Phrenic nerve studies predict survival in amyotrophic lateral sclerosis

Clinical Neurophysiology 123 (2012) 2454–2459

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Phrenic nerve studies predict survival in amyotrophic lateral sclerosis Susana Pinto a, Anabela Pinto a,b, Mamede de Carvalho a,c,⇑ a

Translational and Clinical Physiology Unit, Instituto de Medicina Molecular-Faculty of Medicine, University of Lisbon, Portugal Department of Physical Medicine and Rehabilitation, Centro Hospitalar Lisboa-Norte-Hospital de Santa Maria, Lisbon, Portugal c Department of Neurosciences, Centro Hospitalar Lisboa-Norte-Hospital de Santa Maria, Lisbon, Portugal b

a r t i c l e

i n f o

Article history: Accepted 15 May 2012 Available online 3 July 2012 Keywords: Amyotrophic lateral sclerosis Diaphragm Phrenic nerve Predicted value Survival

h i g h l i g h t s  Phrenic nerve study is an accessible, non-volitional test, to investigate diaphragm motor neuron pool.  Phrenic nerve motor response amplitude is a significant predictor factor of survival for both spinal and bulbar-onset amyotrophic lateral sclerosis (ALS) patients.  Phrenic nerve motor response should be part of the available tools to test respiratory function in ALS patients.

a b s t r a c t Objective: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease associated with short survival due to respiratory failure. We aimed to test the predictive value of the phrenic nerve motor response for survival, in a large population of ALS patients. Methods: We included 254 ALS patients followed in our tertiary centre from 1997 to 2006, in whom phrenic nerve stimulation was performed according to the study inclusion and exclusion criteria. ALS was spinal onset in 175 and bulbar onset in 79 patients. The following features were recorded at entry: gender, age at presentation, onset region, diagnostic delay, forced vital capacity (FVC), ALS functional rating scale (ALS-FRS) including the respiratory subscore of the reviewed ALS-FRS and mean amplitude of motor responses by phrenic nerve stimulation (PhrenAmpl). Results: Survival analysis was evaluated by Kaplan–Meier log-rank test and multivariate Cox proportional hazards. Independent factors negatively affecting survival were bulbar onset, short diagnostic delay, FVC and small PhrenAmpl for the total population. Small PhrenAmpl and short diagnostic delay were also independent factors for both spinal and bulbar-onset patients; age at onset and FVC were also independent predictors in bulbar-onset patients. Conclusion: Phrenic nerve stimulation is a non-volitional test that can be performed quickly in most patients; it is a powerful predictor of survival in ALS. Significance: Phrenic nerve stimulation should be considered as an additional test for respiratory assessment in ALS. Ó 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease with no available treatment to interrupt the motoneurone demise. Respiratory failure (RF) and Abbreviations: ALS, amyotrophic lateral sclerosis; ALS-FRS, amyotrophic lateral sclerosis functional rating scale; RofALS-FRS-R, respiratory subscore of the revised ALS-FRS-R; PhrenAmpl, peak-to-peak amplitude of phrenic nerve motor responses; FVC, forced vital capacity; SNIP, nasal inspiratory pressure during a sniff; ATS, American Thoracic Society; SD, standard deviation; CI, confidence interval. ⇑ Corresponding author at: Department of Neurology, Hospital de Santa Maria, Av. Professor Egas Moniz, 1648-028 Lisbon, Portugal. Tel./fax: +351 217805219. E-mail address: [email protected] (M. de Carvalho).

