- Email: [email protected]
Evidence-based care in amyotrophic lateral sclerosis
Reflection and Reaction
cascade that lead to meningitis-associated intracranial complications and have thus provided the basis for new treatments.11 Among the experimental treatments, the antioxidant N-acetylcysteine seems to be closest to a clincal application. At doses similar to those used clinically—eg, in paracetamol poisoning— N-acetylcysteine reduced meningeal inflammation, oxidative brain damage, cortical neuronal injury, brain oedema, intracranial pressure, cochlear injury, and hearing loss in different animal models of pneumococcal meningitis.12–15 N-acetylcysteine has very few sideeffects in human beings and did not have any adverse effects in these animal studies. Therefore, N-acetylcysteine deserves to be assessed in a clinical adjunctive treatment trial of pneumococcal meningitis. Stefan Kastenbauer Department of Neurology, Ludwig-Maximilians-University, Munich, Germany [email protected]
3 4
5 6 7 8
9 10
11 12
13
14
I have no conflicts of interest. 1
2
Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, De Gans J. Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol 2006; 5: 123–29. van de Beek D, De Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351: 1849–59.
15
De Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347: 1549–56. Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain 2003; 126: 1015–25. Swartz MN. Bacterial meningitis: a view of the past 90 years. N Engl J Med 2004; 351: 1826–28. Tunkel AR, Scheld WM. Corticosteroids for everyone with meningitis? N Engl J Med 2002; 347: 1613–15. Nau R, Bruck W. Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. Trends Neurosci 2002; 25: 38–45. Leib SL, Heimgartner C, Bifrare YD, Loeffler JM, Tauber MG. Dexamethasone aggravates hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rats. Pediatr Res 2003; 54: 353–57. van de Beek D, De Gans J. Dexamethasone and pneumococcal meningitis. Ann Intern Med 2004; 141: 327. van de Beek D, De Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004; 4: 139–43. Koedel U, Scheld WM, Pfister HW. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect Dis 2002; 2: 721–36. Koedel U, Pfister HW. Protective effect of the antioxidant N-acetyl-Lcysteine in pneumococcal meningitis in the rat. Neurosci Lett 1997; 225: 33–36. Auer M, Pfister LA, Leppert D, Tauber MG, Leib SL. Effects of clinically used antioxidants in experimental pneumococcal meningitis. J Infect Dis 2000; 182: 347–50. Christen S, Schaper M, Lykkesfeldt J, et al. Oxidative stress in brain during experimental bacterial meningitis: differential effects of alpha-phenyltert-butyl nitrone and N-acetylcysteine treatment. Free Radic Biol Med 2001; 31: 754–62. Klein M, Koedel U, Pfister H-W, Kastenbauer S. Meningitis-associated hearing loss: protection by adjunctive antioxidant therapy. Ann Neurol 2003; 54: 451–58.
Evidence-based care in amyotrophic lateral sclerosis Half of patients with amyotrophic lateral sclerosis die within 3 years of symptom onset, most as a result of respiratory failure.1 Because no therapeutic drug is available, treatment is primarily symptomatic.2 Nocturnal hypoventilation is usually the first sign of respiratory dysfunction and can have a negative effect on quality of life long before respiratory failure develops.3 Treatment options for nocturnal hypoventilation in amyotrophic lateral sclerosis are palliative treatment or mechanical ventilation: tracheostomal ventilation and non-invasive ventilation. According to widespread belief in North America and Europe, tracheostomal ventilation prolongs survival, but does not improve the quality of life of most patients with the disease.4 The primary objective of non-invasive ventilation is symptomatic treatment of nocturnal hypoventilation. A systematic review of published work on non-invasive ventilation in patients with http://neurology.thelancet.com Vol 5 February 2006
amyotrophic lateral sclerosis lends support to the view that such treatment has a positive effect on all outcome measures, including survival and quality of life. However, all studies had important methodological shortcomings and none was set up as a randomised clinical trial.5 The 1999 Practice Parameters for the care of patients with amyotrophic lateral sclerosis, as established by the American Academy of Neurology, provide sensible guidelines on various features of the management of patients with the disease, including the use of noninvasive ventilation. Nevertheless, evidence provided by well-designed, randomised, controlled, clinical trials is sparse for all of these issues.2 This lack of evidence could be an important reason why the availability and use of non-invasive ventilation for patients with amyotrophic lateral sclerosis differs substantially within and between countries. Non-invasive ventilation might not be
