Publications by authors named "Dianna Quan"

27 Publications

  • Page 1 of 1

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study.

Lancet Neurol 2021 01 16;20(1):49-59. Epub 2020 Nov 16.

Centro Hospitalar Universitário do Porto, Porto, Portugal.

Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261.

Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups.

Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Funding: Alnylam Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(20)30368-9DOI Listing
January 2021

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of In Patients With ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Sep 24:1-13. Epub 2020 Sep 24.

Cytokinetics, Inc, South San Francisco, CA, USA.

Objective: To evaluate safety, dose response, and preliminary efficacy of over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Patients ( = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance ( = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R,  = 0.09; muscle strength mega-score,  = 0.31). Post hoc analyses pooling all active -treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
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http://dx.doi.org/10.1080/21678421.2020.1822410DOI Listing
September 2020

Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial.

JAMA Neurol 2021 Jan;78(1):68-76

University of California-Irvine, Irvine.

Importance: Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN.

Objective: To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN.

Design, Setting, And Participants: From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment's sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018.

Interventions: Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69).

Main Outcomes And Measures: The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates.

Results: Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine.

Conclusions And Relevance: This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point.

Trial Registration: ClinicalTrials.gov Identifier: NCT02260388.
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http://dx.doi.org/10.1001/jamaneurol.2020.2590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432310PMC
January 2021

Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.

J Neurol 2020 Mar 14;267(3):703-712. Epub 2019 Nov 14.

AP-HP, Université Paris Saclay, CHU Bicêtre, Université Paris-Sud, INSERM 1195, Paris, France.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.
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http://dx.doi.org/10.1007/s00415-019-09602-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035216PMC
March 2020

Take two: Utility of the repeat skeletal muscle biopsy.

Muscle Nerve 2019 07 22;60(1):41-46. Epub 2019 Apr 22.

Department of Neurology, University of Colorado School of Medicine, Denver, Colorado, USA.

Introduction: The utility of repeat muscle biopsy has not been adequately evaluated.

Methods: A retrospective review was undertaken of 144 repeat muscle biopsies performed from 1980 to 2017. Repeat biopsy was considered clinically relevant if it provided a new diagnosis, changed the existing diagnosis, or led to treatment changes or further investigations.

Results: Repeat biopsy was abnormal in 118 cases, different from the initial biopsy in 67 cases, and specific in 40 cases. Factors with a significant effect on clinical relevance of the repeat biopsy (P < 0.05) were an abnormal, specific, or inflammatory initial biopsy, proximal muscle weakness, absence of myalgia, and a repeat biopsy that is different, specific, or consistent with polymyositis or inclusion body myositis.

Conclusions: Utility of repeat biopsy was limited to weak patients whose initial biopsy showed inflammatory myositis. Ongoing advances in the diagnosis of immune inflammatory myopathies have led to evolution of the role of repeat biopsy. Muscle Nerve, 2019.
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http://dx.doi.org/10.1002/mus.26484DOI Listing
July 2019

What is the diagnostic accuracy of single nerve conduction studies and muscle ultrasound to identify critical illness polyneuromyopathy: a prospective cohort study.

Crit Care 2018 12 17;22(1):342. Epub 2018 Dec 17.

Division of Pulmonary Sciences & Critical Care Medicine, University of Colorado School of Medicine, RM 9023, Mail Stop C272, 12700 East 19th Avenue, Aurora, CO, 80045, USA.

Background: Critical illness polyneuromyopathy (CIPNM) is a major cause of weakness in intensive care unit (ICU) patients, but current diagnostic tests are limited. We evaluated the generalizability and validity of single nerve conduction studies (NCS) and muscle ultrasound testing to identify CIPNM, and we also assessed the ability of muscle ultrasound to prognosticate patient outcomes.

Methods: This was a prospective cohort study of mechanically ventilated medical, cardiac, surgical, and neurosurgical ICU patients. We performed weekly strength testing, NCS, electromyography (EMG), and muscle ultrasound. We calculated the sensitivity, specificity, and other test characteristics of single NCS and muscle ultrasound, and we used multivariable regression models to assess the prognostic ability of muscle ultrasound.

