Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

OBJECTIVE: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age. METHODS: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months. Secondary outcomes were prevalence of drug-resistant epilepsy, additional developmental outcomes, and safety of vigabatrin. RESULTS: Of 84 infants enrolled, 12 were screen failures, 4 went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). Fifty-six were randomized to early vigabatrin (n = 29) or placebo (n = 27). Nineteen of 27 in the placebo arm transitioned to open label vigabatrin, with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug-resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups. INTERPRETATION: Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children, nor does it delay onset or lower the incidence of focal seizures and drug-resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms. ANN NEUROL 2023.

Impact of the COVID-19 pandemic on patients with myasthenia gravis: A survey of the Myasthenia Gravis Foundation of America MG patient registry.

INTRODUCTION/AIMS: Factors associated with coronavirus disease 2019 (COVID-19) infection among the myasthenia gravis (MG) population are incompletely understood. This study aimed to characterize the behavior of MG patients during the pandemic and to examine risk factors associated with COVID-19 infection. METHODS: A "COVID-19 Survey" was sent to MG Patient Registry participants in the summer of 2020 (CSS20) and winter of 2021 (CWS21). Survey results were summarized descriptively. Demographics, disease characteristics, medication use, and survey results were compared between those reporting COVID-19 diagnosis (COVID), COVID-19 like symptoms without diagnosis (COVID-Like), and asymptomatic participants. RESULTS: A total of 454 and 665 participants completed the CSS20 and CWS21 surveys respectively; 326 participants completed both. Most continued follow-up visits and MG treatments. The frequency of COVID-like symptoms was similar between CSS20 and CWS21, while COVID-19 exposure (6% vs. 27%), COVID-19 testing among symptomatic individuals (35% vs. 78%), and COVID-19 diagnosis (0.2% vs. 6%) were higher in the CWS21. Cough, fever, fatigue, myalgia, anosmia/ageusia, and hospital and intensive care unit (ICU) admissions were more frequent in the COVID compared to the COVID-Like group. COVID-19 exposure (odds ratio [OR] 7.88), number of people in the household (OR 1.31), and report of MG exacerbation before the pandemic (OR 2.6) were independently associated with COVID-19 infection. DISCUSSION: COVID-19 affected MG patients increasingly through the early pandemic. While face-to-face contact with a COVID-19 infected individual was an obvious risk factor, MG patients who had more people in the household and unstable disease were at elevated risk for COVID-19 infection.

One-year follow-up of disease burden and medication changes in patients with myasthenia gravis: From the MG Patient Registry.

INTRODUCTION/AIMS: We studied the progression of myasthenia gravis (MG) disease burden and medication adjustment among MG Patient Registry participants. METHODS: Participants diagnosed with MG (age ≥18 years), registered between July 1, 2013 and July 31, 2018 and completing both 6- and 12-month follow-up surveys, were included in this investigation. Participants were grouped into high-burden (Myasthenia Gravis Activity of Daily Living scale [MG-ADL] score ≥6) and low-burden (MG-ADL <6) groups based on MG-ADL scores at enrollment. Demographics and disease history were compared between groups. MG-ADL score change and medication changes (escalation, no change, de-escalation) between enrollment and 12-month follow-up were compared between groups. Minimal symptom expression (MSE, MG-ADL <2) at 12 months was compared between groups. Logistic regression analysis was performed to study factors associated with MSE at 12 months. RESULTS: In total, 520 participants (56% female) were included in high-burden (n = 248) and low-burden (n = 272) groups. Those in the high-burden group were more likely to be younger, female, and have shorter disease duration. At 12 months, MSE was achieved in 6% of the high-burden group and newly achieved (42 of 201, 21%) or maintained (52 of 71, 73%) in the low-burden group. In the multivariable analysis, being in the high-burden group and use of pyridostigmine were associated with less likelihood of MSE, whereas MG-ADL score improvement (>2 or >20%) at 6 months significantly increased the likelihood of achieving MSE at 12 months (P = .0004). DISCUSSION: In both groups, but more so in the high-burden group, patients infrequently achieved MSE after 1 year of MG treatment. Baseline low disease burden, improvement at 6 months and no pyridostigmine use were associated with a higher likelihood of MSE at 12 months.