See Articles page 140
105
Reflection and Reaction
offered by carers or accepted by patients for the fear that prolonged survival at the expense of increasing disability is undesirable.6 In this issue of The Lancet Neurology, Bourke and colleagues7 report the effects of treatment with noninvasive ventilation in patients with amyotrophic lateral sclerosis who have nocturnal hypoventilation. In this well-designed, randomised, controlled trial, 92 patients were regularly assessed for symptoms of respiratory insufficiency. When patients developed symptoms of orthopnoea, with maximum inspiratory pressure less than 60%, or hypercapnia they were assigned either non-invasive ventilation or standard care. Non-invasive ventilation significantly improved survival compared with standard treatment. Survival was significantly prolonged in patients with normal or only moderately impaired bulbar function. Non-invasive ventilation lengthened median survival in patients with normal or moderately impaired bulbar function to a greater extent than did riluzole, the only available evidence-based treatment for amyotrophic lateral sclerosis.8 In the subgroup of patients with normal or only moderately impaired bulbar function, the median survival in the standard treatment group (11 days) differed substantially from that in the non-invasive ventilation group (216 days). This finding might suggest that regular assessments did not detect respiratory dysfunction in a selection of patients. Six patients allocated standard treatment died shortly after randomisation. Hence, the effect of non-invasive ventilation on survival might be overestimated. Prolonged survival in patients with poor bulbar function was not reported, but this subgroup analysis was clearly underpowered. Another shortcoming of this study lies in the fact that 51 patients enrolled in the study eventually did not participate in the trial. The characteristics of these patients are not described and selection bias might have occurred because severely impaired patients or patients with poor socioeconomic circumstances might have refused to participate. A significant improvement on various domains of quality of life was reported in patients treated with noninvasive ventilation compared with patients on standard treatment. This finding was most pronounced in the subgroup with sufficient bulbar function. Importantly, patients with bulbar signs treated with non-invasive 106
ventilation also reported improvement on some features of quality of life. It seems reasonable to offer patients with poor bulbar function non-invasive ventilation until findings from new randomised controlled trials suggest otherwise. In our experience, patients with amyotrophic lateral sclerosis who have relatively slow disease progression, and those with spinal onset, might benefit more from treatment with non-invasive ventilation than patients with rapid disease progression or bulbar onset. Therefore, the analysis of subgroups of patients with the disease that benefit more from non-invasive ventilation, and the timing of introduction of this treatment in patients with severe bulbar impairment, should be the subject of future study. In conclusion, Bourke and colleagues7 produce important evidence that non-invasive ventilation is effective in prolonging survival with improvement in, or at least conservation of, quality of life in patients with amyotrophic lateral sclerosis. Despite some methodological concerns, this study is groundbreaking and sets an example for future trials to provide evidence-based care in amyotrophic lateral sclerosis. Sanne Piepers, Leonard H van den Berg Rudolph Magnus Institute of Neuroscience, Department of Neurology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, Netherlands [email protected] We have no conflicts of interest. 1
2
3
4
5
6 7
8
del Aguila MA, Longstreth WT, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003; 60: 813–19. Miller RG, Rosenberg JA, Gelinas DF, et al. Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review)—report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 1999; 52: 1311–23. Lyall RA, Donaldson N, Fleming T, et al. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology 2001; 57: 153–56. Borasio GD, Gelinas DF, Yanagisawa N. Mechanical ventilation in amyotrophic lateral sclerosis: a cross-cultural perspective. J Neurol 1998; 245 (suppl 2): S7–12. Piepers S, Van den Berg JP, Kalmijn S, et al. Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature. Amyotroph Lateral Scler Other Motor Neuron Disord (in press). Miller RG. Examining the evidence about treatment in ALS/MND. Amyotroph Lateral Scler Other Motor Neuron Disord 2001; 2: 3–7. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006; 5: 140–47. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994; 330: 585–91.
