The effect of noninvasive ventilation on ALS patients and their caregivers.

BACKGROUND: Noninvasive ventilation (NIV) reduces mortality and improves some aspects of quality of life (QoL) in ALS. However, concerns remain that progressive disability may negate these benefits and unnecessarily burden caregivers. METHODS: Thirty-nine patients requiring NIV were offered treatment. Twenty-six were established on NIV, but 13 declined or could not tolerate NIV. Fifteen patients without respiratory muscle weakness (RMW) but with similar ALS severity and age were studied in parallel. Caregivers of 21 NIV, 7 untreated, and 10 patients without RMW participated. Patients and caregivers had detailed QoL measurements for 12 months. NIV patients underwent cognitive testing before and after treatment. RESULTS: RMW correlated with lower QoL. The median survival of untreated patients (18 days; 95% CI 11 to 25 days) was shorter than for NIV patients (298 days; 95% CI 192 to 404 days) and non-RMW patients (370 days; 95% CI 278 to 462 days; log rank test [2 df] = 81, p = 0.00001). A wide range of QoL measures improved within 1 month of starting NIV, and improvements were maintained for 12 months. QoL of non-RMW patients declined as RMW progressed. Caregivers of NIV and non-RMW patients showed similar increases in burden, but NIV patient caregivers developed a deterioration in the Short Form-36 Vitality score. No improvements were found on measures of learning and recall in the NIV patients. CONCLUSIONS: Respiratory muscle weakness has a greater impact on quality of life (QoL) than overall ALS severity. Noninvasive ventilation (NIV) improves QoL despite ALS progression. NIV has no impact on most aspects of caregiver QoL and does not significantly increase caregiver burden or stress.

Cough augmentation in amyotrophic lateral sclerosis.

Cough flows and pressures were measured during cough augmentation in healthy subjects and patients with bulbar and nonbulbar amyotrophic lateral sclerosis. Manual assistance increased flow 11% in bulbar (p < 0.01) and 13% in nonbulbar (p < 0.001) patients. Mechanical insufflation-exsufflation increased flow 17% in healthy subjects (p < 0.05), 26% (p < 0.001) in bulbar, and 28% (p < 0.001) in nonbulbar patients. The greatest improvements were in patients with the weakest coughs. Patient group and level of weakness influenced the effect of augmentation.

Diaphragm compound muscle action potential measured with magnetic stimulation and chest wall surface electrodes.

To seek a method to reliably measure phrenic nerve conduction time (PNCT) with magnetic stimulation we investigated two stimulus sites, placing the magnetic coil at the cricoid cartilage (high position) or close to the clavicle (low position). We also compared compound muscle action potential (CMAP) recorded from three different sites: in the sixth to eighth intercostal spaces in the anterior axillary line (Ant-a); in the 8th intercostal space close to the midclavicular line; and with one electrode at the lower sternum and the other at the costal margin. Fourteen normal subjects were studied. The PNCT measured by magnetic stimulation in the high position recorded from (Ant-a) was 7.6+/-0.6 on the left side and 8.4+/-0.7 on the right. The PNCT recorded from all three sites become much shorter when the magnetic coil was moved from the high to the low position. Our results show that PNCT can be accurately measured with magnetic stimulation when care is taken to avoid coactivation of the brachial plexus.

Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis.

Although ventilatory failure is the most common cause of death in amyotrophic lateral sclerosis (ALS) and measurement of respiratory muscle strength (RMS) has been shown to have prognostic value, no single test of strength can predict the presence of hypercapnia reliably. RMS was measured in 81 ALS patients to evaluate the relationship between tests of RMS and the presence of ventilatory failure, defined as a carbon dioxide tension > or = 6 kPa. We studied the predictive value of vital capacity (VC), static inspiratory and expiratory mouth pressures (MIP, MEP), maximal sniff oesophageal (sniff P(oes)), transdiaphragmatic (sniff P(di)) and nasal (SNP) pressure, cough gastric (cough P(gas)) pressure and transdiaphragmatic pressure after bilateral cervical magnetic phrenic nerve stimulation (CMS P(di)) to identify the risk of ventilatory failure in the whole group and in subgroups of patients with and without significant bulbar involvement. For patients without significant bulbar involvement, sniff P(di) had greatest predictive power [odds ratio (OR) 57] with specificity, sensitivity and positive and negative predictive values (PPV, NPV) of 87, 90, 74 and 95%, respectively Of the less invasive tests, per cent predicted SNP had greater overall predictive power (OR 25, specificity 85%, sensitivity 81%) than per cent predicted VC (9, 89%, 53%) and per cent predicted MIP (6, 83%, 55%). No test had significant predictive power for the presence of hypercapnia when used to measure RMS in a subgroup of patients with significant bulbar weakness. Thirty-five patients underwent polysomnography. CMS P(di), sniff P(di) and per cent predicted SNP were significantly correlated with the apnoea/hypopnoea index (AHI) (P = 0.035, 0.042 and 0.026, respectively). The correlations between AHI and per cent predicted MIP and VC were less strong (both non-significant). In ALS patients without significant bulbar involvement, novel tests of RMS have greater predictive power than conventional tests to predict hypercapnia. In particular, the non-invasive SNP is more sensitive than VC and MIP, suggesting that it could usefully be included in tests of respiratory muscle strength in ALS and will be helpful in assessing the risk of ventilatory failure. In patients with significant bulbar involvement, tests of respiratory muscle strength do not predict hypercapnia. Sleep-disordered breathing is correlated with RMS and the novel tests of RMS having the strongest relationship with the degree of sleep disturbance.

