive MVD group experienced a shorter total surgical duration (p = 0.025), while postoperative complications were comparable (p = 0.077), mostly transient with no major adverse events or mortality. At the last follow-up, the patients remained pain-free without recurrence of TN symptoms.ConclusionConsecutive bilateral MVD is a safe and effective option, comparable to non-consecutive procedures for treating BTN. This approach provides a viable alternative for patients with severe bilateral symptoms or when medical constraints limit the possibility of two separate surgeries. Further studies with larger cohorts and extended follow-up periods are needed to support these results.

Long-term outcomes of sural nerve vertical cross-face graft for lacrimal gland neurotization in neurodeprivative dry eye.

We recently described a novel surgical procedure to reinnervate the lacrimal gland in neurodeprivative dry eye disease and reported the 1-year outcomes of patients treated accordingly. The purpose of this paper is to describe the long-term outcomes of this innovative surgical technique. Monocentric cross-sectional study including consecutive patients affected by facial palsy with an absolute deficiency of tear secretion (Schirmer test 0mm/5min) who underwent lacrimal gland neurotization, as previously described. Before surgery (T0) and at the last follow-up visit (T1), the following parameters were evaluated: tear film break-up time (TBUT), corneal fluorescein staining (Oxford score), Schirmer test type I, usage of tear substitutes (daily number of instillation). At T1, subjective satisfaction with surgery was collected and tear film osmolarity (TFO) was measured in both operated and contralateral eye. Corneal sensitivity was performed at T0 and T1 in patients who underwent neurotization of both lacrimal gland and cornea due to the concomitant presence of neurotrophic keratopathy (trigeminal nerve palsy). Data from 9 patients (4M, 5 F; mean age 47.1 ± 17.1years) who underwent lacrimal gland neurotization and were followed up for an average time of 87months (± 15) (range 60-108) were analyzed. The study procedure was combined in all cases with facial reanimation, while corneal neurotization was performed in 4 cases. At T1, the mean value of Schirmer test was significantly higher compared to T0 (5.8 ± 2.0 vs 0 ± 0mm/5min; p < 0.0001). TBUT and corneal fluorescein staining were significantly better compared to baseline (respectively, 2.4 ± 1.8 vs 1.2 ± 0.6s, p = 0.04 and 1.7 ± 0.8 vs 3.1 ± 0.6, p = 0.0004). TFO was not significantly different between operated eye and contralateral one (306.7 ± 9.5mOsm/L vs 308.9 ± 11.3mOsm/L, p = 0.67). The mean daily number of tear substitute instillations was lower at T1 compared to T0 (12 ± 7 vs 21.8 ± 4.3; p = 0.011).Overall, all patients were satisfied with surgery at T1 (very satisfied: n = 3 and satisfied: n = 6). No major postoperative complications were recorded throughout the entire follow-up. Lacrimal gland neurotization through the sural nerve is a safe and effective procedure with stable favorable outcomes in the long term.

Distinct expression profile reveals glia involvement in the trigeminal system attributing to post-traumatic headache

