Amyotrophic lateral sclerosis and motor neuron syndromes in Asia.

While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.

HLA and amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of upper and lower motor neurones. It leads to death by respiratory failure and has a typical prognosis of 2-3 years. The immune system has been shown to play a role in the pathophysiology of ALS. Some of the most important immune genes are within the human leukocyte antigen (HLA) region, and a recent genome-wide association study (GWAS) has identified a risk allele for ALS within the HLA region. Older studies have also suggested an HLA association with ALS, with certain HLA alleles showing differing expression between patients and controls. This systematic review and meta-analysis examines the previous studies performed in this field.Methods: We used established publication search engines. Findings were excluded if they did not meet the selection criteria. We then undertook statistical meta-analysis on the eligible papers, using a fixed effects model.Results: There were eight eligible papers. There were three statistically significant meta-analysis findings, although these would not be significant after correction for multiple comparisons. The frequencies of HLA-A9 and HLA-DR4 genotypes were lower in ALS subjects than controls, and HLA-B35 was higher in ALS subjects.Discussion: This systematic review and meta-analysis do not confirm all the previously reported associations of HLA with ALS, but shows three alleles of interest. However, there are limitations to the studies, which include the use of older serotyping methodology and the small numbers of subjects. Given the recent GWAS association with HLA, further modern HLA studies are warranted.

Estimating biofuel contaminant concentration from 4D ERT with mixing models.

We present the results of a lab-scaled feasibility study to assess the performance of electrical resistivity tomography for detection, characterization, and monitoring of fuel grade ethanol releases to the subsurface. Further, we attempt to determine the concentration distribution of the ethanol from the electrical resistivity tomography data using mixing-models. Ethanol is a renewable fuel source as well as an oxygenate fuel additive currently used to replace the known carcinogen methyl tert-butyl ether; however, ethanol is preferentially biodegraded and a cosolvent. When introduced to areas previously impacted by nonethanol-based fuels, it will facilitate the persistence of carcinogenic fuel compounds like benzene and ethylbenzene, as well as remobilize them to the ground water. These compounds would otherwise be retained in the soil column undergoing active or passive remediation processes such as soil vapor extraction or natural attenuation. Here, we introduce ethanol to a saturated Ottawa sand in a tank instrumented for four-dimensional geoelectrical measurements. Forward model results suggest pure phase ethanol released into a water saturated silica sand should present a detectable target for electrical resistivity tomography relative to a saturated silica sand only. We observe the introduction of ethanol to the closed hydraulic system and subsequent migration over the duration of the experiment. One-dimensional and three-dimensional temporal data are assessed for the detection, characterization, and monitoring of the ethanol release. Results suggest one-dimensional geoelectrical measurements may be useful for monitoring a release, while three-dimensional geoelectrical field imaging would be useful to characterize, monitor, and design effective remediation approaches for an ethanol release, assuming field conditions do not preclude the application of geoelectrical methods. We then attempt to use predictive mixing models to calculate the distribution of ethanol concentration within the measurement domain. For this study we examine four different models: a nested parallel mixing model, a nested cubic mixing model, the complex refractive index model (CRIM), and the Lichtenecker-Rother (L-R) model. The L-R model, modified to include an electrical formation factor geometry term, provided the best agreement with expected EtOH concentrations.

Monocyte CD14 and HLA-DR expression increases with disease duration and severity in amyotrophic lateral sclerosis.

Objective: To investigate changes in immune markers and frequencies throughout disease progression in patients with amyotrophic lateral sclerosis (ALS). Methods: In this longitudinal study, serial blood samples were collected from 21 patients with ALS over a time period of up to 16 months. Flow cytometry was used to quantitate CD14, HLA-DR, and CD16 marker expression on monocyte subpopulations and neutrophils, as well as their cell population frequencies. A Generalized Estimating Equation model was used to assess the association between changes in these immune parameters and disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Results: CD14 expression on monocyte subpopulations increased with both disease duration and a decrease in ALSFRS-R score in patients with ALS. HLA-DR expression on monocyte subpopulations also increased with disease severity and/or duration. The expression of CD16 did not change relative to disease duration or ALSFRS-R. Finally, patients had a reduction in non-classical monocytes and an increase in the classical to non-classical monocyte ratio throughout disease duration. Conclusion: The progressive immunological changes observed in this study provide further support that monocytes are implicated in ALS pathology. Monocytic CD14 and HLA-DR surface proteins may serve as a therapeutic target or criteria for the recruitment of patients with ALS into clinical trials for immunomodulatory therapies.