other respiratory complications account for the majority of deaths in ALS. Although RF is a frequent late complication, it may be a presenting feature (de Carvalho et al., 1996). Several different factors have been shown to predict survival in ALS. The most consistent negative predictive factors for survival are elderly age (Kaufmann et al., 2005; Kollewe et al., 2008; Chiò et al., 2009), female gender (Chanceller et al., 1993; Del Aguilla et al., 2003), short diagnostic delay (Kaufmann et al., 2005; Kollewe et al., 2008; Chiò et al., 2009), bulbar and respiratory presentation (Kaufmann et al., 2005; Kollewe et al., 2008; Chiò et al., 2009), rapid clinical (ALS-FRS) and respiratory decline (Kaufmann et al., 2005; Kollewe et al., 2008; Chiò et al., 2009). Regarding respiratory progression rate and prognosis, forced vital capacity (FVC) (Fallat

1388-2457/$36.00 Ó 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2012.05.012

S. Pinto et al. / Clinical Neurophysiology 123 (2012) 2454–2459

et al., 1979; Czaplinski et al., 2006; Kollewe et al., 2008), vital capacity (Schiffman and Belsh, 1993), nasal inspiratory pressure obtained during a sniff (SNIP) (Morgan et al., 2005) and mean nocturnal oxymetric oxygen saturation (Velasco et al., 2002; Pinto et al., 2003) have been related as indicators of survival in ALS. We have previously shown that mean peak-to-peak amplitude of the diaphragmatic motor response elicited by percutaneous electrical phrenic nerve stimulation is predictive of hypoventilation, both in bulbar and in spinal-onset ALS patients (Pinto et al., 2009b). Moreover, phrenic nerve motor response amplitude declines significantly over a short period of time (5 months) in ALS patients (Pinto et al., 2009a) and shows a very high inter-side correlation, as a result of a symmetric degeneration of the phrenic motor neurons in the cervical spinal cord (Pinto and de Carvalho, 2010). Phrenic nerve study is non-invasive, reliable when used by experienced neurophysiologists (Pinto et al., 2009a), quick, easily available in all devices and does not depend on patient’s cooperation. In this study, we aimed to evaluate the survival predictive value of phrenic nerve responses in ALS. 2. Patients and methods 2.1. Subjects We included our total population of patients followed in our ALS unit from 1997 to 2006, with definite or probable ALS, as defined by the modified El Escorial criteria (Brooks et al., 2000). All patients had full neurological, neuroradiological, haematological and biochemical investigations. Routine nerve conduction studies ruled out polyneuropathy. The following patients were excluded: older than 80 or younger than 20 years; with lung disorders, polyneuropathy, cardiac insufficiency, pace-maker, diabetes mellitus and with other debilitating medical conditions; patients that could not tolerate the recumbent position; patients with a confirmed clinical diagnosis longer than 3 months before study entry and when the region of disease-onset (bulbar vs. spinal) could not be identified. Inclusion criteria included informed consent, disease progression on regular follow-up and confirmation of the death time. Depending on the region of onset, patients were split into two groups. Group 1 included patients with spinal-onset ALS (presenting with limb weakness or axial-respiratory symptoms); group 2 included patients with bulbar-onset ALS (presenting with dysarthria and/or dysphagia).

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necessary to obtain supramaximal stimulation. Brachial plexus stimulation artefact was avoided by changing stimulus duration, electrode position and stimulus intensity (de Carvalho, 2004; Pinto et al., 2009a,b). A minimum of five consistent motor responses were obtained from each side and the response with the highest peak-to-peak amplitude was selected for analysis. Phrenic nerve stimulation was always performed at the end-of-expiration movement. The mean value derived from right and left side responses was used for statistical analysis (mean PhrenAmp) as the inter-side correlation is very high (Pinto and de Carvalho, 2010). Fig. 1 illustrates typical recordings. 2.4. Standard pulmonary function tests Patients were evaluated in the same independent respiratory laboratory according to the American Thoracic Society (ATS) recommendations (American Thoracic Society, 1995). From the usual respiratory function tests, FVC was considered in the present study, being determined with the patients sitting. The best of three satisfactory expiratory manoeuvres, each obtained after a maximal inspiratory effort, was used to obtain the value for FVC. Predicted values were calculated by normalising to the reference values proposed by the European Community for Steel and Coal (Quanjer et al., 1993). The resulting percentage was used in the analysis. 2.5. Statistical analyses

