Outcomes, complications, and dosing of intrathecal baclofen in the treatment of multiple sclerosis: a systematic review.

OBJECTIVE: The purpose of this systematic review was to evaluate empirical outcomes of studies in the literature that investigated effectiveness of intrathecal baclofen (ITB) in the treatment of multiple sclerosis (MS)-related spasticity (MSRS) based on various metrics. Since the first description of this route of baclofen delivery for MS patients by Penn and Kroin in 1984, numerous studies have contributed to the medical community's knowledge of this treatment modality. The authors sought to add to the literature a systematic review of studies over the last 2 decades that elucidates the clinical impact of ITB in treating MSRS with the following endpoints: impact on patient-centered outcomes, such as spasticity reduction (primary), complications (secondary), and dosing (secondary). METHODS: The authors queried three databases (PubMed, Scopus, and Cochrane Library) using the following search terms: (intrathecal baclofen) AND (multiple sclerosis). The set inclusion criteria were as follows: 1) original, full-text article; 2) written in the English language; 3) published between and including the years 2000 and 2023; 4) discussion of pre- and post-ITB pump implantation outcomes (e.g., reduction in spasticity and improved comfort) in MSRS patients with long-term ITB treatment; and 5) contained a minimum of 5 MS patients. Data on study type, patient demographics, follow-up periods, primary outcomes, and secondary outcomes were extracted from the included studies. RESULTS: The authors' search yielded 465 studies, of which 17 met inclusion criteria. Overall, they found evidence for the effectiveness of ITB in treating MSRS patients whose condition was refractory to oral medications, with significant reported changes in spasm frequency from pre- to postimplantation. They also found evidence supporting the positive impact of ITB on MSRS patients' quality of life. Moreover, the authors found that most complications were surgical rather than pharmacological. In addition, the average 1-year dose of ITB (reported in 7 of the included studies) was 191.93 µg/day, which is substantially lower than ITB doses reported in the literature for patients with central (non-MS) or spinal origins of spasticity at 1-year follow-up. CONCLUSIONS: The evidence supports ITB as a clinically effective treatment for MSRS, particularly in patients in whom oral antispasmodics and physiotherapy have failed. This systematic review contributes a comprehensive synthesis of clinical benefits, complications, and dosing of ITB reported over the past 2 decades, which furthers an understanding of ITB's clinical utility in practice.

Primary Sellar Neuroblastoma Masquerading as a Pituitary Macroadenoma.

Olfactory neuroblastomas, or esthesioneuroblastomas, are rare and aggressive malignant tumors that typically arise from the olfactory neuroepithelium in the upper nasal cavity. In rare instances, they can be ectopic originating from areas outside the upper nasal cavity such as the sellar region. These tumors, also known as primary sellar neuroblastomas, may be mistaken for pituitary macroadenomas. We present a rare case of a primary sellar neuroblastoma in a 30-year-old woman with a prior diagnosis of presumed prolactinoma, status post transsphenoidal resection, with residual visual deficits, who presented with worsening vision and headaches. Pituitary magnetic resonance imaging showed a large sellar mass causing compression of the optic chiasm, and invasion of the right cavernous sinus and bilateral cavernous internal carotid arteries. The patient underwent a second transsphenoidal resection. Postoperatively, she developed central adrenal insufficiency, central hypothyroidism, central hypogonadism, and transient syndrome of inappropriate antidiuretic hormone secretion. Owing to rapid tumor regrowth, she underwent a craniotomy with plans for radiation treatment. This condition is challenging to diagnose and has poorly defined clinical management guidelines. An early, aggressive approach with surgical intervention is recommended.

Dural Closure Techniques and Cerebrospinal Fluid Leak Incidence After Resection of Primary Intradural Spinal Tumors: A Systematic Review.

