Scholarly Activity
Neurology Publications
Scholarly journal articles and meeting abstracts authored by members of the Department of Neurology at Henry Ford Health.
Neurology Articles
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5/1/2025 7:00 AM
BACKGROUND: Synesthesia is a condition in which the stimulation of one sensory modality triggers unusual experiences in a second sensory modality such as colors or shapes. Synesthesia has been linked to specific conditions such as autism spectrum disorder, although the mechanisms underlying synesthesia remain largely unclear.
OBJECTIVE: This pilot study aimed to investigate the prevalence of grapheme-color synesthesia (GCS) in patients with epilepsy and to characterize the epilepsy features associated with GCS experiences.
METHODS: Participants were asked whether they reported experiences suggesting GCS. Those reporting GCS underwent a standard online consistency and congruency battery test (http://www.synesthete.org). Epilepsy features, electroencephalogram (EEG) findings, and magnetic resonance imaging (MRI) findings were collected and analyzed.
RESULTS: Of the 40 study participants, 21 reported GCS experiences and 3 (7.5 %) resulted synesthetes from the battery test. Analysis of the test results showed that participants with focal seizures had lower median consistency scores (indicating they were less consistent in their color assignments) and higher congruency scores (indicating they were more accurate in quickly identifying matching color and letter/number combinations) compared to patients with generalized-onset seizures (2.9 and 51.4 respectively; p = 0.006, p = 0.001). Participants with non-motor seizures had lower median consistency scores (1.1) and higher congruency scores (79.2) compared to patients with motor seizures (2.8 and 52.8, respectively; p = 0.011, p = 0.036).
CONCLUSION: GCS may be more prevalent in patients with epilepsy than the general population. Focal and non-motor seizures may be associated with predisposition to GCS. Further larger scale studies are needed to confirm and expand these observations.
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Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial4/1/2025 7:00 AM
IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.
OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.
DESIGN SETTINGS AND PARTICIPANTS: Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.
INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.
MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.
RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR < 1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.
CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.
TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.
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3/1/2025 8:00 AM
Dendritic and axonal plasticity, which mediates neurobiological recovery after a stroke, critically depends on the mitochondrial function of neurons. To investigate, in vivo, neuronal mitochondrial function at the stroke recovery stage, we employed Mito-tag mice combined with cerebral cortical infection of AAV9 produced from plasmids carrying Cre-recombinase controlled by two neuronal promoters, synapsin-I (SYN1) and calmodulin-kinase IIa to induce expression of a hemagglutinin (HA)-tagged enhanced green fluorescence protein (EGFP) that localizes to mitochondrial outer membranes of SYN1 positive (SYN(+)) and CaMKIIa positive (CaMKIIa(+)) neurons. These mice were then subjected to permanent middle cerebral artery occlusion (MCAO) and sacrificed 14 days post stroke. Neuronal mitochondria were then selectively isolated from the fresh brain tissues excised from the ischemic core (IC), ischemic boundary zone (IBZ), as well as from the homologous contralateral hemisphere (CON) by anti-HA magnetic beads for functional analyses. We found that the bead pulled neuronal specific mitochondria were co-precipitated with GFP and enriched with mitochondrial markers, e.g. voltage-dependent anion channel, cytochrome C, and COX IV, but lacked the Golgi protein RCAS1 as well as endoplasmic reticulum markers: Heme‑oxygenase 1 and Calnexin, indicating that specific neuronal mitochondria have been selectively isolated. Western-blot data showed that oxidative phosphorylation (OXPHOS) components in SYN(+) and CAMKII(+) neuronal mitochondria were significantly decreased in the IBZ and further decreased in the IC compared to the contralateral tissue, which was associated with the significant reductions of mitochondrial function indicated by oxygen consumption rate (OCR) (p < 0.05, respectively, for both neuron types). These data suggest dysfunction of neuronal mitochondria post stroke is present during the stroke recovery stage. Collectively, for the first time, we demonstrated that using a Mito-tag mouse line combined with AAV9 carrying Cre recombinase approach, neuronal specific mitochondria can be efficiently isolated from the mouse brain to investigate their functional changes post stroke.