BackgroundPost-traumatic headache (PTH) is a common comorbid symptom affecting at least one-third of patients with mild traumatic brain injury (mTBI). While neuroinflammation is known to contribute to the development of PTH, the cellular mechanisms in the trigeminal system crucial for understanding the pathogenesis of PTH remain unclear.MethodsA non-invasive repetitive mTBI (4 times with a 24-h interval) was induced in male mice and effect of mTBI was tested on either bregma or pre-bregma position on the head. Periorbital allodynia and spontaneous pain behavior were assessed using von Frey test and grimace score, respectively. Quantitative PCR was used to assess extent of mTBI pathology. RNA sequencing was performed to obtain transcriptomic profile of the trigeminal ganglion (TG), trigeminal nucleus caudalis (Sp5C) and periaqueductal gray (PAG) at 7 days post-TBI. Subsequently, quantitative PCR, in situ hybridization and immunohistochemistry were used to examine mRNA and protein expression of glia specific markers and pain associated molecules.ResultsThe repetitive impacts at the bregma, but not pre-bregma site led to periorbital hypersensitivity, which was correlated with enhanced inflammatory gene expression in multiple brain regions. RNA sequencing revealed mTBI induced distinct transcriptomic profiles in the peripheral TG and central Sp5C and PAG. Using gene set enrichment analysis, positive enrichment of non-neuronal cells in the TG and neuroinflammation in the Sp5C were identified to be essential in the pathogenesis of PTH. In situ assays also revealed that gliosis of satellite glial cells in the TG and astrocytes in the Sp5C were prominent days after injury. Furthermore, immunohistochemical study revealed a close interaction between activated microglia and reactive astrocytes correlating with increased calretinin interneurons in the Sp5C.ConclusionsTranscriptomics analysis indicated that non-neuronal cells in peripheral TG and successive in situ assays revealed that glia in the central Sp5C are crucial in modulating headache-like symptoms. Thus, selective targeting of glia cells can be a therapeutic strategy for PTH attributed to repetitive mTBI.

Ceftazidime-Cefazolin Empiric Therapy for Pediatric Gradenigo Syndrome.

Gradenigo Syndrome (GS), a rare complication of petrous apicitis secondary to acute otitis media, is characterized by (an often incomplete) triad of otorrhea, abducens nerve palsy, and facial pain along the trigeminal nerve distribution. There are several causative pathogens of petrous apicitis, including Streptococcus and Staphylococcus species, while Pseudomonas aeruginosa is the most common. However, the case report literature often describes antibiotic management of GS with antibiotics that do not cover Pseudomonas, potentially predisposing to further intracranial complications or mortality. The purpose of this work was to describe a case of pediatric Gradenigo Syndrome, successfully treated with sufficiently broad-spectrum antibiotics. This is case report. A previously healthy 5-year-old boy with a history of swimming presented with esotropia and acute otitis media. Initial symptoms included otorrhea, otalgia, and pruritis, which were refractory to ciprofloxacin-dexamethasone drops. He subsequently developed a right sixth nerve palsy, suggestive of Gradenigo Syndrome, and neuroimaging showed evidence of petrous apicitis, clival osteomyelitis, and internal carotid artery stenosis. The causative organism was not elucidated to laboratory error. Given this uncertainty, he was successfully treated with empiric intravenous ceftazidime and cefazolin. After 16 weeks, he recovered fully without the need for surgery. In the setting of delayed or absent culture results with suspicion of skull-base infection, our case supports the use of empiric antibiotic therapy with sufficient coverage of all common pathogens including Streptococcus/Staphylococcus and Pseudomonas aeruginosa species, the latter of which is often not adequately covered by antibiotic regimens described in the literature.

Differential modulation of pain and associated anxiety by GABAergic neuronal circuits in the lateral habenula

Persistent pain frequently precipitates the development of anxiety disorders, yet the underlying mechanisms are not fully understood. In this study, we employed a mouse model that simulates trigeminal neuralgia and observed a marked reduction in the activity of GABAergic neurons in the lateral habenula (LHb), a critical region for modulating pain and anxiety. We utilized precise optogenetic and chemogenetic techniques to modulate these neurons, which significantly alleviated behaviors associated with pain and anxiety. Our investigations revealed an inhibitory pathway from the LHb GABAergic neurons to the posterior paraventricular thalamus. Activation of this pathway primarily mitigated pain-related behaviors, with minimal effects on anxiety. Conversely, interactions between GABAergic and glutamatergic neurons within the LHb were essential in alleviating both pain and anxiety following trigeminal nerve damage. Additionally, we identified that β-sitosterol interacts directly with LHb GABAergic neurons via the estrogen receptor α, providing dual therapeutic effects for both pain and anxiety. These findings highlight the critical role of reduced GABAergic neuronal activity in the LHb in the intersection of pain and anxiety, pointing to promising therapeutic possibilities.

