Faculty Bibliography

Amiodarone (Cordarone^®, Pfizer Inc) is an antiarrhythmic medication with a well-known toxicity profile, including rare cases of hyponatremia as a result of syndrome of inappropriate antidiuretic hormone (SIADH). We report on such a case in which a patient was found to be hyponatremic after evaluation. An 88-year-old male who presented to the emergency department was found to be hyponatremic secondary to amiodarone-induced SIADH following a fall, with possible seizure and traumatic brain injury. He had a history of hypertension, paroxysmal atrial fibrillation, emphysema, myocardial infarction, benign prostatic hyperplasia, chronic kidney disease, Meniere's disease, anemia, and gastroesophageal reflux. Upon admission, his urine sodium level was elevated, and his serum sodium, urine osmolality, and anion gap were below normal. In the setting of hyponatremia, the patient's amiodarone was held: he had been taking amiodarone 200 mg once daily for nine months prior to admission. He was treated with intravenous (IV) normal saline over four days. He was fluid-restricted and his sodium levels were closely monitored every two hours. Within 19 hours, his serum sodium levels had improved. Amiodarone was restarted approximately three days later. Upon follow-up after discharge, the patient remained on amiodarone for the next two months. His serum sodium level ranged from 126 mEq/L to 131 mEq/L over a two-week period. He was supplemented with sodium chloride tablets and has been otherwise stable. Amiodarone may cause acute or chronic SIADH, with a wide range of symptoms. Seizures have not been reported in the literature but our patient had a witnessed seizure, although his electroencephalogram (EEG) was negative. Syndrome of inappropriate antidiuretic hormone can occur with any formulation of amiodarone in a dose-dependent fashion. Our patient's sodium levels stabilized within two weeks after amiodarone was resumed. The mechanism of amiodarone-induced SIADH remains unclear.

Neuropsychological assessment is critical for understanding the impact of seizures on cognition and informing treatment decisions. While focus is often placed on examining groups based on seizure type/epilepsy syndrome, an alternate approach emphasizes empirically derived groups based solely on cognitive performance. This approach has been used to identify cognitive phenotypes in temporal lobe epilepsy (TLE). The current study sought to replicate prior work by Hermann and colleagues (2007) and identify cognitive phenotypes in a separate, larger cohort of 185 patients with TLE (92 left TLE, 93 right TLE). Cluster analysis revealed 3- and 4-cluster solutions, with clusters differentiated primarily by overall level of performance in the 3-cluster solution (Low, Middle, and High performance) and by more varying cognitive phenotypes in the 4-cluster solution (Globally Low, Low Executive Functioning/Speed, Low Language/Memory, and Globally High). Differences in cognitive performance as well as demographic and clinical seizure variables are presented. A greater proportion of the patients with left TLE were captured by Cluster 3 (Low Language/Memory) than by the other 3 clusters, though this cluster captured only approximately one-third of the overall group with left TLE. Consistent with prior findings, executive functioning and speed emerged as additional domains of interest in this sample of patients with TLE. The current results extend prior work examining cognitive phenotypes in TLE and highlight the importance of identifying the comprehensive range of potential cognitive profiles in TLE.

BACKGROUND:Pisa syndrome is a lateral deviation of the trunk described in Parkinson's disease (PD). Its etiology is still unknown; advanced muscular signal analysis techniques, such as inter-muscular coherence, could help clarifying its pathophysiology and suggest therapeutic strategies. METHODS:Fourteen idiopathic PD subjects with a lateral deviation of the trunk of at least 10° were included. Electromyographic (EMG) signal was recorded from bilateral thoracic, and lumbar para-spinal and obliqui externi muscles. The synchronization between EMG right and left side signals was quantified using the magnitude-squared coherence function. RESULTS:In our sample, coherence (range 0-1) did not exceed 0.3, which indicates a lack of intra-muscular coherence. CONCLUSION/CONCLUSIONS:This finding is suggestive of a defective muscular fine-tuning, which has been associated with bradykinesia. These data support the hypothesis of PS as a clinical sign of bradykinesia, impacting on therapeutic and rehabilitative options.

