Clinical and Operative Risk Factors Associated With Prolonged Length of Stay After Endoscopic Pituitary Adenoma Resection.

BACKGROUND AND OBJECTIVES: Pituitary adenomas (PAs) are the most common intrasellar tumor. Clinically relevant adenomas have a prevalence of 1 per 1000 in the general population. Transsphenoidal surgery (TSS) is the most common surgical treatment and is the first-line management for most PAs. Most patients fare well postoperatively, but a subset of patients experience a prolonged length of stay (PLOS). In this article, we aim to identify demographic and clinical factors associated with PLOS after TSS for PA. METHODS: Patients with sellar pathologies surgically treated at a single tertiary center from March 1, 2009, to May 31, 2020, were retrospectively reviewed. All patients older than 18 years receiving nonemergent endoscopic TSS for pituitary adenoma were included. Clinical and demographic characteristics were analyzed using χ2-tests and student t-tests. For those factors with a P-value less than .01, multivariate logistic regression and negative binomial regression models were constructed to estimate the adjusted odds of PLOS across predictive factors. RESULTS: A total of 301 patients were included in the study. This cohort had an average age of 54.65 ± 15.06 years and an average body mass index of 29.47 ± 6.69. The median length of stay was 54.9 hours [25th-75th percentiles: 43.5-72.9]. Postoperative cerebrospinal fluid leak (P < .01), postoperative diabetes insipidus (DI) (P < .01), increased surgery duration (P = .01), and elevated maximal tumor dimension (P = .01) were predictive of PLOS in logistic regression. Increased surgery duration, previous pituitary radiation, intraoperative complications, and postoperative DI (all P < .01) were associated with increased rate of PLOS in negative binomial regression. CONCLUSION: Patients undergoing endoscopic TSS for PA resection demonstrate prolonged lengths of stay if they have higher tumor burden, have lengthier surgeries with intraoperative complications, or develop postoperative complications such as cerebrospinal fluid leak or DI. Careful monitoring of these factors will allow for better resource optimization, reducing costs to both the hospital and the patient.

Amniotic Band Syndrome: Head-to-Toe Manifestations and Clinical Management Guidelines.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand and describe the basic principles underlying the intrinsic versus extrinsic proposed mechanisms for the development of amniotic band syndrome (ABS). 2. Discuss risk factors and conditions that are associated with the development of ABS. 3. Understand the various presentations and associated clinical implications of ABS by anatomic location. 4. Describe the basic tenets underlying various repair technique options for ABS of the extremities. 5. Discuss the common manifestations of ABS in the face and trunk. 6. Understand clinical implications of fetoscopic surgery as it relates to ABS treatment as a novel method for limb salvage in utero. SUMMARY: Amniotic band syndrome (ABS) refers to the development of constrictive bands of fibrotic tissue in utero. It can lead to a variety of clinical manifestations after delivery. There is much debate in the plastic surgery community regarding the exact pathophysiologic mechanism for the development of ABS, and the most appropriate management. This CME article aims to provide an overview of ABS manifestations throughout the body, and to expound on the most recent advances in anticipatory and definitive management of the condition.

NF2 mutation associated with accelerated time to recurrence for older patients with atypical meningiomas.

PURPOSE: Meningiomas occur more frequently in older adults, with the incidence rates increasing from 5.8/100,000 for adults 35-44 years old to 55.2/100,000 for those 85+. Due to the increased risk of surgical management in older adults, there is a need to characterize the risk factors for aggressive disease course to inform management decisions in this population. We therefore sought to determine age-stratified relationships between tumour genomics and recurrence after resection of atypical meningiomas. METHODS: We identified 137 primary and recurrent Grade 2 meningiomas from our existing meningioma genomic sequencing database. We examined the differential distribution of genomic alterations in those older than 65 compared to younger. We then performed an age stratified survival analysis to model recurrence for a mutation identified as differentially present. RESULTS: In our cohort of 137 patients with grade 2 meningiomas, alterations in NF2 were present at a higher rate in older adults compared to younger (37.8% in < 65 vs. 55.3% in > 65; recurrence adjusted p-value =0.04). There was no association between the presence of NF2 and recurrence in the whole cohort. In the age-stratified model for those less than 65 years old, there was again no relationship. For patients in the older age stratum, there is a relationship between NF2 and worsened recurrence outcomes (HR = 3.64 (1.125 - 11.811); p = 0.031). CONCLUSIONS: We found that mutations in NF2 were more common in older adults. Further, the presence of mutant NF2 was associated with an increased risk of recurrence in older adults.