Atypical clinical presentations of the A3243G mutation, usually associated with MELAS.

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a clinical syndrome associated with mitochondrial abnormalities. In approximately 80% of patients, the syndrome is associated with the A3243G mutation. However, it has been realized that the A3243G mutation is not uncommon in the general population and is found in many patients with clinical presentations other than MELAS. We present four patients who presented with rhabdomyolysis, muscle fatigue, external ophthalmoplegia and myoclonic jerks respectively. These patients were all found to have the A3243G mutation on muscle biopsy. These patients illustrate the variety of presentations associated with A3243G mutation.

Postural orthostatic tachycardia syndrome: an underrecognized disorder.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS), a clinical syndrome of orthostatic intolerance characterized by excessive tachycardia and symptoms of cerebral hypoperfusion on standing, is not well recognized in Australia. The aim was to study the clinical symptomatology, results of autonomic testing and outcome in patients with POTS. METHODS: Sixteen subjects from a tertiary referral centre who met the criteria for POTS were studied between January 2003 and January 2006. Ten of these patients consented to be interviewed using a validated autonomic symptom questionnaire. Heart rate responses to deep breathing and the Valsalva manoeuvre were measured using Colin BP-508 machine (WR Medical Electronic Co., Stillwater, MN, USA). Tilt studies were carried out for 10 min to 80 degrees of head-up tilting. Patient outcome was assessed as functionally normal, able to stand 30 min without symptoms, able to work and carry out recreational activities or worse on follow up. RESULTS: The mean age of 10 subjects was 24.9 +/- 6.8 years, six being women. The mean duration of symptoms was 70.7 months (range 3-228 months). The common presenting orthostatic symptoms were light-headedness (100%), palpitations (90%), pallor (90%), weakness (80%) and clammy skin (80%). The mean heart rate increment during the tilt study was 51.7 +/- 14.3 b.p.m. The mean duration of follow up was 8.9 months (range 1-16 months). Only five patients were functioning normally at the follow-up visit. CONCLUSION: POTS is an underrecognized but persistent autonomic disorder in young patients with a variety of symptoms and variable outcome.

Extra-motor abnormalities in amyotrophic lateral sclerosis: another layer of heterogeneity.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by the presence of muscle weakness. The motor features of disease are heterogeneous in site of onset and progression. There are also extra-motor features in some patients. The genetic basis for extra-motor features is uncertain. The heterogeneity of ALS is an issue for clinical trials. Areas covered: This paper reviews the range and prevalence of extra-motor features associated with ALS, and highlights the current information about genetic associations with extra-motor features. Expert commentary: There are extra-motor features of ALS, but these are not found in all patients. The most common is cognitive abnormality. More data is required to ascertain whether extra-motor features arise with progression of disease. Extra-motor features are reported in patients with a range of causative genetic mutations, but are not found in all patients with these mutations. Further studies are required of the heterogeneity of ALS, and genotype/phenotype correlations are required, taking note of extra-motor features.

Serial measurements of phosphorylated neurofilament-heavy in the serum of subjects with amyotrophic lateral sclerosis.

There is a need for a blood biomarker of disease activity in ALS. This marker needs to measure the loss of motor neurones. Phosphorylated neurofilament heavy chain (pNfH) in the serum is a biomarker of axonal injury. Previous studies have found that levels of pNfH are elevated in ALS. We have performed a serial study of pNfH levels in 98 subjects from our ALS clinic. There was significant elevation of levels of pNfH in subjects with ALS compared to controls, although there was considerable variability. In studies of individuals who had two or more serial samples, we found that the levels of pNfH increased over time in the early stage of disease. Levels were low in subjects with long survival. The rate of rise of pNfH was inversely correlated with survival. We suggest that the initial level of pNfH is a marker of disease severity and that changes in pNfH levels are markers of disease progression.

Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the loss of upper cortical and lower motor neurons. ALS causes death within 2-5years of diagnosis. Diet and body mass index influence the clinical course of disease, however there is limited information about the expression of metabolic proteins and fat-derived cytokines (adipokines) in ALS. In healthy controls and subjects with ALS, we have measured levels of proteins and adipokines that influence metabolism. We find altered levels of active ghrelin, gastric inhibitory peptide (GIP), pancreatic polypeptide (PP), lipocalin-2, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6) and 8 (IL-8), and tumor necrosis factor alpha (TNFα) in the plasma of ALS patients relative to controls. We also observe a positive correlation between the expression of plasma nerve growth factor (NGF) relative to disease duration, and an inverse correlation between plasma glucagon and the ALS functional rating scale-revised (ALSFRS-R). Further studies are required to determine whether altered expression of metabolic proteins and adipokines contribute to motor neuron vulnerability and how these factors act to modify the course of disease.

Effect of contralateral carotid artery stenosis on carotid ultrasound velocity measurements.

BACKGROUND AND PURPOSE: Carotid ultrasonography is being increasingly performed as the sole investigation to assess internal carotid artery (ICA) stenosis. A potential source of error in using ultrasound peak systolic velocity (PSV) measurements is that the redistribution of blood flow due to severe stenosis in a contralateral carotid artery may lead to artificially elevated values. METHODS: Ultrasonography was performed before and after carotid endarterectomy in symptomatic patients who participated in the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The mean change in PSV in the unoperated artery was assessed across all degrees of angiographically defined stenosis. A simple theoretical resistance model of the cerebral circulation was also derived. RESULTS: Complete bilateral ultrasound examinations were performed within 90 days of the initial scan in 386 patients. In the presence of a contralateral severe (70% to 99%) ICA stenosis, the PSV in the unoperated artery was artificially elevated by a mean of 84 cm/s (P:=0.03; 95% CI, 10 to 159 cm/s). The mean elevation was less pronounced for lesser degrees of stenosis (11 to 21 cm/s). Small elevations (3 to 12 cm/s) were observed when the contralateral artery had <70% stenosis. The patterns of observed results were congruent with those from the theoretical model. CONCLUSIONS: The present study showed that a severely stenosed contralateral ICA can artificially elevate ultrasound PSV. Since the effect was greatest when bilaterally severe stenoses were present, caution must be exercised when assessing the degree of ICA stenosis on the basis of ultrasonography PSV measurements alone.

Anticipating mechanical ventilation in Guillain-Barré syndrome.

CONTEXT: The combination of multiple clinical factors culminates in neuromuscular respiratory failure in up to 30% of the patients with Guillain-Barré syndrome (GBS). Although guidelines exist as to when to proceed with intubation, early indicators of subsequent progression to respiratory failure have not been established. OBJECTIVES: To identify clinical and respiratory features associated with progression to respiratory failure and to examine patterns of respiratory decline in patients with severe GBS. DESIGN: Retrospective survey. SETTING: Tertiary care hospital. PATIENTS: One hundred fourteen consecutive patients with severe GBS admitted to the intensive care unit between January 1, 1976, and December 31, 1996. MAIN OUTCOME MEASURES: Early markers of impending respiratory failure, requirement for mechanical ventilation, and patterns of respiratory decline. METHODS: The clinical and electrophysiologic features of 60 patients receiving mechanical ventilation were compared with 54 patients with severe GBS who did not receive mechanical ventilation. Daily preventilation maximal inspiratory and maximal expiratory respiratory pressures and vital capacity were analyzed. Multivariate predictors of the necessity for mechanical ventilation were assessed using logistic regression analysis. RESULTS: Progression to mechanical ventilation was highly likely to occur in those patients with rapid disease progression, bulbar dysfunction, bilateral facial weakness, or dysautonomia. Factors associated with progression to respiratory failure included vital capacity of less than 20 mL/kg, maximal inspiratory pressure less than 30 cm H(2)O, maximal expiratory pressure less than 40 cm H(2)O or a reduction of more than 30% in vital capacity, maximal inspiratory pressure, or maximal expiratory pressure. No clinical features predicted the pattern of respiratory decline; however, serial measurements of pulmonary function tests allowed detection of those at risk for respiratory failure. CONCLUSIONS: While inherently unpredictable, the course of patients with severe GBS can, to some extent, be predicted on the basis of clinical information and simple bedside tests of respiratory function. These data may be used in the decisions regarding admission to the intensive care unit and preparation for elective intubation.

Surgical management of the failed gastroplasty.