Abstract: Introduction: Fatigue is one of the most prevalent and under-assessed non-motor symptoms in Parkinson's disease (PD). Current therapies have limited effectiveness. Presently, tDCS has shown potential to improve certain symptoms of PD. We designed a tDCS protocol to allow study participation from the patient's home, while maintaining clinical trial standards. We utilized a live video-conferencing platform and specially designed equipment that 'unlocks' one session at a time. Study objective: To assess feasibility and explore the therapeutic potential of remotely supervised tDCS (RS-tDCS) paired with cognitive training (CT) for PD patients suffering from fatigue.
Method(s): Double-blind, randomized, sham controlled study of RS-tDCS paired with CT. Participants completed 10 daily tDCS sessions (20-minute, 2.0-mA, bi-frontal, F3-F4 montage, left anodal), with the option of 10 additional open label sessions. Evaluation of preliminary clinical effects with the fatigue severity scale (FSS) along with tolerability, safety and compliance were completed.
Result(s): Eighteen participants were screened, 17 enrolled (Table 1), one screen failure. Incidence of the systematically recorded side effects were 22.4% tingling, 11.5% burning sensation, 8.2% itching, 3.3% headache, 0.9% nausea, 0.3% dizziness and 0.3% sleepiness. No serious adverse events reported. Compliance and tolerability were 100%. Preliminary fatigue clinical effects of 10 sessions showed a significant decrease of mean FSS only in the real RS-tDCS group of 8.0 (SD 9.82) points (p < 0.05). Further analysis of 20 RS-tDCS sessions (10 DoubleBlind-real+10 Open-label) showed a further significant decrease in mean FSS of 11.47 (SD 10.7) points (p < 0.05).
Conclusion(s): At-home RS-tDCS therapy paired with CT is safe and well tolerated by PD patients, with the advantages of ease of recruitment and optimal subject compliance. At-home RS-tDCS therapy paired with CT shows potential to remediate fatigue symptoms in PD, but the small sample size limits efficacy conclusions. Our paradigm may be influential in designing future studies. [Figure presented] Introduction: Parkinson's Disease (PD) is a progressively disabling disease that affects patients and their caregivers' quality of life. PD is a chronic neurodegenerative disease affecting a large number of dopaminergic neurons in the nigrostriatal pathway, responsible for common motor dysfunction such as slowness, tremor and rigidity. The disease also leads to various non-motor symptoms, in particular, fatigue and cognitive disability. The available pharmacotherapy often allows for a relatively good control of symptoms, but complications could arise from the side effects of medications, or the progressive nature of the disease [1]. Certain alternative therapies have emerged such as non-invasive brain stimulation (NIBS) that may potentially improve declining function. Transcranial direct current stimulation (tDCS) is a low-cost, safe and practical treatment compared to other NIBS. tDCS is a portable device that utilizes a weak electrical current to modulate neuronal membrane potentials and cortical excitability [2-3]. Fatigue is a highly prevalent symptom that is largely unrecognized in PD with no current evidence-based treatment [4]. Since tDCS has shown beneficial effects in motor, mood and cognitive symptoms in PD, it may have potential to ameliorate fatigue in PD.
Method(s): The study design is a double blind randomized, sham controlled trial using at-home tDCS paired with CT. Remote supervision of tDCS sessions was performed through a video-conferencing platform. The tele-rehabilitation design has been recently validated and allows participation of patients from the comfort of their homes [5]. Feasibility and preliminary effects of RS-tDCS in PD were tested using a dorsolateral prefrontal cortex (DLPFC) montage (F3-F4 from the EEG 10x20 system). All participants received a baseline physical, neurological, fatigue and cognitive assessments. Participants were asked to complete 10 daily sessions. Once finalized, they were offered 10 additional open label (OpL) sessions. Using a detailed study "stop" criteria [6, 7] flow chart, participants were cleared at each step for their participation to proceed. The primary objectives of the study were to determine the feasibility of RS tDCS paired with CT and explore the potential to ameliorate fatigue in PD. Clinical effects on fatigue were measured with the fatigue severity scale (FSS), a scale largely validated and recommended for this population [4]. FSS was obtained at baseline and after 10 tDCS sessions of 20 minutes with 2 milliamperes (mA) intensity, while participants engaged in computerized based CT. During the visits, acceptability of therapy, tolerability, side effects and other adverse events (AEs) were collected. An optional OpL period allows for a more comprehensive exploratory evaluation of RS-tDCS effects beyond 10 sessions.
Result(s): Eighteen patients were screened and seventeen were enrolled (one screen failure). Only one participant decided to opt out of the OpL portion of the study. Patient demographic characteristics did not differ between groups (Table 1). Pain tolerability of 2.0 mA stimulation with <=6 on visual analog scale for pain (VAS-Pain) was 100%. Incidence of the systematically recorded side effects were 22.4% tingling, 11.5% burning sensation, 8.2% itching, 3.3% headache, 0.9%, nausea, 0.3% dizziness and 0.3% sleepiness. Other adverse events (AEs) are listed in figure 1. No serious AEs were reported. All required visits were completed with no attrition or interruptions (100% compliance). Preliminary fatigue clinical effects of 10 sessions showed a significant decrease of mean FSS only in the real RS-tDCS group of 8.0 (SD 9.82) points (p < 0.05). Further analysis of 20 RS-tDCS sessions (10 DoubleBlind-real+10 Open-label) showed a further significant decrease in mean FSS of 11.47 (SD 10.7) points (p < 0.05) (Figure 2). [Figure presented] Discussion and
Conclusion(s): This novel design of remotely supervised tDCS has allowed conducting tDCS sessions safely and away from the lab setting, in the comfort of participant's homes. This paradigm of NIBS is particularly suited for medical conditions limiting mobility like PD, participants with busy schedules or living far distances from clinics. The initial results of this study showed that this protocol is feasible, acceptable and safe in PD with no major adverse events. [Figure presented] Our study has shown that RS-tDCS holds therapeutic potential for fatigue in people with PD, and showed 20 sessions seemed more favorable than 10 sessions. Trials with a greater sample size and extended treatment duration might be more suitable to establish the real efficacy for this therapy as a treatment of fatigue. Study Supported by Grant No. PDF-TRG-1722 from the Parkinson's Foundation. References [1] Kalia, L. V., & Lang, A. E. Parkinson's disease. Lancet, 386(9996), 896-912. (2015) [2] Priori, A., Berardelli, A., Rona, S., Accornero, N., & Manfredi, M. Polarization of the human motor cortex through the scalp. Neuroreport, 9(10), 2257-2260. (1998) [3] Nitsche, M. A., & Paulus, W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol, 527 Pt 3, 633-639. (2000) [4] Friedman, J. H., Beck, J. C., Chou, K. L., et al. Fatigue in Parkinson's disease: report from a mutidisciplinary symposium. NPJ Parkinsons Dis, 2. (2016) [5] Biagioni, M. C., Sharma, K., Migdadi, H. A., & Cucca, A. Non-Invasive Neuromodulation Therapies for Parkinson's Disease. IntechOpen, DOI: 10.5772/intechopen.75052. (2018) [6] Kasschau, M., Sherman, K., Haider, L., et al. A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) in Multiple Sclerosis (MS). J Vis Exp(106), e53542. (2015) [7] Charvet, L. E., Kasschau, M., Datta, A., et al. Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols. Frontiers in Systems Neuroscience, 9(26). (2015)
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Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA₂DS₂-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA₂DS₂-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA₂DS₂-VASc score were associated with increased risk of cerebrovascular events.