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3/1/2025 8:00 AM
Neuronal circuitry remodelling, which comprises excitatory and inhibitory neurons, is critical for improving neurological outcomes after a stroke. Preclinical studies have shown that small extracellular vesicles (sEVs) have a therapeutic effect on stroke recovery. However, it is highly challenging to use sEVs to specifically target individual neuronal populations to enhance neuronal circuitry remodelling after stroke. In the present study, using a chemogenetic approach to specifically activate peri-infarct cortical interneurons in combination with the administration of sEVs derived from cerebral endothelial cells (CEC-sEVs), we showed that the CEC-sEVs were preferentially taken up by the activated neurons, leading to significant improvement of functional outcome after stroke, which was associated with augmentation of peri-infarct cortical axonal/dendritic outgrowth and of axonal remodelling of the corticospinal tract. The ultrastructural and Western blot analyses revealed that neurons with internalization of CEC-sEVs exhibited significantly reduced numbers of damaged mitochondria and proteins that mediate dysfunctional mitochondria, respectively. Together, these data indicate that the augmented uptake of CEC-sEVs by activated peri-infarct cortical interneurons facilitates neuronal circuitry remodelling and functional recovery after stroke, which has the potential to be a novel therapy for improving stroke recovery.
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2/27/2025 8:00 AM
BACKGROUND: Neurological complications in patients with infective endocarditis (IE), such as ischemic and hemorrhagic stroke, are well described; however, predicting which patients are most likely to experience stroke remains uncertain.
AIMS: We conducted a systematic review and meta-analysis to identify the factors associated with the risk of stroke in patients hospitalized with IE.
METHODS: A systematic search of Ovid MEDLINE, EMBASE, and Web of Science up to 27 June 2024 was conducted. Articles evaluating risk of acute ischemic stroke (AIS) or intracranial hemorrhage (ICH) in patients with IE were included. Meta-analysis of odds ratios was feasible for only some predictive factors due to study heterogeneity. Cochrane's Risk of Bias in Non-Randomized Studies of Exposure tool was used for risk-of-bias assessment.
SUMMARY OF REVIEW: Of 3538 studies identified, 35 were included: 9 prospective and 26 retrospective cohort.
CONCLUSION: Our study has identified factors which are associated with increased stroke risk in IE and may help physicians predict risk. While echocardiographic and neuroimaging findings may be particularly informative, underlying comorbidities and various laboratory values may also contribute to predicting IE-associated strokes.
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2/17/2025 8:00 AM
IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.
OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.
DESIGN, SETTING, AND PARTICIPANTS: CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.
INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks.
MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.
RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR < 1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).
CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.
TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.
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2/17/2025 8:00 AM
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.
OBJECTIVE: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.
DESIGN, SETTINGS, AND PARTICIPANTS: Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.
INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.
MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.
RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR < 1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).
CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.
TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.
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2/13/2025 8:00 AM
X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Similar mutations in ABCD1 may result in a spectrum of phenotypes in males with slow progressing adrenomyeloneuropathy (AMN) and fatal cerebral adrenoleukodystrophy (cALD) dominating most cases. Mouse models of X-ALD do not capture the phenotype differences and an appropriate model to investigate the mechanism of disease onset and progress remains a critical need. Here, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two each of apparently healthy control, AMN, and cALD patients with non-integrating mRNA-based reprogramming. iPSC lines expanded normally and expressed pluripotency markers Oct4, SOX2, NANOG, SSEA, and TRA-1-60. Expression of markers SOX17, Brachyury, Desmin, OXT2, and beta tubulin III demonstrated the ability of the iPSCs to differentiate into all three germ layers. iPSC-derived lines from CTL, AMN, and cALD male patients were differentiated into astrocytes. Differentiated AMN and cALD astrocytes lacked ABCD1 expression and accumulated saturated very long chain fatty acids (VLCFAs), a hallmark of X-ALD, and demonstrated differential mitochondrial bioenergetics, cytokine gene expression, and differences in STAT3 and AMPK signaling between AMN and cALD astrocytes. These patient astrocytes provide disease-relevant tools to investigate the mechanism of differential neuroinflammatory response in X-ALD and will be valuable cell models for testing new therapeutics.