Orbital Foraminal Morphometrics in Nonsyndromic Unilateral Coronal Craniosynostosis.

ABSTRACT: Nonsyndromic unilateral coronal craniosynostosis (UCS) is a rare congenital disorder that results from premature fusion of either coronal suture. The result is growth restriction across the suture, between the ipsilateral frontal and parietal bones, leading to bony dysmorphogenesis affecting the calvarium, orbit, and skull base. Prior studies have reported associations between UCS and visual abnormalities. The present study utilizes a novel geometric morphometric analysis to compare dimensions of orbital foramina on synostotic versus nonsynostotic sides in patients with UCS. Computed tomography head scans of pediatric UCS patients were converted into 3-dimensional mesh models. Anatomical borders of left and right orbital structures were plotted by a single trained team member. Dimensions between synostotic and nonsynostotic sides were measured and compared. Medical records were examined to determine prevalence of visual abnormalities in this patient cohort. Visual abnormalities were reported in 22 of the 27 UCS patients (77.8%). Astigmatism (66.7%), anisometropic amblyopia (44.4%), and motor nerve palsies (33.3%) represented the 3 most prevalent ophthalmologic abnormalities. Orbits on synostotic sides were 11.3% narrower ( P < 0.001) with 21.2% less volume ( P = 0.028) than orbits on nonsynostotic sides. However, average widths, circumferences, and areas were similar between synostotic and nonsynostotic sides upon comparison of supraorbital foramina, infraorbital foramina, optic foramina, and foramina ovalia. Therefore, previously proposed compression or distortion of vital neurovascular structures within bony orbital foramina does not seem to be a likely etiology of visual abnormalities in UCS patients. Future studies will examine the role of ocular and/or neuro-ophthalmologic pathology in this disease process.

NF2 mutations are associated with resistance to radiation therapy for grade 2 and grade 3 recurrent meningiomas.

PURPOSE: High grade meningiomas have a prognosis characterized by elevated recurrence rates and radiation resistance. Recent work has highlighted the importance of genomics in meningioma prognostication. This study aimed to assess the relationship between the most common meningioma genomic alteration (NF2) and response to postoperative radiation therapy (RT). METHODS: From an institutional tissue bank, grade 2 and 3 recurrent meningiomas with both > 30 days of post-surgical follow-up and linked targeted next-generation sequencing were identified. Time to radiographic recurrence was determined with retrospective review. The adjusted hazard of recurrence was estimated using Cox-regression for patients treated with postoperative RT stratified by NF2 mutational status. RESULTS: Of 53 atypical and anaplastic meningiomas (29 NF2 wild-type, 24 NF2 mutant), 19 patients underwent postoperative RT. When stratified by NF2 wild-type, postoperative RT in NF2 wild-type patients was associated with a 78% reduction in the risk of recurrence (HR 0.216; 95%CI 0.068-0.682; p = 0.009). When stratified by NF2 mutation, there was a non-significant increase in the risk of recurrence for NF2 mutant patients who received postoperative RT compared to those who did not (HR 2.43; 95%CI 0.88-6.73, p = 0.087). CONCLUSION: This study demonstrated a protective effect of postoperative RT in NF2 wild-type patients with recurrent high grade meningiomas. Further, postoperative RT may be associated with no improvement and perhaps an accelerated time to recurrence in NF2 mutant tumors. These differences in recurrence rates provide evidence that NF2 may be a valuable prognostic marker in treatment decisions regarding postoperative RT. Further prospective studies are needed to validate this relationship.