Results: Ninety-five patients were enrolled. The incidence of probable CIPNM was 18% and did not differ significantly by type of ICU (p = 0.49). For diagnosing probable CIPNM, the peroneal motor NCS had a sensitivity of 94% (95% confidence interval (CI) 71-100%) and specificity of 91% (95% CI 82-96%), the sural sensory NCS had a sensitivity of 100% (95% CI 80-100%) and specificity of 42% (95% CI 31-54%), and abnormal muscle ultrasound echogenicity had a sensitivity of 82% (95% CI 48-98%) and specificity of 57% (95% CI 43-70%). Abnormal echogenicity was associated with reduced likelihood of discharge to home (9% vs 50%, p = 0.0001), fewer ICU-free days (median 3 (interquartile range 0-15) days vs 16 (9.3-19.3) days, p = 0.0002), and increased ICU mortality (42% vs 12%, p = 0.004).

Conclusions: In a diverse cohort of critically ill patients, single NCS and muscle ultrasound achieved diagnostic accuracy for patients at risk for CIPNM. The routine utilization of these tests could be beneficial for all critically ill patients at risk for CIPNM.
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http://dx.doi.org/10.1186/s13054-018-2281-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296115PMC
December 2018

The authors reply.

Crit Care Med 2018 04;46(4):e347-e348

Colorado Pulmonary Outcomes Research Group, Department of Medicine, University of Colorado School of Medicine, Aurora, CO and Division of Pulmonary Sciences & Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO; Department of Medicine, University of Colorado School of Medicine, Aurora, CO; Colorado Pulmonary Outcomes Research Group, Department of Medicine, University of Colorado School of Medicine, Aurora, CO and Peak Statistical Services, Evergreen, CO; Department of Neurology, University of Colorado School of Medicine, Aurora, CO; Colorado Pulmonary Outcomes Research Group, Department of Medicine, University of Colorado School of Medicine, Aurora, CO and Division of Pulmonary Sciences & Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO; Colorado Pulmonary Outcomes Research Group, Department of Medicine, University of Colorado School of Medicine, Aurora, CO and Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO; Colorado Pulmonary Outcomes Research Group, Department of Medicine, University of Colorado School of Medicine, Aurora, CO and Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO; Colorado Pulmonary Outcomes Research Group, Department of Medicine, University of Colorado School of Medicine, Aurora, CO and Division of Pulmonary Sciences & Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.

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http://dx.doi.org/10.1097/CCM.0000000000002984DOI Listing
April 2018

Outcomes of ICU Patients With a Discharge Diagnosis of Critical Illness Polyneuromyopathy: A Propensity-Matched Analysis.

Crit Care Med 2017 Dec;45(12):2055-2060

Colorado Pulmonary Outcomes Research Group, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.

Objectives: To assess the impact of a discharge diagnosis of critical illness polyneuromyopathy on health-related outcomes in a large cohort of patients requiring ICU admission.

Design: Retrospective cohort with propensity score-matched analysis.

Setting: Analysis of a large multihospital database.

Patients: Adult ICU patients without preexisting neuromuscular abnormalities and a discharge diagnosis of critical illness polyneuropathy and/or myopathy along with adult ICU propensity-matched control patients.

Interventions: None.

Measurements And Main Results: Of 3,567 ICU patients with a discharge diagnosis of critical illness polyneuropathy and/or myopathy, we matched 3,436 of these patients to 3,436 ICU patients who did not have a discharge diagnosis of critical illness polyneuropathy and/or myopathy. After propensity matching and adjusting for unbalanced covariates, we used conditional logistic regression and a repeated measures model to compare patient outcomes. Compared to patients without a discharge diagnosis of critical illness polyneuropathy and/or myopathy, patients with a discharge diagnosis of critical illness polyneuropathy and/or myopathy had fewer 28-day hospital-free days (6 [0.1] vs 7.4 [0.1] d; p < 0.0001), had fewer 28-day ventilator-free days (15.7 [0.2] vs 17.5 [0.2] d; p < 0.0001), had higher hospitalization charges (313,508 [4,853] vs 256,288 [4,470] dollars; p < 0.0001), and were less likely to be discharged home (15.3% vs 32.8%; p < 0.0001) but had lower in-hospital mortality (13.7% vs 18.3%; p < 0.0001).