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2/4/2025 8:00 AM
Diagnosis of ductal carcinoma in situ (DCIS) presents a challenge as we cannot yet distinguish between those lesions that remain dormant from cases that may progress to invasive ductal breast cancer (IDC) and require therapeutic intervention. Our overall interest is to develop biomimetic three-dimensional (3D) models that more accurately recapitulate the structure and characteristics of pre-invasive breast cancer in order to study the underlying mechanisms driving malignant progression. These models allow us to mimic the microenvironment to investigate many aspects of mammary cell biology, including the role of the extracellular matrix (ECM), the interaction between carcinoma-associated fibroblasts (CAFs) and epithelial cells, and the dynamics of cytoskeletal reorganization. In this review article, we outline the significance of 3D culture models as reliable pre-clinical tools that mimic the in vivo tumor microenvironment and facilitate the study of DCIS lesions as they progress to invasive breast cancer. We also discuss the role of CAFs and other stromal cells in DCIS transition as well as the clinical significance of emerging technologies like tumor-on-chip and co-culture models.
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2/3/2025 8:00 AM
IMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.
OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.
DESIGN, SETTING, AND PARTICIPANTS: Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.
INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.
MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; < 1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164).
RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683.
Neurology Abstracts
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11/1/2024 7:00 AM
BACKGROUND: OncoPath provides a visual analysis of a brain tumor patient's longitudinal clinical data overlayed on disease specific pathways with the goal of reducing knowledge discordant care and insurance authorization burden. By ingesting, curating and visually presenting the patient experience on guidelines, OncoPath aims to streamline clinical decision making and related processes. Understanding the patient's journey compared to treatment guidelines is of value in addressing health equity and guideline adoption in real world settings. METHODS: Data from 44 glioma patients diagnosed and treated between 2016-2021 were uploaded to OncoPath using natural language processing and other tools to capture abstractable data elements. The data was overlayed on guidelines using recursive graph modeling. Using the knowledge graph of a patient's history, the model also recommends treatment options in an interactive visual dashboard representing NCCN guidelines. The dashboard includes the guidelines in graphical format with associated references and notation. RESULTS: 28 males and 16 females age 21-38 years at diagnosis were abstracted. Cases represented 4 oligodendrogliomas, 13 astrocytomas, and 27 glioblastomas. Data was available through second line therapy, discharge to hospice or death. Cases were matched to the NCCN 2021 guidelines which was used for treatment decisions until November 2022. The patient data matched OncoPath except in 3 cases where KPS was not available resulting in premature pathway truncation. For these cases we inferred KPS based on subsequent treatment received to optimize the historic data. CONCLUSION: To our knowledge, this is a first-of-a-kind technology in neuro-oncology that may improve time to treatment, reduce health utilization resources and can serve as a benchmarking tool for care delivery. The feasibility of clinically implementing such tools for decision support was demonstrated. This type of tool could be particularly useful in low-resource areas where disease specific expertise may not be available or to illuminate care discrepancies.
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6/1/2024 7:00 AM
Purpose : Traumatic optic neuropathy (TON) has been regarded a vision threatening condition caused by either ocular or blunt/penetrating head trauma which is characterized by direct or indirect TON. Injury happens during sports, vehicle accidents and mainly in military war and combat exposure. TON results optic nerve damage that leads to profound loss of central vision. There is stiil a lack of TON managment. Here, we used remote ischemic post-conditioning (RIC) therapy to reduce TON related retinal dysfunction. Earlier, we have demonstrated that RIC therapy is protective in TON via AMPKα1 activation in mice. AMPKα1 is the catalytic subunit of the heterotrimeric enzyme AMPK, the master regulator of cellular energetics and metabolism. The α1 isoform predominates in immune cells including macrophages (Mφs). Methods : We generated myeloid specific AMPKα1 KO mice by using LysMcre to carry out the study. We induced TON in mice by using controlled impact system as reported previously. RIC therapy was given every day (5-7 days following TON). Western blotting, Immunohistochemistry, Flow cytometry and TEM technique, and Unisense sensor system for retinal oxygenation were used to generate research data. Results : Immunofluorescence and western blot data showed increased microglial activation and decreased retinal ganglion cell (RGCs) marker Brn3 and axonal regeneration marker GAP43 expression in TON [AMPKα1F/F] vs Sham group but TON+RIC [AMPKα1F/F] attenuated expression level of these markers. Interestingly, higher microglia activation was observed in myeloid AMPKα1F/F KO group with TON and RIC didn't show any significant difference. Flow cytometry, ELISA and retinal tissue oxygen data revealed that RIC therapy significantly reduced the pro-inflammatory signaling markers and increased anti-inflammatory markers, and improved oxygen level however, myeloid AMPKα1 KO mice didn't show any changes after TON with RIC. Transmission electron microscopy (TEM) data of optic nerve showed increased demyelination and axonal degeneration in TON [AMPKα1F/F] group and TON+RIC [AMPKα1F/F] showed improved myelination. RIC has no significant effect in myeloid AMPKα1 KO group following TON. Conclusions : Overall, these data suggested that RIC therapy provides protection against inflammation and neurodegeneration via myeloid AMPKα1. Further investigation of RIC and AMPKα1 signaling is warranted in TON.