ARID1A mutation associated with recurrence and shorter progression-free survival in atypical meningiomas.

PURPOSE: The oncologic outcomes for atypical meningiomas can be poor. Generally, patients that have had a prior recurrence have a substantially elevated risk of a future recurrence. Additionally, certain tumor genomic profiles have been shown as markers of poor prognosis. We sought to characterize the genomic differences between primary and recurrent tumors as well as assess if those differences had implications on recurrence. METHODS: We identified primary and recurrent gross totally resected WHO grade II meningiomas with > 30 days of post-surgical follow-up at our institution. For genes with a prevalence of > 5% in the cohort, we compared the mutational prevalence in primary and recurrent tumors. For a gene of interest, we assessed the time to radiographic recurrence using adjusted cox-regression. RESULTS: We identified 88 meningiomas (77 primary, 16 recurrent) with a median follow-up of 5.33 years. Mutations in ARID1A found in association with recurrent tumors (7/16 recurrent tumors vs 5/72 primary tumors, p < 0.001). In the whole cohort, mutations in ARID1A were not associated with alterations in time to recurrence after adjusting for recurrence status (p = 0.713). When restricted to primary tumors, ARID1A is associated with a 625% increase in the hazard of recurrence (HR = 7.26 [1.42-37.0]; p = 0.017). CONCLUSION: We demonstrate mutations in ARID1A, a chromatin remodeling gene, in a higher prevalence in recurrent tumors. We further demonstrate that when mutations in ARID1A are present in primary atypical meningiomas, these tumors tend to have worse prognosis. Further prospective study may validate ARID1A as a prognostic marker.

Association between tumor mutations and meningioma recurrence in Grade I/II disease.

BACKGROUND: Meningiomas are common intracranial tumors with variable prognoses not entirely captured by commonly used classification schemes. We sought to determine the relationship between meningioma mutations and oncologic outcomes using a targeted next-generation sequencing panel. MATERIALS AND METHODS: We identified 184 grade I and II meningiomas with both >90 days of post-surgical follow-up and linked targeted next-generation sequencing. For mutated genes in greater than 5% of the sample, we computed progression-free survival Cox-regression models stratified by gene. We then built a multi-gene model by including all gene predictors with a p-value of less than 0.20. Starting with that model, we performed backward selection to identify the most predictive factors. RESULTS: ATM (HR = 4.448; 95% CI: 1.517-13.046), CREBBP (HR = 2.727; 95% CI = 1.163-6.396), and POLE (HR = 0.544; HR = 0.311-0.952) were significantly associated with alterations in disease progression after adjusting for clinical and pathologic factors. In the multi-gene model, only POLE remained a significant predictor of recurrence after adjusting for the same clinical covariates. Backwards selection identified recurrence status, resection extent, and mutations in ATM (HR = 7.333; 95% CI = 2.318-23.195) and POLE (HR = 0.413; 95% CI = 0.229-0.743) as predictive of recurrence. CONCLUSIONS: Mutations in ATM and CREBBP were associated with accelerated meningioma recurrence, and mutations in POLE were protective of recurrence. Each mutation has potential implications for treatment. The effect of these mutations on oncologic outcomes and as potential targets for intervention warrants future study.

Utility of liquid biopsy in diagnosing isolated cerebral phaeohyphomycosis: illustrative case.