Conclusions: In a propensity-matched analysis of a large national database, a discharge diagnosis of critical illness polyneuropathy and/or myopathy is strongly associated with deleterious outcomes including fewer hospital-free days, fewer ventilator-free days, higher hospital charges, and reduced discharge home but also an unexpectedly lower in-hospital mortality. This study demonstrates the clinical importance of a discharge diagnosis of critical illness polyneuropathy and/or myopathy and the need for effective preventive interventions.
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http://dx.doi.org/10.1097/CCM.0000000000002763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693740PMC
December 2017

A case of congenital spinal muscular atrophy with pain due to a mutation in TRPV4.

Neuromuscul Disord 2016 Dec 16;26(12):841-843. Epub 2016 Sep 16.

Department of Neurology, University of Colorado Denver, Aurora, CO, USA.

We present a patient with congenital spinal muscular atrophy associated with pain, subjective sensory loss, right talipes equinovarus, delayed walking, and progressive gait impairment. A sister and niece reportedly had Charcot-Marie-Tooth 1A, but the patient's electromyogram showed an axonal motor neuropathy or neuronopathy. We identified a c.806G>A TRPV4 gene mutation causing an Arg269His amino acid substitution. TRPV4 mutations cause variable phenotypes including axonal sensorimotor neuropathy and motor neuropathy or neuronopathy. Associated features may include arthrogryposis, skeletal dysplasia, vocal cord paresis, sensorineural hearing loss and respiratory weakness. Skeletal X-rays can identify orthopedic causes of pain in patients with TRPV4 mutations, and imaging evidence of bone deformities in patients with suspected hereditary axonal neuropathy, pain and an unknown genetic diagnosis may help lead to a diagnosis of a TRPV4 mutation. Even when a patient's genetic diagnosis is presumed to be known, electrodiagnostic testing is warranted to verify the diagnosis.
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http://dx.doi.org/10.1016/j.nmd.2016.09.013DOI Listing
December 2016

Electrophysiological abnormalities can differentiate pre-hospital discharge functional status in critically ill patients with normal strength.

Intensive Care Med 2016 Sep 22;42(9):1504-5. Epub 2016 Jun 22.

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, RM 9023, Mail Stop C272, 12700 East 19th Avenue, Aurora, 80045, CO, USA.

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http://dx.doi.org/10.1007/s00134-016-4425-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992460PMC
September 2016

Exertional rhabdomyolysis associated with high intensity exercise.

Muscle Nerve 2015 Dec 10;52(6):1134-5. Epub 2015 Sep 10.

Department of Neurology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado.

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http://dx.doi.org/10.1002/mus.24784DOI Listing
December 2015

Screening for critical illness polyneuromyopathy with single nerve conduction studies.

Intensive Care Med 2014 May 13;40(5):683-90. Epub 2014 Mar 13.

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver School of Medicine, AMC, RC2, C-272, 12700 E 19th Ave, Aurora, CO, 80045, USA,

Purpose: The ability to diagnose patients with critical illness polyneuromyopathy (CIPNM) is hampered by impaired patient sensorium, technical limitations, and the time-intensive nature of performing electrophysiological testing. Therefore, we sought to determine whether single nerve conduction studies (NCS) could accurately screen for CIPNM.

Methods: Critically ill patients at increased risk for developing CIPNM were identified. Bilateral NCS of six nerves, and concentric needle electromyography were performed within 24 h of meeting inclusion criteria, and subsequently on a weekly basis until CIPNM was diagnosed or the patient was discharged from the intensive care unit (ICU).