Pediatric multiple sclerosis is associated with challenges in prompt diagnosis and uncertainty regarding optimal treatment. This review aimed to identify treatment guidelines or consensus statements for pediatric patients with multiple sclerosis, US Food and Drug Administration (FDA)-approved treatment options for pediatric multiple sclerosis, and any randomized controlled trials and observational studies examining available pharmacologic treatments in the pediatric multiple sclerosis population. Literature searches were performed in MEDLINE (1946-2016), EMBASE (1974-2016), and the Cochrane Central Register of Controlled Trials to identify treatment guidelines or consensus statements, pediatric multiple sclerosis treatment approvals, and randomized controlled trials and observation studies that examine the safety and effectiveness of available disease-modifying therapies. Only 3 consensus statements provided recommendations for pharmacologic treatments for children, all 3 published before the most recent revisions of the pediatric multiple sclerosis diagnostic guidelines. Despite the changes to the clinical landscape of pediatric multiple sclerosis with the introduction of diagnostic guidelines, fingolimod is the only FDA-approved treatment for pediatric multiple sclerosis in the United States. The effectiveness and safety of other disease-modifying therapies suggested by consensus statements have been reported in relatively small prospective and retrospective observational studies. Clinical evidence from a recently completed randomized controlled trial and future global registries can inform treatment decisions for the pediatric multiple sclerosis population.

BACKGROUND:Growing evidence supports the efficacy of restorative cognitive training in people with multiple sclerosis (PwMS), but the effects vary across individuals. Differences in treatment efficacy may be related to baseline individual differences. We investigated clinical characteristics and MRI variables to predict response to a previously validated approach to home-based restorative cognitive training. METHODS:In a single-arm repeated measures study, 51 PwMS completed a 12-week at-home restorative cognitive training program called BrainHQ, shown to be effective in a placebo-controlled clinical trial. Baseline demographic, clinical, neuropsychological, and brain MRI factors were captured and the effects of treatment were quantified with Symbol Digit Modalities Test (SDMT). Also measured were indices of treatment compliance. Regression modeling was employed to identify the factors associated with greatest SDMT improvement. RESULTS:As a group, patients improved significantly after training: mean SDMT improving from 49.6 ± 14.7 to 52.6 ± 15.6 (t = 3.91, p<0.001). Greater SDMT improvement correlated positively with treatment exposure (r = 0.38, p = 0.007). Increased post-rehabilitation improvement on SDMT was predicted by baseline relapsing-remitting course (β=-0.34, p = 0.017), higher trait Conscientiousness-Orderliness (β=0.29, p = 0.040), and higher baseline gray matter volume (GMV; β=0.31, p = 0.030). CONCLUSION/CONCLUSIONS:The study was designed to explore the variables that predict favorable outcome in a home-based application of a validated restorative cognitive training program. We find good outcomes are most likely in patients with higher trait Conscientiousness-Orderliness, and relapsing-remitting course. The same was found for individuals with higher GMV. Future work in larger cohorts is needed to support these findings and to investigate the unique needs of individuals according to baseline factors.

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients ( P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P<0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.