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We read with interest the findings of Chiò et al. in their prospective database of 221 ALS patients.  Though a previous study did not find the El Escorial classification at presentation to be of prognostic value , we agree with Chiò et al. and found this measure to have clear prognostic significance in our published series of 841 ALS patients seen over a ten-year period.  Furthermore, their assessment of riluzole therapy on survival also concurs with our study.
The authors note in passing the time delay between symptom onset and diagnosis, quoting a mean value of 11.1 months. Referral delay is a well- recognized, highly significant and potentially confounding surrogate marker of survival in itself.  More severely affected patients may present earlier and be more easily diagnosed with ALS. The specific inclusion of this measure should therefore be considered in any subsequent multivariate analysis using the Cox proportional hazards model, despite the inclusion of a rate for symptom progression.
This research, as in another recent database study , also raises the importance of accurately matching patients when using survival as a primary endpoint in clinical trials. A more rigorous approach to this than simply matching age and site of onset, is the calculation of a prognostic score for an individual based on relative risk and mean values for each covariate within the Cox proportional hazards model. [3} Additional covariates such as referral delay and El Escorial category, have the advantage of allowing stratification of patients at their first clinic visit (or enrollment in the context of a clinical trial), whereas measures reliant on rate of change require one further assessment at the very least.
1. Chio A, Mora G, Leone M, et al. Early symptom progression rate is related to ALS outcome: a prospective population-based study. Neurology 2002;59:99-103.
2. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: A population-based study. Arch Neurol 2000;57:1171-1176.
3. Turner MR, Bakker M, Sham P, Shaw CE, Leigh PN, Al-Chalabi A. Prognostic modeling of therapeutic interventions in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2002;3:15-21.
4. Iwasaki Y, Ikeda K, Ichikawa Y, Igarashi O, Kinoshita M. The diagnostic interval in amyotrophic lateral sclerosis. Clin Neurol Neurosurg 2002;104:87-89.
5. Magnus T, Beck M, Giess R, Puls I, Naumann M, Toyka KV. Disease progression in amyotrophic lateral sclerosis: predictors of survival. Muscle Nerve 2002;25:709-714.
We thank Drs. Turner and Al-Chalaby for their interest in our study.  The question raised, concerning the importance of prognostic studies in planning clinical trials in ALS, is of great importance. The simply matching for age and site of onset does not prevent from an unbalance of prognostic factors in the random allocations of patients, as observed in several ALS trials, [2, 3] although the use of multivariate analysis can partly overcome this problem.
Studies suggested that referral delay could be a surrogate marker of survival in ALS.  However, in our study referral delay did not result an independent prognostic factors and was not retained in the final Cox's model. We think that a further obstacle in considering referral delay for stratification in clinical trials is the difficulty to ascertain it with a reasonable confidence, since it is obtained retrospectively questioning the patient and other relevant informants. We agree with Turner and Al- Chalaby about the necessity of further assessments of rate of changes in ALS. However, some studies suggested that the motor function in ALS declines linearly, with a rate specific for each patient and unmodified during the course of the disease.  Once well established, the individual rate of progression could be considered both for determining of the outcome of the single patient and for designing future clinical trials.
1. Chiò A, Mora G, Leone M, Mazzini L, Cocito D, Giordana MT, Bottacchi E, Mutani R, for the Piemonte and Valle D'Aosta Register for ALS (PARALS). Early symptom progression rate is related to ALS outcome. A prospective population-based study. Neurology 2002;59:99-103.
2. Borasio GD, Robberecht W, Leigh PN, Emile J, Guiloff RJ, Jerusalem F, et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology 1998;51:583-586.
3. Italian ALS Study Group. Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? Neurology 1993;43:2466 -2470.
4. Iwasaki Y, Ikeda K, Ichikawa Y, Igarashi O, Kinoshita M. The diagnostic interval amyotrophic lateral sclerosis. Clin Neurol Neurosurg 2002;104:87-89.
5. Munsat TL, Andres PL, Finison L, et al. The natural history of motor neuron loss in amyotrophic lateral sclerosis. Neurology 1988;38:409- 413.
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