All patients were evaluated immediately after diagnosis. All the tests were carried out within the interval of 1 month. The functional rating ALS scale (ALS-FRS) (Cedarbaum and Stambler, 1997) was used to derive the total clinical rating score (maximum score of 40). The respiratory subscore of the revised ALS-FRS-R (RofALS-FRS-R) was used to assess respiratory symptoms (Cedarbaum et al., 1999). However, only patients included after August 2000 had this score available.

Demographic variables were expressed as mean ± standard deviation (SD) (minimum–maximum). Normally, distributed variables were compared by Student’s t-test for two groups. Logarithmic transformation allowed normalisation of non-normally distributed variables, namely, total survival time and time from first symptoms to first visit. Non-parametric tests were used if normality was not achieved by logarithmic transformation (ALS-FRS and RofALS-FRS-R). A p-value <0.05 was accepted as significant. Survival analysis was done by Kaplan–Meier log-rank test and the multivariate Cox proportional hazards model, the enter method was used to assess the simultaneous effects of several independent variables on survival and to obtain adjusted survival curves. The categorical variables were included as dummy variables. Survival was measured from symptom onset to death or censor date (January 31, 2012). Continuous variables were dichotomised. Cutoff values were determined by the median value of the variables in the studied population whenever a normative cut-off value is not possible (age, diagnostic delay, ALS-FRS and respiratory subscore). Otherwise, the lower limit of normal was used as the cutoff value: 80% of the predictive value for FVC; 0.4 mV for mean PhrenAmpl (Pinto et al., 2009a). Variables tested were age at onset, gender, onset form (bulbar vs. spinal), diagnostic delay, ALS-FRS, RofALS-FRS, FVC and mean PhrenAmpl. Results were expressed as median (confidence intervals (CIs)). Only those meaningful for a < 0.05 were evaluated in Cox regression. Analyses were performed in Statistical Package for the Social Sciences (SPSS) v20.0 (IBMÒ SPSSÒ Statistics).

2.3. Neurophysiology

2.6. Ethics approval

Bilateral diaphragm motor responses were obtained by percutaneous bipolar electrical stimulation of the phrenic nerve at neck (posterior to the lateral border of the sternocleidomastoid muscle, immediately behind its mid portion) and recorded through surface electrodes on the homolateral costosternal angle (active electrode), with the reference electrode ipsilateral, on the costal girdle, 16 cm apart from G1. A ground electrode was place around the right wrist. The stimulus duration was set between 0.2 and 0.5 ms as

This protocol was approved by the institutional Ethics Committee. All the patients included in the study gave their informed consent.

2.2. Clinical evaluation

3. Results From the original population of 494 ALS patients, 254 (51.4%) fulfilled the study entry criteria (mean age 61 years, SD 11.2 and

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Fig. 1. At the top, normal phrenic nerve responses from a control subject. At the bottom small-phrenic nerve response from a spinal-onset ALS patient. Eight consecutive motor responses are superimposed to show the very minor test-to-test variation (all stimuli were performed at the end-expiratory movement).

Table 1 Demographic characteristics of the ALS patients.

Age at onset (years) Male gender Diagnostic delay (months) ALS-FRS RofALS-FRS-R FVC (% predicted) Mean PhreanAmpl (mV) Total survival time (months)

All patients (n = 254)

Spinal-onset (G1, n = 175)

Bulbar-onset (G2, n = 79)

p

62, 60.9 ± 11.2 (28–80) 132 (52%) 12, 15.7 ± 13.2 (0–81) 32, 31.3 ± 5.6 (13–40) 12, 11.4 ± 1.1 (5–12) 87.5, 85.6 ± 24.3 (18.5–152.6) 0.4, 0.44 ± 0.25 (0–1.25) 33.5, 44.1 ± 33.7 (7.1–213.3)

