Polymyxin-induced neuromuscular weakness: a case report.

Polymyxin-induced neuromuscular blockade is a rare but potentially fatal condition, with majority of cases that were reported between 1962 and 1973. We describe a patient who developed hypercapnic respiratory failure after initiation of polymyxin for multi-drug resistant Escherichia Coli bacteremia, due to polymyxin-induced neuromuscular dysfunction. After cessation of polymyxin, he regained full strength, had complete resolution of ptosis, and was successfully extubated. In light of the renewed use of polymyxin in this era of antimicrobial-resistance, this case aims to raise awareness about this rare but life-threatening condition, which is easily reversible with early recognition and prompt discontinuation of the drug.

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review.

The diagnosis of inherited neuromuscular disorders is challenging due to their genetic and phenotypic variability. Traditionally, neurophysiology and histopathology were primarily used in the initial diagnostic approach to these conditions. Sanger sequencing for molecular diagnosis was less frequently utilized as its application was a time-consuming and cost-intensive process. The advent and accessibility of next-generation sequencing (NGS) has revolutionized the evaluation process of genetically heterogenous neuromuscular disorders. Current NGS diagnostic testing approaches include gene panels, whole exome sequencing (WES), and whole genome sequencing (WGS). Gene panels are often the most widely used, being more accessible due to availability and affordability. In this mini-review, we describe the benefits and risks of clinical genetic testing. We also discuss the utility, benefits, challenges, and limitations of using gene panels in the evaluation of neuromuscular disorders.

Novel Autoantibodies in Idiopathic Small Fiber Neuropathy.

OBJECTIVE: Small fiber neuropathy (SFN) is clinically and etiologically heterogeneous. Although autoimmunity has been postulated to be pathophysiologically important in SFN, few autoantibodies have been described. We aimed to identify autoantibodies associated with idiopathic SFN (iSFN) by a novel high-throughput protein microarray platform that captures autoantibodies expressed in the native conformational state. METHODS: Sera from 58 SFN patients and 20 age- and gender-matched healthy controls (HCs) were screened against >1,600 immune-related antigens. Fluorescent unit readout and postassay imaging were performed, followed by composite data normalization and protein fold change (pFC) analysis. Analysis of an independent validation cohort of 33 SFN patients against the same 20 HCs was conducted to identify reproducible proteins in both cohorts. RESULTS: Nine autoantibodies were screened with statistical significance and pFC criteria in both cohorts, with at least 50% change in serum levels. Three proteins showed consistently high fold changes in main and validation cohorts: MX1 (FC = 2.99 and 3.07, respectively, p = 0.003, q = 0.076), DBNL (FC = 2.11 and 2.16, respectively, p = 0.009, q < 0.003), and KRT8 (FC = 1.65 and 1.70, respectively, p = 0.043, q < 0.003). Further subgroup analysis into iSFN and SFN by secondary causes (secondary SFN) in the main cohort showed that MX1 is higher in iSFN compared to secondary SFN (FC = 1.61 vs 0.106, p = 0.009). INTERPRETATION: Novel autoantibodies MX1, DBNL, and KRT8 are found in iSFN. MX1 may allow diagnostic subtyping of iSFN patients. ANN NEUROL 2022;91:66-77.

Reliability of bedside ultrasound of limb and diaphragm muscle thickness in critically ill children.

INTRODUCTION: We evaluated the reliability of measuring muscle thickness with ultrasound in limbs and diaphragms of critically ill children and determined the sensitivity of these measures to quantitate muscle atrophy over time. METHODS: An expert and trained novice sonographers prospectively measured limb and diaphragm muscle thickness in 33 critically ill children. RESULTS: Expert and novice intrarater and interrater reliability were similar. Intraclass correlations (ICC) and coefficients of variation (CoV) were better in limbs (ICC > 0.9; CoV 3.57%-5.40%) than in diaphragm (ICC > 0.8; CoV novice 11.88%, expert, 12.28%). Mean relative difference in all muscles was small (1%-8%). Limits of agreement of the relative difference were smaller in limb (<13%-18%) than in diaphragm (<38%) muscles. DISCUSSION: Muscle thickness is reliably measured with ultrasound by trained examiners in critically ill children. Our approach detects atrophy >13% in limb and >38% in diaphragm muscles. The smaller detectable change in limb muscles is likely due to their greater thickness. Muscle Nerve 59:88-94, 2019.