http://neurology.thelancet.com Vol 5 February 2006
cascade that lead to meningitis-associated intracranial complications and have thus provided the basis for new treatments.11 Among the experimental treatments, the antioxidant N-acetylcysteine seems to be closest to a clincal application. At doses similar to those used clinically—eg, in paracetamol poisoning— N-acetylcysteine reduced meningeal inflammation, oxidative brain damage, cortical neuronal injury, brain oedema, intracranial pressure, cochlear injury, and hearing loss in different animal models of pneumococcal meningitis.12–15 N-acetylcysteine has very few sideeffects in human beings and did not have any adverse effects in these animal studies. Therefore, N-acetylcysteine deserves to be assessed in a clinical adjunctive treatment trial of pneumococcal meningitis. Stefan Kastenbauer Department of Neurology, Ludwig-Maximilians-University, Munich, Germany [email protected]
3 4
5 6 7 8
9 10
11 12
13
14
I have no conflicts of interest. 1
2
Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, De Gans J. Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol 2006; 5: 123–29. van de Beek D, De Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351: 1849–59.
15
De Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347: 1549–56. Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain 2003; 126: 1015–25. Swartz MN. Bacterial meningitis: a view of the past 90 years. N Engl J Med 2004; 351: 1826–28. Tunkel AR, Scheld WM. Corticosteroids for everyone with meningitis? N Engl J Med 2002; 347: 1613–15. Nau R, Bruck W. Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. Trends Neurosci 2002; 25: 38–45. Leib SL, Heimgartner C, Bifrare YD, Loeffler JM, Tauber MG. Dexamethasone aggravates hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rats. Pediatr Res 2003; 54: 353–57. van de Beek D, De Gans J. Dexamethasone and pneumococcal meningitis. Ann Intern Med 2004; 141: 327. van de Beek D, De Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004; 4: 139–43. Koedel U, Scheld WM, Pfister HW. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect Dis 2002; 2: 721–36. Koedel U, Pfister HW. Protective effect of the antioxidant N-acetyl-Lcysteine in pneumococcal meningitis in the rat. Neurosci Lett 1997; 225: 33–36. Auer M, Pfister LA, Leppert D, Tauber MG, Leib SL. Effects of clinically used antioxidants in experimental pneumococcal meningitis. J Infect Dis 2000; 182: 347–50. Christen S, Schaper M, Lykkesfeldt J, et al. Oxidative stress in brain during experimental bacterial meningitis: differential effects of alpha-phenyltert-butyl nitrone and N-acetylcysteine treatment. Free Radic Biol Med 2001; 31: 754–62. Klein M, Koedel U, Pfister H-W, Kastenbauer S. Meningitis-associated hearing loss: protection by adjunctive antioxidant therapy. Ann Neurol 2003; 54: 451–58.
Evidence-based care in amyotrophic lateral sclerosis Half of patients with amyotrophic lateral sclerosis die within 3 years of symptom onset, most as a result of respiratory failure.1 Because no therapeutic drug is available, treatment is primarily symptomatic.2 Nocturnal hypoventilation is usually the first sign of respiratory dysfunction and can have a negative effect on quality of life long before respiratory failure develops.3 Treatment options for nocturnal hypoventilation in amyotrophic lateral sclerosis are palliative treatment or mechanical ventilation: tracheostomal ventilation and non-invasive ventilation. According to widespread belief in North America and Europe, tracheostomal ventilation prolongs survival, but does not improve the quality of life of most patients with the disease.4 The primary objective of non-invasive ventilation is symptomatic treatment of nocturnal hypoventilation. A systematic review of published work on non-invasive ventilation in patients with http://neurology.thelancet.com Vol 5 February 2006
amyotrophic lateral sclerosis lends support to the view that such treatment has a positive effect on all outcome measures, including survival and quality of life. However, all studies had important methodological shortcomings and none was set up as a randomised clinical trial.5 The 1999 Practice Parameters for the care of patients with amyotrophic lateral sclerosis, as established by the American Academy of Neurology, provide sensible guidelines on various features of the management of patients with the disease, including the use of noninvasive ventilation. Nevertheless, evidence provided by well-designed, randomised, controlled, clinical trials is sparse for all of these issues.2 This lack of evidence could be an important reason why the availability and use of non-invasive ventilation for patients with amyotrophic lateral sclerosis differs substantially within and between countries. Non-invasive ventilation might not be
See Articles page 140