BACKGROUND: Cladophialophora bantiana is a dematiaceous, saprophytic fungus and a rare but reported cause of intracranial abscesses due to its strong neurotropism. Although it predominantly affects immunocompetent individuals with environmental exposure, more recently, its significance as a highly lethal opportunistic infection in transplant recipients has been recognized. Successful treatment requires timely but often challenging diagnosis, followed by complete surgical excision. Next-generation sequencing of microbial cell-free DNA (cfDNA) from plasma is a novel diagnostic method with the potential to identify invasive fungal infections more rapidly and less invasively than conventional microbiological testing, including brain biopsy. OBSERVATIONS: The authors described the case of a recipient of a liver transplant who presented with seizures and was found to have innumerable ring-enhancing intracranial lesions. The Karius Test, a commercially available method of next-generation sequencing of cfDNA, was used to determine the causative organism. Samples from the patient's plasma identified C. bantiana 6 days before culture results of the surgical specimen, allowing optimization of the empirical antifungal regimen, which led to a reduction in the size of the abscesses. LESSONS: The authors' findings suggest that microbial cfDNA sequencing may be particularly impactful in improving the management of brain abscesses in which the differential diagnosis is wide because of immunosuppression.

Perivascular spaces as a marker of psychological trauma in depression: A 7-Tesla MRI study.

INTRODUCTION: Emerging evidence in depression suggests that blood-brain barrier (BBB) breakdown and elevated inflammatory cytokines in states of persistent stress or trauma may contribute to the development of symptoms. Signal-to-noise ratio afforded by ultra-high field MRI may aid in the detection of maladaptations of the glymphatic system related to BBB integrity that may not be visualized at lower field strengths. METHODS: We investigated the link between glymphatic neuroanatomy via perivascular spaces (PVS) and trauma experience in patients with major depressive disorder (MDD) and in healthy controls using 7-Tesla MRI and a semi-automated segmentation algorithm. RESULTS: After controlling for age and gender, the number of traumatic events was correlated with total PVS volume in MDD patients (r = 0.50, p = .028) and the overall population (r = 0.34, p = .024). The number of traumatic events eliciting horror was positively correlated with total PVS volume in MDD patients (r = 0.50, p = .030) and the overall population (r = 0.32, p = .023). Age correlated positively with PVS count, PVS total volume, and PVS density in all participants (r > 0.35, p < .01). CONCLUSIONS: These results suggest a relationship between glymphatic dysfunction related to BBB integrity and psychological trauma, and that glymphatic impairment may play a role in trauma-related symptomatology.

Post-operative vision loss: analysis of 587 patients undergoing endoscopic surgery for pituitary macroadenoma.

PURPOSE: Vision loss following surgery for pituitary adenoma is poorly described in the literature and cannot be reliably predicted with current prognostic models. Detailed characterization of this population is warranted to further understand the factors that predispose a minority of patients to post-operative vision loss. MATERIALS AND METHODS: The medical records of 587 patients who underwent endoscopic transsphenoidal surgery at the Mount Sinai Medical Centre between January 2013 and August 2018 were reviewed. Patients who experienced post-operative vision deterioration, defined by reduced visual acuity, worsened VFDs, or new onset of blurry vision, were identified and analysed. RESULTS: Eleven out of 587 patients who received endoscopic surgery for pituitary adenoma exhibited post-operative vision deterioration. All eleven patients presented with preoperative visual impairment (average duration of 13.1 months) and pre-operative optic chiasm compression. Seven patients experienced visual deterioration within 24 h of surgery. The remaining four patients experienced delayed vision loss within one month of surgery. Six patients had complete blindness in at least one eye, one patient had complete bilateral blindness. Four patients had reduced visual acuity compared with preoperative testing, and four patients reported new-onset blurriness that was not present before surgery. High rates of graft placement (10/11 patients) and opening of the diaphragma sellae (9/11 patients) were found in this series. Four patients had hematomas and four patients had another significant post-operative complication. CONCLUSIONS: While most patients with pituitary adenoma experience favourable ophthalmological outcomes following endoscopic transsphenoidal surgery, a subset of patients exhibit post-operative vision deterioration. The present study reports surgical and disease features of this population to further our understanding of factors that may underlie vision loss following pituitary adenoma surgery. Graft placement and opening of the diaphragma sellae may be important risk factors in vision loss following ETS and should be an area of future investigation.