Muscle atrophy in mechanically-ventilated critically ill children.

IMPORTANCE: ICU-acquired muscle atrophy occurs commonly and worsens outcomes in adults. The incidence and severity of muscle atrophy in critically ill children are poorly characterized. OBJECTIVE: To determine incidence, severity and risk factors for muscle atrophy in critically ill children. DESIGN, SETTING AND PARTICIPANTS: A single-center, prospective cohort study of 34 children receiving invasive mechanical ventilation for ≥48 hours. Patients 1 week- 18 years old with respiratory failure and without preexisting neuromuscular disease or skeletal trauma were recruited from a tertiary Pediatric Intensive Care Unit (PICU) between June 2015 and May 2016. We used serial bedside ultrasound to assess thickness of the diaphragm, biceps brachii/brachialis, quadriceps femoris and tibialis anterior. Serial electrical impedance myography (EIM) was assessed in children >1 year old. Medical records were abstracted from an electronic database. EXPOSURES: Respiratory failure requiring endotracheal intubation for ≥48 hours. MAIN OUTCOME AND MEASURES: The primary outcome was percent change in muscle thickness. Secondary outcomes were changes in EIM-derived fat percentage and "quality". RESULTS: Of 34 enrolled patients, 30 completed ≥2 ultrasound assessments with a median interval of 6 (IQR 6-7) days. Mean age was 5.42 years, with 12 infants <1 year (40%) and 18 children >1 year old (60%). In the entire cohort, diaphragm thickness decreased 11.1% (95%CI, -19.7% to -2.52%) between the first two assessments or 2.2%/day. Quadriceps thickness decreased 8.62% (95%CI, -15.7% to -1.54%) or 1.5%/day. Biceps (-1.71%; 95%CI, -8.15% to 4.73%) and tibialis (0.52%; 95%CI, -5.81% to 3.40%) thicknesses did not change. Among the entire cohort, 47% (14/30) experienced diaphragm atrophy (defined a priori as ≥10% decrease in thickness). Eighty three percent of patients (25/30) experienced atrophy in ≥1 muscle group, and 47% (14/30)-in ≥2 muscle groups. On multivariate linear regression, increasing age and traumatic brain injury (TBI) were associated with greater muscle loss. EIM revealed increased fat percentage and decreased muscle "quality". CONCLUSIONS AND RELEVANCE: In children receiving invasive mechanical ventilation, diaphragm and other skeletal muscle atrophy is common and rapid. Increasing age and TBI may increase severity of limb muscle atrophy. Prospective studies are required to link muscle atrophy to functional outcomes in critically ill children.

Timing of recanalization after intravenous thrombolysis and functional outcomes after acute ischemic stroke.

BACKGROUND: Recanalization of occluded intracranial arteries remains the aim of intravenous (IV) tissue plasminogen activator (tPA) therapy in acute ischemic stroke (AIS). OBJECTIVE: To examine the timing and impact of recanalization on functional outcomes in AIS. DESIGN: A longitudinal cohort of consecutive IV tPA­treated patients with AIS from January 2007 through December 2010. Data were collected for demography, risk factors, stroke subtypes, blood pressure, and National Institutes of Health Stroke Scale scores. Early recanalization (ER) was identified by transcranial Doppler monitoring during the first 2 hours of treatment. Recanalization was reevaluated at 24 hours by computed tomographic angiography (CTA). Patients with ER and patent index artery at 24 hours on CTA were labeled as having persistent recanalization (PR). Recanalization at 24 hours on CTA regardless of transcranial Doppler status was labeled as CTR. Favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 3 months. SETTING: University hospital stroke center. PATIENTS: A total of 240 patients with AIS who underwent IV tPA treatment. RESULTS: Of 2238 patients with AIS, 240 (11%) received IV tPA. The median age was 65 years (range, 19-92 years) and 44% of the study group was male. The median National Institutes of Health Stroke Scale score was 17 (range, 3-35) and the median onset-to-treatment time was 149 minutes (range, 46-270 minutes). Of the 240 patients, 122 (50.8%) achieved favorable outcomes at 3 months. Data for ER, PR, and CTR were analyzed for 160 patients. Early recanalization was seen in 82 patients (51.3%); 67 cases (81.7%) had PR and 84 cases (52.5%) had CTR. National Institutes of Health Stroke Scale score at onset (odds ratio per 1-point increase, 0.938; 95% CI, 0.888-0.991), ER (odds ratio, 3.048; 95% CI, 1.537-6.046), PR (odds ratio, 5.449; 95% CI, 2.382-12.464), and CTR (odds ratio, 4.329; 95% CI, 2.131-8.794) were independent predictors of favorable outcomes. CONCLUSIONS: Intravenous tPA­induced arterial recanalization within the first 24 hours in AIS is a strong predictor of favorable outcomes at 3 months.