105
Reflection and Reaction
offered by carers or accepted by patients for the fear that prolonged survival at the expense of increasing disability is undesirable.6 In this issue of The Lancet Neurology, Bourke and colleagues7 report the effects of treatment with noninvasive ventilation in patients with amyotrophic lateral sclerosis who have nocturnal hypoventilation. In this well-designed, randomised, controlled trial, 92 patients were regularly assessed for symptoms of respiratory insufficiency. When patients developed symptoms of orthopnoea, with maximum inspiratory pressure less than 60%, or hypercapnia they were assigned either non-invasive ventilation or standard care. Non-invasive ventilation significantly improved survival compared with standard treatment. Survival was significantly prolonged in patients with normal or only moderately impaired bulbar function. Non-invasive ventilation lengthened median survival in patients with normal or moderately impaired bulbar function to a greater extent than did riluzole, the only available evidence-based treatment for amyotrophic lateral sclerosis.8 In the subgroup of patients with normal or only moderately impaired bulbar function, the median survival in the standard treatment group (11 days) differed substantially from that in the non-invasive ventilation group (216 days). This finding might suggest that regular assessments did not detect respiratory dysfunction in a selection of patients. Six patients allocated standard treatment died shortly after randomisation. Hence, the effect of non-invasive ventilation on survival might be overestimated. Prolonged survival in patients with poor bulbar function was not reported, but this subgroup analysis was clearly underpowered. Another shortcoming of this study lies in the fact that 51 patients enrolled in the study eventually did not participate in the trial. The characteristics of these patients are not described and selection bias might have occurred because severely impaired patients or patients with poor socioeconomic circumstances might have refused to participate. A significant improvement on various domains of quality of life was reported in patients treated with noninvasive ventilation compared with patients on standard treatment. This finding was most pronounced in the subgroup with sufficient bulbar function. Importantly, patients with bulbar signs treated with non-invasive 106
ventilation also reported improvement on some features of quality of life. It seems reasonable to offer patients with poor bulbar function non-invasive ventilation until findings from new randomised controlled trials suggest otherwise. In our experience, patients with amyotrophic lateral sclerosis who have relatively slow disease progression, and those with spinal onset, might benefit more from treatment with non-invasive ventilation than patients with rapid disease progression or bulbar onset. Therefore, the analysis of subgroups of patients with the disease that benefit more from non-invasive ventilation, and the timing of introduction of this treatment in patients with severe bulbar impairment, should be the subject of future study. In conclusion, Bourke and colleagues7 produce important evidence that non-invasive ventilation is effective in prolonging survival with improvement in, or at least conservation of, quality of life in patients with amyotrophic lateral sclerosis. Despite some methodological concerns, this study is groundbreaking and sets an example for future trials to provide evidence-based care in amyotrophic lateral sclerosis. Sanne Piepers, Leonard H van den Berg Rudolph Magnus Institute of Neuroscience, Department of Neurology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, Netherlands [email protected] We have no conflicts of interest. 1
2
3
4
5
6 7
8
del Aguila MA, Longstreth WT, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003; 60: 813–19. Miller RG, Rosenberg JA, Gelinas DF, et al. Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review)—report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 1999; 52: 1311–23. Lyall RA, Donaldson N, Fleming T, et al. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology 2001; 57: 153–56. Borasio GD, Gelinas DF, Yanagisawa N. Mechanical ventilation in amyotrophic lateral sclerosis: a cross-cultural perspective. J Neurol 1998; 245 (suppl 2): S7–12. Piepers S, Van den Berg JP, Kalmijn S, et al. Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature. Amyotroph Lateral Scler Other Motor Neuron Disord (in press). Miller RG. Examining the evidence about treatment in ALS/MND. Amyotroph Lateral Scler Other Motor Neuron Disord 2001; 2: 3–7. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006; 5: 140–47. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994; 330: 585–91.
http://neurology.thelancet.com Vol 5 February 2006