Association of mutations in DNA polymerase epsilon with increased CD8+ cell infiltration and prolonged progression-free survival in patients with meningiomas.

OBJECTIVE: Prior studies have demonstrated a relationship between underlying tumor genetics and lymphocyte infiltration in meningiomas. In this study, the authors aimed to further characterize the relationship between meningioma genomics, CD4+ and CD8+ T-cell infiltration, and oncological outcomes of meningiomas. Understanding specific characteristics of the inflammatory infiltration could have implications for treatment and prognostication. METHODS: Immunohistochemically stained meningioma slides were reviewed to assess the CD4+ and CD8+ cell infiltration burden. The relationship between immune cell infiltration and tumor genomics was then assessed using an adjusted ANOVA model. For a specific gene identified by the ANOVA, the relationship between that mutation and tumor recurrence was assessed using Cox regression. RESULTS: In immunohistochemically stained samples from a subcohort of 25 patients, the mean number of CD4+ cells was 42.2/400× field and the mean number of CD8+ cells was 69.8/400× field. Elevated CD8+ cell infiltration was found to be associated with the presence of a mutation in the gene encoding for DNA polymerase epsilon, POLE (51.6 cells/hpf in wild-type tumors vs 95.9 cells/hpf in mutant tumors; p = 0.0199). In a retrospective cohort of 173 patients, the presence of any mutation in POLE was found to be associated with a 46% reduction in hazard of progression (HR 0.54, 95% CI 0.311-0.952; p = 0.033). The most frequent mutation was a near-C-terminal nonsense mutation. CONCLUSIONS: A potential association was found between mutant POLE and both an increase in CD8+ cell infiltration and progression-free survival. The predominant mutation was found outside of the known exonuclease hot spot; however, it was still associated with a slight increase in mutational burden, CD8+ cell infiltration, and progression-free survival. Alterations in gene expression, resulting from alterations in POLE, may yield an increased presentation of neoantigens, and, thus, greater CD8+ cell-mediated apoptosis of neoplastic cells. These findings have suggested the utility of checkpoint inhibitors in the treatment of POLE-mutant meningiomas.

Craniofacial Dysmorphology in Infants With Non-Syndromic Unilateral Coronal Craniosynostosis.

BACKGROUND: Unilateral coronal craniosynostosis (UCS) is a congenital disorder resulting from the premature suture fusion, leading to complex primary and compensatory morphologic changes in the shape of not only the calvarium and but also into the skull base. This deformity typically requires surgery to correct the shape of the skull and prevent neurologic sequelae, including increased intracranial pressure, sensory deficits, and cognitive impairment. METHODS: The present multicenter study sought to reverse-engineer the bone dysmorphogenesis seen in non-syndromic UCS using a geometric morphometric approach. Computed tomography scans for 26 non-syndromic UCS patients were converted to three-dimensional mesh models. Two hundred thirty-six unique anatomical landmarks and semi-landmarked curves were then plotted on each model, creating wireframe representations of the Patients' skulls. RESULTS: Generalized Procrustes superimposition, Principal Component Analysis, and heatmaps identified significant superior displacement of the ipsilateral orbit ("harlequin" eye deformity), anterior displacement of the ear ipsilateral to the fused coronal suture, acute deviation of midline skull base structures ipsilateral to the fused coronal suture and flattening of the parietal bone and associated failure to expand superiorly. CONCLUSIONS: The described technique illustrates the impact of premature coronal suture fusion on the development of the entire skull and proposes how bone dysmorphology contributes to the Patients' neurologic sequelae. By bridging novel basic science methodologies with clinical research, the present study quantitatively describes craniofacial development and bone dysmorphogenesis.

Surgical outcomes in patients with endoscopic versus transcranial approach for skull base malignancies: a 10-year institutional experience.

