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Indirect Comparison of Lenadogene Nolparvovec Gene Therapy versus Natural History in m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy Patients

NfL Levels Significantly Decrease in Response to Treatment with Patisiran or Vutrisiran in hATTR Amyloidosis with Polyneuropathy

Comparison of Efficacy Outcomes with Vutrisiran vs. Patisiran in hATTR Amyloidosis with Polyneuropathy: Post-hoc Analysis of the HELIOS-A Study

Effect of Patisiran on Polyneuropathy and Cardiomyopathy in Patients with hATTR Amyloidosis with V122I/T60A Variants: A Phase 4 Observational Study

Effect of Treatments on All-Cause of Mortality in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Progressive Longitudinally Extensive Myelopathy following Stroke in a Patient later found to have m.14484T>C Mutation in Leber’s Hereditary Optic Neuropathy (LHON) gene

Reliability of tablet-based Digital Clock Drawing Task (DCTclock) for Automated Detection of Cognitive Impairment

Feasibility of at-home motor assessments using wireless technology in patients with myelopathy: year 1 follow up of CYGNET, an observational study of patients with adrenomyeloneuropathy

Shared genetics of migraine with irritable bowel syndrome, peptic ulcer, gastric reflux, diverticular disease, and autoimmune GI disorders

Comparing Mutability of Clinically Significant Voltage-Gated Sodium Channel Subunits

Remote multimodal monitoring of motor neuron disease progression using wearable sensors and digital assessments

Association of Cognitive and Structural Correlates of Brain Aging and Incident Epilepsy. The Framingham Heart Study

Anti-seizure medication use in hospitalized patients undergoing continuous EEG monitoring: A multicenter validation study

ognitive Impairment is Associated with Longitudinal Disability in LGI-1-IgG Encephalitis

Combined effects of GBA mutations and STN-DBS negatively impact executive function in Parkinson’s disease

Motor Function and Quality of Life Improvement following Asleep versus Awake Deep Brain Stimulation (DBS) Procedures

1. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy versus Natural History in m.11778G>A MT-ND4 Leber Hereditary Optic Neuropathy Patients

PRESENTER: NANCY J. NEWMAN, MD, FAAN, AAN ANNUAL MEETING 2023

Introduction and Lenadogene Nolparvovec Gene Therapy

Dr. Newman performed an analysis on treated patients from three phase 3 studies. The fourth study, REFLECT, in which patients received lenadogene nolparvovec unilaterally or bilaterally, is included in this updated analysis. The goal was to compare the visual acuity of LHON patients with the mutation m.11778G>A MT-ND4 treated with lenadogene nolparvovec in clinical studies to the natural progression of visual acuity in a separate control group of m.11778G>A MT-ND4 LHON patients with the same mutation.

Study Data from the four phase 3 studies REVERSE, RESCUE, RESTORE, and REFLECT

They were combined to represent 174 patients with MT-ND4 LHON who had intravitreal injections in one or both eyes. The external control group consisted of 208 untreated m.11778G>A MT-ND4 LHON patients from 11 natural history studies who were of comparable age (> 15 years old).

Study results showed lenadogene nolparvovec had better visual acuity

When compared to natural history eyes, lenadogene nolparvovec-treated eyes had higher visual acuity at all-time points. With a maximum follow-up of 3.9 years following injection, the mean improvement versus natural history was -0.30 LogMAR (+15 letters) at the last observation (p0.01). The average gain after accounting for confounders was -0.43 LogMAR (+21.5 letters). Patients who underwent bilateral treatment experienced a bigger treatment impact than patients who just received one treatment.

Conclusion confirmed a clinical meaningfulness of lenadogene nolparvovec

The clinically significant and long-lasting improvement in visual acuity brought on by lenadogene nolparvovec intravitreal injection in individuals with m.11778G>A MT-ND4 LHON was validated by this comparison of treated patients with natural history patients.

2. NfL Levels Significantly Decrease in Response to Treatment with Patisiran or Vutrisiran in hATTR Amyloidosis with Polyneuropathy PRESENTER: MICHAEL J. POLYDEFKIS, MD, FAAN, AAN ANNUAL MEETING 2023

hATTR amyloidosis and objective

Dr. Polydefkis Assessed the potential value of neurofilament light chain (NfL) as a biomarker of disease progression in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy from the Phase 3 APOLLO and HELIOS-A investigations. A lethal, rare, and progressive condition is hATTR amyloidosis. In patients with hATTR amyloidosis with polyneuropathy, NfL is a possible biomarker of disease progression and therapeutic response.

