Faculty Bibliography

Fulminant IIH in pregnancy requires multidisciplinary collaboration and immediate CSF diversion.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455.

OBJECTIVE:The main goal of this study was to explore the latent structure and genetic basis of cognitive processes involved in the Wisconsin Card Sorting Task (WCST) within phenotypic, behavioral genetic, and molecular genetic research paradigms. METHOD/METHODS:The sample used in phenotypic and behavioral genetic analyses comprised 468 twins (154 monozygotic and 80 dizygotic twin pairs), while molecular genetic analyses were performed on 404 twins from the same sample. The zygosity of most twin pairs (96.8%) was determined via deoxyribonucleic acid (DNA) analysis of buccal swabs. Trained researchers administered the Wisconsin Card Sorting Test (WCST; Heaton et al., 1993) to the entire sample. RESULTS:Met- genotype. CONCLUSIONS:Met + genotype showed significant main effects on different WCST measures. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

OBJECTIVE:We examined the prevalence of risky alcohol and cannabis use among Brazilian varsity college athletes and whether this group had a greater likelihood of risky use than non-athletes. METHODS:In 2009, Brazilian college students (n=12,711) were recruited for a national stratified random survey. Their sociodemographic characteristics, mental health, substance use, and participation in varsity sports were assessed. Binary logistic regression models were used to examine the association between varsity athlete status and moderate to high-risk alcohol and cannabis use. RESULTS:Among varsity athletes, 67.6 and 10.7% reported risky alcohol and cannabis use, respectively. Varsity athletes had greater odds of risky alcohol consumption than non-athletes (aOR = 2.02, 95%CI 1.08-3.78). Varsity athletes also had greater odds of risky cannabis use than non-athletes in unadjusted analyses (OR = 2.57, 95%CI 1.05-6.28), although this relationship was attenuated after covariate adjustment. CONCLUSIONS:Among college students in Brazil, varsity athletes had a higher prevalence of risky alcohol and cannabis use than non-athletes. The rates were considerably higher than those observed among samples of U.S. college athletes. Future research should examine the use of these substances among varsity college athletes in other middle-income countries since these findings will likely guide prevention and treatment efforts.

Testing multiple treatments for heterogeneous (varying) effectiveness with respect to many underlying risk factors requires many pairwise tests; we would like to instead automatically discover and visualize patient archetypes and predictors of treatment effectiveness using multitask machine learning. In this paper, we present a method to estimate these heterogeneous treatment effects with an interpretable hierarchical framework that uses additive models to visualize expected treatment benefits as a function of patient factors (identifying personalized treatment benefits) and concurrent treatments (identifying combinatorial treatment benefits). This method achieves state-of-the-art predictive power for COVID-19 in-hospital mortality and interpretable identification of heterogeneous treatment benefits. We first validate this method on the large public MIMIC-IV dataset of ICU patients to test recovery of heterogeneous treatment effects. Next we apply this method to a proprietary dataset of over 3000 patients hospitalized for COVID-19, and find evidence of heterogeneous treatment effectiveness predicted largely by indicators of inflammation and thrombosis risk: patients with few indicators of thrombosis risk benefit most from treatments against inflammation, while patients with few indicators of inflammation risk benefit most from treatments against thrombosis. This approach provides an automated methodology to discover heterogeneous and individualized effectiveness of treatments.

Several lines of evidence link deficient serotonin function and SUDEP. Chronic treatment with serotonin reuptake inhibitors (SRIs) reduces ictal central apnoea, a risk factor for SUDEP. Reduced medullary serotonergic neurones, modulators of respiration in response to hypercapnia, were reported in a SUDEP post-mortem series. The amygdala and hippocampus have high serotonergic innervation and are functionally implicated in seizure-related respiratory dysregulation. We explored serotonergic networks in mesial temporal lobe structures in a surgical and post-mortem epilepsy series in relation to SUDEP risk. We stratified 75 temporal lobe epilepsy patients with hippocampal sclerosis (TLE/HS) into high (N = 16), medium (N = 11) and low risk (N = 48) groups for SUDEP based on generalised seizure frequency. We also included the amygdala in 35 post-mortem cases, including SUDEP (N = 17), epilepsy controls (N = 10) and non-epilepsy controls (N = 8). The immunohistochemistry labelling index (LI) and axonal length (AL) of serotonin transporter (SERT)-positive axons were quantified in 13 regions of interest with image analysis. SERT LI was highest in amygdala and subiculum regions. In the surgical series, higher SERT LI was observed in high risk than low risk cases in the dentate gyrus, CA1 and subiculum (p < 0.05). In the post-mortem cases higher SERT LI and AL was observed in the basal and accessory basal nuclei of the amygdala and peri-amygdala cortex in SUDEP compared to epilepsy controls (p < 0.05). Patients on SRI showed higher SERT in the dentate gyrus (p < 0.005) and CA4 (p < 0.05) but there was no difference in patients with or without a psychiatric history. Higher SERT in hippocampal subfields in TLE/HS cases with SUDEP risk factors and higher amygdala SERT in post-mortem SUDEP cases than epilepsy controls supports a role for altered serotonergic networks involving limbic regions in SUDEP. This may be of functional relevance through reduced 5-HT availability.