Middle fossa approach for a petrous apex bony spur causing trigeminal neuralgia: illustrative case.

Trigeminal neuralgia (TN) can arise from trigeminal nerve compression at the root entry zone due to neurovascular conflict, which most often presents in the 6th decade of life. The authors report the case of a young patient with TN with a petrous apex bony spur near the entrance of Meckel's cave, causing compression of the proximal trigeminal nerve. A 21-year-old woman presented with a 5-year history of progressive right-sided TN. Axial T2 sampling perfection with application optimized contrast using different flip angle evolution magnetic resonance imaging (MRI) did not reveal vascular compression of the trigeminal nerve. However, sagittal reformats demonstrated a prominent bony ridge along the petrous apex, causing compression of the right trigeminal nerve at the porus trigeminus. Removal of the bony spur via a middle fossa approach completely resolved the patient's symptoms. Although TN is most frequently caused by neurovascular compression, it is vital to examine the entire course of the trigeminal nerve on MRI to identify alternative causes of nerve compression in the absence of neurovascular conflict. Bony compression is a rare cause of TN that should be considered, particularly in younger patients. The presence of prominent osseous structures along the course of the trigeminal nerve can be evaluated reliably on sagittal MRI. https://thejns.org/doi/10.3171/CASE24321.

Assessment of Vidian canal morphology in axial section and its associated structures using cone beam computed tomography: A descriptive study

The Vidian Nerve (VN), a branch of the trigeminal nerve, passes by the Vidian Canal (VC), located at the base of the skull. The VC branches into the greater petrosal nerve and the VN in the pterygopalatine fossa, where the greater petrosal nerve carries parasympathetic fibers to the lacrimal glands and nasal mucosa, and the VN carries sensory fibers from the nasopharynx, nasal cavity, and palate. In this study, 60 subjects of both sexes who underwent cone beam computed tomography (CBCT) were selected by a convenient sampling technique. The data were subjected to statistical analysis following the examination of the various parameters in the axial sections. Among the various morphological characteristics appraised in the axial section, there was no significant sexual dimorphism, except for the angle between the VC and the medial wall of the maxillary sinus, which shows statistical significance. The present study aims to investigate morphometric analysis and its associated structures, offering insightful information about the complex structure of the Vidian canal (VC), which provides adequate knowledge for surgeons to plan with more caution complex skull base procedures, and eventually to lower the therapeutical risks associated with it.

How to prevent and how to treat dyspnea in critically ill patients undergoing invasive mechanical ventilation.

To summarize current data regarding the prevalence, risk factors, consequences, assessment and treatment of dyspnea in critically ill patients receiving invasive mechanical ventilation. In intubated patients, dyspnea is frequent, perceived as intense, and associated with unfavorable outcomes such as immediate and unbearable distress (e.g. fear of dying), prolonged weaning, and delayed severe psychological consequences ( i.e. posttraumatic stress disorders). In noncommunicative patients, dyspnea is named respiratory-related brain suffering (RRBS) and can be detected using dyspnea observations scales. Before initiating pharmacological treatments, nonpharmacological interventions may be tried as they are efficient to alleviate dyspnea. As opposed to pain, dyspnea has often been overlooked in terms of detection and management, resulting in its significant underestimation in daily practice. When it is diagnosed, dyspnea can be relieved through straightforward interventions, such as adjusting ventilator settings. Assessing dyspnea in patients undergoing invasive mechanically ventilated may be challenging, especially in noncommunicative patients (RRBS). Implementing a systematic dyspnea assessment in routine, akin to pain, could serve as a first step to reduce RRBS and prevent potential severe psychological consequences. In addition to pharmacological treatments like opioids, a promising approach is to modulate both the sensory (air on the face, trigeminal nerve stimulation) and the affective (relaxing music, hypnosis, directed empathy) components of dyspnea.