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6/1/2024 7:00 AM
Background: GBM AGILE (NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies efficiently against a common control (C) with a primary endpoint of overall survival (OS). VAL-083 (VAL) is a DNA targeting agent that, independent of O6-methylguanine DNA methyltransferase promoter methylation status, targets the N7 position of guanine residues and facilitates inter-strand DNA crosslinks, leading to DNA doublestrand breaks and cell death. It entered the trial in January 2021, and it is the 2nd arm (of 6) to complete its evaluation. Methods: Patient subtypes considered in GBM AGILE are newly diagnosed methylated (NDM), ND unmethylated (NDU), & recurrent disease (RD). C is temozolomide (in ND) & lomustine (in RD). Arms open to all 3 subtypes are evaluated in = prospectively defined signatures (sig): NDU, NDM, RD, all ND and All. Randomization to C is 20% in each subtype. Exp arms in GBM AGILE have 1 or 2 stages. Efficacy is based on OS hazard ratio (HR) of arm/C. Efficacy goal is a final Bayesian probability ≥ 98% for HR <1.00 in combined Stages 1 & 2. Arms stop accruing in Stage 1 if they reach max sample size (N) or drop for futility or safety. Exp arms in Stage 1 are adaptively randomized with allocation being proportional to an arm's current probability of having ≥ 30% benefit in OS, P(HR <0.70). In stage 1, exp arms are evaluated monthly, and arms showing Bayesian predictive power (PP) ≥ 0.8, graduate into Stage 2 with fixed randomization in one sig. For all exp arms, follow up continues for 12 mos after accrual stops (clinical cutoff). Arms are declared futile at any monthly analysis when PP is <0.25 for all sigs. Open to all 3 subtypes, VAL entered as the 1st arm in NDM and was randomized 1:1 to C in this subtype until additional arms entered. The target max N for VAL in its Stages 1 & 2 were 150 and 50, resp. Results: At the interim after VAL reached max sample size in Stage 1, the PP for all signatures was <0.8 and >0.25 for at least one sig. Thus, VAL did not graduate nor drop for futility, but accrual stopped for maximum N in Stage 1 (see table). Final results will be presented at the meeting. Columns 2-5 show results at the interim after which VAL stopped for max N. Columns 6-8 show near final results. Conclusions: GBM AGILE is an efficient & effective model for phase 3 drug development. VAL did not increase OS compared to C in any glioblastoma subtype. GBM AGILE evaluated this agent in less time, at lower cost, & with fewer patients than typical registration trials & is currently evaluating several other arms. (Table Presented).
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5/1/2024 7:00 AM
Background: We determined the efficacy, safety, and tolerability of ND0612, an investigational, continuous 24-hours/day subcutaneous infusion of levodopa/carbidopa (LD/CD), versus oral immediate-release (IR) LD/CD in people with Parkinson’s disease (PwP) experiencing motor fluctuations.
Methods: This is a phase 3, double-blind, double-dummy (DBDD) trial (NCT04006210). PwP on ≥4 oral LD/CD doses/day (≥400mg/day LD) and experiencing ≥2.5h of daily OFF-time underwent 4-6 weeks of open-label IR-LD/CD dose adjustment followed by 4-6 weeks of open-label ND0612 conversion (+ IR-LD/CD as needed). Patients were randomized (1:1) to 12-week DBDD treatment with either their optimized ND0612 or IR-LD/CD regimens.