Persistence of hyperdense middle cerebral artery sign on follow-up CT scan after intravenous thrombolysis is associated with poor outcome.

BACKGROUND: The rates and extent of recovery in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA) remain highly variable. Hyperdense middle cerebral artery sign (HMCAS) on pretreatment unenhanced computerized tomography (CT) of the brain represents the presence of thrombus, often associated with severe neurological deficits and poor clinical outcome at 3 months. However, HMCAS is reliable only in AIS patients managed conservatively. In patients treated with systemic thrombolysis, HMCAS may disappear (representing clot dissolution) or persist (persisting clot) on the follow-up CT scan of the brain. We aimed at evaluating whether disappearance or the persistence of HMCAS on follow-up CT scan of the brain can predict the final outcome at 3 months. METHODS: Data from consecutive AIS patients treated with IV-tPA, in a standardized protocol, from January 2007 to March 2010 were included in the prospective thrombolysis registry at our tertiary care center. For this evaluation, posterior circulation stroke was excluded. HMCAS was assessed on admission as well as follow-up CT by 2 independent stroke neurologists, blinded to the patient data or outcomes. Functional outcomes assessed by the modified Rankin Scale (mRS) at 3 months were dichotomized as good (mRS score 0-1) and poor (mRS score 2-6). The data were analyzed for the early predictors of poor functional outcome with SPSS version 19 for Windows. RESULTS: Of the total of 2,238 patients admitted during the study period, 226 (11%) with anterior circulation AIS treated with intravenous thrombolysis were included. Median age of the patients was 65 years (range 19-92), 63% were males and they had a median National Institutes of Health Stroke Scale (NIHSS) score of 16 points (range 4-32). HMCAS was observed on admission CT scan in 109 (48.2%) patients and persisted on follow-up CT in 52 (47.7%) of them. Overall, 108 (47.8%) patients achieved poor functional outcome at 3 months. Admission NIHSS score (OR per 1-point increase = 1.241; 95% CI = 1.151-1.337, p < 0.0005), lesser change in NIHSS score at 24 h (OR per 1-point reduction = 0.730; 95% CI = 0.666-0.800, p < 0.0005) and persistence of HMCAS on follow-up CT scan (OR = 3.352; 95% CI = 1.991-11.333, p = 0.039) were associated with poor outcome at 3 months. CONCLUSION: Persistence of HMCAS on the follow-up CT scan of the brain in acute ischemic stroke patients treated with IV-tPA can be used as an early predictor of poor functional outcome.

Intravenous thrombolysis for acute ischemic stroke in Asia.

Data regarding thrombolysis for acute ischemic stroke in Asia are scarce and only a small percentage of patients are thrombolysed. Clinical trials that led to the recommended dose of intravenously administered tissue plasminogen activator (IV-tPA) included predominantly Caucasian patients. However, the single-arm case-controlled observational studies in Japanese patients suggested the clinical efficacy and safety of low-dose IV-tPA (0.6 mg/kg bodyweight; maximum 60 mg) comparable with standard dose (0.9 mg/kg bodyweight; maximum 90 mg). There has been no randomized clinical trial for determining the dose, efficacy or safety of IV-tPA in Asia. Accordingly, the dose of IV-tPA in Asia remains controversial. Reduced treatment cost, lower symptomatic intracerebral hemorrhage risk and comparable efficacy encouraged many Asian centers to adopt low-dose or even variable-dose IV-tPA regimens. We present the current status of thrombolysis for acute ischemic stroke in Asia.

Usefulness of CT angiography for therapeutic decision making in thrombolyzing intubated patients with suspected basilar artery thrombosis.