The effect of non-invasive positive pressure ventilation (NIPPV) on cognitive function in amyotrophic lateral sclerosis (ALS): a prospective study.

OBJECTIVES: Neuropsychological investigations have shown a degree of cognitive dysfunction in a proportion of non-demented patients with ALS. Respiratory muscle weakness in ALS can lead to nocturnal hypoventilation, resulting in sleep disturbance and daytime somnolence. Sleep deprivation of this type may cause impairments in cognitive function, but this has not been formally evaluated in ALS. METHODS: Cognitive functioning was evaluated in nine patients with ALS with sleep disturbance caused by nocturnal hypoventilation (NIPPV group), and in a comparison group of 10 similar patients without ventilation problems (control group). The NIPPV group then started non-invasive positive pressure ventilation (NIPPV) at night. After about 6 weeks, change in cognitive function was evaluated. RESULTS: Statistically significant improvement in scores on two of the seven cognitive tests was demonstrated in the NIPPV group postventilation, and a trend towards significant improvement was found for two further tests. Scores in the control group did not improve significantly for these four tests, although an improvement was found on one other test. CONCLUSIONS: Nocturnal hypoventilation and sleep disturbance may cause cognitive dysfunction in ALS. These deficits may be partially improved by NIPPV over a 6 week period. This has important implications for investigations of both cognitive dysfunction in non-demented patients with ALS, and the effect of ventilation on quality of life.

A prospective study of quality of life in ALS patients treated with noninvasive ventilation.

Noninvasive positive pressure ventilation prolongs survival in ALS but its effect on quality of life is unknown. The authors prospectively studied quality of life using the SF-36 questionnaire in a cohort of 16 ventilated patients with ALS. Noninvasive positive pressure ventilation improved scores in the "Vitality" domain by as much as 25%, for periods of up to 15 months, despite disease progression. Noninvasive positive pressure ventilation did not cause reduced quality of life, as any fall in scores in the ventilated group were comparable to those seen in a control group. In conclusion, noninvasive positive pressure ventilation enhances quality of life when used to treat sleep-disordered breathing in patients with ALS.

Whistle mouth pressure as test of expiratory muscle strength.

Expiratory muscle strength is a determinant of cough function. Mouth pressures during a maximal static expiratory effort (PE,max) are dependent on patient motivation and technique and low values are therefore difficult to interpret. This study hypothesized that a short, sharp and maximal expiration through a narrow aperture, a "whistle", might provide a complementary test of expiratory muscle strength. To obtain a maximal whistle, subjects (27 healthy volunteers and 10 patients with amyotrophic lateral sclerosis) were asked to perform a short, sharp blow as hard as possible, from total lung capacity, through a reversed paediatric inhaler whistle, connected to a flange-type mouthpiece. In both healthy subjects and patients, whistle mouth pressure (Pmo,W) was closely related to the pressure measured in the oesophagus and stomach during the same manoeuvre. In healthy subjects, Pmo,W and PE,max correlated with wide limits of agreement, although Pmo,W values were significantly higher than PE,max (131+/-31 cmH2O versus 101+/-27 cmH2O, p<0.0001). In patients, it was also found that Pmo,w and PE,max values were strongly related (r=0.937, p<0.0001). In healthy subjects, the intraclass correlation coefficient and the variation coefficient for Pmo,W repeated measurements were respectively 0.88 and 7.0%. However Pmo,W and PE,max were always smaller than the gastric pressure generated by a maximal cough. It is concluded that mouth whistle pressure, a noninvasive, reproducible and simple test, provides a reliable measure of expiratory muscle strength in healthy subjects that is acceptable to patients and can be used in a complementary fashion to maximal static expiratory effort.