Results: In the open-label adjustment/conversion phases, mean ON-time without troublesome dyskinesia (OTwoTD) increased from 9.4h (both arms) at enrollment to 11.8h (ND0612) and 12.1h (IR-LD/CD) following optimization of the ND0612 regimen. During the 12-week DBDD treatment OTwoTD was maintained in the ND0612 group (11.5h at endpoint) but decreased in the IR-LD/CD group who had their ND0612 infusion withdrawn (9.8h at endpoint). The study met its primary endpoint, with the ND0612 regimen providing an additional 1.72h [95%CI: 1.08h, 2.36h] of OTwoTD compared with IR-LD/CD (p<0.0001). Significant treatment effects (TE) vs. IR-LD/CD were also seen in the hierarchical secondary endpoints: OFF-time (TE: -1.40 [-1.99, -0.80]h, p<0.0001), MDS-UPDRS Part II (TE: -3.05 [-4.28, -1.81], p<0.0001) and global impressions by patients (Odds ratio [OR] of improvement: 5.31 [2.67, 10.58], p<0.0001) and clinicians (OR: 7.23 [3.57, 14.64], p<0.0001). Infusion site reactions were the most reported adverse events (82.6% during open-label conversion to infusion, during the DBDD period the rates were 57.0% for ND0612 vs. 42.7% for IR-LD/CD). Discontinuation rates after randomization (DBDD phase; ND0612 vs IR-LD/CD) were 6.3% vs 6.1% overall, and 5.5% vs 3.1% due to adverse events.
Conclusions: ND0612 treatment led to clinically meaningful improvement in motor fluctuations and functional endpoints vs oral IR-LD/CD and was generally well tolerated.
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4/9/2024 7:00 AM
Objective: Intracranial dural arteriovenous fistula (AVF) is a rare condition; it is usually described as an arterio-venous shunt within the dura with sinus or cortical drainage. AVFs can occur anywhere in the central nervous system. Most commonly, they are found at the transverse sinus, and this location is reported in 50% of all cases. Symptoms of the Dural AVFs vary widely according to their location. Progressive thalamic dementia due to venous hypertension of thalamic draining veins is an example. Herein, we present a patient with reversible progressive encephalopathy due to this pathology. Background: This is a 55-year-old man who was admitted for progressive encephalopathy for 3 months. Inpatient work-up included a negative Computed Tomography of the head, unremarkable infectious, toxic and metabolic abnormalities including cerebrospinal fluid analysis, patient underwent MRI of the brain with contrast showing bilateral thalamic infarcts. MR angiography showed dural AVF at the torcular herophili, with high-grade stenosis of the junction of straight sinus and torcula Herophili. The patient underwent cerebral angiography showing a complex dural AVF at the tentorium and left sigmoid sinus, this was with a retrograde venous arterialization through the internal cerebral veins, the straight vein and vein of Galen. Embolization of the fistula was done intra-procedurally, with a gradual improvement of his mental status over 4 months when followed up on in the office. Design/Methods: N/A Results: N/A Conclusions: Bilateral thalamic infarcts due to underlying venous hypertension caused by dural AVF can present as a subacute or even a chronic encephalopathy. Since the symptoms are not specific, the diagnosis might be challenging. This condition must be added to the differential list when no other obvious etiology can be found. Early diagnosis and management are generally associated with good prognosis. .