STUDY DESIGN: This is a systematic review of primary intradural spinal tumors (PIDSTs) and the frequency of postoperative cerebrospinal fluid (CSF) leaks. OBJECTIVE: This study aimed to compare CSF leak rates among techniques for dural watertight closure (WTC) after the resection of PIDSTs. SUMMARY OF BACKGROUND DATA: Resection of PIDSTs may result in persistent CSF leak. This complication is associated with infection, wound dehiscence, increased length of stay, and morbidity. Dural closure techniques have been developed to decrease the CSF leak rate. METHODS: A PubMed search was performed in 2022 with these inclusion criteria: written in English, describe PIDST patients, specify the method of dural closure, report rates of CSF leak, and be published between 2015 and 2020. Articles were excluded if they had <5 patients. We used standardized toolkits to assess the risk of bias. We assessed patient baseline characteristics, tumor pathology, CSF leak rate, and dural closure techniques; analysis of variance and a 1-way Fisher exact test were used. RESULTS: A total of 4 studies (201 patients) satisfied the inclusion criteria. One study utilized artificial dura (AD) and fibrin glue to perform WTC and CSF diversion, with lumbar drainage as needed. The rate of CSF leak was different among the 4 studies (P=0.017). The study using AD with dural closure adjunct (DCA) for WTC was associated with higher CSF leak rates than those using native dura (ND) with DCA. There was no difference in CSF leak rate between ND-WTC and AD-DCA, or with any of the ND-DCA studies. CONCLUSIONS: After resection of PIDSTs, the use of autologous fat grafts with ND resulted in lower rates of CSF leak, while use of fibrin glue and AD resulted in the highest rates. These characteristics suggest that a component of hydrophobic scaffolding may be required for WTC. A limitation included articles with low levels of evidence. Continued investigation to understand mechanisms for WTC is warranted. LEVEL OF EVIDENCE: Level 3.

Predictive Model Evaluating Risk of Hemorrhage in Intracranial Aneurysms: Analysis from Prospectively Collected HEAT Trial Database.

OBJECTIVE: We analyzed the data of patients enrolled in the Hydrogel Endovascular Aneurysm Treatment (HEAT) trial to develop and validate a model to predict the risk of aneurysmal hemorrhage. METHODS: Analysis included data from 600 patients enrolled for the HEAT trial and included single saccular aneurysms of 3-14 mm size. Baseline characteristics were compared between patients with ruptured and unruptured aneurysms. Regression analysis was performed in the training set to identify significant risk factors and was validated in the validation dataset. The complete dataset was used to formulate a scoring model in which positive and negative predictors were assigned 1 and -1 points, respectively. RESULTS: Data from 593 patients were analyzed in which 169 (28.5%) patients had ruptured aneurysms. The training (n = 297) and validation dataset (n = 296) had a comparable proportion of ruptured aneurysms (29.3% and 27.7%). Dome-to-neck ratio >2.5 (odds ratio [OR] 3.66), irregular shape (OR 3.79), daughter sac (OR 5.89), and anterior and posterior communicating artery locations (OR 3.32 and 3.56, respectively) had a higher rupture rate. Use of aspirin was associated with lower risk of hemorrhage (OR 0.16). The area under the curve from the receiver operating curve analysis was 0.88, 0.87, and 0.87 in the training, validation, and combined data set, respectively. The scoring model created a score of -1 to 2, yielding an of aneurysmal hemorrhage probability from 1.5% (score -1) to 70% (score 2). CONCLUSIONS: This prospective study identifies dome-to-neck ratio >2.5, irregular shape, presence of daughter sac, absence of aspirin use, and aneurysm location at anterior communicating and posterior communicating artery as factors associated with increased risk of hemorrhagic presentation in small- to medium-sized intracranial aneurysms. Our model provides an estimate of rupture risk based on the presence or absence of these factors.

Hospital Length of Stay Independently Predicts Mortality in Patients Emergently Admitted for Esophageal Hemorrhage: Sex, Frailty, and Age as Additional Mortality Factors.