Study methods

Healthy controls and patients with hATTR amyloidosis with polyneuropathy who participated in the APOLLO or HELIOS-A investigations, granted consent, and had enough samples were assessed for NfL levels utilising the Quanterix® SimoaTM platform. The baseline, 21-day, 4-month, and 18-month samples from APOLLO and the baseline, 43-day, 4-month, 9-month, and 18-month samples from HELIOS-A were used for the analysis.

Study results depicted that NfL levels were slightly higher in APOLLO

» NfL levels did not substantially differ across treatment groups within each trial at baseline, while they were slightly higher in APOLLO than in HELIOS-A (69.4 pg/mL and 58.2 pg/mL, respectively) and in both studies. At 4 months and 18 months, NfL levels in the APOLLO placebo arm significantly increased compared to baseline.

» NfL levels significantly dropped in the APOLLO patisiran arm at 4 months and 18 months compared to baseline.

» At 4 months and at 18 months, NfL levels in the patisiran and vutrisiran groups significantly dropped vs baseline.

Conclusion

As early as 4 months following the start of treatment, NfL levels with patisiran and vutrisiran considerably fell from baseline; the decreased levels persisted for 18 months. In contrast, NfL levels considerably rose in untreated patients. These findings imply that NfL may be helpful in patients with hATTR amyloidosis with polyneuropathy for tracking therapy response and disease development.

3. Comparison of Efficacy Outcomes with Vutrisiran vs. Patisiran in hATTR Amyloidosis with Polyneuropathy: Post-hoc Analysis of the HELIOS-A Study

PRESENTER: MICHAEL J. POLYDEFKIS, MD, FAAN. AAN ANNUAL MEETING 2023

Introduction and objective of hATTR Amyloidosis

Dr. Polydefkis Assessed the relative efficacy of RNAi therapeutics for hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. A progressive, potentially fatal condition known as hATTR amyloidosis is brought on by amyloid deposits originating from both the misfolded variant and wild- type TTR protein. To treat hATTR amyloidosis with polyneuropathy, the RNAi treatments vutrisiran and patisiran suppress the production of TTR protein.

Study methods

» N=164 patients (vutrisiran, n=122; patisiran, n=42).

» Patients with hATTR amyloidosis with polyneuropathy were randomised (3:1) to receive either vutrisiran (25 mg subcutaneously, Q3M) or patisiran (0.3 mg/kg intravenously, Q3W) in the Phase 3 HELIOS-A trial.

» The clinical effectiveness of vutrisiran over an external placebo was already demonstrated through prespecified comparisons (from the Phase 3 APOLLO study of patisiran).

» The comparison of TTR reduction between vutrisiran and within-study patisiran was included as a secondary objective, with the HELIOS-A patisiran arm serving as the reference group.

» Here, additional post-hoc analyses comparing the HELIOS-A vutrisiran and patisiran arms on clinical outcomes are reported: neuropathy impairment (modified Neuropathy Impairment Score+7 [mNIS+7]), quality of life (Norfolk-QOL-DN), gait speed (10-meter walk test [10-MWT]), nutritional status (modified body mass index [mBMI]), and disability (Rasch-built overall disability scale [R-ODS]).

Study results regarding TTR reduction

» TTR reduction with vutrisiran was non-inferior to that observed with patisiran

» In the current analysis, least-squares mean (±SE) changes from baseline to Month 18 for vutrisiran

and patisiran, respectively, showed similar treatment effects.

Conclusion

Vutrisiran and patisiran both had comparable numerical and statistical efficacy at Month 18 in treating the polyneuropathy symptoms of hATTR amyloidosis. These post-hoc results show that vutrisiran and patisiran, which both target the main pathogenic protein and have equivalent pharmacologic effects in terms of reducing TTR, are equally effective.

4. Effect of Patisiran on Polyneuropathy and Cardiomyopathy in Patients with hATTR Amyloidosis with V122I/T60A Variants: A Phase 4 Observational Study

PRESENTER: RAYMOND L. COMENZO, AAN ANNUAL MEETING 2023

hATTR amyloidosis and study objective

Raymond L. Comenzo assessed the effectiveness of patisiran, an RNAi therapeutic approved for patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, in those with a V122I or T60A variant. Transthyretin gene variations are the source of the quickly progressing disease known as hATTR amyloidosis. Although the V122I and T60A polymorphisms are linked to cardiomyopathy, there is growing evidence of a mixed cardiac and neurological phenotype.

Study methods

» V122I, n=45; T60A, n=13; total of 58 patients.

» The proportion of patients with improved/stable polyneuropathy disability (PND) score vs baseline after 12 months of patisiran medication is the primary outcome in this multicenter, observational, Phase 4 research of US individuals with V122I/T60A variations with polyneuropathy.