Results: A total of 75 patients were enrolled into the study. Patients who developed CIPNM had a higher hospital mortality (50 vs. 13%, p = 0.002), and fewer ICU-free days (0 vs. 11, p = 0.04). There were no differences between the right and left amplitudes (p = 0.59, 0.91, and 0.21) for nerves that could be simultaneously tested bilaterally (sural, peroneal, and tibial). The amplitudes for each of the six individual nerves were significantly diminished in patients with CIPNM when compared to patients without CIPNM. The nerves with the best diagnostic accuracy were the peroneal nerve [AUC = 0.8856; sensitivity = 94% (95% CI = 88-100%); specificity = 74% (95% CI = 63-85%)], and the sural nerve [AUC = 0.8611; sensitivity = 94% (95 % CI = 88-100%); specificity = 70% (95 % CI = 59-81%)]. The combined diagnostic accuracy for the amplitudes of the peroneal and sural nerves increased significantly [AUC = 0.9336; sensitivity = 100% (95% CI = 100-100%) and specificity = 81% (95% CI = 71-91%)].

Conclusions: Unilateral peroneal and sural NCS can accurately screen for CIPNM in ICU patients and detect a limited number of patients that would need concentric needle electromyography to confirm a diagnosis of CIPNM. These results identify a more streamlined method to diagnose CIPNM that may facilitate routine diagnostic testing and monitoring of weakness in critically ill patients.
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http://dx.doi.org/10.1007/s00134-014-3251-6DOI Listing
May 2014

Intensive care unit-acquired weakness: implications for physical therapist management.

Phys Ther 2012 Dec 26;92(12):1494-506. Epub 2012 Jan 26.

A. Nordon-Craft, PT, DSc, Department of Physical Therapy, School of Health Professions, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, MET 535, Fort Worth, TX 76107, USA.

Patients admitted to the intensive care unit (ICU) can develop a condition referred to as "ICU-acquired weakness." This condition is characterized by profound weakness that is greater than might be expected to result from prolonged bed rest. Intensive care unit-acquired weakness often is accompanied by dysfunction of multiple organ systems. Individuals with ICU-acquired weakness typically have significant activity limitations, often requiring physical assistance for even the most basic activities associated with bed mobility. Many of these individuals have activity limitations months to years after hospitalization. The purpose of this article is to review evidence that guides physical rehabilitation of people with ICU-acquired weakness. Included are diagnostic criteria, medical management, and prognostic indicators, as well as criteria for beginning physical rehabilitation, with an emphasis on patient safety. Data are presented indicating that rehabilitation can be implemented with very few adverse effects. Evidence is provided for appropriate measurement approaches and for physical intervention strategies. Finally, some of the key issues are summarized that should be investigated to determine the best intervention guidelines for individuals with ICU-acquired weakness.
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http://dx.doi.org/10.2522/ptj.20110117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513482PMC
December 2012

Muscular dystrophies and neurologic diseases that present as myopathy.

Authors:
Dianna Quan

Rheum Dis Clin North Am 2011 May;37(2):233-44, vi

Electromyography Laboratory, Department of Neurology, University of Colorado Denver, Academic office 1 - MS B-185, 12631 East 17th Avenue, Room 5121, Aurora, CO 80045, USA.

Chronic muscle weakness is a common complaint among patients seen in rheumatology and neuromuscular specialty clinics. This article focuses on adult-onset muscular dystrophies, select hereditary myopathies, and other neuromuscular conditions that must be distinguished from acquired causes of inflammatory muscle disease such as polymyositis. A few organizing principles help to focus the evaluation and narrow the differential diagnosis.
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http://dx.doi.org/10.1016/j.rdc.2011.01.006DOI Listing
May 2011

Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients.

Clin Transplant 2010 Mar-Apr;24(2):223-8. Epub 2009 Aug 3.

