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1.  Sensitivity and specificity of diagnostic ultrasound in the diagnosis of phrenic neuropathy 
Neurology  2014;83(14):1264-1270.
To determine the sensitivity and specificity of B-mode ultrasound in the diagnosis of neuromuscular diaphragmatic dysfunction, including phrenic neuropathy.
A prospective study of patients with dyspnea referred to the EMG laboratory over a 2-year time frame for evaluation of neuromuscular respiratory failure who were recruited consecutively and examined with ultrasound for possible diaphragm dysfunction. Sonographic outcome measures were absolute thickness of the diaphragm and degree of increased thickness with maximal inspiration. The comparison standard for diagnosis of diaphragm dysfunction was the final clinical diagnosis of clinicians blinded to the diaphragm ultrasound results, but taking into account other diagnostic workup, including chest radiographs, fluoroscopy, phrenic nerve conduction studies, diaphragm EMG, and/or pulmonary function tests.
Of 82 patients recruited over a 2-year period, 66 were enrolled in the study. Sixteen patients were excluded because of inconclusive or insufficient reference testing. One hemidiaphragm could not be adequately visualized; therefore, hemidiaphragm assessment was conducted in a total of 131 hemidiaphragms in 66 patients. Of the 82 abnormal hemidiaphragms, 76 had abnormal sonographic findings (atrophy or decreased contractility). Of the 49 normal hemidiaphragms, none had a false-positive ultrasound. Diaphragmatic ultrasound was 93% sensitive and 100% specific for the diagnosis of neuromuscular diaphragmatic dysfunction.
B-mode ultrasound imaging of the diaphragm is a highly sensitive and specific tool for diagnosis of neuromuscular diaphragm dysfunction.
Classification of evidence:
This study provides Class II evidence that diaphragmatic ultrasound performed by well-trained individuals accurately identifies patients with neuromuscular diaphragmatic respiratory failure (sensitivity 93%; specificity 100%).
PMCID: PMC4180486  PMID: 25165390
2.  A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS 
Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.
PMCID: PMC4354803  PMID: 18608093
Amyotrophic lateral sclerosis; ALS; minocycline; celecoxib; creatine; clinical trial; neuroprotection; combination therapy; selection trial
3.  Clinical and imaging characterization of progressive spastic dysarthria 
To describe speech, neurological and imaging characteristics of a series of patients presenting with progressive spastic dysarthria (PSD) as the first and predominant sign of a presumed neurodegenerative disease.
Participants were 25 patients with spastic dysarthria as the only or predominant speech disorder. Clinical features, pattern of MRI volume loss on voxel-based morphometry, and pattern of hypometabolism with F18-Fluorodeoxyglucose (FDG-PET) scan are described.
All patients demonstrated speech characteristics consistent with spastic dysarthria, including strained voice quality, slow speaking rate, monopitch and monoloudness, and slow and regular speech alternating motion rates. Eight patients did not have additional neurological findings on examination. Pseudobulbar affect, upper motor neuron pattern limb weakness, spasticity, Hoffman sign and positive Babinski reflexes were noted in some of the remaining patients. Twenty-three patients had electromyographic assessment and none had diffuse motor neuron disease or met El Escorial criteria for ALS. Voxel-based morphometry revealed striking bilateral white matter volume loss, , affecting the motor cortex (BA 4), including the frontoparietal operculum (BA 43) with extension into the middle cerebral peduncle. FDG-PET showed subtle hypometabolism affecting the premotor and motor cortices in some patients, particularly in those who had a disease duration longer than two years.
We have characterized a neurodegenerative disorder that begins focally with spastic dysarthria due to involvement of the motor and premotor cortex and descending corticospinal and corticobulbar pathways. We propose the descriptive label “progressive spastic dysarthria” to best capture the dominant presenting feature of the syndrome.
PMCID: PMC3945960  PMID: 24053325
dysarthria; neuromuscular disease; MRI; PET
4.  ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): The study methodology, recruitment, and baseline demographic and disease characteristics 
In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression.
An extensive structured telephone interview ascertained environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3 to 6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin.
355 patients were recruited. Subjects were enrolled over a 36 month-period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, with the only difference being type of health insurance among enrolled patients. Sites were divided into 3 groups by the number of enrolled subjects. Comparing these 3 groups, the Columbia site had fewer “definite ALS” diagnoses.
This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and was accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.
PMCID: PMC4310702  PMID: 24564738
ALS; Oxidative Stress; Disease Progression; Survival; Epidemiology
5.  Accuracy of Motor Axon Regeneration Across Autograft, Single Lumen, and Multichannel Poly(lactic-co-glycolic Acid) (PLGA) Nerve Tubes 
Neurosurgery  2008;63(1):144-155.
