Scholarly Activity

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.

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.

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).

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.

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. .

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.

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.

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.

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.

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.