Division of Infectious Diseases, Department of Internal Medicine, University of Colorado Denver, Anschutz Medical Campus, Denver, CO 80045, USA.

Evidence suggests that West Nile virus (WNV) neuroinvasive disease occurs more frequently in both solid organ and human stem cell transplant recipients. The effect of concomitant anti-B-cell therapy with rituximab, a CD20(+) monoclonal antibody, on WNV infection in this population, however, has not been reported. We describe a case of a patient with alpha-1-antitrypsin deficiency who underwent single lung transplantation in 2005 and was maintained on tacrolimus, cytoxan and prednisone. More recently, she had received two courses of rituximab for recurrent A2-A3 grade rejection with concomitant capillaritis and presented six months later with rapid, fulminant WNV meningoencephalitis. Her diagnosis was made by cerebrospinal fluid (CSF) PCR but serum and CSF WNV IgM and IgG remained negative. She received WNV-specific hyperimmune globulin (Omr-Ig-Am) through a compassionate protocol. She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis.
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http://dx.doi.org/10.1111/j.1399-0012.2009.01044.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873850PMC
August 2010

Using the Frontal Assessment Battery to identify executive function impairments in amyotrophic lateral sclerosis: A preliminary experience.

Amyotroph Lateral Scler 2010 ;11(1-2):244-7

Department of Neurology, University of California Davis, Sacramento, 95817, USA.

Up to 50% of persons with amyotrophic lateral sclerosis (ALS) develop cognitive impairments, particularly of executive function (EF). The Frontal Assessment Battery (FAB) provides a method for rapid assessment of EF. We investigated the FAB as an assessment of cognitive impairment among 16 subjects with ALS, and evaluated their performance on the FAB and the Mini-Mental State Examination (MMSE). Raw FAB and MMSE scores were Z-transformed using published age- and education-based norms. FAB Z-scores were significantly lower than MMSE Z-scores (p<0.03). Eight subjects (50%) were impaired (Z < or = -2) on the FAB while no subjects were impaired on the MMSE. MMSE and FAB scores did not vary as function of disease duration, laterality of onset, or Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Further study of the suitability of the FAB as a domain-specific screening measure of executive dysfunction for ALS is warranted.
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http://dx.doi.org/10.3109/17482960903059588DOI Listing
August 2010

Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy.

Hum Mol Genet 2009 Apr 12;18(7):1200-8. Epub 2009 Jan 12.

Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.
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http://dx.doi.org/10.1093/hmg/ddp014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722193PMC
April 2009

Neuromuscular hyperexcitability associated with acetylcholine receptor antibodies in a child.

J Child Neurol 2009 Jan 20;24(1):90-2. Epub 2008 Oct 20.

Department of Neurology, University of Colorado Denver, Colorado, USA.

This report describes the clinical and electrophysiological features of an 8-year-old boy with autoimmune neuromuscular hyperexcitability. He presented with features of lower extremity pain, stiffness, and rippling muscles. The diagnosis was made by electromyography and supported by the presence of an antibody directed against nicotinic acetylcholine receptors. His symptoms responded to immunomodulatory treatment with intravenous immunoglobulin. Response to immunomodulatory therapy has not previously been described in the pediatric population with autoimmune neuromuscular hyperexcitability. This case highlights that this is a treatable condition.
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http://dx.doi.org/10.1177/0883073808320755DOI Listing
January 2009

American Association of Neuromuscular & Electrodiagnostic Medicine evidenced-based review: use of surface electromyography in the diagnosis and study of neuromuscular disorders.

Muscle Nerve 2008 Oct;38(4):1219-24

Department of Neurology, University of Washington, Seattle, Washington, USA.

