825
Letters to the Editor Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1,000 words (typed double-spaced) in length and may be subject to editing or abridgment.
GM1 Ganglioside Therapy in Acute Ischemic Stroke To the Editor The results of the study by Argentino et al1 are in broad agreement with those of our earlier investigation,2 which they did not quote although ours was the first, long-term, double-blind trial of the ganglioside GM1 in acute stroke. However, unlike these authors, we were unable to find a significant change in neurologic score at any time between the control and treated groups. This may reflect a slight difference in treatment regimens (we treated our patients daily with GM1 [100 mg] intramuscularly for 28 days as opposed to intravenously for 15 days) and in the inclusion in our study population of patients with intracerebral hemorrhage, hemorrhagic infarction, or computed tomographic evidence of previous asymptomatic stroke. The remaining demographic characteristics are similar for the two studies, as far as they can be assessed. On the other hand, we agree with Argentino et al in finding no difference in disability scores between the two groups at any stage during the follow-up period (in our case 180 days, compared to their 120 days). Surprisingly, although the authors found a good concordance between the neurologic scores and the disability index, statistical significance was found only for the former. This implies a borderline result at best. What is important in the evaluation of the efficacy of a putative protective or restorative medication in acute stroke is not the neurologic score but the disability index; not the Medical Research Council grading of weakness but the effective recovery of useful function. These decide the length of hospital stay and whether the patient will again be able to function in society. We respectfully submit, therefore, that there is no evidence for the efficacy of GM1 following acute stroke from either our prior study or from the current report, and that its prolonged administration as advocated by Argentino et al will not change this fact. Stephen Oppenheimer, MB, MRCP, FRCP(C) The John P. Roberts Research Institute London, Ontario, Canada
results of his neurologic examination. On the other hand, the activities of daily living scales are demanding and could not be used for stroke patients in the acute phase because performance is often limited by factors that are not dependent on their neurologic deficit. Furthermore, taking into account functional scales for long-term follow-up, we cannot know how much of their recovery is due to rehabilitation. In this context, it is interesting, rather than surprising, that we found a good correlation between mean neurologic global scores and the disability index, neither of which was statistically significant, confirming the functional value of the Canadian Neurological Scale score.1 Nevertheless, we think that no available parameters for evaluation of functional outcome in stroke patients, whether based on neurologic or disability scales, are sufficient. At present, one way to overcome this handicap could be to define more homogeneous and comparable subgroups of patients by stratifying them according to prognostic parameters such as age, severity of neurologic status at admission, and interval time between onset of symptoms and treatment. We think that only multicenter studies, capable of larger enrollment of a continuous series of patients, could help to reach this goal. Our study only partially fulfilled these criteria; for instance, the time interval of 12 hours between stroke onset and treatment, although shorter than that of previous studies, was well over the socalled "therapeutic window."2 Moreover, our data are hardly comparable with those of previous studies3-5 due to significant differences in the study design, such as treatment not started in the acute phase, too small a sample size, and different outcome measures. We therefore believe that the results we obtained need to be further tested in a larger population of 800 patients, stratified according to sex, age, and Canadian Neurological Scale score at entry, and who are treated within 5 hours of stroke and for a longer period (21 days). Our Early Stroke Treatment trial will have the enrollment of the established number of patients, and we think that at the end of 1990 we will be able to provide our definitive results.