61, 59.1 ± 11.5 (28–80) 103 (58.9%) 12.8, 17.5 ± 14.7 (0–81) 32, 31.4 ± 5.7 (13–40) 12, 11.4 ± 1.1 (5–12) 91.2, 88.3 ± 24.4 (18.5–152.6) 0.4, 0.45 ± 0.27 (0.0–1.25) 39.6, 50.1 ± 37.8 (8.6–213.3)

65, 64.9 ± 9.7 (36–80) 29 (36.7%) 11.2, 11.8 ± 7.4 (0–47) 33, 31.2 ± 5.5 (17–38) 12, 11.29 ± 1.1 (7–12) 81.6, 79.3 ± 23.3 (31.7–79.3) 0.4, 0.41 ± 0.19 (0.1–1) 28.7, 30.9 ± 15.9 (7.1–87.7)

<0.001* 0.001* 0.004* 0.834 0.136 0.006* 0.138 0.001*

Values represent median, mean ± SD (min-max). ALS-FRS – functional rating scales; RofALS-FRS – the respiratory subscore of ALS-FRS-R (maximum of normality, 0); mean PhreanAmpl – mean phrenic amplitude [(right + left)/2]. * Significant values for p < 0.05.

range 28–80 years). In this group, 82 had definite and 172 had probable or probable-laboratory supported ALS, based on the revise El Escorial criteria. About half the patients were men. The mean diagnostic delay was 15.7 months (SD 13.2 and range 1– 81 months). The disease had bulbar onset in 79 patients (31.1%) and spinal onset in 175. The clinical characteristics of the 254 patients (Table 1) showed no statistical differences when compared with the remaining patients not included in this study but observed in our unit within the same time frame (p > 0.05, for all comparisons). In the bulbar-onset ALS group, women were more frequent (p = 0.001), patients were older (p < 0.001), the predicted FVC values were lower (p = 0.006) and the diagnostic delay shorter (p = 0.004) when compared with spinal-onset patients. Survival was shorter in bulbar-onset patients (p = 0.001). However, mean PhrenAmp, ALS-FRS and RofALS-FRS-R were similar between both populations. Seventy-one patients out of the total population of

254 ALS patients had no RofALS-FRS-R values because they entered the study before August 2000. The proportion of patients alive at censoring data was 5.5% (one patient with bulbar-onset and 13 with spinal-onset disease). Median survival for the 254 ALS patients included by Kaplan–Meier analysis was 33.5 months (95%, CI 30–38), mean 44.1 months (95%, CI 40–48), range 206.2 months. Median survival for spinalonset was 39.6 (95% CI 34–44), mean 50.1 months (95% CI 45– 56), range 204.7; while for bulbar-onset patients was 28.4 (95% CI 24–31), 30.9 (95% CI 27–34) and 80.6, respectively (Fig. 2). Significant prognostic variables in univariate Kaplan–Meier analysis were: region of onset; age at onset (total population and bulbar-onset patients), diagnostic delay (total population and spinal-onset patients), FVC (total population and bulbar-onset patients) and mean PhrenAmpl (total population, for spinal- and for bulbar-onset groups) (Table 2). Gender and ALS-FRS at entry were not found to be significant prognostic factors for survival (p > 0.05).

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(HR = 1.653, 95%, CI = 1.249–2.186; p < 0.001), for the total population; HR = 1.574, 95%, CI = 1.141–2.172, p = 0.006, for spinal-onset patients; HR = 2.161, 95%, CI = 1.195–3.909, p = 0.011, for bulbaronset patients). 4. Discussion

Fig. 2. Kaplan–Meier survival plots (endpoint: death) in our ALS population (n = 254): bulbar (dotted line) vs spinal-onset (solid line) patients.