Gastroplasty has been used in surgical management of reflux for 25 years. The creation of a gastric tube before fundoplication complicates further corrective procedures should the original operation fail. Experience has been gained with 51 patients, 34 having partial fundoplication gastroplasty and 17 having total fundoplication, who have had major persistent or recurrent symptoms. All were evaluated by history, radiology, endoscopy, manometry with pH, and acid perfusion testing before surgical management. The patients undergoing partial fundoplication gastroplasty had heartburn (85.3%), reflux (70.6%), and dysphagia (94.1%). Radiologic recurrence was present in 26.5%, endoscopic incompetence in 94.1%, and a stricture in 26.5%. The patients who had a total fundoplication gastroplasty had heartburn (52.9%), reflux (29.4%), and dysphagia (82.4%). Radiologic recurrence was present in 29.4%, endoscopic incompetence in 35.3%, and a stricture in 5.9%. On average, these patients had had 2.3 prior operations (range one to five operations). The dominant cause of failure (in the absence of anatomic recurrence) with partial fundoplication gastroplasty was continued or recurrent reflux and with total fundoplication gastroplasty, too tight or too long a fundoplication. All patients had a thoracoabdominal revision total fundoplication gastroplasty and a 1 cm completion fundoplication. Pyloromyotomy was added if not previously performed. There were no deaths or major morbidity. Follow-up in 51 patients averages 4.2 years (range 0.3 to 8.8 years). None has radiologic recurrence, one has minor reflux, one a traumatic diverticulum, and one has moderate esophageal obstruction. Of these patients, 82.4% are asymptomatic, 13.7% have minor symptoms, and 3.9% (two patients) have significant residual symptoms. This conservative surgical approach avoids the higher mortality of resection with interposition and provides satisfactory results.

Dysphagia complicating hiatal hernia repair.

Dysphagia may be a continuing or added problem after operations for the control of reflux. In a series of 208 patients treated surgically for recurrent hiatal hernia, 34 (16.3%) presented with dominant dysphagia either caused by or aggravated by the operation. They were evaluated by history, radiology, manometry, and endoscopy. The causes of dysphagia were diagnosed in all patients: reflux stricture in nine patients, tight or long Nissen wrap in 15, muscle injury in three, inappropriate myotomy with reflux in three, myotomy with overcompetent repair in two, and early Nissen intussusception in two patients. Surgical correction was by total fundoplication gastroplasty in 32 patients, Nissen repair in one, and colon interposition in one. In four patients the myotomy was closed. Complete follow-up averages 5.4 years. There has been one anatomic recurrence, 28 patients are asymptomatic, and five are much improved but have minor persistent dysphagia. Only by complete investigation can the cause of dysphagia be recognized and treated.

Total fundoplication gastroplasty. Long-term follow-up in 500 patients.

Total fundoplication gastroplasty was designed to combine the low anatomic recurrence rate of gastroplasty with the effectiveness of reflux control obtained by total wrap. The problems requiring evaluation are anatomic recurrence, continued reflux, dysphagia, inability to belch or vomit, and gas bloat, all of which have been described in procedures employing a total wrap. Five hundred consecutive patients were analyzed 6 to 60 months following operation. There were no deaths and a 3.6% incidence of short-term operative morbidity. Follow-up was available clinically in 98.4% (495 patients), radiologically in 89.6% (448), and manometrically in 69.5% (347). Two patients have anatomic recurrence (0.4%) and none has reflux. Excellent results occurred in 93.4% (467), improvement in 5% (25), and poor results in 1.6% (eight). Repeat operation was necessary in 0.4% (two) for recurrence and in 0.8% (four) for severe dysphagia. The other problems were minor dysphagia in 2.2% (11), gastritis in 1.2% (six), late cholelithiasis in 0.4% (two), and continued pain with poor results in 0.4% (two). The length of the gastroplasty tube and the subdiaphragmatic position of the high-pressure zone (HPZ) did not affect the result of the operation. A long tube and unwrapped supradiaphragmatic HPZ was present in 18.8% (94); none had reflux or major dysphagia. Total length of the gastroplasty wrap was 3 to 4 cm in the first 200 and the incidence of major dysphagia was 5% (10). Reducing the length of fundoplication to 1.5 to 2 cm reduced the incidence of dysphagia to 1.7% (five). Other problems of gastritis and difficulty with belching and vomiting occurred in a random fashion. This procedure is effective in reflux control, prevents anatomic recurrence and, if the completed fundoplication is maintained at 1.5 to 2 cm, yields a low incidence of significant dysphagia.