INTRODUCTION: Upper gastrointestinal bleeding results in greater than $7.6 billion of in-hospital economic burden in the United States yearly. With a worldwide incidence between 40-100/100,000 individuals and a mortality rate of approximately 2-10%, upper gastrointestinal bleeding represents a major source of mortality and morbidity. The goal of this study was to describe mortality risk factors in patients emergently admitted with esophageal hemorrhage, the second most common etiology of upper gastrointestinal bleeding. MATERIALS AND METHODS: Patients emergently admitted with esophageal hemorrhage between 2005-2014 were evaluated using the National Inpatient Sample database. Patient characteristics, clinical outcomes, and therapeutic trends were obtained. Relationships between morality and all other variables were determined via univariable and multivariable logistic regression analyses. RESULTS: In total, 4,607 patients were included, of which 2,045 (44.4%) were adults, 2,562 (55.6%) were elderly, 2,761 (59.9%) were males, and 1,846 (40.1%) were females. The average age of adult and elderly patients were 50.1 and 78.7 years, respectively. The multivariable logistic regression analysis revealed, for every additional day of hospitalization, the odds of mortality for nonoperatively treated adult and elderly patients increased by 7.5% (p=<0.001) and 6.6% (p=<0.001), respectively. Every additional year of age was associated with a 5.4% (p=0.012) increase in mortality odds for nonoperatively managed adult patients. Frailty increased the odds of mortality by 31.1% (p=0.009) in nonoperatively treated elderly patients. Undergoing invasive diagnostic procedures in conservatively treated adults reduced mortality significantly (odds ratio=0.400, p=0.021). Frailty, age, and hospital length of stay demonstrated no significant association with mortality in surgically managed adult and elderly patients. CONCLUSION: Nonoperatively managed patients emergently admitted for esophageal hemorrhage with longer hospital length of stay and higher modified frailty index exhibited higher odds of mortality. Invasive diagnostic procedures were negatively correlated with mortality in nonoperatively treated adult patients. Age is only associated with higher mortality rates in adults, while elderly patients revealed no association between age and mortality.

Cerebrospinal Venous Fistula Presenting with Cognitive Decline: Systematic Literature Review and Report of Two Cases.

OBJECTIVE: A cerebrospinal fluid (CSF) venous fistula (CVF) is an aberrant connection between the subarachnoid space and a vein resulting in CSF loss. The presentation and management of CVF with cognitive decline is incompletely understood. METHODS: A systematic review was completed following the PRISMA guidelines. Articles that included at least 1 case of imaging-confirmed CVF with details on patient treatment were included. A separate review of cases of patients with spontaneous intracranial hypotension (SIH) with frontotemporal dementia (FTD) or dementia symptoms was also completed. RESULTS: Ten CVF articles (69 patients; average age, 51.5 years) and 5 SIH with FTD or dementia articles (n = 41; average age, 55.9 years) were identified. Only 1 patients with CVF with cognitive abnormalities was identified. The most common symptom was headache in both reviews. Brain sag was identified in all patients, whereas CSF leak was identified in only 2 patients with SIH with FTD or dementia (4.9%). An epidural blood or fibrin glue patch was used in all patients with CVF and in 33 patients with SIH with FTD or dementia. Fifty-five patients with CVF (79.7%) and 27 patients with SIH with FTD or dementia (65.9%) had surgery. CONCLUSIONS: The 2 cases and literature reviews show the difficulty in diagnosis and treatment of CVF with cognitive decline. Novel imaging techniques should be used in patients with cognitive decline in whom a CSF leak is suspected. Transvenous embolization or surgery should be considered before patching for treatment of CVF-induced brain sag and resulting dementia.

Risk factors for posttraumatic hydrocephalus after decompressive hemicraniectomy in pediatric patients with traumatic brain injury.

