Faculty Bibliography

Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.

The published version of this article unfortunately contained a mistake in Table 2. CGI-S and CGI-I values has been interchanged. The Table is corrected here.

Introduction: Psychological resilience is a dynamic process of positive adaptation to adversity based on maintenance of positive adjustments under challenging life circumstances. Multiple sclerosis is a chronic and unpredictable illness, accompanied by physical and emotional challenges, yet the role of psychological resilience in MS is understudied. We analyzed the impact of psychological resilience on disability measures in Multiple Sclerosis (MS).
Objective(s): To investigate the effect of psychological resilience on standard measures of disability in MS.
Aim(s): To assess a role of psychological resilience in MS.
Method(s): One hundred and one patients with relapsing-remitting MS: 52 African-American (AA) patients with mean age 38.56 +/- 11.05 yrs and mean disease duration 7.79 +/- 5.38 yrs and 49 Caucasian (CA) patients with mean age 38.92 +/- 10.43 yrs and mean disease duration 6.65 +/- 5.31 yrs were enrolled as part of an ongoing study. Psychological resilience was assessed with the Connor-Davidson Resilience Scale 10 item, a validated measure of psychological resilience. Partial correlations were evaluated between resilience and standard measures of disability in MS (Symbol Digit Modalities Test -SDMT, Nine Hole Peg Test- NHPT, Timed 25 Foot Walk -T25FW), controlling for demographics (age, gender, disease duration), disease burden (brain atrophy and T2 lesion volume), and depression.
Result(s): Psychological resilience was not related to demographics or disease burden however psychological resilience was related to depression (r=-0.65, p< 0.001). Psychological resilience was associated with better performance on SDMT (r=0.39, p=0.001) and NHPT (r=-0.31, p=0.010) with a trend toward significance on T25FW (r=-0.22, p=0.074). After controlling for demographics and disease burden, no difference in resilience or depression was seen between AA and CA patients. Stratified by race, higher psychological resilience was associated with better performance on SDMT (r=0.38, p=0.021) and NHPT (r=-0.43, p=0.008) in AA patients and on SDMT (r=0.46, p=0.019) and T25FW in CA patients (r=-0.42, p=0.035).
Conclusion(s): Our results show a positive impact of psychological resilience on disability in MS, independent from disease severity and mood changes. Identification of patients with lower resilience suggests potential targets for therapeutic intervention. Longitudinal studies are needed to confirm a protective effect of psychological resilience against MS disability

BACKGROUND:Autonomic dysfunction is a hallmark feature of hereditary ATTR amyloidosis. The aim of this study was to summarize the characteristics and natural history of autonomic dysfunction in patients with hereditary ATTR amyloidosis. METHODS:A systematic review of the natural history and clinical trials of patients with ATTR amyloidosis was performed. Alternative surrogate markers of autonomic function were analyzed to understand the prevalence and outcome of autonomic dysfunction. RESULTS:Patients with early-onset disease displayed autonomic dysfunction more distinctively than those with late-onset disease. The nutritional status and some autonomic items in the quality-of-life questionnaires were used to assess the indirect progression of autonomic dysfunction in most studies. Gastrointestinal symptoms and orthostatic hypotension were resent earlier than urogenital complications. Once symptoms were present, their evolution was equivalent to the progression of the motor and sensory neuropathy impairment. CONCLUSION:The development of autonomic dysfunction impacts morbidity, disease progression, and mortality in patients with hereditary ATTR amyloidosis.

Objective: The FOCUS study of fremanezumab, a fullyhumanised monoclonal antibody (IgG2DELTAa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic and episodic migraine (CM and EM) and documented inadequate response to 2-4 classes of migraine preventive medications. Efficacy in a subgroup of patients with medication overuse (use of any acute medication on >=15 days/month or triptans/ergots/combination medications on >=10 days/month) at baseline (BL) was evaluated.
Method(s): Patients were randomised (1:1:1) to quarterly (qtly) fremanezumab (Month [Mo] 1: 675 mg; Mo 2 and 3: placebo), monthly (mthly) fremanezumab (Mo 1: CM, 675 mg; EM, 225 mg; Mo 2 and 3: 225 mg), or matched mthly placebo for 12 weeks. Changes from BL in mthly migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures.
Result(s): Of 838 randomised patients, 427 had medication overuse. Reductions from BL in mthly average migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were significantly greater with both fremanezumab regimens vs placebo (all P<=0.0001; Table).
Conclusion(s): Qtly and mthly fremanezumab provided early and sustained reductions in migraine and headache days vs placebo in patients with medication overuse and documented inadequate response to 2-4 classes of migraine preventive medications. (Table Presented)