References 1. Argentino C, Sacchetti ML, Toni D, Savoini G, D'Arcangelo E, Erminio F, Federico F, Ferro Milone F, Gallai V, Gambi D, Mamoli A, Ottonello GA, Ponari O, Rebucci G, Senin U, Fieschi C: GM1 ganglioside therapy in acute ischemic stroke. Stroke 19893:1143-1149 2. Hoffbrand BI, Bingly PJ, Oppenheimer SM, Sheldon CD: Trial of ganglioside GM1 in acute stroke. J Neurol Neurosurg Psychiatry 1988^51:1213-1214 The following is in response: To the Editor
The statistically significant difference between GMl-treated and placebo-treated patients that we found did not refer to the mean values of neurologic scores, which were similar among the groups, as clearly depicted in our Tables 4 and 5, but to the degree of neurologic improvement, as obtained by subtracting the Canadian Neurological Scale score at entry from the scores on days 1-15, 21, and 120, respectively. However, it is not clear what these differences in degree of neurologic improvement could mean in terms of functional recovery. We completely agree with Hoffbrand and colleagues that the success of a stroke treatment depends more on whether the patient is able to return home to useful function than on the
Corrado Argentino, MD Maria Lulsa Sacchetti, MD Danilo Toni, MD Universita degli Studi di Roma Rome, Italy
References 1. Cote R, Battista RN, Wolfson C, Boucher J, Adam J, Hachinski V: The Canadian Neurological Scale: Validation and reliability assessment. Neurology 1989-^9:638-643 2. Fieschi C, Argentino C, Lenzi GL, Fantozzi L, Sacchetti ML, Pace A, Rasura M, Bastianello S, Bozzao L, Zanette E, Buttinelli C, Giubilei F, Pantano P: Therapeutic window for pharmacological treatment in acute focal cerebral ischemia. Ann NYAcad Sci 1988^22:662-666 3. Bassi S, Albizzati MG, Sbacchi M, Frattola L, Massarotti M: Double blind evaluation of monosialoganglioside (GM1) therapy in stroke. / Neurosci Res 1984;12:493-498 4. Battistin I, Cesari A, Galligioni F, Marin G, Massarotti M, Paccagnella D, Pellegrini A, Testa G, Tonin P: Effects of GM1 ganglioside in cerebrovascular disease: A double blind trial in 40 cases. Eur Neurol 1985;24:343-351 5. Hoffbrand BI, Bingley PJ, Oppenheimer SM, Sheldon CD: Trial of ganglioside GM1 in acute stroke. J Neurol Neurosurg Psychiatry 1988^51:1213-1214
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
826
Stroke Vol 21, No 5, May 1990 TABLE 1. Circadian Rhythm and Cerebrovascular Disease Time of day (hr) 0.01-6 Cerebrovascular disease
No.
Atherothrombotic infarct
31 11 1
Lacunar infarct Intraparenchymal hemorrhage Cardioembolic infarct Transient ischemic attack Subarachnoid hemorrhage p values obtained by x2
5 1 3
test
% 45 24.5 3 18 6 23
No.
%
No.
16 9 21
23
15 13 7 11
11 8 7
18.01-24
12.01-18
6.01-12
20 63.5 39 50 54
2 3
No.
% 22 29
7 12 4 1
21.25 39 12.5
5 0
23
% 10 26.5 12.25 4 31.5 0
P
Letters to the Editor Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1,000 words (typed double-spaced) in length and may be subject to editing or abridgment.
GM1 Ganglioside Therapy in Acute Ischemic Stroke To the Editor The results of the study by Argentino et al1 are in broad agreement with those of our earlier investigation,2 which they did not quote although ours was the first, long-term, double-blind trial of the ganglioside GM1 in acute stroke. However, unlike these authors, we were unable to find a significant change in neurologic score at any time between the control and treated groups. This may reflect a slight difference in treatment regimens (we treated our patients daily with GM1 [100 mg] intramuscularly for 28 days as opposed to intravenously for 15 days) and in the inclusion in our study population of patients with intracerebral hemorrhage, hemorrhagic infarction, or computed tomographic evidence of previous asymptomatic stroke. The remaining demographic characteristics are similar for the two studies, as far as they can be assessed. On the other hand, we agree with Argentino et al in finding no difference in disability scores between the two groups at any stage during the follow-up period (in our case 180 days, compared to their 120 days). Surprisingly, although the authors found a good concordance between the neurologic scores and the disability index, statistical significance was found only for the former. This implies a borderline result at best. What is important in the evaluation of the efficacy of a putative protective or restorative medication in acute stroke is not the neurologic score but the disability index; not the Medical Research Council grading of weakness but the effective recovery of useful function. These decide the length of hospital stay and whether the patient will again be able to function in society. We respectfully submit, therefore, that there is no evidence for the efficacy of GM1 following acute stroke from either our prior study or from the current report, and that its prolonged administration as advocated by Argentino et al will not change this fact. Stephen Oppenheimer, MB, MRCP, FRCP(C) The John P. Roberts Research Institute London, Ontario, Canada
results of his neurologic examination. On the other hand, the activities of daily living scales are demanding and could not be used for stroke patients in the acute phase because performance is often limited by factors that are not dependent on their neurologic deficit. Furthermore, taking into account functional scales for long-term follow-up, we cannot know how much of their recovery is due to rehabilitation. In this context, it is interesting, rather than surprising, that we found a good correlation between mean neurologic global scores and the disability index, neither of which was statistically significant, confirming the functional value of the Canadian Neurological Scale score.1 Nevertheless, we think that no available parameters for evaluation of functional outcome in stroke patients, whether based on neurologic or disability scales, are sufficient. At present, one way to overcome this handicap could be to define more homogeneous and comparable subgroups of patients by stratifying them according to prognostic parameters such as age, severity of neurologic status at admission, and interval time between onset of symptoms and treatment. We think that only multicenter studies, capable of larger enrollment of a continuous series of patients, could help to reach this goal. Our study only partially fulfilled these criteria; for instance, the time interval of 12 hours between stroke onset and treatment, although shorter than that of previous studies, was well over the socalled "therapeutic window."2 Moreover, our data are hardly comparable with those of previous studies3-5 due to significant differences in the study design, such as treatment not started in the acute phase, too small a sample size, and different outcome measures. We therefore believe that the results we obtained need to be further tested in a larger population of 800 patients, stratified according to sex, age, and Canadian Neurological Scale score at entry, and who are treated within 5 hours of stroke and for a longer period (21 days). Our Early Stroke Treatment trial will have the enrollment of the established number of patients, and we think that at the end of 1990 we will be able to provide our definitive results.