» Quality of life (QOL; Norfolk QOL-Diabetic Neuropathy [QOL-DN]; Kansas City Cardiomyopathy Questionnaire [KCCQ]); autonomic symptoms; Composite Autonomic Symptom Score-31 [COMPASS-31]; and severity of cardiac dysfunction; New York Heart Association [NYHA] class) were evaluated in relation to neuropathy and cardiomyopathy.

» For patients who complete the study, the difference in PND score between baseline and 12 months is reported.

» Study results with Patisiran acceptability

» At baseline, evaluable patients reported dysautonomia and impaired QOL.

» A wide spectrum of ambulatory dysfunction was present in the patients, with 25 (43.1%) having a PND score of II/IIIA/IIIB. 52 individuals (89.7%) suffered heart failure.

» Out of 45 patients who completed the study, 42 (93.3%) showed stabilisation or improvement in PND score compared to baseline at 12 months.

» Patients showed improvement from baseline in the COMPASS-31 (-11.0 [4.5]), Norfolk QOL-DN (mean change [SE], -7.9 [4.9]), and mBMI.

» Treatment with patisiran in this cohort revealed an acceptable safety profile that was consistent with the evidence at hand.

Conclusion

In this study, patients with V122I/T60A mutations showed a mixed phenotype in over 90% of cases, with 10.3% of patients having peripheral neuropathy without heart failure. Patients showed improved/stabilized PND score, improvement in QOL, and improvement in autonomic function after 12 months of patisiran, regardless of genotype/phenotype.

5. Effect of Treatments on All-Cause of Mortality in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

PRESENTER: ANAM KHALID SHAIKH, AAN ANNUAL MEETING 2023

Treatment options in CIDP

Miss Shaikh investigated the effect on mortality of different treatments of chronic inflammatory demyelinating polyneuropathy (CIDP). Studying the effects of various treatment alternatives, such as plasmapheresis, IVIg, steroids, immunosuppressants, or a combination of these, and their efficacy in lowering overall mortality, is of great interest.

Study methods

» All patients with CIDP from 1998 to 2018 were gathered retrospectively using the SPARCS database of the New York State Planning and Research Cooperation.

» Comorbidities were identified using ICD 9 and 10 codes. The discharge status of either expired or sent to hospice was used to collect mortality statistics.

» For comorbidities, gender, and age, a multivariate analysis using binary logistic regression was performed.

» From the time of diagnosis, the presence of comorbidities such as type 2 diabetes, hypertension, heart failure, COPD, Parkinson’s disease, multiple sclerosis, autoimmune hypothyroidism, pneumonia, and a wide range of cardiovascular disorders was evaluated. To determine significance, the Pearson Chi Squared test was applied.

Study results

» Between 1998 and 2018, 8,096 patients with CIDP were discovered. Only plasmapheresis was used to treat 169 patients (2.0%), only steroids were used to treat 602 patients (7.4%), only immunosuppressants were used to treat 27 patients (0.3%), only IVIg was used to treat 1,802 patients (22.2%), and only combination treatment was used to treat 538 patients (6.6%).

» Age and gender did not significantly differ between individuals who received treatment and those who did not. There was no discernible difference in the risk of mortality depending on whether a patient had ever had treatment or not.

To conclude

When confounding for all concomitant illnesses, gender, and age, CIDP patients who had a history of treatment with plasmapheresis, steroids, immunosuppressants, IVIg, or a combination at any point did not substantially differ from those who did not in terms of death. Work on subgroup analysis and locating other mortality risk factors, such as hospital admission and socioeconomic status, is ongoing.

6. Progressive Longitudinally Extensive Myelopathy following Stroke in a Patient later found to have m.14484T>C Mutation in Leber’s Hereditary Optic Neuropathy (LHON) gene

PRESENTER: KATHRYN ESZES, MD, AAN ANNUAL MEETING

Leber’s hereditary optic neuropathy (lhon) and objective

DR. ESZES presented a unique case of progressive myelopathy following stroke and its relationship to subsequently revealed Lhon gene mutation (m.14484t>c). A maternally inherited mitochondrial illness called Leber’s Hereditary Optic Neuropathy (LHON) causes acute or subacute bilateral painless vision loss. LHON +, also known as LHON-MS, is when LHON also has non-optic nerve problems such as longitudinal myelopathy and an elevated risk of multiple sclerosis. Rarely reported cases of LHON + manifesting as longitudinal myelopathy without prior optic neuropathy.

