Dental Evaluation: Endodontic and Periodontal.

Endodontic and periodontal disease are distinct etiologies that can lead to odontogenic sinusitis (ODS). Apical periodontitis and periodontitis are both polymicrobial infections but with different pathogens affecting different parts of the tooth and alveolar bone. Diagnosing both conditions requires specific clinical examination in addition to radiographic assessment. Understanding the terminology and pathophysiology of these conditions and how they are identified should improve diagnostic and therapeutic outcomes, as well as future ODS research.

Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol.

PURPOSE: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy. METHODS: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex. RESULTS: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001). CONCLUSIONS: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.

Subtotal Middle Turbinate Resection in Patients with Chronic Rhinosinusitis with Nasal Polyps is Unlikely to Cause Empty Nose Syndrome: A Multi-Institutional Prospective Study.

BACKGROUND: Empty nose syndrome (ENS) is a poorly understood, debilitating condition affecting a minority of patients who underwent nasal airway surgery, most commonly following inferior turbinate surgery. Few publications have demonstrated middle turbinate resection (MTR) causing ENS, but MTR is still considered a potential cause of ENS. The Empty Nose Syndrome 6-item Questionnaire (ENS6Q) is validated for ENS diagnosis, with ENS6Q ≥ 11 considered highly suggestive of ENS. The purpose of this multicenter study was to determine the incidence of patients with ENS6Q ≥ 11 following subtotal MTR during endoscopic sinus surgery (ESS) for chronic rhinosinusitis with nasal polyps (CRSwNP) by comparing preoperative and postoperative ENS6Q scores. METHODS: A multi-institutional prospective cohort study (8 US institutions) was conducted on patients who underwent bilateral subtotal MTR during ESS for CRSwNP. Preoperative and postoperative ENS6Q scores were compared after at least 12 months of postoperative follow-up. RESULTS: Of 110 patients, mean age was 51.6 years and 59.1% were male. Mean follow-up was 14.5 ± 2.5 months (range 12.1-22.3 months). Mean preoperative and postoperative ENS6Q were 7.7 and 2.2, respectively, demonstrating a mean 5.5 point decrease postoperatively (p < 0.0001). At final follow-up, no patient had an ENS6Q ≥ 11. Of note, 20% of patients had preoperative ENS6Q scores ≥11, but all decreased to <11 postoperatively. CONCLUSIONS: Based on prospective multicenter data over 1-2 years postoperatively, subtotal MTR for CRSwNP never led to ENS6Q scores ≥11, and patients experienced significant decreases in ENS6Q postoperatively. Subtotal MTR during ESS for CRSwNP was, therefore, unlikely to cause ENS even with long-term follow-up. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Management of Endodontic Disease for Odontogenic Sinusitis.

Primary dental treatments for odontogenic sinusitis (ODS) due to endodontic infections (pulpal necrosis and apical periodontitis ± periapical abscess) include extraction and root canal treatment (RCT). Published evidence is lacking on the success of primary endodontic treatment for purulent ODS, with the majority of RCT-related series reporting on its success at resolving reactive maxillary sinus mucositis. Dental extraction is the most definitive treatment of endodontic disease causing ODS, but compromises the functional dentition and still often fails to resolve the purulent sinusitis. This article highlights key concepts of RCT and dental extraction techniques, as well as their published success at resolving ODS.

Collaboration between otolaryngologists and oral surgeons in maxillary sinus elevation planning.

BACKGROUND: The collaboration between otolaryngologists and dental providers is crucial for the planning and execution of maxillary sinus elevation (MSE) procedures, which are integral to successful dental implant placements. PURPOSE: This article examines the essential role of otolaryngological assessments in identifying potential sinonasal risks that could impact the outcomes of MSE. MATERIALS AND METHODS: A comprehensive narrative review of existing literature was conducted. DISCUSSION: The review underscores the importance of thorough preoperative evaluations, including patient history, computed tomography (CT) or cone-beam CT (CBCT) scans, and nasal endoscopy, to mitigate sinonasal health risks. It details various clinical scenarios and patient assessments, emphasizing a systematic approach to diagnosing and managing sinonasal conditions proactively. The discussion reveals that while some sinus conditions may not significantly affect MSE success, conditions impacting mucociliary clearance and sinus drainage are critical risk factors requiring otolaryngological intervention. Additionally, the article introduces a grading system to assist clinicians in identifying patients who would benefit from otolaryngological evaluations prior to MSE. CONCLUSION: This review highlights the value of interdisciplinary collaboration and standardized protocols in enhancing the predictability and safety of MSE procedures, ultimately improving patient outcomes.