A retrospective clinico epidemiological study of pattern of dermatosis involving trigeminal distribution in a tertiary care center

Trigeminal nerve is the principal sensory nerve of face. Many dermatological conditions known occur in relation to trigeminal nerve distribution clinically presenting as unilateral facial lesions with strict midline demarcation. To study the clinical pattern and epidemiological determinants of dermatoses along trigeminal nerve among the patients of both the sexes, involving all the age groups. Thirty two patients presenting with skin lesions along trigeminal nerve presenting to Dermatology department of a tertiary care center, Bangalore, Karnataka, are selected for the study. Study design is retrospective hospital record based study conducted from January 2023 to January 2024. In this study, out of 32 patients most common dermatoses along trigeminal nerve were infection of which herpes zoster was seen thirteen (40.62%) patients, followed by nevi (n=6, 18.75%), pigmentary disorders (n=5, 15.62%), vascular disorder (n=4, 12.5%) and auto inflammatory disorder (n=4, 12.5%) was seen. Most common branch affected was ophthalmic followed maxillary branch .Females were more common and mean age was 24 years. Small sample size and rare clinical cases are included Studies focusing on the pattern of dermatoses involving the trigeminal nerve contribute to the advancement of medical knowledge and facilitate the development of novel diagnostic techniques and therapeutic modalities. By elucidating the underlying pathophysiological mechanisms and identifying potential risk factors, research in this field can lead to the development of more effective treatment strategies tailored to the specific needs of patients.

Comparison of Different 3D Surface Registration-Based Methods to Assess Facial Asymmetry.

Facial asymmetry is gaining an increasing diagnostic interest in many clinical contexts. Several three-dimensional surface-based methods have been proposed for its assessment; however, they might provide non-equivalent data. Since there is a lack of comparative studies in these terms, this study aims to compare three methods for assessing the asymmetry of the face and facial thirds, thus addressing whether the potential differences can be considered clinically acceptable or not. Two 'maxillofacial' methods based on the trigeminal nerve distribution and one 'orthodontic' method based on reference horizontal planes were used to identify the facial thirds on 3D facial models of 80 Italian healthy adults to calculate the asymmetry of the face, and the upper, middle, and lower thirds of the face differently selected by each method. As a measure of asymmetry, the Root Mean Square value was calculated through a mirroring surface-based registration. Intra- and inter-operator reliability was verified for each method. Differences and interchangeability between the methods were tested, respectively, by two-way repeated measures ANOVA (Analysis of Variance) and Bland-Altman and Similarity Percentage model analysis. Additionally, the time required to perform each method was assessed. All methods demonstrated excellent intra- and inter-operator reliability. While the ANOVA analysis found significant differences (p < 0.001) for the majority of facial Regions of Interest between each method, the Bland-Altman analysis revealed that the differences were clinically acceptable (<0.50 mm) for all facial regions between the trigeminal methods, and for the face and the upper third of the face between the orthodontic method, which was revealed to be faster, and the trigeminal ones. The additional similarity percentage model provided visual support for the complete interchangeability of the two trigeminal methods, as evidenced by the lower Coefficient of Variation value. There is no best method for assessing facial asymmetry that applies to all types of clinical settings, as we have shown that different methods may not be completely interchangeable. However, we suggest that the methods based on the trigeminal subdivision can be used interchangeably in contexts where the morpho-functional analysis of maxillofacial regions with different embryological origins is considered. Thus, the clinical setting imposes the choice of one method over another and, as we have pointed out, the consequent comparison of data with those obtained with methods whose interchangeability has been demonstrated.