OBJECTIVE: Traumatic brain injuries (TBIs) play a significant role in pediatric mortality and morbidity. Decompressive hemicraniectomy (DHC) is a treatment option for severe pediatric TBI (pTBI) not amenable to medical management of intracranial pressure. Posttraumatic hydrocephalus (PTH) is a known sequela of DHC that may lead to further injury and decreased capacity for recovery if not identified and treated. The goal of this study was to characterize risk factors for PTH after DHC in patients with pTBI by using the Kids' Inpatient Database (KID). METHODS: The records collected in the KID from 2016 to 2019 were queried for patients with TBI using International Classification of Diseases, 10th Revision codes. Data defining demographics, complications, procedures, and outcomes were extracted. Multivariate regression was used to identify risk factors associated with PTH. The authors also investigated length of stay and hospital charges. RESULTS: Of 68,793 patients with pTBI, 848 (1.2%) patients underwent DHC. Prolonged mechanical ventilation (PMV) was required in 475 (56.0%) patients with pTBI undergoing DHC. Three hundred (35.4%) patients received an external ventricular drain (EVD) prior to DHC. PTH was seen in 105 (12.4%), and 50 (5.9%) received a ventriculoperitoneal shunt. DHC before hospital day 2 was negatively associated with PTH (OR 0.464, 95% CI 0.267-0.804; p = 0.006), whereas PMV (OR 2.204, 95% CI 1.344-3.615; p = 0.002) and EVD placement prior to DHC (OR 6.362, 95% CI 3.667-11.037; p < 0.001) were positively associated with PTH. PMV (OR 7.919, 95% CI 2.793-22.454; p < 0.001), TBI with subdural hematoma (OR 2.606, 95% CI 1.119-6.072; p = 0.026), and EVD placement prior to DHC (OR 4.575, 95% CI 2.253-9.291; p < 0.001) were independent predictors of ventriculoperitoneal shunt insertion. The mean length of stay and total hospital charges were significantly increased in patients with PMV and in those with PTH. CONCLUSIONS: PMV, presence of subdural hematoma, and EVD placement prior to DHC are risk factors for PTH in patients with pTBI who underwent DHC. Higher healthcare resource utilization was seen in patients with PTH. Identifying risk factors for PTH may improve early diagnosis and efficient resource utilization.

Real-Time MRI-Guided Stereotactic Aspiration of Spontaneous Intracerebral Hematoma: A Preclinical Feasibility Study.

BACKGROUND: Minimally invasive surgical techniques have reinvigorated the role of surgical options for spontaneous intracranial hematomas; however, they are limited by the lack of real-time feedback on the extent of hematoma evacuation. OBJECTIVE: To describe the development of a MRI-guided catheter-based aspiration system, the ClearPoint Pursuit Neuroaspiration Device (ClearPoint Neuro) and validation in phantom models. METHODS: In this preclinical experimental trial, 8 phantom brains with skull models were created to simulate an intracranial hematoma with 2 clot sizes, 30 cc (small clot) and 60 cc (large clot). After registration, the aspiration catheter (Pursuit device) was aligned to the desired planned trajectory. The aspiration of the clot was performed under real-time MRI scan in 3 orthogonal views. The primary end point was reduction of the clot volume to less than 15 cc or 70% of the original clot volume. RESULTS: Successful completion of clot evacuation was achieved in all models. The average postaspiration clot volume was 9.5 cc (8.7 cc for small clots and 10.2 cc for large clots). The average percentage reduction of clot volume was 76.3% (range 58.7%-85.2%). The average total procedure time (from frame registration to final postaspiration clot assessment) was 50 min. The average aspiration time was 6.9 min. CONCLUSION: This preclinical trial confirms the feasibility and efficacy of MRI-guided aspiration under real-time image guidance in simulation models for intracranial hematoma. Clinical use of the system in patients would further validate its efficacy and safety.

Clinical outcomes of first- and second-generation hydrogel coils compared with bare platinum coils: a systematic literature review.