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4/9/2024 7:00 AM
Objective: To present a case of Ramsey hunt syndrome that presented with SUNCT type of headache Background: Ramsay Hunt syndrome represents reactivation of latent varicella zoster virus in the geniculate ganglion, but sometimes extends to involve other cranial nerves Frequently reported symptoms are unilateral and ipsilateral facial paralysis, and painful vesicles in the auditory canal or on the auricle. Design/Methods: Case report Results: A health 55-year-old female who presented initially with acute-onset pressure-like right ear pain associated with rhinorrhea. On day 4 of symptoms, she reported worsening of symptoms, with change of pain to be excruciating, and sharp limited to 5 seconds or less per attack, innumerable times throughout the day, with associated symptoms of increased lacrimation and ipsilateral conjunctival injection. On examination, she exhibited mild scleral injection of the right eye, reduced sensation to pinprick over the right (V2) and (V1), which appeared worse during attacks, with subtle right lower motor neuron facial weakness. CT head without contrast and CTA were unremarkable. A presumed diagnosis of SUNCT was made, and patient was provided with Lamotrigine and Indomethacin, which improved symptom partially then was discharged. 3 days later she noticed facial weakness and was prescribed a course of oral steroids for 6 days. The following day, she noticed a vesicular rash developing in the pinna of the right ear, for which she was given ten-day course of Valacyclovir then All of her symptoms gradually improved till completely resolved over the next 4 weeks. Conclusions:The patient did meet the criteria for a SUNCT diagnosis according to the (ICHD-3) criteria. Additionally, she symptomsconsistent with Ramsey-Hunt syndrome with findings of vesicular rash, facial pain and facial weakness. Our case broadensthe understanding of SUNCT, allowing one to consider RHS or herpes zoster as part of the differential for SUNCT.
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4/9/2024 7:00 AM
Objective: Report an unusual case of recurrent falls secondary to obstructive hydrocephalus, attributed to tumefactive perivascular spaces. Background: Perivascular spaces also known as Virchow Robin spaces are benign, fluid-filled structures surrounding blood vessels in the white matter of the brain. They are usually small and not easily identified on brain imaging. Tumefactive Perivascular Spaces (TPVS) are characterized by the significant dilation and enlargement of these perivascular spaces. When the dilation is large enough, they can be visualized on MRI. The appearance of TPVS can resemble the appearance of more serious conditions like brain tumors and demyelinating disease making them clinically significant. Additionally, in 43% of giant TPVS, hydrocephalus can be seen. Obstructive hydrocephalus can be due to a myriad of conditions, but enlarged perivascular spaces is unusual. Most common presentation of obstructive hydrocephalus secondary to TPVS is headaches; however, as our case illustrates, poor balance and recurrent falls can be the presenting complaint. Design/Methods: NA Results: A 36-year-old man with no significant medical history presented to the Emergency Department with recurrent falls and imbalance for 6 weeks. Neurological exam was unremarkable with intact brainstem, normal strength, sensation, and reflexes; but, he had extreme difficulty maintaining a steady posture. MRI showed cystic foci filled with CSF in the right midbrain, cerebral peduncle, thalamus, and dentate nucleus but without transependymal flow on FLAIR sequences, suggestive of chronic TPVS. These lesions were causing mass effect and hence, an obstructive hydrocephalus. DWI and apparent diffusion coefficient sequences did not reveal any signal restriction. The patient was admitted and underwent endoscopic third ventriculostomy. After three months, he showed remarkable improvement of his symptoms. Conclusions: TPVS are oftentimes easily misinterpreted as a sinister process given the complications patients present with. Surgery is the mainstay of treatment and remarkable improvement can be achieved after third ventriculostomy for patients who are symptomatic.
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4/9/2024 7:00 AM
Objective: Neurosyphilis can mimic different diseases, not only in its clinical presentation but also on imaging. Treponema Pallidum is also known as the great imitator . Having an ultimate diagnosis of neurosyphilis is quite critical as this can affect management drastically. Herein, we discuss the case of a 69-year-old female who was treated for neurosyphilis, while having an atypical imaging finding of anterior temporal lobe enhancement that simulated an infection with HSV. Background: A 69-year-old female with untreated syphilis infection (diagnosed almost 20 years prior presentation), was brought in with progressive decline in memory and confusion over one month. According to the family, the patient was unable to recall the name of her children or attend to her daily activities. On initial examination, she was alert but not oriented to herself, family members, location nor time, she had perseveration while answering questions, was able to only mimic commands. The rest of her examination was otherwise unremarkable. MRI of the brain with contrast showed anterior temporal lobes, insular cortex and pons T2 and FLAIR hyperintensities, that were all enhancing. Syphilis serology was positive and reactive for IgG/IgM. Treponema pallidum hemagglutination test was positive, and HIV was negative. CSF studies showed protein of 94.6 mg/dL, WBC of 15 cells/mm3 with lymphocytic predominance, RBC of 35 cu/mm, VDRL in the CSF was negative. Viral studies in the CSF were all negative. Benzathine penicillin G 24 million units was given for the total of 14 days with improvement in her mental status on follow up at one and two months. Design/Methods: N/A Results: N/A Conclusions:This unusual imaging finding of anterior temporal lobe hyperintensities with enhancement, plus the clinical presentationmake it worth listing neurosyphilis next to many disease processes including HSV on the differential list.