MIGRAINE

Background Migraine is a prevalent neurological disorder characterized by chronic headaches, significantly impacting the global population. This comprehensive review aims to advance the understanding of migraine pathogenesis and treatment, focusing on molecular markers and novel therapeutic strategies. Material Molecular markers such as calcitonin gene-related peptide (CGRP) and their role in migraine development. Traditional medical treatments and emerging therapeutic strategies, including neuromodulation, are analyzed for their effectiveness and limitations. Clinical studies and imaging techniques are leveraged to identify key mechanisms and triggers in migraine pathology. Approximately 95% of people experience a headache at some point, with migraines being a significant contributor. Migraine is recognized by the World Health Organization as one of the top ten causes of disability globally, particularly affecting women. CGRP is identified as a crucial factor in migraine development. Inhibitors targeting CGRP have shown significant effectiveness in managing migraines. Other molecular markers, including proinflammatory cytokines and neurotransmitters, are discussed for their roles in pain transmission and migraine pathophysiology. Traditional treatments, such as triptans and NSAIDs, are evaluated alongside new therapies, including CGRP inhibitors and neuromodulation techniques. Neuromodulation, involving devices like external trigeminal nerve stimulators, shows promise in migraine management. Genetic markers associated with familial hemiplegic migraine (FHM) and common migraine forms are reviewed. Recent genome-wide association studies (GWAS) have identified several genetic variants linked to migraine susceptibility. Conclusion This presentation enhances the understanding of migraine pathogenesis and introduces novel therapeutic possibilities. By focusing on molecular markers like CGRP and exploring advanced treatment options, the study aims to improve migraine management and patient care. The findings underscore the need for continued research and innovation in migraine treatments to reduce the global burden of this debilitating condition.

Neuroapraxia of Trigeminal Nerve Controlled by Neuromonitoring During Microvascular Decompression in Multiple Sclerosis Patients Affected by Drug-Resistant Trigeminal Neuralgia Recurrent After Previous Operations

BACKGROUND AND IMPORTANCE: Trigeminal neuralgia (TN) can complicate the clinical course of multiple sclerosis (MS) and can be very difficult to treat. Usually, these patients experience multiple recurrences after surgical procedures with a poor overall outcome. To the best of our knowledge, we report the first 3 cases of drug-resistant MS-related TN recurrent after previous operations in which intraoperative neuromonitoring controlled neuroapraxia of trigeminal nerve was performed. We describe the surgical technique, report the clinical outcomes of patients, and review the pertinent literature. CLINICAL PRESENTATION: Neuroapraxia of trigeminal nerve was conducted using a standard straight Yasargil temporary titanium aneurysm clip on the main trunk of the trigeminal nerve. Trigeminal somatosensory evoked potentials and cortico-bulbar motor evoked potentials registered from trigeminal and facial nerves were recorded during the procedure. The trigeminal nerve clipping was conducted for a maximum of 30 seconds or less in the case of a decrease in neurophysiological responses. The preoperative Barrow Neurological Institute score was V, IV, and IV for the 3 patients, respectively. We obtained acute pain relief in all patients after the procedure. All patients had a Barrow Neurological Institute I at the latest follow-up (10, 10, and 9 months, respectively). No complications were reported postoperatively and at follow-up. CONCLUSION: Intraoperative neuromonitoring controlled neuroapraxia of trigeminal nerve with temporary titanium aneurysm clip application during microvascular decompression is a promising and safe procedure in MS patients with recurrent MS-related TN. Further studies with longer follow-up are needed to confirm our encouraging results.

Short-Latency Trigeminocervical Reflex Obtained Without Muscle Activation: Topographic Distribution and Methodological Approach

Purpose: Electrical stimulation of trigeminal nerve branches elicits early and late reflex responses in the cervical muscles, known as the trigeminocervical reflex (TCR). This study aimed to evaluate the neurophysiological aspects, stimulation patterns, and topographic distribution of short-latency TCR components in humans in the absence of voluntary muscle activation. Methods: This prospective observational study included 30 participants. Trigeminocervical reflex responses were simultaneously recorded from the bilateral sternocleidomastoid, trapezius, and splenius capitis muscles (without voluntary muscle activation), after electrical stimulation of the supraorbital and infraorbital nerves. Two different stimulation protocols were evaluated: a 3 Hz stimulation protocol (using averaging) and a single-pulse stimulation protocol. Results: Using a 3 Hz stimulation protocol, short-latency TCR responses were recorded in the sternocleidomastoid, trapezius, and splenius capitis muscles, ipsilateral and/or contralateral, but with variable recordability depending on the recording site. The most reliable response was obtained in ipsilateral sternocleidomastoid muscle. To the best of our knowledge, this is the first study to demonstrate the elicitation of short-latency TCR components in the sternocleidomastoid muscle in the absence of voluntary muscle activation in humans without craniocervical junction disorders or lower brainstem abnormalities. Conclusions: The choice of an appropriate stimulation protocol is particularly relevant for recording short-latency TCR components, considering that the visualization of early or late responses seems to be facilitated by different stimulation methodologies.