OBJECT: The authors performed an extensive comparison between patients treated with open versus an endoscopic approach for skull base malignancy with emphasis on surgical outcomes. METHODS: A single-institution retrospective review of 60 patients who underwent surgery for skull base malignancy between 2009 and 2018 was performed. Disease features, surgical resection, post-operative morbidities, adjuvant treatment, recurrence, and survival rates were compared between 30 patients who received purely open surgery and 30 patients who underwent purely endoscopic resection for a skull base malignancy. RESULTS: Of the 60 patients with skull base malignancy, 30 underwent open resection and 30 underwent endoscopic resection. The most common hisotype for endoscopic resection was squamous cell carcinoma (26.7%), olfactory neuroblastoma (16.7%), and sarcoma (10.0%), and 43.3%, 13.3%, and 10.0% for the open resection cohort, respectively. There were no statistical differences in gross total resection, surgical-associated cranial neuropathy, or ability to achieve negative margins between the groups (p > 0.1, all comparisons). Patients who underwent endoscopic resection had shorter surgeries (320.3 ± 158.5 minutes vs. 495.3 ± 187.6 minutes (p = 0.0003), less intraoperative blood loss (282.2 ± 333.6 ml vs. 696.7 ± 500.2 ml (p < 0.0001), and shorter length of stay (3.5 ± 3.7 days vs. 8.8 ± 6.0 days (p < 0.0001). Additionally, patients treated endoscopically initiated adjuvant radiation treatment more quickly (48.0 ± 20.3 days vs. 72.0 ± 20.5 days (p = 0.01). CONCLUSIONS: An endoscopic endonasal approach facilitates a clinically meaningful improvement in surgical outcomes for skull base malignancies.

Detection of Hippocampal Subfield Asymmetry at 7T With Automated Segmentation in Epilepsy Patients With Normal Clinical Strength MRIs.

While the etiology of hippocampal sclerosis (HS) in epilepsy patients remains unknown, distinct phenotypes of hippocampal subfield atrophy have been associated with different clinical presentations and surgical outcomes. The advent of novel techniques including ultra-high field 7T magnetic resonance imaging (MRI) and automated subfield volumetry have further enabled detection of hippocampal pathology in patients with epilepsy, however, studies combining both 7T MRI and automated segmentation in epilepsy patients with normal-appearing clinical MRI are limited. In this study, we present a novel application of the automated segmentation of hippocampal subfields (ASHS) software to determine subfield volumes of the CA1, CA2/3, CA4/DG, and the subiculum using ultra high-field 7T MRI scans, including T1-weighted MP2RAGE and T2-TSE sequences, in 27 patients with either mesial temporal lobe epilepsy (mTLE) or neocortical epilepsy (NE) compared to age and gender matched healthy controls. We found that 7T improved visualization of structural abnormalities not otherwise seen on clinical strength MRIs in patients with unilateral mTLE. Additionally, our automated segmentation algorithm was able to detect structural differences in volume and asymmetry across hippocampal subfields in unilateral mTLE patients compared to controls. Specifically, amongst unilateral mTLE patients with longer disease durations, volume loss was observed in the ipsilateral CA1 and CA2/3 subfields and contralateral CA1. There were no differences in subfield volumes in patients with NE compared to controls. We report the first application of 7T with automated segmentation to characterize the relationship between disease duration burden and asymmetry across specific hippocampal subfields in this population. Disease duration was found to have a statistically significant positive relationship with subfield asymmetry within the unilateral mTLE cohort. These findings highlight the ability of 7T MRI and automated segmentation to provide novel qualitative and quantitative information in epilepsy patients who are otherwise MRI-negative at clinical field strengths.

The Expanding Role of Geometric Morphometrics in Craniofacial Surgery.