Case

At the age of 63, a 66-year-old woman with a history of hypertension experienced an acute right hemispheric subcortical stroke with left sided hemiparesis as a result. Months later, she started to exhibit progressively worsening hemiparesis and bilateral sensory abnormalities that at first resembled Brown-Sequard syndrome. The corticospinal tract from the location of the stroke, running through the brainstem to contralateral spinal cord, was shown to have extensive Wallerian degeneration by MRI. Except for increased ANA and vitamin B12 insufficiency, extensive autoimmune, neoplastic, ischemic, and metabolic workups were generally non-revealing. The symptoms worsened during the next two years, leading to almost total sensory loss in the lower limbs, right-side weakness, and eventually the development of orthopnea, sporadic diplopia, and dysphagia. Despite the use of IVIG and high dose steroids, this persisted.

Case resolved

» At the age of 63, a 66-year-old woman with a history of hypertension experienced an acute right hemispheric subcortical stroke with left sided hemiparesis as a result. Months later, she started to exhibit progressively worsening hemiparesis and bilateral sensory abnormalities that at first resembled Brown-Sequard syndrome.

» The corticospinal tract from the location of the stroke, running through the brainstem to contralateral spinal cord, was shown to have extensive Wallerian degeneration by MRI. Except for increased ANA and vitamin B12 insufficiency, extensive autoimmune, neoplastic, ischemic, and metabolic workups were generally non-revealing.

» The symptoms worsened during the next two years, leading to almost total sensory loss in the lower limbs, right-side weakness, and eventually the development of orthopnea, sporadic diplopia, and dysphagia. Despite the use of IVIG and high dose steroids, this persisted.

Conclusion

This case adds to the few reports of myelopathy as the presenting feature of LHON. Patient is the absence of visual symptomatology after three years of disease onset, possibly expanding the spectrum of pathology resulting from MT-ND6 mutation.

7. Reliability of tablet-based Digital Clock Drawing Task (DCTclock) for Automated Detection of Cognitive Impairment

PRESENTER: Connor Patrick Higgins, Other, AAN Annual Meeting 2023

DCTclockTM: a fast cognitive assessment

Mr. Higgins analyzed the reliability, validity, learning effects, and psychometrics of a novel digital Clock Drawing Task (dCDT), and evaluate the accuracy and reliability of its automated feature-analysis. The validated digital Clock Drawing Task (dCDT) captures cognitive- and motor-related aspects to allow for the identification of cognitive impairment (CI). It may be administered in under three minutes. The original dCDT used specialised paper and a digitising pen, which can be expensive and ineffective. They created the tablet-based dCDT, DCTclockTM, which is used on an iPad with a stylus to lower costs and increase accessibility. They have already determined that the DCTclockTM applications for tablets and pens are equivalent in terms of CI classification. In this section, they assessed the classification of clock elements’ reliability, psychometrics, and accuracy.

Study method

The psychometrics of Dataset 1 (N=4963), Dataset 2 (N=170), and Dataset 3 (N=501) persons who were cognitively normal (CN) and CI were examined. Reliability and learning effects were examined in datasets 1 and 4 (N = 432). The categorization accuracy of automated clock elements was examined across all datasets.

Study results: DCTclock scores showed good test-retest reliability

DCTclock scores in a sample of CN and CI participants and an independent CN sample both shown strong test-retest reliability (r=0.8 and r=0.7, respectively). In contrast to 40% (n=306) and 17% (n=130) for CI individuals, only 1% (n=10) and 56% (n=581) of CN participants achieved the floor and ceiling, respectively. The average score changes throughout the first and third weeks were +9.8 and +0.5 (n.s.), respectively. In all, 1.56% of the clocks could not be analysed because parts were missing. For the CN and CI groups, the accuracy in classifying clock elements was 99.6% and 99.3%, respectively.

Conclusion

The DCTclockTM is a quick cognitive test with high sensitivity and accuracy for detecting cognitive impairment and good test-retest reliability. The classification of drawing elements automatically is very precise. A powerful cognitive-screening tool called DCTclockTM allows for frequent assessments while preserving accuracy in clinical situations.

8. Feasibility of at-home motor assessments using wireless technology in patients with myelopathy: year 1 follow

up of CYGNET, an observational study of patients with adrenomyeloneuropathy

PRESENTER: CHRISTOPHER D. STEPHEN, MB, CHB, MRCP, AAN ANNUAL MEETING 2023

Adrenomyeloneuropathy and objective

Dr. Stephen quantify change in symptoms over time using home-based gait and mobility assessments from a prospective natural history study of patients with adrenomyeloneuropathy (AMN). Adults with ABCD1 gene mutations have an uncommon neurodegenerative illness of the brain and spinal cord known as AMN. Due to phenotypic and illness progression heterogeneity, quantifying the progression of AMN disease is difficult. This can be addressed by deploying wireless motion sensors more frequently during clinic and remote visits to monitor conventional functional motor tasks. Here, they evaluate the viability and test-retest dependability of motion sensors over a 1-year period and compare it to customary measurements taken in clinics.