BACKGROUND AND AIMS: Acute ischemic stroke (AIS) due to basilar artery thrombosis (BAT) causes high mortality and severe disability. Early neurological assessment and timely thrombolysis might improve outcome. BAT is difficult to diagnose due to wide spectrum of presentation and decreased conscious level. Emergency physicians often intubate BAT patients with airway compromise before arrival of stroke neurologist. We evaluated role of computerized tomography (CT) angiography (CTA) of brain and cervical arteries in early diagnosis of acute BAT in intubated patients and facilitating decision for thrombolysis. METHODS: Consecutive AIS patients presenting between 2007 and 2009 within 6 hours of symptom onset, with sudden deterioration in conscious level and intubation before assessment by neurologist, were included. All patients underwent brain CT and CTA. Outcomes were assessed at 3 months. RESULTS: Thrombolytic therapy, mainly intravenous tissue plasminogen activator (IV-TPA), was administered to 161 (8.4%) of 1,917 AIS patients during the study period. Acute BAT contributed 10.9% of our cohort. CTA was performed in 152 (94.4%) patients and the rest were excluded due to their impaired renal functions. Five patients (3 males, mean age 72 years) presenting with acute obtundation and airway compromise were intubated, sedated, and paralyzed before assessment by neurologist. CTA showed BAT in all. IV-TPA was initiated at 213 ± 59 minutes in 4 patients while 1 received intraarterial thrombolysis at 13 hours. There was no intracranial hemorrhage. Mean length of hospital stay was 11.8 days. Despite severe stroke at presentation, good functional recovery at 3 months (modified Rankin scale [mRS] 1) occurred in 2 patients; mRS 4 in 1, and 2 died. CONCLUSION: In patients with BAT, intubated before assessment by neurologist, CTA might help in confirming the diagnosis and facilitating therapeutic decision making for initiating thrombolysis.

Current status of intravenous thrombolysis for acute ischemic stroke in Asia.

BACKGROUND: Data regarding thrombolysis for acute ischemic stroke in Asia are scarce and only a small percentage of patients are thrombolysed. The dose of intravenous tissue plasminogen activator (IV-tPA) in Asia remains controversial. Case-controlled observation studies in Asia included only Japanese patients and suggested the clinical efficacy and safety of low-dose IV-tPA (0.6 mg/kg body weight; max 60 mg) comparable to standard dose (0.9 mg/kg body weight; max. 90 mg). Reduced treatment cost, lower symptomatic intracerebral hemorrhage risk and comparable efficacy encouraged many Asian centers to adopt low-dose or even variable-dose IV-tPA regimens. We evaluated various Asian thrombolysis studies and compared with SITS-MOST registry and NINDS trial. METHODS: We included the published studies on acute ischemic stroke thrombolysis in Asia. Unadjusted relative risks and 95% Confidence intervals were calculated for each study. Pooled estimates from random effects models were used because the tests for heterogeneity were significant. RESULTS: We found only 18 publications regarding acute ischemic stroke thrombolysis in Asia that included total of 9300 patients. Owing to ethnic differences, stroke severity, small number of cases in individual reports, outcome measures and tPA dose regimes, it is difficult to compare these studies. Functional outcomes were almost similar (to Japanese studies) when lower-dose IV-tPA was used in non-Japanese populations across Asia. Interestingly, with standard dose IV-tPA, considerably better functional outcomes were observed, without increasing symptomatic intracerebral hemorrhage rates. CONCLUSIONS: Variable dose regimens of IV-tPA are used across Asia without any reliable or established evidence. Establishing a uniform IV-tPA regimen is essential since the rapid improvements in health-care facilities and public awareness are expected to increase the rates of thrombolysis in Asia.

Role of investigating thrombophilic disorders in young stroke.

Our knowledge about various inherited and acquired causes of thrombophilic disorders has increased significantly during the past decade. Technology for various diagnostic tests for these rare disorders has matched the rapid advances in our understanding about the thrombophilic disorders. Inherited thrombophilic disorders predispose young patients for various venous or arterial thrombotic and thromboembolic episodes. Our understanding has also improved about various gene-gene and gene-environment interactions and their impact on the resultant heterogenous clinical manifestations. We describe various thrombophilic disorders, their diagnostic tests, pathogenic potential in isolation or with other concurrent inherited/acquired defects and possible therapeutic and prophylactic strategies. Better understanding, optimal diagnostic and screening protocols are expected to improve the diagnostic yield and help to reduce morbidity, disability, and mortality in relatively younger patients harbouring these inherited and acquired thrombophilic disorders.