Maxillary Antrostomy Versus Complete Sinus Surgery for Odontogenic Sinusitis With Frontal Sinus Extension.

OBJECTIVES: Endoscopic sinus surgery (ESS) is often necessary when managing odontogenic sinusitis (ODS), but ESS extent for ODS with extramaxillary sinus involvement has been incompletely studied. This study compared outcomes after wide maxillary antrostomy (MA) alone versus complete ESS for ODS with frontal sinus involvement. METHODS: A multicenter prospective cohort study was conducted on patients with uncomplicated ODS (no extrasinus spread) who underwent ESS when computed tomography demonstrated maxillary, anterior ethmoid (AE), and frontal sinus opacification. Multiple preoperative and postoperative variables were recorded, including 22-item sinonasal outcome tests (SNOT-22) and endoscopic findings. Ultimate SNOT-22 and endoscopic resolution, and time to SNOT-22 and endoscopic resolution were compared between patients who underwent MA alone versus "complete" ESS (maxillary, ethmoid, frontal; not sphenoid). RESULTS: Of 70 patients, mean age was 59.2 years, and 55.7% were male. Thirty-five underwent MA alone, and 35 had complete ESS. At first postoperative visits (mean 9.3 days), AE sinus purulence was more likely resolved after complete ESS compared with MA (97.1% vs. 71.4%, p = 0.006). However, time to resolution of AE purulence was comparable by 6 weeks postoperatively (p = 0.158). There were no significant differences in times to foul smell resolution and achieving ≥9 point SNOT-22 reduction (p > 0.05). CONCLUSIONS: For ODS with frontal sinus involvement, MA alone and complete ESS both resulted in rapid and long-term symptomatic resolution. While ultimate resolution of sinus purulence was equivalent between surgery groups, complete ESS did lead to faster resolution of frontoethmoidal purulence in a significant number of cases. LEVEL OF EVIDENCE: 2 Laryngoscope, 2024.

Unilateral Sinus Disease: What Is, and Is Not Odontogenic Sinusitis?

The differential diagnosis of unilateral sinus disease (USD) is broad, and while concerning etiologies like sinonasal neoplasia, invasive fungal sinusitis, and cerebrospinal fluid rhinorrhea should always be considered, most cases are due to noninvasive inflammatory or infectious conditions. To diagnose USD appropriately, clinicians must integrate the clinical history and examination, nasal endoscopy, computed tomography (CT), and possibly MRI. Odontogenic sinusitis (ODS) is the most common cause of unilateral maxillary sinus opacification on CT, with 45% to 75% of such cases being odontogenic in nature. This study provides USD diagnostic considerations and reinforces the diagnostic approach to ODS.

Sinus Evaluation for Odontogenic Sinusitis.

This article summarizes how to diagnose common and nuanced cases of odontogenic sinusitis (ODS) through a collaborative approach between otolaryngologists and dental specialists, with a heightened focus on the role of otolaryngologists in the diagnostic process. A critical part of the diagnostic framework is that otolaryngologists must confirm the infectious sinusitis but also suspect ODS to ensure he or she refers the patient to a dental specialist to confirm or refute ipsilateral infectious maxillary dental pathology. To confirm the purulent sinusitis of ODS, nasal endoscopy is most critical. Computed tomography imaging is an important part of the workup.

The use of parent-completed questionnaires to investigate developmental outcomes in large populations of children exposed to antiseizure medications in pregnancy.

OBJECTIVE: This study was undertaken to assess the utility of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and the Vineland Adaptive Behavior Scales-2nd Edition (VABS-II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large-population signal generation initiatives. METHODS: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development-3rd Edition (BSID-III), the VABS-II, and the ASQ-3 (n = 223). The sensitivity and specificity of the ASQ-3 and VABS-II to identify developmental delay at 24 months were examined, using the BSID-III to define cases. RESULTS: The ASQ-3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ-3 and BSID-III at 24 months, the ASQ-3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut-points resulted in improved properties and may be preferred in certain contexts. The VABS-II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID-III referral data (sensitivity = 100.0%, specificity = 96.6%). SIGNIFICANCE: Both the ASQ-3 and VABS-II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at-risk groups. These findings identify the ASQ-3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS-II has excellent psychometric properties, it is more labor-intensive for both the research team and participants and is available in fewer languages than the ASQ-3.