Study methods

» Up to 80 male patients with AMN will be included in the current prospective, multicenter, observational trial CYGNET, which will keep track of them for about two years through yearly clinic visits and quarterly remote visits.

» Gait and balance evaluations include measures of postural body sway and conventional functional motor tasks.

» Time and distance are calculated in the clinic using standardised techniques. Both in the clinic and at home, wireless motion sensors allow for the quantification of the temporal and spatial gait evaluation components.

Study results

With an Expanded Disability Status Score of 1-6.5, more than 50 patients between the ages of 18 and 69 have been enrolled. Timed Up-and-Go to 2-Minute Walk Test had a correlation between a wireless sensor and operator-assessed mobility parameters of 0.746 to 0.998 at the baseline clinic visit. The first 20 patients who were enrolled will have their in-clinic and home data collected over the course of a year using wireless technology demonstrated.

Conclusion

Wireless motion sensors can be used to objectively and delicately evaluate a person’s gait, stability, balance, and functional abilities both in their natural surroundings and in a therapeutic setting. The design of next clinical studies examining prospective therapies, such as gene therapy for AMN, will be influenced by these data.

9. Shared genetics of migraine with irritable bowel syndrome, peptic ulcer, gastric reflux, diverticular disease, and autoimmune GI disorders

PRESENTER: Daniel Chasman, PhD, AAN Annual Meeting 2023

Migraine with IBS, GERD, and PUD

Dr. Daniel Chasman investigated potential genetic relationships and therefore biology that may underlie comorbidity of migraine and several gastrointestinal (GI) disorders. Irritable bowel syndrome, gastroesophageal reflux disease, and peptic ulcer disease are all more common in those who suffer from migraines, but autoimmune GI illnesses are not. Additionally, IBS can benefit from migraine medications that target the CGRP and serotonin pathways. It is uncertain how much genetics contributes to and broadens these risk and therapeutic linkages.

Study design

» IBS, PUD, GERD, diverticular disease (DD), and autoimmune GI illnesses (inflammatory bowel disease, Crohn’s disease, and ulcerative colitis) were also compared to the summary statistics from large-scale genome-wide association studies for migraine.

» By analysing pairwise global and local genetic correlations, finding possible shared candidate loci, assuming tissues relevant to genetic overlaps, and evaluating probable causative links with genetic instrumental analysis, shared genetics was studied.

Study results stated that strong correlation for migraine with IBS, GERD, and PUD

» For migraine and IBS, GERD, and PUD, there found a substantial genome-wide genetic association. This correlation was attenuated for DD and nil for autoimmune GI illnesses.

» The overlaps suggested that the central nervous system and cardiovascular tissues had similar rolesn PUD and GERD as well as IBS.

» Locally, among the loci associated with migraine, there were 10 unique loci: three for IBS, four for GERD or PUD, and seven for DD, which partially overlapping nine loci for inflammatory illnesses.

» However, correlation was either nominally significant or nil for loci encoding migraine treatment targets. GERD, PUD, and DD were supported as probable migraine causes by genetic causal inference, but not the other way around.

In conclusion

Migraine shares genetics with IBS, GERD, PUD, and DD, although in distinct ways, thereby identifying novel loci, causal pathways, and potentially, tissues with shared biological functions.

10. Comparing Mutability of Clinically Significant Voltage-Gated Sodium Channel Subunits

PRESENTER: GUSTAVO PATINO, OAKLAND UNIVERSITY WILLIAM BEAUMONT SCHOOL OF MEDICINE, AAN ANNUAL MEETING 2023

Voltage-Gated Sodium Channel Subunits

Mr. Patino compared the mutability profile of the clinically significant beta1 and beta2 subunits of the voltage-gated sodium channel. In excitable tissues, the voltage-gated sodium channel (VGSC) contributes to the production of action potentials. VGSC subunit mutations, particularly those in the beta1 and beta3 subunits, have been linked to conditions like epilepsy and cardiac arrhythmia.

Study design

They analysed differences in cancer cell variants from the cBioPortal Cancer Genomics database with amino acid variants in the beta1 and beta2 subunits observed in patients and the general population in the gnomAD database. Using the cBioPortal database, they also examined variations for both subunits in cancer cells.

Results showed beta3 had a higher mutation load

» According to gnomAD data, both subunits have variants reported in a comparable proportion of the main sequence (39.4% for beta1 and 39% for beta3), although pathogenic variants are more prevalent in beta1 (5% of residues) than beta3 (2% of residues). Beta1 and beta3 are encoded by the genes SCN1B and SCN3B, respectively.