Correlation of Quantitative Myasthenia Gravis and Myasthenia Gravis Activities of Daily Living scales in the MGTX study.

INTRODUCTION: Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Activities of Daily Living (MG-ADL) scales were compared using the data from the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) study. METHODS: Correlation between QMG and MG-ADL raw and change-from-baseline scores was calculated every 3 months for 60 months based on treatment groups and minimal manifestation status (MMS). RESULTS: QMG and MG-ADL change-from-baseline scores correlated significantly, with increasing strength of correlation over time, in both treatment groups. QMG and MG-ADL raw scores correlated significantly in both treatment groups, with increasing correlation only in the prednisone-alone group. Correlation between raw scores was weaker in patients who were in MMS, demonstrating a "floor effect" on the MG-ADL scale. Raw QMG scores could be modeled assuming a normal distribution, whereas raw MG-ADL scores could not be modeled this way. DISCUSSION: The floor effect and skewed distribution of the MG-ADL measure should be taken into account in the design of myasthenia gravis clinical trials.

Neurocognitive Predictors of Declining Financial Capacity in Persons with Mild Cognitive Impairment.

OBJECTIVE: To identify cognitive predictors of declining financial capacity (FC) in persons with mild cognitive impairment (MCI). METHODS: Participants were 66 cognitively normal older adults and 49 persons with MCI who completed neuropsychological testing and a performance measure of financial capacity (Financial Capacity Instrument; FCI) at baseline and two-year follow-up. We calculated two-year change scores for neuropsychological tests and FCI total score. We examined bivariate correlations between demographic/clinical variables and FCI change score, and between neuropsychological and FCI change scores. The five strongest bivariate correlates were entered into a linear regression analysis to identify longitudinal predictors of financial decline within group. RESULTS: Persons with MCI showed significant decline on the FCI and most cognitive variables, while controls demonstrated relatively stable performance. For persons with MCI, education correlated with FCI change score. The top four cognitive variable-FCI change score correlations were written arithmetic, confrontation naming, immediate visual memory, and visual attention. In the regression model, written arithmetic was the primary predictor and visual memory and visual attention were secondary predictors of two-year FCI change scores. CONCLUSION: Semantic arithmetic knowledge, and to a lesser extent visual memory and attention, are key longitudinal cognitive predictors of financial skill decline in individuals with MCI. CLINICAL IMPLICATIONS: Clinicians should consider neurocognitive abilities of written arithmetic, visual memory, and processing speed in their assessments of financial capacity in person with MCI.

Prevalence of restless legs and association with patient-reported outcome measures in myasthenia gravis.

STUDY OBJECTIVES: Inflammatory and immune mechanisms are considered in restless legs syndrome (RLS) pathophysiology with several autoimmune diseases associated with RLS. There is a paucity of studies examining RLS prevalence in myasthenia gravis (MG), an autoimmune neuromuscular disease. This study investigated RLS prevalence and association with patient-reported measures in a large registry of participants with MG using a validated RLS diagnostic questionnaire. METHODS: The Myasthenia Gravis Foundation of America MG Patient Registry is used on a semi-annual basis to survey participants with MG. Patients aged ≥18 years, living in the United States, and answering "Yes" to physician diagnosed MG were invited by email to enroll in an RLS-customized web-based survey. Collection of data included demographics, disease variables, patient-reported measures with a simple depression scale, MG 15-item Quality of Life (MG-QOL15r), MG-Activities of Daily Living (MG-ADL) instruments, and 13-item short-form Cambridge-Hopkins diagnostic questionnaire for RLS (CH-RLSq13). Multivariable logistic regression models explored the association between RLS and MG variables of interest. RESULTS: 630 eligible participants with MG (age: 62.8±13.2; 54.9% female; 91.6% White) completed the survey. The overall prevalence of RLS was 14.8%. The prevalence of clinically significant RLS was 8.4%. The odds of having RLS were increased with higher (worse) MG-ADL, MG-QOL15r, and depression scores. History of "Thymic tumor with thymectomy" and "CPAP therapy" were also independent predictors of RLS. CONCLUSIONS: RLS is common in patients with MG and is associated with worse functional status, quality of life, and depression. The thymus could play a key role in an autoimmune process associating MG with RLS.

Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial.

BACKGROUND: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE. METHODS: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models. RESULTS: Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes. CONCLUSIONS: Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management.

Attitudes and Beliefs Toward Thymectomy in the Myasthenia Gravis Patient Registry.

OBJECTIVES: To evaluate patient attitudes and beliefs toward thymectomy for myasthenia gravis (MG). METHODS: The Myasthenia Gravis Foundation of America administered a questionnaire to the MG Patient Registry, an ongoing longitudinal survey of adult MG patients. Questions assessed reasons for or against thymectomy and how hypothetical scenarios would have affected their decision. RESULTS: Of 621 respondents, 190 (31%) reported a history of thymectomy. Of those who underwent thymectomy for nonthymomatous MG, 97 (51.6%) ranked symptom improvement as most important and 100 (53.2%) ranked reducing medication as least important. Among 431 nonthymectomy patients, the most frequent reason for not undergoing thymectomy was that their doctor did not discuss it (152 of 431 = 35.2%) and 235 (56.8%) said that they would have considered it more strongly if their doctor spent more time discussing it. CONCLUSIONS: Thymectomies are motivated more by symptoms than by medication, and a lack of neurologist discussion is the most common barrier to thymectomy.

BA.5 bivalent booster vaccination enhances neutralization of XBB.1.5, XBB.1.16 and XBB.1.9 variants in patients with lung cancer.

This study reports that most patients with NSCLC had a significant increase in the nAb response to the currently circulating Omicron variants after bivalent booster vaccination and had Ab titers comparable to healthy participants. Interestingly, though the durability of the nAb response persisted in most of the healthy participants, patients with NSCLC had significantly reduced nAb titers after 4-6 months of vaccination. Our data highlight the importance of COVID-19 bivalent booster vaccination as the standard of care for patients with NSCLC given the evolution of new variants of concern.

Fat mass loss correlates with faster disease progression in amyotrophic lateral sclerosis patients: Exploring the utility of dual-energy x-ray absorptiometry in a prospective study.

BACKGROUND/OBJECTIVE: Weight loss is a predictor of shorter survival in amyotrophic lateral sclerosis (ALS). We performed serial measures of body composition using Dual-energy X-ray Absorptiometry (DEXA) in ALS patients to explore its utility as a biomarker of disease progression. METHODS: DEXA data were obtained from participants with ALS (enrollment, at 6- and 12- months follow ups) and Parkinson's disease (enrollment and at 4-month follow up) as a comparator group. Body mass index, total lean mass index, appendicular lean mass index, total fat mass index, and percentage body fat at enrollment were compared between the ALS and PD cohorts and age-matched normative data obtained from the National Health and Nutrition Examination Survey database. Estimated monthly changes of body composition measures in the ALS cohort were compared to those of the PD cohort and were correlated with disease progression measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). RESULTS: The ALS cohort (N = 20) had lower baseline total and appendicular lean mass indices compared to the PD cohort (N = 20) and general population. Loss in total and appendicular lean masses were found to be significantly associated with follow-up time. Low baseline percentage body fat (r = 0.72, p = 0.04), loss of percentage body fat (r = 0.81, p = 0.01), and total fat mass index (r = 0.73, p = 0.04) during follow up correlated significantly with monthly decline of ALSFRS-R scores in ALS cohort who had 2 or more follow-ups (N = 8). CONCLUSION: Measurement of body composition with DEXA might serve as a biomarker for rapid disease progression in ALS.

Pilot Study of Neurodevelopmental Impact of Early Epilepsy Surgery in Tuberous Sclerosis Complex.