Maxillary sinus opacification after surgery in asymptomatic patients: Transient swelling of the sinus mucosa or graft dispersion into the maxillary sinus. A radiographic report of three cases after a follow-up period of at least 5 years.

Maxillary sinus grafting is a predictable regenerative technique to facilitate maxillary posterior implant placement when there is insufficient vertical bone height inferior to the maxillary sinuses to allow placement of implants of adequate dimensions. It enables an increase in vertical bone height, which makes implant placement easier. Maxillary sinus mucosal membrane perforation is one of the most common intraoperative complications during maxillary sinus grafting and may result in extrusion of graft material into the sinus. When this occurs, the mucociliary function of the maxillary sinus may expel the extruded graft material through its natural ostium, though graft particles may remain in the sinus or possibly occlude the natural ostium. After grafting, transient maxillary sinus mucosal oedema may occur. A postoperative CBCT scan may reveal varying degrees of sinus opacification, namely partial, subtotal or total. Although it is always possible to identify graft material, which may enter the sinus as a result of membrane perforation that might not even be visible to the implantologist during the surgical procedure, it is challenging to assess whether sinus opacification is due to mucosal thickening or mucus accumulation. The aim of the present case series was to offer a pragmatic approach to managing asymptomatic patients whose CBCT scans demonstrated partial, subtotal or total maxillary sinus opacification with bone graft particles that seemed to have been extruded into the sinus.

Sleep, inflammation, and hemodynamics in rodent models of traumatic brain injury.

Traumatic brain injury (TBI) can induce dysregulation of sleep. Sleep disturbances include hypersomnia and hyposomnia, sleep fragmentation, difficulty falling asleep, and altered electroencephalograms. TBI results in inflammation and altered hemodynamics, such as changes in blood brain barrier permeability and cerebral blood flow. Both inflammation and altered hemodynamics, which are known sleep regulators, contribute to sleep impairments post-TBI. TBIs are heterogenous in cause and biomechanics, which leads to different molecular and symptomatic outcomes. Animal models of TBI have been developed to model the heterogeneity of TBIs observed in the clinic. This review discusses the intricate relationship between sleep, inflammation, and hemodynamics in pre-clinical rodent models of TBI.

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.

Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

Reliability of large language models in managing odontogenic sinusitis clinical scenarios: a preliminary multidisciplinary evaluation.

PURPOSE: This study aimed to evaluate the utility of large language model (LLM) artificial intelligence tools, Chat Generative Pre-Trained Transformer (ChatGPT) versions 3.5 and 4, in managing complex otolaryngological clinical scenarios, specifically for the multidisciplinary management of odontogenic sinusitis (ODS). METHODS: A prospective, structured multidisciplinary specialist evaluation was conducted using five ad hoc designed ODS-related clinical scenarios. LLM responses to these scenarios were critically reviewed by a multidisciplinary panel of eight specialist evaluators (2 ODS experts, 2 rhinologists, 2 general otolaryngologists, and 2 maxillofacial surgeons). Based on the level of disagreement from panel members, a Total Disagreement Score (TDS) was calculated for each LLM response, and TDS comparisons were made between ChatGPT3.5 and ChatGPT4, as well as between different evaluators. RESULTS: While disagreement to some degree was demonstrated in 73/80 evaluator reviews of LLMs' responses, TDSs were significantly lower for ChatGPT4 compared to ChatGPT3.5. Highest TDSs were found in the case of complicated ODS with orbital abscess, presumably due to increased case complexity with dental, rhinologic, and orbital factors affecting diagnostic and therapeutic options. There were no statistically significant differences in TDSs between evaluators' specialties, though ODS experts and maxillofacial surgeons tended to assign higher TDSs. CONCLUSIONS: LLMs like ChatGPT, especially newer versions, showed potential for complimenting evidence-based clinical decision-making, but substantial disagreement was still demonstrated between LLMs and clinical specialists across most case examples, suggesting they are not yet optimal in aiding clinical management decisions. Future studies will be important to analyze LLMs' performance as they evolve over time.