Accuracy of motor axon regeneration becomes an important issue in the development of a nerve tube for motor nerve repair. Dispersion of regeneration across the nerve tube may lead to misdirection and polyinnervation. In this study, we present a series of methods to investigate the accuracy of regeneration, which we used to compare regeneration across autografts and single lumen poly(lactic-co-glycolic acid) (PLGA) nerve tubes. We also present the concept of the multichannel nerve tube that may limit dispersion by separately guiding groups of regenerating axons.
Simultaneous tracing of the tibial and peroneal nerves with fast blue (FB) and diamidino yellow (DY), 8 weeks after repair of a 1-cm nerve gap in the rat sciatic nerve, was performed to determine the percentage of double-projecting motoneurons. Sequential tracing of the peroneal nerve with DY 1 week before and FB 8 weeks after repair was performed to determine the percentage of correctly directed peroneal motoneurons.
In the cases in which there was successful regeneration across single lumen nerve tubes, more motoneurons had double projections to both the tibial and peroneal nerve branches after single lumen nerve tube repair (21.4%) than after autograft repair (5.9%). After multichannel nerve tube repair, this percentage was slightly reduced (16.9%), although not significantly. The direction of regeneration was nonspecific after all types of repair.
Retrograde tracing techniques provide new insights into the process of regeneration across nerve tubes. The methods and data presented in this study can be used as a basis in the development of a nerve tube for motor nerve repair.
PMCID: PMC3463233  PMID: 18728579
misdirection; axon targeting; double labeling; peripheral nerve regeneration; rat sciatic nerve model; retrograde tracing
A small proportion of patients with ALS survive more than five years. The frequency of five year or longer survival with ALS in a United States population is unknown but may provide a baseline for studies that employ survival as a primary endpoint of analysis.
All persons diagnosed with ALS in Olmsted County between 1925 and 2004 were studied for demographic and clinical features. Longer term survivors were defined as patients who lived five years or longer, tracheostomy-free, following symptomatic onset.
94 patients (mean survival from symptomatic onset 2.95 years (95% CI 2.54–3.35), mean survival from diagnosis 1.89 years, (95% CI 1.54–2.24)) were diagnosed with ALS. Five-year or longer survivors accounted for 14% of the population of patients (95% CI 7.9%–22.8%). The frequency of five year or longer survivors did not change over time. Mean survival of these individuals was 7.04 years (95% CI 6.14–7.94 years; range 5.11–9.35 years). They had a significantly longer mean time to diagnosis (1.77 years, 95% CI 0.95–2.58 years) as compared to less than five year survivors (0.94 years, 95% CI 0.75–1.13 years) (p=0.02) but could not be reliably identified at the time of diagnosis by age, sex, clinical presentation, or El Escorial category.
Patients surviving more than five years following the symptomatic onset of ALS account for 14% of the total ALS population. This frequency has not changed over time. Patients with five year or longer survival are clinically similar to the total population ALS population in terms of age, gender, presentation, and site of onset but have a longer time from symptomatic onset to diagnosis.
PMCID: PMC2946435  PMID: 20627966
amyotrophic lateral sclerosis; natural history; prognosis; survival
7.  Survival Profiles of Patients With Frontotemporal Dementia and Motor Neuron Disease 
Archives of neurology  2009;66(11):1359-1364.
Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43– and ubiquitin-immunoreactive pathologic lesions.
To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis.
Design, Setting, and Patients
Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries.
Main Outcome Measures
Clinical phenotypes and survival patterns of patients.
A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P<.001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P=.005).
Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.
PMCID: PMC2881327  PMID: 19901167
8.  ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine 
Neurologic complications associated with regional anesthesia and pain medicine practice are extremely rare. The ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine addresses the etiology, differential diagnosis, prevention, and treatment of these complications. This Advisory does not focus on hemorrhagic and infectious complications, because they have been addressed by other recent ASRA Practice Advisories. The current Practice Advisory offers recommendations to aid in the understanding and potential limitation of neurologic complications that may arise during the practice of regional anesthesia and pain medicine.
PMCID: PMC2869280  PMID: 18774509
Complications of anesthesia; Nerve injury; Spinal anesthesia; Epidural anesthesia; Peripheral nerve block; Regional anesthesia; Pain medicine; Transforaminal block
9.  Beyond Parkinson Disease: Amyotrophic Lateral Sclerosis and the Axon Guidance Pathway 
PLoS ONE  2008;3(1):e1449.
We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD.
Methodology/Principal Findings
Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92×10−60), survival free of ALS (hazards ratio = 149.80, p = 1.25×10−74), and age at onset of ALS (R2 = 0.86, p = 5.96×10−66). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.
Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.
PMCID: PMC2175528  PMID: 18197259

Results 1-9 (9)