Preoperative assessment of esophageal pathology.

Panmural esophagitis results in esophageal thickening and shortening and prevents adequate reduction of a hernia. Twenty patients with panmural esophagitis, treated by Belsey repair, have been followed up for more than 5 years; 9 of them remain asymptomatic and 11 have symptomatic reflux, 7 of whom have required further surgery. Belsey also has reported a 45 per cent recurrence rate in patients with this type of disease. Preoperative recognition of panmural esophagitis allows a planned surgical approach and the use of a surgical technique designed for the management of an irreducible hernia. The ability to predict these changes was studied in 124 patients, who were evaluated by history, radiology, endoscopy, and manometry prior to transthoracic hernia repair. The esophagus was inspected at operation to determine the presence of panmural changes. History was of no value in assessment. Radiologically, a large and irreducible hernia was associated with panmural changes, but these changes also occurred in the absence of ulceration. Manometric studies allowed accurate prediction of mural changes. Over 90 per cent of patients with panmural esophagitis have more than 40 per cent disordered motor activity (DMA) in the distal part of the esophagus, and 75 per cent of such patients have more than 60 per cent DMA. Combining these investigative data allowed the accurate prediction of panmural changes in 90 per cent of the 124 patients.

Cricopharyngeal myotomy as a method of treating cricopharyngeal dysphagia secondary to gastroesophageal reflux.

Food obstruction at the cricopharyngeal level is a common symptom of gastroesophageal reflux. In selected patients, cricopharyngeal myotomy is effective in relief of symptoms. We have used myotomy in patients whose only symptom was dysphagia, in patients too debilitated for major surgery, and in patients with persistent pharyngoesophageal dysphagia following hiatal hernia repair. All were studied by barium esophagogram, endoscopy, and manometry. Radiologic aspiration of barium was apparent in five of 19 patients. High-speed manometric tracings showed intermittent cricopharyngeal incoordination in the six consecutive patients most recently studied. This finding of incoordination has been shown to be present in 38 patients with reflux and in all with major cricopharyngeal symptoms. Myotomy was effective in relieving symptoms in patients in whom this was the only reflux symptom and in the five patients too debilitated for major surgery. Good symptomatic improvement was obtained in nine of the 12 with persistent dysphagia following hernia repair, but in three relief was partial, with persistent symptoms being secondary to distal esophageal obstruction. Investigation is necessary to exclude other causes of dysphagia. However, withcareful selection, myotomy has proved to be an effective method of treatment.

Esophageal disease as a cause of severe retrosternal chest pain.

During one six-month period 11 patients were referred with a diagnosis of coronary artery disease, because of recurrent episodes of severe, prolonged retrosternal chest pain necessitating from one to seven hospital admissions per patient for "suspect myocardial infarction". In no instance was this diagnosis proved by electrocardiogram or serum enzyme changes, but 7 of the 11 patients had abnormal resting electrocardiograms. Selective coronary arteriograms were normal in 10 patients and revealed nonobstructive coronary artery disease in the 11th patient. Esophageal studies revealed hiatus hernia in 9 and mild to severe disordered motored activity of the esophagus in all 11. Acid perfusion into the esophagus reproduced the chest pain in nine patients and in the other two, the hiatus hernia was incarcerated. On direct questioning, all patients indicated that the pain was worsened by lying down and bending over, and in eight patients there was a history of pharyngoesophageal or gastroesophageal dysphagia. In this day when the problem of chest pain with normal coronary arteries is very topical, our report emphasizes the need to consider symptomatic esophageal disease in the differential diagnosis of this problem.

Surgical management of 100 consecutive esophageal strictures.

We report our experience with 100 consecutive patients with reflux-induced esophageal structure managed surgically. Preoperative dilatation, total fundoplication gastroplasty, and postoperative dilatation were used in 98 patients. Only two required resection of the esophageal structure. We have identified preoperative factors that adversely affect the results. These include scleroderma; previous operation, either esophageal or gastric, and the severity of the esophageal stricture. Results of nonresectional operations are excellent in uncomplicated cases or with the addition of only one complicating factor. The more complicating factors, the worse the results. Those patients with three preoperative complicating factors do poorly and may benefit from esophageal resection. We conclude that results obtained from this conservative nonresectional management program justify continuance of the use of total fundoplication gastroplasty with preoperative and postoperative dilatation in the management of such patients.