Abstract 4135239: Pausing Under Pressure: Ocular Hypertension as an Atypical Cause of Heart Block

A 67-year-old male with a history of hypertension presented to the emergency department with abnormal cardiac monitor results. Prior to this, he was diagnosed with primary open-angle glaucoma by ophthalmology and underwent left-sided aqueous tube shunt placement, which was complicated by hypotony requiring revision and holding of all topical glaucoma medications. Concurrently, he was noted to have an irregular heart rhythm during a routine physical. In office ECG showed normal sinus rhythm, but subsequent 14-day continuous ECG monitor showed sinus bradycardia with nadir heart rate of 21 beats-per-minute and 114 ventricular pauses (longest 4.8 seconds) primarily due to second-degree atrioventricular (AV) block, Mobitz type 1, but also periods of high-grade AV block. He was sent to the emergency department for expedited pacemaker evaluation. On further review, heart block and ventricular pauses occurred exclusively over a 12-hour period that temporally coincided with a hospitalization for acute ocular hypertension following shunt revision. His intraocular pressure peaked at 56 mmHg (normal range 10-21 mmHg), then normalized to 21 mmHg after acetazolamide and anterior chamber paracentesis. Bradycardia resolved following ophthalmic intervention. Bradyarrhythmias were attributed to excess vagal tone from acute ocular hypertension via an atypical but recognized cause of the oculocardiac reflex, and pacemaker placement was avoided. The oculocardiac reflex is a reflex bradycardia involving the trigeminal and vagus nerves. Cardiac effects are consistent with other vagally-mediated bradyarrhythmias, including sinus bradycardia, AV block, and even asystole. This reflex occurs commonly during traction on extraocular muscles during strabismus surgery, but can be seen in other orbital and ocular stimuli. To our knowledge, this is the first documented case of ocular hypertension leading to atrioventricular block through this mechanism. This case illustrates the importance of (1) clinical context of abnormal events during extended cardiac monitoring, (2) understanding the oculocardiac reflex as a cause of bradyarrhythmias, and (3) ruling out reversible medical causes of dysrhythmias prior to permanent device implantation.

EXTH-57. EXPLORING NOVEL ROUTES FOR NON-INVASIVE DRUG ADMINISTRATION: INTRADERMAL DELIVERY FOR THE TREATMENT OF BRAIN TUMORS

Abstract Effective non-invasive drug delivery to brain tumors remains challenging, despite extensive exploration of these methods, due to the blood-brain barrier (BBB). Intranasal drug delivery has emerged as a promising alternative approach, as it circumvents limitations on tumor access imposed by the BBB when administering therapeutics systemically and limits the occurrence of systemic toxic responses to treatment. The intranasal route of administration allows therapeutic access to brain tumors through pathways involving the olfactory and trigeminal nerves (TNs) that connect the nasal passage to the brain. However, effective nose-to-brain delivery is impeded by rapid mucosal drug clearance in the nasal cavity, drug aspiration, and ingestion. Since the TN arises from the brainstem and its branches innervate the facial skin, in addition to muscles, meninges, and respiratory mucosa, we tested the hypothesis that facial intradermal administration targeting the V2 branch of the TN could be an alternative strategy to harness TN-mediated brain delivery to bypass the BBB. Here, we developed Spherical Nucleic Acids (SNAs) consisting of a 15nm spherical gold nanoparticle core functionalized with radially oriented fluorophore-tagged ssDNA as a model therapeutic. We observed the delivery of the SNAs to the brain starting 4 hours post intradermal injection, with the SNA accumulation in the tumor persisting over time. Using ex vivo fluorescent imaging, comprehensive immunofluorescence microscopy, and flow cytometry we confirmed the SNA accumulation in the brain, dura, TN, and cervical lymph nodes. In particular, we demonstrated that SNAs were enriched in the neuronal cell bodies of the trigeminal ganglia and within the epineurium and perineurium of the TN. The SNAs were also enriched in CD45-positive immune cells. In conclusion, this study credentialed facial intradermal administration of SNAs as a promising non-invasive method for brain drug delivery to target intracranial tumors.