RofALS-FRS-R was a significant prognostic factor for the total population and spinal-onset patients in whom this score was calculated (after its introduction in August 2000). Cox proportional hazards model was used to analyse survival data for the significant variables. In a final model including all relevant demographic and clinical covariates, site of symptom onset (bulbar-onset with worse prognosis), age at entry (for bulbar-onset patients), diagnostic delay (for the total population, for spinal and bulbar-onset patients), FVC (for the total population and bulbar-onset patients) and mean PhrenAmpl at entry (for the total population, for spinal and bulbar-onset patients) were significant independent predictors of mortality (Table 3 and Fig. 3). Values of phrenic nerves responses equal or lower than 0.4 mV increased the hazard by about 1.653-fold compared to those above to 0.4 mV

Death in ALS is determined by hypoventilation (Fallat et al., 1979), as such it would be anticipated that markers of RF could prove to be the most reliable predictors of survival. In fact, most studies found that a lower FVC at diagnosis was the most relevant prognostic factor in ALS (Stambler et al., 1998; Czaplinski et al., 2006; Schiffman and Belsh, 1993). The slope of FVC (Magnus et al., 2002) and vital capacity (Schiffman and Belsh, 1993) decline have been related to survival, as well. In addition, SNIP (Morgan et al., 2005) and mean nocturnal oxymetric oxygen saturation (Velasco et al., 2002; Pinto et al., 2003) have been suggested as indicators of survival in ALS. However, some authors have not found FVC as an independent predictor of survival (Kaufmann et al., 2005), probably because it depends on patient cooperation and satisfactory lips sealing around a mouthpiece, which is a drawback in bulbar-onset patients. SNIP is not predictive of hypoventilation in bulbar-onset patients (Lyall et al., 2001). Percutaneous nocturnal oximetry does not change significantly over a short period of disease progression (Pinto et al., 2009a) and is influenced by non-invasive ventilation. Phrenic nerve stimulation is an accessible non-invasive test, which is non-volitional and well tolerated. A few patients with severe orthopnoea cannot tolerate the recumbent position, but we did not meet additional technical problems in patients with respiratory impairment. We believe this test has the potential of being universally applied but requires some experience to avoid unreliable results. Standardisation of the technique is essential. The mean PhrenAmpl depends on the number of excitable motor units in the diaphragm (Evangelista et al., 1995). We have shown before that a small motor response following phrenic nerve

Table 2 Kaplan–Meier analyses.

Onset form Gender Age Diagnostic delay ALS-FRS at first visit RofALS-FRS-R at first visit FVC Mean PhrenAmpl

All patients (n = 254) v2; p

Spinal-onset (G1, n = 175) v2; p

Bulbar-onset (G2, n = 79) v2; p

26.897; <0.001** 0.068; 0.795 7.128; 0.008** 29.914; <0.001** 0.77; 0.38 3.213; 0.04* 6.943; 0.008** 6.34; 0.012*

0.073; 0.786 2.019; 0.155 22.598; <0.001** 0.416; 0.519 7.166; 0.007** 0.733; 0.392 3.989; 0.046*

1.349; 0.245 10.271;0.001** 2.83; 0.093 0.296; 0.586 1.391; 0.238 21.019; <0.001** 11.295; 0.001**

See footnote of Table 1. * Significant values for a = 0.05. ** Significant values for a = 0.01.

Table 3 Predictors of death our ALS population (Cox proportional hazards model). All patients HR (95% CI); p Onset form Age Diagnostic delay FVC (cut-off, 80% predicted) Mean PhrenAmpl (cut-off, 0.4 mV)

2.081 1.286 2.247 1.492 1.653

(1.546–2.186);<0.001** (0.985–1.677); 0.064 (1.698–2.973);<0.001** (1.118–1.991); 0.007** (1.249–2.186);<0.001**

Spinal patients HR (95% CI); p

2.365 (1.704–3.283);<0.001** 1.574 (1.141–2.172); 0.006**

See footnote of Table 1. All variables were included in the same Cox proportional hazards model for each group. * Significant values for a = 0.05. ** Significant values for a = 0.01.