Objective: To investigate sensory-motor disability in African Americans (AA) with MS.
Background(s): A more severe disease course has been reported in AA in comparison with Caucasians (CA) MS patients. Sociodemographic differences, such as longer disease duration related to younger age at onset or disparity in income wich may lead to delayed diagnosis and limited access to treatment have been often used to explain the different disability profile in the two groups. To date, an objective assessment of sensorymotor disability in AA and potential differences with CA patients is still lacking.
Method(s): Fifty-two AA patients (41F, mean age 38.56 +/- 11.05 yrs, mean disease duration 7.79 +/- 5.38 yrs), 38 AA healthy controls (HC) (26F, mean age 36.13 +/- 12.31 yrs), 49 CA patients (33F, mean age 38.92 +/- 10.43 yrs, mean disease duration 6.65 +/- 5.31 yrs) and 26 CA HC (16F, mean age 31.69 +/- 10.82 yrs) were prospectively enrolled as part of an ongoing longitudinal study. In all subjects, an extensive sensory-motor evaluation was performed, including 9-hole peg test (9-HPT), grooved pegboard test (GPT), finger tapping test (FTT), 25-foot walk test (25-FWT), 2-minutes walk test (2-MWT), evaluation of segmental strength, grip strength, vibration sensitivity and balance. Each patient's group was compared with a race-matched HC group via ANCOVA analysis, accounting for age, gender and socioeconomic status expressed as yearly income.
Result(s): AA and CA patients did not differ in age, gender, disease duration, while they did differ in yearly income (p=0.008). AA patients and AA HC did not differ in gender, age or socioeconomic status. CA patients and CA HC did not differ in gender, while they did differ in age (p=0.002) and socioeconomic status (p=0.031). Significant differences in 9-HPT (p=0.001), GPT (p=0.015), FTT (p=0.034), grip strength (p=0.033), 2-MWT (p=0.010), balance (p=0.001) and foot vibration sensitivity (p=0.046) were identified between AA patients and AA HC. Significant differences in 9-HPT (p=0.011), GPT (p< 0.001), 25-FWT (p=0.049) and 2-MWT (p< 0.001) were identified between CA patients and CA HC.
Conclusion(s): AA and CA patients showed similar deficits in ambulation and manual dexterity but AA patients showed additional involvement of motor speed and coordination, balance, strenght and sensitivity. These results suggest that, even accounting for sociodemographic features, AA patients with MS indeed show more severe and widespread disability than CAs patients with MS

PURPOSE/OBJECTIVE:There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS:Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS:There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS:Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

OBJECTIVE:The objective of the study was to compare the performance of intravenous (IV) lorazepam (IVL) and intranasal midazolam (INM) for seizure termination and prevention of seizure clusters in adults admitted to the epilepsy monitoring unit (EMU) in whom seizures were captured on continuous video-electroencephalogram. METHODS:Retrospective cohort of consecutive adults (≥18 years) with epilepsy admitted to the EMU at a single tertiary academic center, who experienced epileptic seizures (confirmed electroencephalographically) and required rescue therapy. The study spanned from January 2015 until December 2016, which included one year before and one year after transitioning from IVL to INM as the standard rescue therapy at our institution. RESULTS:A total of 50 subjects received rescue therapy and were included in the analysis. In the first year, out of 216 patients with epilepsy admitted to the EMU, 27 (13%) received IVL; in the second year, 23/217 (11%) received INM. There were no differences in baseline characteristics and markers of epilepsy severity, the median duration of index seizure (1.7 min [interquartile range (IQR): 1.1-2.7] in IVL vs. 2.0 min [IQR: 1.5-2.6] in INM group, p = 0.20), or in the number of subjects requiring repeat benzodiazepine administrations (IVL 8/27 [29.6%] vs. INM 7/23 [30.4%], p = 0.95). There were no differences in the median number of recurrent seizures in 24 h (1 [IQR: 1-3] in IVL vs. 2 [IQR: 1-4] in INM, p = 0.27), occurrence of status epilepticus (IVL 4/27 [14.8%] subjects vs. INM 1/23 [4.3%] subjects, p = 0.36), incidence of seizure clusters (IVL 8/27 [29.6%] subjects vs. INM 7/23 [30.4%] subjects, p = 0.95), need for transfer to an intensive care unit (ICU), or other adverse events. SIGNIFICANCE:In our retrospective study, INM was comparable with IVL for seizure termination and prevention of seizure clusters in the adult EMU. Intranasal midazolam circumvents the need for IV access to be maintained throughout hospitalization and is an attractive alternative to IVL as a rescue therapy in this setting. Ideally, future large, prospective, randomized, and double blind studies are needed to confirm these findings.

OBJECTIVE:We aimed to identify the current status and major unmet needs in the management of neurological complications in Sturge-Weber syndrome. METHODS:An expert panel consisting of neurologists convened during the Sturge-Weber Foundation Clinical Care Network conference in September 2018. Literature regarding current treatment strategies for neurological complications was reviewed. RESULTS:Although strong evidence-based standards are lacking, the implementation of consensus-based standards of care and outcome measures to be shared across all Sturge-Weber Foundation Clinical Care Network Centers are needed. Each patient with Sturge-Weber syndrome should have an individualized seizure action plan. There is a need to determine the appropriate abortive and preventive treatment of migraine headaches in Sturge-Weber syndrome. Likewise, a better understanding and better diagnostic modalities and treatments are needed for stroke-like episodes. As behavioral problems are common, the appropriate screening tools for mental illnesses and the timing for screening should be established. Brain magnetic resonance imaging (MRI) preferably done after age one year is the primary imaging modality of choice to establish the diagnosis, although advances in MRI techniques can improve presymptomatic diagnosis to identify patients eligible for preventive drug trials. CONCLUSION/CONCLUSIONS:We identified the unmet needs in the management of neurological complications in Sturge-Weber syndrome. We define a minimum standard brain MRI protocol to be used by Sturge-Weber syndrome centers. Future multicenter clinical trials on specific treatments of Sturge-Weber syndrome-associated neurological complications are needed. An improved national clinical database is critically needed to understand its natural course, and for retrospective and prospective measures of treatment efficacy.