References 1. Argentino C, Sacchetti ML, Toni D, Savoini G, D'Arcangelo E, Erminio F, Federico F, Ferro Milone F, Gallai V, Gambi D, Mamoli A, Ottonello GA, Ponari O, Rebucci G, Senin U, Fieschi C: GM1 ganglioside therapy in acute ischemic stroke. Stroke 19893:1143-1149 2. Hoffbrand BI, Bingly PJ, Oppenheimer SM, Sheldon CD: Trial of ganglioside GM1 in acute stroke. J Neurol Neurosurg Psychiatry 1988^51:1213-1214 The following is in response: To the Editor
The statistically significant difference between GMl-treated and placebo-treated patients that we found did not refer to the mean values of neurologic scores, which were similar among the groups, as clearly depicted in our Tables 4 and 5, but to the degree of neurologic improvement, as obtained by subtracting the Canadian Neurological Scale score at entry from the scores on days 1-15, 21, and 120, respectively. However, it is not clear what these differences in degree of neurologic improvement could mean in terms of functional recovery. We completely agree with Hoffbrand and colleagues that the success of a stroke treatment depends more on whether the patient is able to return home to useful function than on the
Corrado Argentino, MD Maria Lulsa Sacchetti, MD Danilo Toni, MD Universita degli Studi di Roma Rome, Italy
References 1. Cote R, Battista RN, Wolfson C, Boucher J, Adam J, Hachinski V: The Canadian Neurological Scale: Validation and reliability assessment. Neurology 1989-^9:638-643 2. Fieschi C, Argentino C, Lenzi GL, Fantozzi L, Sacchetti ML, Pace A, Rasura M, Bastianello S, Bozzao L, Zanette E, Buttinelli C, Giubilei F, Pantano P: Therapeutic window for pharmacological treatment in acute focal cerebral ischemia. Ann NYAcad Sci 1988^22:662-666 3. Bassi S, Albizzati MG, Sbacchi M, Frattola L, Massarotti M: Double blind evaluation of monosialoganglioside (GM1) therapy in stroke. / Neurosci Res 1984;12:493-498 4. Battistin I, Cesari A, Galligioni F, Marin G, Massarotti M, Paccagnella D, Pellegrini A, Testa G, Tonin P: Effects of GM1 ganglioside in cerebrovascular disease: A double blind trial in 40 cases. Eur Neurol 1985;24:343-351 5. Hoffbrand BI, Bingley PJ, Oppenheimer SM, Sheldon CD: Trial of ganglioside GM1 in acute stroke. J Neurol Neurosurg Psychiatry 1988^51:1213-1214
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
826
Stroke Vol 21, No 5, May 1990 TABLE 1. Circadian Rhythm and Cerebrovascular Disease Time of day (hr) 0.01-6 Cerebrovascular disease
No.
Atherothrombotic infarct
31 11 1
Lacunar infarct Intraparenchymal hemorrhage Cardioembolic infarct Transient ischemic attack Subarachnoid hemorrhage p values obtained by x2
5 1 3
test
% 45 24.5 3 18 6 23
No.
%
No.
16 9 21
23
15 13 7 11
11 8 7
18.01-24
12.01-18
6.01-12
20 63.5 39 50 54
2 3
No.
% 22 29
7 12 4 1
21.25 39 12.5
5 0
23
% 10 26.5 12.25 4 31.5 0
P