Bulbar patients HR (95% CI); p 2.172 2.425 2.967 2.161

(1.306–3.612); 0.003** (1.437–4.092); 0.001** (1.621–5.43);<0.001** (1.195–3.909); 0.011*

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Fig. 3. Survival curves (endpoint: death) for mean PhrenAmpl adjusted for age, diagnostic delay, FVC and onset form. (a) Total population (n = 254); (b) Spinal-onset patients (n = 175); (c) Bulbar-onset patients (n = 79). Solid line represents patients with PhrenAmpl > 0.4 mV and dotted-line represents patients with PhrenAmpl 6 0.4 mV.

stimulation suggests impending RF and indicates the need for a more complete respiratory evaluation (Pinto et al., 2009b). The cut-off value of 0.4 mV for phrenic nerve peak-to-peak amplitude was defined by investigating a large population of controls (de Carvalho, 2004) and validated by testing it in a large population of ALS patients (Pinto et al., 2009b). In our study, survival was negatively affected by the independent factors bulbar onset, elderly age (in bulbar-onset patients), short diagnostic delay (rapid progressors), lower predicted values of FVC and small phrenic nerves responses. Bulbar-onset patients had a significantly shorter mean survival time than spinal-onset patients as mentioned in several studies before (Chiò et al., 2009). Therefore, we analysed the prognostic factors for these two different subpopulations. In both, shorter diagnostic delay was a negative prognostic factor as found in other studies (Chiò et al., 2009). Elderly age was a poor prognostic factor for the bulbar-onset subgroup only. Age is generally not considered as an

independent predictor (Chiò et al., 2009). However, in our experience, older bulbar patients are not compliant to non-invasive ventilation, an observation possibly related to cognitive dysfunction (Olney et al., 2005). FVC as determined at entry was an independent predictor of survival, for the total population and for bulbar-onset patients. Possible, poorer expiratory function in spinal-onset patients would influence FVC determination and its value as a predictive factor. The main contribution of our study is to show the negative predictive value of a small phrenic nerve response in the initial assessment of ALS patients. Our results did not provide information on the possible increased advantage of monitoring its decay by repeated longitudinal evaluation, did not investigate the individual impact of this additional investigation nor showed a higher predictive value compared with the routine longitudinal ALS-FRS evaluation. However, when following ALS patients, we experience the limitations of volitional respiratory tests to quantify the respiratory

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function in this disease, in particular, in bulbar-onset patients (Lyall et al., 2001). Our results suggest that phrenic nerve stimulation has a supportive role in measuring respiratory function in ALS. Acknowledgements The first author had a grant from the ‘Fundação para a Ciência e a Tecnologia’, SFRH/BD/30714/2006. This work was supported by ‘Fundação para a Ciência e Tecnologia’ – PIC/IC/82765/2007. References American Thoracic Society. Standardization of spirometry. Am J Respir Crit Care Med 1995;152:1107–36. Brooks BR, Miller RG, Swash M. Munsat TL for the World Federation of Neurology Research Group on motor neuron diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotr Lat Scler 2000;1:293–300. Cedarbaum JM, Stambler N. Performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in multicenter clinical trials. J Neurol Sci 1997;152(Suppl.):S1–9. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRSR: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999;169:13–21. Chanceller AM, Slattery JM, Frazer H, Swingler RJ, Holloway SM, Wallow CP. The prognosis of adult-onset motor neuron disease: a prospective study based on the Scottish Motor Neuro Disease Register. J Neurol 1993;240:339–46. Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, et al. Prognostic factors in ALS: a critical review. Amyotr Lat Scler 2009;10:310–23. Czaplinski A, Yen AA, Appel SH. Forced vital capacity (FVC) as an indicator of survival and disease progression in an ALS clinic population. J Neurol Neurosurg Psychiatry 2006;77:390–2. de Carvalho M. Electrodiagnostic assessment of respiratory dysfunction in motor neuron diseases. In: Eisen A, editor. Clinical neurophysiology of motor neuron diseases. Amsterdam: Elsevier; 2004. p. 513–28. de Carvalho M, Matias T, Coelho F, Evangelista T, Pinto A, Luis ML. Motor neuron disease presenting with respiratory failure. J Neurol Sci 1996;139(Suppl.): 117–22. Del Aguilla MA, Longstreth Jr WT, McGuire V, Koepsel TF, van Belle G. Prognosis in amyotrophic lateral sclerosis. A population-based study. Neurology 2003;60: 813–9.