Surface electromyography (sEMG) measures myoelectrical signals recorded from sensors placed on the skin surface. The non-invasive nature of sEMG makes it a potentially useful technology for studying diseases of muscle and nerve. Reviews published by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) and the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN), covering 1964-1994 and 1952-1998, respectively, concluded that sEMG adds no clinical utility over conventional needle EMG (nEMG) for the diagnosis of neuromuscular disease. The AANEM sEMG task force reevaluated the diagnostic utility and added value of this technology for the study of neuromuscular disease based on a contemporary review of relevant literature published between January 1994 and February 2006. The present review concludes that sEMG may be useful to detect the presence of neuromuscular disease (level C rating, class III data), but there are insufficient data to support its utility for distinguishing between neuropathic and myopathic conditions or for the diagnosis of specific neuromuscular diseases. sEMG may be useful for additional study of fatigue associated with post-poliomyelitis syndrome and electromechanical function in myotonic dystrophy (level C rating, class III data).
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http://dx.doi.org/10.1002/mus.21055DOI Listing
October 2008

Prevention of shingles: safety and efficacy of live zoster vaccine.

Ther Clin Risk Manag 2007 Aug;3(4):633-9

Primary infection with varicella zoster virus (VZV) causes chickenpox (varicella) after which virus becomes latent in cranial nerve, dorsal root and autonomic ganglia along the entire neuraxis. Virus may later reactivate, causing shingles (zoster), characterized by pain and rash restricted to 1-3 dermatomes. More than 40% of zoster patients over age 60 develop postherpetic neuralgia (PHN), pain that persists for months to years. The socioeconomic impact of primary varicella infection has been lessened by introduction of VZV vaccine for children. However, the effect of childhood vaccination on the incidence of zoster is unknown. Virus reactivation correlates with waning cell-mediated immunity (CMI) to VZV with normal aging. Adults exposed to children with varicella may have a boost in CMI to VZV. For at least several more decades, the incidence of zoster may increase as the elderly population grows. The anticipated increase in zoster burden of illness in future decades was a major impetus for the Shingles Prevention Study, a prospective, double-blind, placebo-controlled trial of attenuated VZV vaccine to prevent zoster in older adults. This review discusses clinical and virological aspects of zoster and its complications, current treatment options, and VZV vaccine development along with its future role in disease prevention.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374947PMC
August 2007

Danon disease presenting with dilated cardiomyopathy and a complex phenotype.

J Hum Genet 2007 ;52(10):830-835

University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA.

X-linked dilated cardiomyopathy (XLCM) was first described in 1987 and associated with dystrophin gene (DMD) mutations a decade later in one of the original two families. Here we report long-term follow-up of the second family (XLCM-2), for which a DMD mutation was never found. Analysis of the lysosome-associated membrane protein-2 (LAMP-2) gene detected a novel mutation, confirming a diagnosis of Danon disease. The broad phenotype in this family included dilated and hypertrophic cardiomyopathy, cardiac pre-excitation, skeletal myopathy with high serum creatinine kinase, cognitive impairement (in males), and and a pigmentary retinopathy in affected females. Cardiac biopsy in a 13-month-old mutation-carrying male showed no vacuolization by standard histology. We conclude that XLCM may be the presenting sign of Danon disease and, in the presence of familial history of HCM, pre-excitation, skeletal muscle involvement and retinal pigmentary dystrophy should prompt LAMP-2 clinical testing. Furthermore, the absence of vacuolar myopathy in biopsies from young patients may not exclude Danon disease.
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http://dx.doi.org/10.1007/s10038-007-0184-8DOI Listing
December 2007

Improvement of postherpetic neuralgia after treatment with intravenous acyclovir followed by oral valacyclovir.

Arch Neurol 2006 Jul 8;63(7):940-2. Epub 2006 May 8.

Department of Neurology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

Background: Postherpetic neuralgia (PHN) is a complication of shingles (herpes zoster), a painful rash due to varicella-zoster virus reactivation. Studies of patients with PHN and zoster sine herpete (radicular pain without rash) support the notion that low-grade viral ganglionitis contributes to pain. If chronic pain reflects active infection, then antiviral therapy may help patients with PHN.

Objective: To determine whether antiviral treatment helps reduce PHN-associated pain.