OBJECTIVE:A recent FDA warning concerning an arrhythmogenic potential of lamotrigine created concern in the neurological community. This warning was based on in vitro studies, but no clinically relevant risk was considered. This rapid systematic review aims to elucidate the risk of lamotrigine on sudden death or electrocardiogram abnormalities. METHODS:We conducted a systematic search of Ovid Medline and Ovid Embase, including randomized controlled trials and observational studies, studies of people with or without epilepsy, with one of the following outcome measures: SUDEP and sudden cardiac death, as well as the development or worsening of electrocardiogram abnormalities. All titles and abstracts were independently screened, and the full texts of relevant studies were obtained. We re-evaluated the sudden death definitions used in all included studies, as some could have used unclear or overlapping definitions. We used the American Academy of Neurology risk of bias tool to evaluate the class of evidence and the GRADE approach to evaluate our confidence in the evidence. RESULTS:We included 26 studies with 24,962 participants, of whom 2,326 used lamotrigine. Twelve studies showed no significant risk of SUDEP for lamotrigine users. One study reporting on sudden cardiac death and three studies with unclear sudden death definitions did not report an elevated risk of death in lamotrigine users compared to controls. In 10 studies reporting on electrocardiogram parameters, there was no statistically significant increased risk among lamotrigine users except for two studies. These two studies reported either "slight increases" in PR interval or an increased PQ interval that the primary study authors felt to be more related to structural cardiac differences rather than an effect of lamotrigine. One study was rated class II while all others were class III or IV. We had "very low confidence" in the evidence following the GRADE assessment. None of the studies examined the risk of lamotrigine in people with pre-existing cardiac conditions. CONCLUSION/CONCLUSIONS:There is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes, in people with or without epilepsy as compared to ASM or placebo. This is due to the high risk of bias in most studies and low precision and inconsistency in the reported results.

BACKGROUND:Neuropathic pain (NP) and constipation are common among people with neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and have a negative impact on quality-of-life measures. The possible association between the two symptoms has not been explored. METHODS:Patients with NMOSD and MOGAD, who were members of a closed international Facebook group, were recruited to complete an anonymous survey on REDCap. Participants were queried regarding demographic and disease-related characteristics, the presence and severity of NP and constipation, and whether they believe there is a relationship between the two symptoms. RESULTS:Of the 317 participants who completed the survey, 213 (67.2%) reported a diagnosis of aquaporin-4 (AQP-4) positive NMOSD, 93 (29.4%) - MOGAD, and 11 (3.4%) - double-seronegative NMOSD. The mean age was 43.9 ± 16.4 years; 259 were female (81.7%). 206 participants (65%) reported NP, of whom 133 (64.6%) were being treated for it with one or more medications. 167 participants (52.7%) reported constipation, of whom 67 (40.2%) received one or more medications. 137 of 206 participants with NP (66%) also had constipation. Both symptoms were significantly more common among patients with a history of myelitis. Among patients with NP and constipation, 47 participants (34.3%) thought there was a relationship between the two conditions, with the majority reporting increased severity of NP when constipation severity was increased and, conversely, alleviation of NP when constipation lessened. CONCLUSIONS:NP and constipation were seen in the majority of NMOSD and MOGAD patients with a history of myelitis. Interestingly, one-third of patients with both symptoms reported a link between them, with the majority reporting that NP severity was increased with worse constipation. The possible association opens a possibility of a new approach to managing NP, which tends to be poorly responsive to symptomatic therapies and is associated with worse quality of life in NMOSD and MOGAD. Further studies are warranted to confirm our results.

This retrospective, single-center study aimed to characterize and compare the kinetics of B-cell reemergence following anti-CD20 infusion (anti-CD20i) in African American (AA) and white patients with MS or NMOSD. In a logistic regression model that included race, time since anti-CD20i, body mass index, and diagnosis, only AA race (p=0.01) and time since anti-CD20i (p=0.0003) were significant predictors of B-cell repletion. However, B-cell subset composition was similar between AA and white patients with detectable CD19+ B-cell counts. These findings highlight the importance of including a diverse study population in future studies of anti-CD20 therapies.

INTRODUCTION/BACKGROUND:The ability to deploy transcranial direct current stimulation (tDCS) at home is a key usability advantage to support scaling for pivotal clinical trials. We have established a home-based tDCS protocol for use in clinical trials termed remotely supervised (RS)-tDCS. OBJECTIVE:To report the tolerability and feasibility of tDCS sessions completed to date using RS-tDCS in clinical trials. METHODS:We analyzed tolerability (i.e., adverse events, AEs) reported in six Class I/II/III trials using RS-tDCS to study symptom outcomes over 10 to 60 daily applications. Across the six clinical trials, 308 participants (18-78 years old) completed an average of 23 sessions for a total of 6779 RS-tDCS administrations. The majority of participants were diagnosed with multiple sclerosis, and open-label trials included those diagnosed with a range of other conditions (e.g., Parkinson's disease, post-stroke aphasia, traumatic brain injury, cerebellar ataxia), with minimum-to-severe neurologic disability. Clinical trial feasibility (i.e., treatment fidelity and blinding integrity) was examined using two Class I randomized controlled trials (RCTs). RESULTS:No serious AEs occurred. Across administrations, three sessions (0.04%) were aborted due to discomfort, but no participant discontinued due to tolerability. The AEs most commonly reported by participants were tingling (68%), itching (41%) and warmth sensation (42%) at the electrode site, and these were equally reported in active and sham tDCS conditions. The two Class I RCTs resulted in rapid enrollment, high fidelity to treatment completion, and blinding integrity. CONCLUSIONS:At-home RS-tDCS is tolerable, including when used over extended periods of time. Home-based RS-tDCS is feasible and can enable Class I tDCS clinical trial designs.