BACKGROUND: To determine if early epilepsy surgery mitigates detrimental effects of refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex who underwent surgery before age two years. METHODS: Prospective multicenter observational study of 160 children with tuberous sclerosis complex. Surgical outcome was determined for the seizure type targeted by surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II); Mullen Scales of Early Learning; and Preschool Language Scales, Fifth Edition, at age three, six, nine, 12, 18, 24, and 36 months. Surgical cases were compared with children without seizures, with controlled seizures, and with medically refractory seizures. RESULTS: Nineteen children underwent surgery (median age 17 months, range 3.7 to 21.3), and mean follow-up was 22.8 months (range 12 to 48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in seven (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from those surgically targeted. All children with seizures demonstrated longitudinal decline or attenuated gains in neurodevelopment, the surgical group scoring the lowest. Favorable surgical outcome was associated with increased Mullen Scales of Early Learning receptive and expressive language subscores compared with the medically refractory seizure group. A nonsignificant but consistent pattern of improvement with surgery was seen in all tested domains. CONCLUSIONS: These pilot data show neurodevelopmental gains in some domains following epilepsy surgery. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics.

Minimal manifestation status and prednisone withdrawal in the MGTX trial.

OBJECTIVE: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG). METHODS: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups. RESULTS: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone. CONCLUSIONS: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone. CLINICALTRIALSGOV IDENTIFIER: NCT00294658. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.

Declining Financial Capacity in Mild Cognitive Impairment: A Six-Year Longitudinal Study.

OBJECTIVE: To investigate financial skill decline over a 6-year period in persons with mild cognitive impairment (MCI) presumed due to Alzheimer's disease (AD). METHODS: Study participants were cognitively normal (CN) older adults (n = 82) and adults with MCI (n = 91) based on consensus conference diagnosis. Participants completed baseline and up to six annual follow-up assessments that included standardized financial skills measurement (Financial Capacity Instrument; FCI; nine FCI domain and two global scores). We examined FCI change over time using mixed-model repeated measures analysis adjusted for baseline age and follow-up duration. RESULTS: At baseline, the CN group performed better than the MCI group across both global and seven domain scores. Group × Time interaction effects (all p's <.02) were found for all global and domain scores. The largest interaction effects were observed for complex domains of Financial Conceptual Knowledge, Checkbook Management, Bank Statement Management, and Bill Payment (all p's <.0001). Annualized decline in the MCI group's global scores, calculated in relation to CN group performance, was 10-17% over the initial 3-year time span and 22-24% at 6 years. Decline in FCI domain scores ranged from 6% (Knowledge of Assets/Estate) to 22% (Investment Decision-Making) at 3 year follow-up, and from 15% (Basic Monetary Skills) to 37% (Financial Judgment) at 6 year follow-up. CONCLUSIONS: Over a 6-year period, persons with MCI demonstrated significant declines in multiple financial skills and in particular financial judgment. The findings highlight the importance of ongoing oversight by family members and clinicians of financial skills and activities in persons with MCI.

Gender differences in prednisone adverse effects: Survey result from the MG registry.

OBJECTIVE: Prednisone is a first-line immunosuppressive treatment for myasthenia gravis (MG), whereas short-term and long-term adverse effects (AEs) are a limiting factor in its usage. METHOD: The MG patient registry is a patient-driven, nation-wide database with patients of age ≥18 years, who were diagnosed with MG and live in the United States. Custom-designed "prednisone-steroid use and MG" survey was sent out to MG registry participants as part of semi-annual follow-up. Data were collected and analyzed for frequency. RESULTS: A total of 398 MG participants (21% response rate) completed the survey, including 173 men and 225 women. Among them, 298 reported current (174) or past (288) prednisone intake. Current prednisone dosage varied from 0.5 to 75 mg (median 10 mg, IQR 7-20), dosing frequency was daily in 132 (76%) and every other day in 31 (18%). Peak prednisone dose was commonly between 25 mg and 60 mg (Median 50 mg, IQR 25-60); however, doses more than 60 mg daily were reported in 59 (20%). Prednisone AEs were reported more commonly in women (95% vs 81%, p < 0.0001). Women reported more intolerable AEs (77% vs 50%, p < 0.00001) and less willingness to accept a dose increase (26% vs 44%, p = 0.03) compared with men. CONCLUSIONS: Prednisone is commonly used in the treatment of MG, with highly variable dosages and dosing frequencies reflecting the absence of a standard guideline. Intolerable AEs were more commonly reported among women and was associated with unwillingness to accept a dose increase. Consensus guidelines and their validation are required to guide prednisone treatment for MG.