Design: Prospective, open-label phase I/II clinical trial.

Setting: Tertiary care university hospital.

Patients: Fifteen patients with moderate to severe PHN.

Interventions: Intravenous acyclovir at a dosage of 10 mg/kg every 8 hours for 14 days followed by oral valacyclovir at a dosage of 1000 mg 3 times per day for 1 month.

Main Outcome Measure: Numeric Rating Scale for Pain score.

Results: As defined by a decrease of 2 or more points on the Numeric Rating Scale for Pain, 8 (53%) of 15 patients reported improvement.

Conclusion: Clinical improvement reported by most of our patients warrants further investigation in a larger, randomized, double-blind, placebo-controlled trial.
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http://dx.doi.org/10.1001/archneur.63.7.noc60049DOI Listing
July 2006

A 71-year-old male with 4 decades of symptoms referable to both central and peripheral nervous system.

Brain Pathol 2005 Oct;15(4):369-70, 373

Department of Neurology, University of Colorado Health Sciences Center, Denver, USA.

May 2005. Combined demyelination of the central and peripheral nervous system is an uncommon disorder and has been referred to by many appellations. We present the case of a 71-year-old man with a progressive nervous system disorder beginning in his 30s. The diagnosis in life was unclear, but had over the years been variously considered to be Guillain-Barrè Syndrome (GBS), Friedreich ataxia, or multiple sclerosis (MS). At autopsy old CNS demyelination consistent with MS was found as well as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with onion bulb formation in hypertrophic nerves. Microscopic examination showed some onion bulb formation in the CNS as well as in peripheral nerves. The nosology of these disorders is discussed and relevant animal models briefly reviewed.
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http://dx.doi.org/10.1111/j.1750-3639.2005.tb00123.xDOI Listing
October 2005

Spinal and cranial hypertrophic neuropathy in multiple sclerosis.

Muscle Nerve 2005 Jun;31(6):772-9

Department of Neurology, University of Colorado Health Sciences Center, Box F727, 4200 East Ninth Avenue, Denver, Colorado 80262, USA.

Two patients with multiple sclerosis developed symptomatic chronic inflammatory demyelinating polyneuropathy with massive spinal or cranial nerve hypertrophy revealed by neuroimaging. Sural nerve biopsy in one showed only moderate demyelination, axonal loss, and onion-bulb formation, illustrating dichotomy between severe proximal and milder distal nerve involvement. Patients with coexistent central and peripheral demyelination usually are symptomatic from dysfunction at one site or the other, but not from both. Our patients showed minimal response to steroids, intravenous immunoglobulin, or azathioprine. These cases suggest that the mechanism of disease in symptomatic central and peripheral demyelination may differ from that of disease in only one region, and that optimal therapy in this situation must be explored further.
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http://dx.doi.org/10.1002/mus.20312DOI Listing
June 2005

Topical ketamine treatment of postherpetic neuralgia.

Neurology 2003 Apr;60(8):1391-2

Department of Neurology, University of Colorado Health Sciences Center, Denver 80262, USA.

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http://dx.doi.org/10.1212/01.wnl.0000055848.00032.39DOI Listing
April 2003

Clinical variant of familial amyloid polyneuropathy.

Muscle Nerve 2002 Sep;26(3):417-20

University of Colorado Neurosciences Center, 1635 North Ursula Street, Box F-727, Aurora, CO 80010, USA.

Hereditary amyloidosis with early and prominent peripheral nerve involvement is often designated familial amyloid polyneuropathy (FAP). The abnormality usually lies in the transthyretin (TTR) gene. We describe a patient with a tyr77 TTR gene mutation who presented with sensorimotor polyneuropathy but no other systemic symptoms of amyloidosis. This is one of a few documented cases of the tyr77 mutation in North America. The clinical and electrophysiologic features of this unusual cause of sensorimotor polyneuropathy are discussed.
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http://dx.doi.org/10.1002/mus.10208DOI Listing
September 2002