Effect of diaphragm fatigue on neural respiratory drive.

To test the hypothesis that diaphragm fatigue leads to an increase in neural respiratory drive, we measured the esophageal diaphragm electromyogram (EMG) during CO(2) rebreathing before and after diaphragm fatigue in six normal subjects. The electrode catheter was positioned on the basis of the amplitude and polarity of the diaphragm compound muscle action potential recorded simultaneously from four pairs of electrodes during bilateral anterior magnetic phrenic nerve stimulation (BAMPS) at functional residual capacity. Two minutes of maximum isocapnic voluntary ventilation (MIVV) were performed in six subjects to induce diaphragm fatigue. A maximal voluntary breathing against an inspiratory resistive loading (IRL) was also performed in four subjects. The reduction of transdiaphragmatic pressure elicited by BAMPS was 22% (range 13-27%) after 2 min of MIVV and was similar, 20% (range 13-26%), after IRL. There was a linear relationship between minute ventilation (VE) and the root mean square (RMS) of the EMG during CO(2) rebreathing before and after fatigue. The mean slope of the linear regression of RMS on VE was similar before and after diaphragm fatigue: 2.80 +/- 1.31 vs. 3.29 +/- 1.40 for MIVV and 1.51 +/- 0.31 vs 1.55 +/- 0.31 for IRL, respectively. We conclude that the esophageal diaphragm EMG can be used to assess neural drive and that diaphragm fatigue of the intensity observed in this study does not affect respiratory drive.

Effect of lung volume on the oesophageal diaphragm EMG assessed by magnetic phrenic nerve stimulation.

Previous studies have shown conflicting results on the effect of lung volume on the diaphragm compound muscle action potential (CMAP). Consequently, the ability to quantify the oesophageal diaphragm electromyography (EMG) has been questioned. If lung volume changes have little effect on the diaphragm CMAP the accurate measurement of voluntary EMG, as an index of respiratory drive, may be possible. Furthermore, the measurement of CMAP could provide useful clinical information when evaluating patients with neuromuscular disease. To reassess the effect of lung volume on the oesophageal diaphragm CMAP, six normal subjects were studied using an oesophageal catheter incorporating seven electrodes (number one being proximal and seven distal) that were 1 cm in length and 1 cm apart. Electrode number three was positioned at the centre of the electrically active region of the diaphragm (EARdi) at functional residual capacity (FRC). The diaphragm CMAP elicited by bilateral magnetic stimulation of the phrenic nerves was simultaneously recorded from four electrode pairs. Pair one was created from electrodes one and three, pair two from electrodes two and four, pair three from electrodes three and five, and pair four from electrodes five and seven. Phrenic nerve stimulation was at residual volume (RV), FRC, FRC+1.0 L, FRC+2.0 L, and total lung capacity (TLC). The CMAP recorded from pair one was least influenced by changes in lung volume and the amplitude was 2.41+/-0.39 (mean+/-SD), 2.60+/-0.27, 2.64+/-0.29, and 2.71+/-0.45 mV at RV, FRC, FRC+1.0 L and FRC+2.0 L, respectively. At TLC the CMAP was more variable. The CMAP amplitude recorded from pair two increased with increasing lung volume and at FRC+2.0 L was 3.7 times larger than that at FRC. Pair four usually recorded substantially smaller CMAPs at all lung volumes. This study shows that the diaphragm compound muscle action potential recorded from an oesophageal electrode just above the diaphragm is relatively stable over the lung volume range residual volume to functional residual capacity+2.0 L.

Assessment of diaphragm paralysis with oesophageal electromyography and unilateral magnetic phrenic nerve stimulation.

The purpose of this study was to establish a sensitive and reliable method of diagnosing diaphragm paralysis by recording the diaphragm compound muscle action potential (CMAP) using a multipair oesophageal electrode and unilateral magnetic phrenic nerve stimulation. An oesophageal electrode catheter was designed containing six coils (1 cm wide and 3 cm apart), creating an array of four sequential electrode pairs. The oesophageal catheter was taped at the nose with the proximal electrode pair 40 cm from the nares. Eight patients with unilateral (n=5) or bilateral (n=3) diaphragm paralysis were studied. Five to seven phrenic nerve stimulations were performed at 80% of maximum magnetic stimulator output and the CMAPs were recorded simultaneously from the four pairs of electrodes. In the five patients with unilateral diaphragm paralysis, the CMAP amplitudes and latencies were 1.16+/-0.29 mV and 7.6+/-1.5 ms for functioning sides. No diaphragm CMAP could be detected when stimulating nonfunctioning phrenic nerves. This study shows that diaphragm paralysis can be reliably diagnosed by unilateral magnetic stimulation combined with a multipaired oesophageal electrode.