» Of the 43789 patients with sequencing data for these genes, 2.2% and 3.3%, respectively, had non-synonymous mutations in beta1 and beta3, respectively. In cancer cells, a minority of residues within each subunit had a variation reported.

» Variations in human and cancer cells have been found for 4.58% and 6.51% of the beta1 and beta3 residues, respectively. One of the beta1 residues identified to have harmful variations also had a variant discovered in cancer cells, whereas beta3 did not.

Conclusion

The findings indicated that the pathogenic variant-containing residues are a non-overlapping set between the two subunits and may serve as targets for their unique function. Beta3 had a higher mutation burden in cancer cells than beta1, indicating that the two proteins have experienced various evolutionary stresses. This study has a drawback because they only focused on the primary splice variant of the SCN1B and SCN3B genes.

11. Remote multimodal monitoring of motor neuron disease progression using wearable sensors and digital assessments Presenter: Akshan Vazir, AAN Conference 2023

Frequent remote assessments of different disease symptoms and progression are critical in improving care for patients with neurological disorders and clinical trial readiness. There is a need for a multi- modal technological solution to objectively measure and monitor disease progression in MND. So a technology was developed to assess the feasibility of a robust multi-modal platform to remotely monitor motor neuron disease (MND) symptoms and disease progression using wearable sensors and digital assessments of speech, handwriting, and pattern-tracing skills. Participants with MND wereenrolledforupto12monthsofremotemonitoring. TheyworePAMSysTMpendantsensorsfor the duration of study to measure physical activity, walking parameters, postural transition, and falls during activities of daily living. Digital speech and handwriting and pattern tracing skill assessments were performed using the BioDigit HomeTM (BioSensics LLC) tablet on biweekly basis.

To date, nine participants have been enrolled (4 female), with a median age of 69 years (range 44-2 years). High compliance for the pendant-sensor-based physical activity monitoring was observed and provided a reliable tool to assess fall risk in patients with MND (with some subjects having up to 1.5 confirmed falls per week and one reported near fall per week). Furthermore, on average, subjects completed 91.9% (range 53.8%-100%) of assigned speech task. 88% of the participants were able to perform handwriting and pattern-tracing tasks.

Conclusions

The preliminary results demonstrated the feasibility of the multi-modal telemonitoring solution to remotely monitor mobility and disease symptoms in MND. The longitudinal monitoring may address the problem of subjective biases, measure functional changes over time, and compensate for the impact of biological variability in intermittent single visits.

12. Association of Cognitive and Structural Correlates of Brain Aging and Incident Epilepsy. The Framingham Heart Study

Presenter: Maria Stefanidou, AAN Conference 2023

Late life epilepsy is often due to acquired insults such as strokes and clinical dementia, but its cause remains unknown in up to 30% of cases. There is growing evidence that occult cerebrovascular disease contributes to higher incidence of epilepsy with increasing age. To relate imaging and cognitive correlates of subclinical brain injury to incident epilepsy in the Framingham Heart Study (FHS), a community-based cohort study was conducted.

Participants of the Offspring Cohort who attended FHS exam 7(1998-2001), were at least 45 years old at that time, had neuropsychological evaluation (NP), brain MRI, and no prior history of stroke, dementia or epilepsy were included in the study. Cognitive measures included Visual Reproductions Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making B-A(TrB-TrA) and the Hooper Visual Organization Test. MRI measures included total cerebral brain volume, cortical grey matter volume (CGMV), white matter hyperintensities (WMHV) and hippocampal volume. Adjudication of epilepsy cases included medical chart review to exclude seizure mimics. Cox proportional hazards regression models were used for the analyses. Among participants who underwent NP testing (n=2353,45.81% male) 30 incident epilepsy cases were identified during follow-up. Better performance in TrB-TrA was associated with lower risk of developing epilepsy (HR 0.25,95%CI[0.08,0.73],p= 0.011). In the subgroup of participants with available MRI (n=2056,46% male), 27 developed epilepsy. Higher WMHV was associated with increased epilepsy risk (HR 1.5,95%CI[1.01,2.20],p= 0.042), but higher CGMV (HR 0.73,95%CI[0.57,0.93],p= 0.001) was protective against epilepsy. All analyses were adjusted for age, sex and educational level.

Conclusions

Better performance in TrB-TrA, a measure of executive function and processing speed, and higher cortical volumes are protective against epilepsy. Conversely, higher WMHV, a measure of occult vascular injury, increases the risk. This study showed that non-invasive tests performed in mid-life may help identify people at risk for developing epilepsy later in life.