Endovascular coiling has revolutionized intracranial aneurysm treatment; however, recurrence continues to represent a major limitation. The hydrogel coil was developed to increase packing density and improve neck healing and therefore decrease recurrence rates. In this paper, we review treatment outcomes of first- (1HCs) and second-generation (2HCs) hydrogel coils and compare them to those of bare platinum coils (BPC). A query of multiple databases was performed. Articles with at least 10 aneurysms treated with either 1HC or 2HC were selected for analysis. Collected data included aneurysm size, rupture status, initial occlusion, initial residual neck/aneurysm, packing density, mortality, morbidity, recurrence, and retreatment rates. The primary endpoint was recurrence at final follow-up. Secondary endpoints included residual neck and dome rates as well as procedure-related complications and functional dependence at final follow-up. Studies that compared 1HC to BPC showed significant lower recurrence (24% vs. 30.8%, p = 0.02) and higher packing density (58.5% vs. 24.1%, p < 0.001) in 1HC but no significant difference in initial occlusion rate (p = 0.08). Studies that compared 2HC to BPC showed lower recurrence (6.3% vs. 14.3%, p = 0.007) and retreatment rates (3.4% vs. 7.7%, p = 0.010) as well as higher packing density (36.4% vs. 29.2%, p = 0.002) in 2HC, with similar initial occlusion rate (p = 0.86). The rate of complications was not statistically different between HC (25.5%) and BPC (22.6%, p = 0.06). Based on our review, the 1HC and 2HC achieved higher packing density and lower recurrence rates compared to BPC. The safety profile was similar between both groups.

A comparison of treating physician versus independent core lab assessments of post-aneurysm treatment imaging outcomes: an analysis of prospectively collected data from a randomized trial.

OBJECTIVE: Aneurysm occlusion has been used as surrogate marker of aneurysm treatment efficacy. Aneurysm occlusion scales are used to evaluate the outcome of endovascular aneurysm treatment and to monitor recurrence. These scales, however, require subjective interpretation of imaging data, which can reduce the utility and reliability of these scales and the validity of clinical studies regarding aneurysm occlusion rates. Use of a core lab with independent blinded reviewers has been implemented to enhance the validity of occlusion rate assessments in clinical trials. The degree of agreement between core labs and treating physicians has not been well studied with prospectively collected data. METHODS: In this study, the authors analyzed data from the Hydrogel Endovascular Aneurysm Treatment (HEAT) trial to assess the interrater agreement between the treating physician and the blinded core lab. The HEAT trial included 600 patients across 46 sites with intracranial aneurysms treated with coiling. The treating site and the core lab independently reviewed immediate postoperative and follow-up imaging (3-12 and 18-24 months, respectively) using the Raymond-Roy occlusion classification (RROC) scale, Meyer scale, and recanalization survey. A post hoc analysis was performed to calculate interrater reliability using Cohen's kappa. Further analysis was performed to assess whether degree of agreement varied on the basis of various factors, including scale used, timing of imaging, size of the aneurysm, imaging modality, location of the aneurysm, dome-to-neck ratio, and rupture status. RESULTS: Minimal interrater agreement was noted between the core lab reviewers and the treating physicians for assessing aneurysm occlusion using the RROC grading scale (k = 0.39, 95% CI 0.38-0.40) and Meyer scale (k = 0.23, 95% CI 0.14-0.38). The degree of agreement between groups was slightly better but still weak for assessing recanalization (k = 0.45, 95% CI 0.38-0.52). Factors that significantly improved degree of agreement were scales with fewer variables, greater time to follow-up, imaging modality (digital subtraction angiography), and wide-neck aneurysms. CONCLUSIONS: Assessment of aneurysm treatment outcome with commonly used aneurysm occlusion scales suffers from risk of poor interrater agreement. This supports the use of independent core labs for validation of outcome data to minimize reporting bias. Use of outcome tools with fewer point categories is likely to provide better interrater reliability. Therefore, the outcome assessment tools are ideal for clinical outcome assessment provided that they are sensitive enough to detect a clinically significant change.