Quantification of the esophageal diaphragm electromyogram with magnetic phrenic nerve stimulation.

Measurement of the amplitude of the esophageal diaphragm compound muscle action potential (CMAP) could be useful for the diagnosis and monitoring of neuromuscular disease. However, quantification of the diaphragm CMAP has been hampered by difficulty in positioning the esophageal electrode at the diaphragm's electrically active center and many investigators report arbitrary units rather than voltage. To quantify the esophageal diaphragm CMAP we designed a multipair electrode which we evaluated during unilateral magnetic stimulation. The esophageal catheter consisted of four sequential electrode pairs. Overall the electrode spanned 17 cm and covered the entire electrically active region of the diaphragm. The diaphragm CMAP was simultaneously recorded from the four pairs at distances of 40, 39, 38, and 37 cm from the nose to the proximal electrode pair. Studies were undertaken in 10 normal subjects and 10 patients with diaphragm dysfunction. The amplitude of the CMAP (peak to peak) was defined as the average of five twitches recorded from the optimal pair of electrodes. The amplitude of the diaphragm CMAP elicited by unilateral maximal magnetic stimulation was 1.45 +/- 0.35 mV (mean +/- SD) for the right side and 1.68 +/- 0.47 mV for the left. When measured on different occasions the coefficient of variation (CV) was 8.6%. The amplitude of the CMAP measured from dysfunctional hemidiaphragms was much less than that measured from normal subjects. This study suggests that the diaphragm CMAP can be quantified using an appropriate esophageal electrode.

Effect of brachial plexus co-activation on phrenic nerve conduction time.

BACKGROUND: Diaphragm function can be assessed by electromyography of the diaphragm during electrical phrenic nerve stimulation (ES). Whether phrenic nerve conduction time (PNCT) and diaphragm electrical activity can be reliably measured from chest wall electrodes with ES is uncertain. METHODS: The diaphragm compound muscle action potential (CMAP) was recorded using an oesophageal electrode and lower chest wall electrodes during ES in six normal subjects. Two patients with bilateral diaphragm paralysis were also studied. Stimulations were deliberately given in a manner designed to avoid or incur co-activation of the brachial plexus. RESULTS: For the oesophageal electrode the PNCT was similar with both stimulation techniques with mean (SE) values of 7.1 (0.2) and 6.8 (0.2) ms, respectively (pooled left and right values). However, for surface electrodes the PNCT was substantially shorter when the brachial plexus was activated (4.4 (0.1) ms) than when it was not (7.4 (0.2) ms) (mean difference 3.0 ms, 95% CI 2.7 to 3.4, p<0.0001). A small short latency CMAP was recorded from the lower chest wall electrodes during stimulation of the brachial plexus alone. CONCLUSIONS: The results of this study show that lower chest wall electrodes only accurately measure PNCT when care is taken to avoid stimulating the brachial plexus. A false positive CMAP response to phrenic stimulation could be caused by inadvertent stimulation of the brachial plexus. This finding may further explain why the diaphragm CMAP recorded from chest wall electrodes can be unreliable with cervical magnetic stimulation during which brachial plexus activation occurs.

Diaphragm electromyogram measured with unilateral magnetic stimulation.

The purpose of this study was to establish the phrenic nerve conduction time (PNCT) for magnetic stimulation and further assess the relatively new technique of anterior unilateral magnetic stimulation (UMS) of the phrenic nerves in evaluating the diaphragm electromyogram (EMG). An oesophageal electrode was used to record the diaphragm compound muscle action potential (CMAP) elicited by supramaximal percutaneous electrical phrenic nerve stimulation (ES) and UMS from eight normal subjects. The oesophageal electrode used for recording the CMAP was positioned at the level of the hiatus and 3 cm below. The diaphragm CMAP was also recorded from chest wall surface electrodes in five subjects. All of the phrenic nerves could be maximally stimulated with UMS. A clear plateau of the amplitude of the CMAP was achieved for the right and left phrenic nerves. The mean amplitudes of the CMAP recorded from the oesophageal electrode were, for the right side, 0.74+/-0.29 mV (mean+SD) for ES and 0.76+/-0.30 mV for UMS with maximal power output, and for the left side 0.88+/-0.33 mV for ES and 0.80+/-0.24 mV for UMS. PNCT measured by the oesophageal electrode with ES and UMS with maximal output were, for the right side, 7.0+/-0.8 ms and 6.9+/-0.8 ms, respectively, and for the left side 7.8+/-1.2 ms and 7.7+/-1.3 ms, respectively. However, the CMAP recorded from chest wall surface electrodes with UMS was unsuitable for the measurement of PNCT. The results suggest that unilateral magnetic stimulation of the phrenic nerves combined with an oesophageal electrode can be used to assess diaphragmatic electrical activity and measure the phrenic nerve conduction time.