13. Anti-seizure medication use in hospitalized patients undergoing continuous EEG monitoring: A multicenter validation study

Presenter Natalie Karina Erlich-Malona, AAN Conference 2023

Studies have shown that continuous EEG (cEEG) monitoring leads to an increase in the use of anti- seizure medications (ASM) in hospitalized patients. However, the factors leading to ASM use in these patients are not clearly identified. To determine the predictors of ASM initiation and continuation after discharge in those undergoing cEEG a retrospective study was conducted. It included hospitalized patients (age >18 years) who underwent cEEG between 07/01- 09/30/2021 at five centers. Patients with history of epilepsy were excluded. ASM initiation was defined as treatment for > 48 hours during hospitalization. ASM continuation was defined as ASM prescription at discharge. Multivariable logistic regression models were developed to determine predictors of ASM initiation and ASM continuation using data from three centers (derivation cohort). The models were validated externally using data from the remaining two centers (validation cohort).

Among 1,030 patients (median age 64, 55.1% females), 528 (51.2%) were started on ASM and 288 (27.9%) were discharged on ASMs. On multivariable analysis, predictors of ASM initiation included progressive brain injury (odds ratio [OR] 2.38; 95% CI 1.08-5.49), traumatic brain injury (TBI) (OR 6.38; 95% CI 2.39- 20.5), clinical acute symptomatic seizure (ASyS) (OR 16.5; 95% CI 9.11- 31.1), EEG ASyS (OR 30.3; 95% CI 8.18-15.7), and lateralized periodic discharges (LPDs) (OR 9.38; 95% CI 1.86- 74.6). Area under the curve (AUC) of the model for ASM initiation was 0.90 and 0.85 in the derivation and validation cohorts, respectively. The predictors of ASM continuation included all of the above variables except TBI and LPDs, with AUC of 0.96 and 0.89 in the derivation and validation cohorts, respectively.

Conclusions

Patients with progressive brain injury, clinical ASyS, or EEG ASyS are more likely to be treated and discharged on ASM. Further studies are required to study the impact of ASM use on outcomes.

14. Cognitive Impairment is Associated with Longitudinal Disability in LGI-1-IgG Encephalitis

Monday, April 24th, 2023, Boston

This paper was presented by Albert Aboseif, DO, Alexander D. Rae-Grant, MD, and Vineet Punia, MD on Monday, April 24th at the AAN Annual Meeting 2023 in Boston.

BACKGROUND

Longitudinal studies prognosticating outcomes in LGI-1-IgG AE are needed to identify key drivers of disability. Examine disability utilizing modified Rankin Scale (mRS) and an AE specific scale, the clinical assessment scale in AE (CASE).

OBJECTIVE

To determine predictors of longitudinal clinical outcomes in leucine-rich glioma inactivated-1 immunoglobulin G (LGI-1)-IgG autoimmune encephalitis (AE).

METHODS

A retrospective observational study of seropositive LGI-1-IgG AE patients was conducted between 2013- 2022. Clinical predictors included demographics, clinical and paraclinical data, magnetic resonance imaging (MRI), and Montreal Cognitive Assessment (MoCA). Clinical outcomes included mRS and CASE scores. Logistic and linear regressions were used for modeling mRS and CASE, respectively. Baseline clinical characteristics were included as independent variables in the regression models.

RESULTS

Thirty patients (60% male, median age=69.5; IQR=63.0-76.0) were included, with a median follow- up time of 8.7 months (IQR=4.3-24.1). Seizures (29, [96.7%]), and cognitive impairment (CI) (30, [100%]) were present in the majority. Median initial MoCA was 23/30 (IQR=21.0-25.0). The majority received acute immunotherapy (27, [90%]), and maintenance immunotherapy, (26 [86.7%]). Baseline mRS (median=2.0, IQR=2.0-3.0) and CASE (mean=4.3, SD=3.7) correlated with each other (r=0.58, P<.001) and with initial MoCA score (mRS r=-0.60, P=.009, CASE r=-0.51, P=.031). After 12 months from symptom onset, mRS (OR=0.88, [CI=0.82-0.94], P<.001) and CASE (β=-0.03, [SE=0.01], P<.001) decreased significantly. Temporal lobe(s) Fluid Attenuation Inversion Recovery (FLAIR) hyperintensity correlated with higher mRS longitudinally (OR=17.49, [CI=2.37, 129.05], P=.005). Higher initial MOCA was associated with lower mRS (OR=0.66, [CI=0.45-0.98], P=.04) and CASE (β=-0.24, [SE=0.13], P=.061) longitudinally. At last follow-up, most patients had ongoing cognitive symptoms (25, [83.3%]), while few had ongoing seizure activity (3, [10%]).