NRF2 Loss Accentuates Parkinsonian Pathology and Behavioral Dysfunction in Human α-Synuclein Overexpressing Mice.

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a central regulator of cellular stress responses and its transcriptional activation promotes multiple cellular defense and survival mechanisms. The loss of NRF2 has been shown to increase oxidative and proteotoxic stress, two key pathological features of neurodegenerative disorders such as Parkinson's disease (PD). Moreover, compromised redox homeostasis and protein quality control can cause the accumulation of pathogenic proteins, including alpha-synuclein (α-Syn) which plays a key role in PD. However, despite this link, the precise mechanisms by which NRF2 may regulate PD pathology is not clear. In this study, we generated a humanized mouse model to study the importance of NRF2 in the context of α-Syn-driven neuropathology in PD. Specifically, we developed NRF2 knockout and wild-type mice that overexpress human α-Syn (hα-Syn+/Nrf2-/- and hα-Syn+/Nrf2+/+ respectively) and tested changes in their behavior through nest building, challenging beam, and open field tests at three months of age. Cellular and molecular alterations in α-Syn, including phosphorylation and subsequent oligomerization, as well as changes in oxidative stress, inflammation, and autophagy were also assessed across multiple brain regions. It was observed that although monomeric α-Syn levels did not change, compared to their wild-type counterparts, hα-Syn+/Nrf2-/- mice exhibited increased phosphorylation and oligomerization of α-Syn. This was associated with a loss of tyrosine hydroxylase expressing dopaminergic neurons in the substantia nigra, and more pronounced behavioral deficits reminiscent of early-stage PD, in the hα-Syn+/Nrf2-/- mice. Furthermore, hα-Syn+/Nrf2-/- mice showed significantly amplified oxidative stress, greater expression of inflammatory markers, and signs of increased autophagic burden, especially in the midbrain, striatum and cortical brain regions. These results support an important role for NRF2, early in PD progression. More broadly, it indicates NRF2 biology as fundamental to PD pathogenesis and suggests that targeting NRF2 activation may delay the onset and progression of PD.

Quality of Life of Patients with Unruptured Intracranial Aneurysms Before and After Endovascular Coiling: A HEAT Trial Secondary Study and Systematic Review of the Literature.

BACKGROUND: The study of quality of life (QOL) in patients with asymptomatic diseases receiving interventional treatment provides an essential metric for the assessment of procedural benefits in the surgical patient population. In this study, we analyzed QOL data collected from patients with unruptured intracranial aneurysms (UIAs) before and after endovascular coiling in the HEAT Trial, alongside a systematic review on QOL in unruptured brain aneurysms. METHODS: HEAT was a randomized controlled trial comparing recurrence rates in aneurysms treated with either bare platinum coils or hydrogel coils. Patients enrolled in this trial completed a short form-36 (SF-36) QOL questionnaire before treatment and at the 3- to 12- and 18- to 24-month follow-ups. The change in QOL before and after treatment was assessed. Regression analysis evaluated the effect of select baseline characteristics on QOL change. RESULTS: A total of 270 patients were eligible for analysis. There was an increase in the role physical (P = 0.043), vitality (P = 0.022), and emotional well-being (P < 0.001) QOL components at the 18- to 24-month follow-up compared with baseline scores. Regression analysis showed that age younger than 60 and absence of serious adverse events were associated with improved social functioning and vitality. The literature review showed a mixed effect of intervention on QOL in patients with UIAs. CONCLUSIONS: Our analysis has revealed that patients with 3- to 14-mm UIAs had improvements in some physical and emotional components of QOL at 18-24 months following aneurysm coiling in the HEAT study. The literature remains indeterminate on this issue. Further studies are needed to better understand the effects of the diagnosis of UIAs and their treatment on QOL.