Respiratory aspects of neurological disease.

Neurological disease may result in respiratory dysfunction; however the manifestations of respiratory dysfunction in such patients may be atypical because of wider effects of their underlying condition. In the present review we have considered separately acute neuromuscular respiratory disease (as well as aspects of respiratory muscle function relevant to intensive care), chronic neuromuscular respiratory disease, sleep related disorders, respiratory consequences of specific neurological diseases, and neurological features of respiratory disease. Approaches to specific clinical problems are discussed; in many instances this can be expedited by close cooperation with a respiratory physician. We suggest that management of respiratory dysfunction in neurological disease depends critically on three factors: firstly, knowledge of when respiratory dysfunction is likely to occur; secondly, maintaining a high index of clinical suspicion (specifically apparently vague symptoms should not be uncritically attributed to the underlying neurological condition); and, thirdly, the pursuing of appropriate investigations.

Diaphragm EMG measured by cervical magnetic and electrical phrenic nerve stimulation.

The purpose of the study was to compare electrical stimulation (ES) and cervical magnetic stimulation (CMS) of the phrenic nerves for the measurement of the diaphragm compound muscle action potential (CMAP) and phrenic nerve conduction time. A specially designed esophageal catheter with three pairs of electrodes was used, with control of electrode positioning in 10 normal subjects. Pair A and pair B were close to the diaphragm (pair A lower than pair B); pair C was positioned 10 cm above the diaphragm to detect the electromyogram from extradiaphragmatic muscles. Electromyograms were also recorded from upper and lower chest wall surface electrodes. The shape of the CMAP measured with CMS (CMS-CMAP) usually differed from that of the CMAP measured with ES (ES-CMAP). Moreover, the latency of the CMS-CMAP from pair B (5.3 +/- 0.4 ms) was significantly shorter than that from pair A (7.1 +/- 0.7 ms). The amplitude of the CMS-CMAP (1.00 +/- 0.15 mV) was much higher than that of ES-CMAP (0.26 +/- 0.15 mV) when recorded from pair C. Good-quality CMS-CMAPs could be recorded in some subjects from an electrode positioned very low in the esophagus. The differences between ES-CMAP and CMS-CMAP recorded either from esophageal or chest wall electrodes make CMS unreliable for the measurement of phrenic nerve conduction time.

Expiratory muscle function in amyotrophic lateral sclerosis.

Few data exist concerning expiratory muscle function in amyotrophic lateral sclerosis (ALS). We studied 26 patients with ALS (16 with respiratory symptoms and 10 without) and measured the maximal static expiratory mouth pressure (MEP), the gastric pressure during a maximal cough (Cough Pga), and the gastric pressure after magnetic stimulation of the lower thoracic nerve roots (Tw Pga). These measurements were related to the ability to generate transient supramaximal flow during a cough (cough spikes), to arterialized capillary blood gases, and to inspiratory muscle strength. Vocal cord motion was examined endoscopically in 11 of the 16 symptomatic patients. Expiratory muscle weakness was related to inability to generate cough spikes with a threshold effect such that spikes were absent for Cough Pga < 50 cm H2O (p = 0.009) or Tw Pga < 7 cm H2O (p = 0.006) and was usually associated with inspiratory muscle weakness. However, in multivariate analysis, PaCO2 was only significantly associated with the maximal sniff esophageal pressure (p = 0.02). Symptomatic patients had significantly lower inspiratory muscle strength, whereas, of the expiratory muscle tests, only Tw Pga was significantly lower (p = 0.0009) in symptomatic patients. Abnormal vocal cord motion was observed in two of the 11 patients examined. We conclude that abdominal muscle weakness in ALS, when substantial, results in an inability to generate transient supramaximal flow during a cough. However, the primary determinant of both ventilatory failure and respiratory symptoms seems to be inspiratory muscle weakness.