RADT-42. DISSEMINATED TUMORAL AMYLOIDOSIS OF THE CRANIAL NERVES IN THE ABSENCE OF SYSTEMIC DISEASE: CASE REPORT

Abstract Tumoral amyloidosis, characterized by tumor-like deposits without systemic disease, is rare in the central nervous system. Most often located in the periventricular white matter, tumoral amyloidosis typically consist of immunoglobulin light chains (AL). While prior reports describe cases of tumoral amyloidosis isolated to the trigeminal nerve, we report herein a first known case of diffuse cranial nerve involvement. The patient is a 43-year-old man who presented with left trigeminal dysesthesias, which led to self-excoriation and erosion of the left naris. On exam, he had absent sensation in the V1-V3 distributions, left trochlear nerve palsy, and bilateral abducens nerve palsies. Imaging demonstrated significant thickening of the left trigeminal nerve and diffuse cisternal contrast enhancement of the other cranial nerves, including the oculomotor, abducens, facial, and glossopharyngeal nerves. Work-up began with a lumbar puncture that found elevated protein with otherwise benign results, including flow cytometry. He was therefore recommended to undergo open biopsy of the left trigeminal nerve and cavernous sinus. Pathology from this surgery demonstrated congo red- positive AL amyloid deposits. Following this pathologic diagnosis, he subsequently underwent a full workup for systemic amyloidosis including bone marrow biopsy, abdominal fat pad biopsy, and a PET CT scan. Biopsy of a long nodule was negative for amyloidosis. Systemic amyloid testing did not demonstrate non-CNS sites of amyloid deposition. Medical therapy with daratumumab, cyclophosphamide, bortezomib, and dexamethasone was started but then discontinued due to ineffectiveness. He underwent radiation treatment of 4500 cGy to the left cavernous sinus where the tumoral amyloidosis was most severe. He has had no further progression of his disease. Tumoral amyloidosis of the cranial nerves remains a rare and poorly-understood disease. Prior reports have described the disease isolated to the trigeminal nerve. This report raises attention to this diagnosis in cases of rare multi-nerve involvement and suggests that radiation may be a useful first-line treatment.

DDEL-03. INTRANASAL DELIVERY OF PDGFRA-TARGETED NANOTHERAPEUTICS FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMA

Abstract Pediatric high-grade glioma (pHGG) is the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the brainstem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of nanoliposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the effect of anti-PDGFRA monoclonal antibody-conjugated immunoliposome encapsulated SN-38 (PDGFRA-iLS-SN-38) in pHGG cell lines. PDGFRA signals were assessed in pHGG cells using western blotting. Cells were treated with rhodamine (Rho)-labeled PDGFRA-iLS and cellular uptake was confirmed with a fluorescent microscope. PDGFRA-iLS-SN38 had the additive effect on the LS-SN-38 in DIPG007 cells (PDGFRA positive), but not in SF8628 cells (PDGFRA negative) in vitro. We treated mice bearing human DMG xenografts with IND of PDGFRA-iLS-SN38. Tumor growth and response to therapy are quantitatively measured by bioluminescence imaging, and efficacy is assessed by survival analysis. Results of survival analysis will be reported at the meeting. PDGFRA-targeted nanotherapeutics represented a specific effect on glioma cells expressing PDGFRA, providing a promising therapeutic approach for targeting pHGG.