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Evangelista T, de Carvalho M, Pinto A, Sales-Luis ML. Phrenic nerve conduction in amyotrophic lateral sclerosis. J Neurol Sci 1995;129(Suppl.):35–7. Fallat RJ, Jewitt B, Bass M, Kamm B, Norris FH. Spirometry in amyotrophic lateral sclerosis. Arch Neurol 1979;36:74–80. Kaufmann P, Levy G, Thompson JL, Delbene ML, Battista V, Gordon PH, et al. The ALSFRSr predicts survival time in an ALS clinic population. Neurology 2005;64:38–43. Kollewe K, Mauss U, Krampfl K, Petri S, Dengler R, Mohamadi B. ALSFRS-R score and its ratio: a useful predictor for ALS-progression. J Neurol Sci 2008;275: 69–73. Lyall RA, Donaldson N, Polkey MI, Leigh PN, Moxham J. Respiratory muscle strength and ventilatory failure in ALS. Brain 2001;124:200–13. Magnus T, Beck M, Giess R, Puls I, Naumann M, Toyka KV. Disease progression in amyotrophic lateral sclerosis: predictors of survival. Muscle Nerve 2002;25:709–14. Morgan RK, McNally S, Alexander M, Conroy R, Hardiman O, Costello RW. Use of Sniff nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2005;171:269–74. Olney RK, Murphy J, Forshew D, Garwood E, Miller BL, Langmore S, et al. The effects of executive and behavioural dysfunction on the course of ALS. Neurology 2005;65:1774–7. Pinto S, de Carvalho M. Symmetry of phrenic nerve motor response in amyotrophic lateral sclerosis. Muscle Nerve 2010;42:882–4. Pinto A, de Carvalho M, Evangelista T, Lopes A, Sales Luis ML. Nocturnal pulse oximetry: a new approach to establish the appropriate time for non-invasive ventilation in amyotrophic lateral sclerosis patients. Amyotr Lat Scler 2003;4:31–5. Pinto S, Geraldes R, Vaz N, Pinto A, de Carvalho M. Changes of the phrenic nerve motor response in amyotrophic lateral sclerosis. Clin Neurophysiol 2009a;120:2082–5. Pinto S, Turkman A, Pinto A, Swash M, de Carvalho M. Predicting respiratory insufficiency in amyotrophic lateral sclerosis: the role of phrenic nerve studies. Clin Neurophysiol 2009b;120:941–6. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report working party standardization of lung function tests. European Community for Steel and Coal. Official statement of the European Respiratory Society. Eur Respir J 1993;16(Suppl.): 5–40. Schiffman PL, Belsh JM. Pulmonary function at diagnosis of ALS: rate of deterioration. Chest 1993;103:508–13. Stambler N, Charatan M, Cedarbaum JM. Prognostic indicators of survival in ALS. ALS CNTF Treatment Study Group. Neurology 1998;50:66–72. Velasco R, Salachas F, Munerati E, Le Forestier N, Pradat PF, Lacomblez L, et al. Nocturnal oximetry in patients with amyotrophic lateral sclerosis: role in predicting survival. Rev Neurol 2002;158:575–8.