CONCLUSIONS

CI is associated with disability at baseline and long-term follow up, underscoring cognition as an important determinant of disability outcomes in LGI-1-IgG AE. Severity of CI on baseline MoCA may offer prognostic information on long-term disability.

15. Combined effects of GBA mutations and STN-DBS negatively impact executive function in Parkinson’s disease

Monday, April 24th, 2023, Boston

This poster was presented by Ahmad Muhammad Awd Almelegy, MD, Srujanesh Gunda, and Sepehr Sani on Monday, April 24th at the AAN Annual Meeting 2023 in Boston.

BACKGROUND

» In a previous non-randomized study, we demonstrated that the combined effects of GBA mutations and STN-DBS negatively impact global cognition.

» However, the domain-specific pattern of cognitive dysfunction in PD-GBA mutation carriers that drives this cognitive decline remains to be explored.

OBJECTIVE

To determine the specific pattern of cognitive dysfunction in Parkinson’s disease (PD) patients who are glucocerebrosidase mutation carriers (PD-GBA) compared with non-mutation carriers with and without subthalamic nucleus deep brain stimulation (STN-DBS).

METHODS

» Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and non-carriers with or without DBS (GBA-DBS+, GBA-DBS-).

» Executive function, processing speed, and episodic memory were examined using the NIH Toolbox.

» Analysis of variance was used to compare differences in performance on NIH Toolbox measures

according to GBA and DBS status.

RESULTS

» Data were available for 68 subjects (8 GBA+DBS+, 14 GBA+DBS-, 19 GBA-DBS+, and 27 GBA-DBS- subjects).

» Performance on the executive function task (Flanker inhibitory control) was significantly lower in GBA+DBS+ subjects vs. the remaining groups (p = 0.007).

» After adjusting for covariates, significance was retained when comparing GBA+DBS+ with GBA- DBS- subjects (p = 0.013), with a trend towards significance when comparing GBA+DBS+ with the remaining 2 groups.

» »

Performance on the processing speed task (Pattern Comparison Processing Speed) was significantly lower in the GBA+DBS+ vs. GBA-DBS- after adjusting for covariates (p = 0.040).

Performance on episodic memory task (Picture Sequence Memory Test) was not significantly different when comparing the 4 groups (p = 0.423).

CONCLUSIONS

This preliminary study suggests that PD-GBA subjects with STN-DBS may be particularly susceptible to further executive dysfunction due to impaired response inhibition. Larger studies are needed to further investigate this association.

16. Motor Function and Quality of Life Improvement following Asleep versus Awake Deep Brain Stimulation (DBS) Procedures Monday, April 24th, 2023, Boston

This poster was presented by Jan Vesper, Roshini Jain, and Lilly Chen on Monday, April 24th at the AAN Annual Meeting 2023 in Boston.

BACKGROUND

» DBS procedures are typically conducted with patients being awake to allow for intraoperative clinical testing and/or micro-electrode recording to confirm lead location.

» However, asleep DBS procedures (i.e., under general anesthesia) are becoming increasingly popular due, at least in part, to technological improvements in imaging allowing alternative lead placement confirmation and shorter procedure duration.

OBJECTIVE

» To compare real-world outcomes in patients with Parkinson’s disease (PD) whose Deep Brain Stimulation (DBS) leads were implanted using asleep procedures versus those patients that underwent the procedure using awake conditions.

METHODS

» A sub-analysis of patients receiving their DBS lead implant under asleep versus awake conditions was conducted in an ongoing, large, multicenter, prospective real-world outcomes study (Vercise, Boston Scientific).

» Motor function (MDS-UDPRS III), quality of life (PDQ-39) and related outcomes (GIC) were collected at baseline and up to 3-years. Safety events were also collected.

RESULTS

» To date, 157 patients (mean age 61.2±8.3 years; 69% male) were asleep and 433 (mean age 60.1±8.5 years; 66% male) were awake during lead placement.

» Patients in both groups presented with similar baseline age, duration of disease and disease state.

» Improvement in quality-of-life was noted in both groups with a 5.3-point improvement (n = 104) in

asleep group and a 4.5-point improvement (n = 319) in awake group at 1-year.

» Similarly, an 18.8- and 20.9-point improvement in motor function was noted in the asleep and awake groups, respectively.

CONCLUSIONS

Outcomes from this large dataset of real-world outcomes examining the outcomes following asleep versus awake DBS demonstrate an alignment with results from previous studies. Patient outcomes show little to no difference between awake versus asleep groups. Sleep DBS procedures may offer potential for shortening the total time taken for DBS procedures and offer a viable alternative for patients.