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4/9/2024 7:00 AM
Objective: Minimally invasive and surgical spine procedures are commonplace with various risks and complications. Cranial nerve palsies, however, are infrequently encountered, particularly after procedures such as lumbar punctures, epidural anesthesia, or intrathecal injections and are understandably worrisome for clinicians and patients as they may be interpreted as secondary to a sinister etiology. However, a less commonly considered source is pneumocephalus which may, in rare cases abut cranial nerves and cause a palsy as a benign and often self-resolving complication. Background: A middle-aged patient with a new diagnosis of high-grade mature T-cell non-Hodgkin lymphoma was admitted to the hospital for chemotherapy initiation. The patient received the first cycle of CHOP chemotherapy and a first infusion intrathecal methotrexate infusion and post-procedurally, she developed a new onset of painless right-sided horizontal diplopia. The intrathecal injection was performed in prone positioning using a fluoroscopic guided 20-gauge spinal needle into the L2-L3 space. Next, approximately 10ml of CSF fluid was collected followed by 12mg of methotrexate injection. CSF studies returned unremarkable. Upon physical examination, there was a notable partial right-sided abducens palsy without any other focal neurological deficits. Non-contrast CT scan of the head demonstrated a pneumocephalus anterior to the pons and at the level of the clivus abutting the right abducens nerve (Figure 1). Follow-up brain MRI with contrast was unremarkable for other potential causes of this acute palsy presentation, including infections, stroke, or herniation from intracranial hypotension. The patient was monitored and managed expectantly without any acute interventions and upon follow-up in 24 hours there was complete resolution of her symptoms. Design/Methods: N/A Results:N/AConclusions:Pneumocephalus causing a cranial nerve palsy is very rare. Its complications may be as trivial as headaches, to morecomplex presentations such a cranial nerve palsy, to exceedingly dangerous complications like tension pneumocephalus.Signs and symptoms resolve spontaneously with conservative management.
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4/9/2024 7:00 AM
Objective: To conduct a literature review using real-world evidence on the most common pharmacotherapies used in treating essential tremor (ET). Background: ET is among the most common movement disorders in the US. Current treatments include pharmacological treatments and surgical interventions, though many patients continue to lack adequate tremor control. Syntheses of published real-world evidence on ET pharmacotherapies are lacking. Design/Methods: We conducted a comprehensive literature review of English-language studies published between 1966-2022 using PubMed. The review targeted non-clinical trial studies of adults with ET evaluating propranolol, primidone, gabapentin, and/or topiramate, and reporting at least upper limb tremor efficacy, safety/adverse events, tolerability, and/or treatment patterns. Studies reporting 10 subjects were excluded. Results: We identified 236 studies. Following title and screening, 75 full-text studies were assessed, with 15 included in data extraction. Patient- or clinician-validated scales were used in 2/15 studies. Activities of daily living and quality of life outcomes were not commonly reported. Up to 81% and 55% of patients used propranolol and primidone, respectively. Gabapentin (30%) and topiramate (20%) were used less frequently. Though clinical response definitions varied, propranolol demonstrated response in 37-56% of patients, and primidone in 43-55% of patients among studies with 50 evaluable patients. Approximately one-quarter of patients reported responding to gabapentin or topiramate. Discontinuation rates varied widely across studies, from 10-70% for both propranolol and primidone. Gabapentin and topiramate had discontinuation rates from 26-86% and 26-58%, respectively. Usage, efficacy, and discontinuation were not characterized by line of therapy (i.e. initial vs subsequent treatments) in the assessed studies. Conclusions: Currently available ET pharmacotherapies may not provide adequate efficacy for many patients, highlighting substantial unmet need. We identified several gaps in the published evidence base, including evaluation of commonly-used ET medications by line of therapy and reporting on validated measures to enable comparisons to new ET pharmacotherapies.