INTRODUCTION: Geometric morphometrics (GM) is an advanced landmark-based quantitative method used to study biological shape and form. Historically, GM has been limited to non-biomedical fields such as comparative biology; however, this technique confers advantages over traditional cephalometric methods, warranting a review of current applications of GM to human craniofacial disorders. METHODS: The RISmed package was used to extract metadata associated with PubMed publications referencing GM analysis techniques in craniofacial and reconstructive surgery. PubMed search terms included "geometric AND morphometric AND craniofacial;" and "geometric AND morphometric AND reconstructive surgery." Duplicate search results were eliminated. RESULTS: Search yielded 139 studies between 2005 and 2020, of which 27 met inclusion criteria. Human craniofacial studies constituted 2% of all queried GM studies. Among these, cleft lip and palate were the most commonly studied craniofacial conditions (7 studies, 26%), followed by sagittal craniosynostosis (4 studies, 15%). Seventeen studies (63%) used GM to assess skeletal structures, seven studies (26%) examined both skeletal and soft tissues, and three studies (11%) analyzed soft tissues only. Eleven studies (40.1%) employed a GM approach to evaluate postoperative changes in craniofacial morphology. Two studies (7%) systematically compared GM analysis with conventional shape measurements. CONCLUSION: The ability to study shape while controlling for variability in structure size and imaging technique make GM a promising tool for understanding growth patterns in complex craniofacial diseases. Furthermore, GM overcomes many limitations of traditional cephalometric techniques, and hence may claim an expanded role in the study of human craniofacial disorders in clinical and research settings.

Leveraging high-resolution 7-tesla MRI to derive quantitative metrics for the trigeminal nerve and subnuclei of limbic structures in trigeminal neuralgia.

BACKGROUND: Trigeminal Neuralgia (TN) is a chronic neurological disease that is strongly associated with neurovascular compression (NVC) of the trigeminal nerve near its root entry zone. The trigeminal nerve at the site of NVC has been extensively studied but limbic structures that are potentially involved in TN have not been adequately characterized. Specifically, the hippocampus is a stress-sensitive region which may be structurally impacted by chronic TN pain. As the center of the emotion-related network, the amygdala is closely related to stress regulation and may be associated with TN pain as well. The thalamus, which is involved in the trigeminal sensory pathway and nociception, may play a role in pain processing of TN. The objective of this study was to assess structural alterations in the trigeminal nerve and subregions of the hippocampus, amygdala, and thalamus in TN patients using ultra-high field MRI and examine quantitative differences in these structures compared with healthy controls. METHODS: Thirteen TN patients and 13 matched controls were scanned at 7-Tesla MRI with high resolution, T1-weighted imaging. Nerve cross sectional area (CSA) was measured and an automated algorithm was used to segment hippocampal, amygdaloid, and thalamic subregions. Nerve CSA and limbic structure subnuclei volumes were compared between TN patients and controls. RESULTS: CSA of the posterior cisternal nerve on the symptomatic side was smaller in patients (3.75 mm2) compared with side-matched controls (5.77 mm2, p = 0.006). In TN patients, basal subnucleus amygdala volume (0.347 mm3) was reduced on the symptomatic side compared with controls (0.401 mm3, p = 0.025) and the paralaminar subnucleus volume (0.04 mm3) was also reduced on the symptomatic side compared with controls (0.05 mm3, p = 0.009). The central lateral thalamic subnucleus was larger in TN patients on both the symptomatic side (0.033 mm3) and asymptomatic side (0.035 mm3), compared with the corresponding sides in controls (0.025 mm3 on both sides, p = 0.048 and p = 0.003 respectively). The inferior and lateral pulvinar thalamic subnuclei were both reduced in TN patients on the symptomatic side (0.2 mm3 and 0.17 mm3 respectively) compared to controls (0.23 mm3, p = 0.04 and 0.18 mm3, p = 0.04 respectively). No significant findings were found in the hippocampal subfields analyzed. CONCLUSIONS: These findings, generated through a highly sensitive 7 T MRI protocol, provide compelling support for the theory that TN neurobiology is a complex amalgamation of local structural changes within the trigeminal nerve and structural alterations in subnuclei of limbic structures directly and indirectly involved in nociception and pain processing.