Cadaveric and Computed Tomography Analysis of the Anterior Ethmoidal Artery Flap.

BACKGROUND: The anterior ethmoidal artery (AEA) flap has been successful in repairing anterior nasal septal perforations and has been presumed to be axially based on AEA branches coursing through or around the cribriform plate (CP). However, limited evidence supports the flap's axial supply. The purposes of this cadaveric and computed tomography (CT) study were to assess the arterial anatomy from the CP to the septum, and to determine AEA flap length to predict ideal flap base width. METHODS: Ten fresh latex-injected cadavers were utilized for endoscopic dissection to identify arteries traversing the CPs on each side. First, arterial trajectories along the dorsal septum were recorded. Measurements were then made bilaterally along the septum from the middle turbinate (MT) axilla to the nasal branch of the AEA (NBAEA) traversing the CP. Additionally, 100 sinus CTs were reviewed to measure AEA flap lengths bilaterally. RESULTS: From 10 cadavers, 20 sides were utilized for measurements. In all cadavers, the AEA septal branches coursed diagonally or horizontally along the dorsal septum, and never directly vertically. The mean distance from the MT axilla to the NBAEA was 1.24 ± 1.93 cm (range = 1-1.5 cm). Based on CTs, the mean AEA flap length was 6.40 ± 0.60 cm. CONCLUSIONS: Based on the non-vertical courses of AEA septal branches, the AEA flap is more likely a random transposition flap than an axial flap. Average AEA flap length ranged from 6.0 to 7.0 cm. Assuming 3:1 length:width ratios, AEA flap base widths should be about 2.0-2.3 cm. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2100-2104, 2024.

Nasoseptal Flap to Repair Large Maxillary Sinus Floor Defects.

This case highlights the successful use of a large nasoseptal flap to repair a large maxillary sinus floor defect. Surgeons can therefore rely on this flap for repairing maxillary sinus floor defects of most sizes and locations. Laryngoscope, 134:87-91, 2024.

Using Ipratropium Bromide Nasal Spray Response as a Screening Tool in the Diagnostic Workup of Cerebrospinal Fluid Rhinorrhea.

OBJECTIVES: Unilateral clear thin rhinorrhea (UCTR) can be concerning for a nasal cerebrospinal fluid (CSF) leak. Beta-2 transferrin electrophoresis has been the gold standard for initial non-invasive confirmatory testing for CSF rhinorrhea, but there can be issues with fluid collection and testing errors. Ipratropium bromide nasal spray (IBNS) is highly effective at reducing rhinitis-related rhinorrhea, and should presumably not resolve CSF rhinorrhea. This study assessed whether different clinical features and IBNS response helped predict presence or absence of CSF rhinorrhea. METHODS: A prospective cohort study was conducted where all patients with UCTR had nasal fluid tested for beta-2 transferrin, and were prescribed 0.06% IBNS. Patients were diagnosed with CSF rhinorrhea or other rhinologic conditions. Clinical variables like IBNS response (rhinorrhea reduction), positional worsening, salty taste, postoperative state, female gender, and body-mass index were assessed for their ability to predict CSF rhinorrhea. Sensitivity, specificity, and predictive values and odds ratios were calculated for all clinical variables. RESULTS: Twenty patients had CSF rhinorrhea, and 53 had non-CSF etiologies. Amongst clinical variables assessed for predicting CSF absence or presence, significant associations were shown for IBNS response (OR = 844.66, p = 0.001), positional rhinorrhea worsening (OR = 8.22, p = 0.049), and body-mass index ≥30 (OR = 2.92, p = 0.048). IBNS response demonstrated 96% sensitivity and 100% specificity, and 100% positive and 91% negative predictive values for predicting CSF rhinorrhea. CONCLUSIONS: In patients with UCTR, 0.06% IBNS response is an excellent screening tool for excluding CSF rhinorrhea, and should be considered in the diagnostic workup of CSF rhinorrhea. LEVEL OF EVIDENCE: 2 Laryngoscope, 134:56-61, 2024.

Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin.

Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug. Methods: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants. Results: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing. Conclusion: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.