Outcomes in Stroke Thrombolysis with Pre-specified Imaging Criteria
Silver, Bart Demaerschalk, José G. Merino, Edward Wong,
Arturo Tamayo, Ashok Devasenapathy, Christina O'Callaghan,
Andrew Kertesz, G. Bryan Young, Allan J. Fox, J. David Spence,
Background: A 1995 National Institute of Neurological
Disorders (NINDS) study found benefit for intravenous tissue
plasminogen activator (tPA) in acute ischemic stroke (AIS).
The symptomatic intracranial hemorrhage (SICH) rate in the
NINDS study was 6.4%, which may be deterring some physicians
from using this medication. Methods: Starting
December 1, 1998, patients with AIS in London, Ontario were
treated according to NINDS criteria with one major exception;
those with approximately greater than one-third involvement
of the idealized middle cerebral artery (MCA) territory on
neuroimaging were excluded from treatment. The method used
to estimate involvement of one-third MCA territory involvement
bears the acronym ICE and had a median kappa value of 0.80
among five physicians. Outcomes were compared to the NINDS
study. Results: Between December 1, 1998 and
February 1, 2000, 30 patients were treated. Compared to the
NINDS study, more London patients were treated after 90 minutes
(p<0.00001) and tended to be older. No SICH was observed.
Compared to the treated arm of the NINDS trial, fewer London
patients were dead or severely disabled at three months (p=0.04).
Compared to the placebo arm of the trial, more patients made
a partial recovery at 24 hours (p=0.02), more had normal outcomes
(p=0.03) and fewer were dead or severely disabled at three
months (p=0.004). Conclusions: The results of
the NINDS study were closely replicated and, in some instances,
improved upon in this small series of Canadian patients, despite
older age and later treatment. These findings suggest that
imaging exclusion criteria may optimize the benefits of tPA.
Amélioration des résultats de la trombolyse
chez les patients porteurs d'un accident vasculaire cérébral
et rencontrant des critères spécifiques à
l'imagerie. Introduction: Une étude
du NINDS effectuée en 1995 a démontré
les bénéfices de l'administration intraveineuse
de l'activateur du plasminogène tissulaire (tPA) en
phase aiguë de l'accident vasculaire cérébral
ischémique (AVCI). Le taux d'hémorragie intracrânienne
symptomatique (HICS) dans l'étude NINDS était
de 6.4%, ce qui peut décourager certains médecins
d'utiliser ce médicament. Méthodes:
Depuis le premier décembre 1998, les patients porteurs
d'un AVCI à London, Ontario ont été traités
selon les critères de l'étude NINDS avec une
exception importante: ceux qui avaient une lésion impliquant
plus d'un tiers du territoire de l'artère cérébrale
moyenne reproduit par la neuro-imagerie ont été
exclus du traitement. La méthode utilisée pour
estimer le territoire impliqué porte l'acronyme ICE
et avait une valeur kappa médiane de 0.80 parmi cinq
médecins. Les résultats ont été
comparés à ceux de l'étude NINDS. Résultats:
30 patients ont été traités entre le
premier décembre 1998 et le premier février
2000. Plus de patients de London ont été traités
après 90 minutes (p<0.00001) et ils étaient
en général plus âgés que ceux qui
ont participé à l'étude NINDS. Aucun
cas de HICS n'a été observé. Moins de
patients sont décédés ou avaient une
invalidité sévère à trois mois
(p=0.04) par rapport aux patients du bras avec traitement
dans l'étude NINDS. Plus de patients ont eu une récupération
partielle à 24 heures (p=0.02), plus de patients ont
eu une récupération complète (p=0.03)
et il y a eu moins de décès ou d'invalidité
sévère à trois mois (p=0.004) par rapport
aux patients à qui on avait administré le placebo
dans l'étude. Conclusions: Les résultats
de l'étude NINDS ont été reproduits et
même améliorés dans certains cas, dans
cette série de patients Canadiens, malgré l'âge
plus avancé des patients et un traitement plus tardif.
Ces observations suggèrent que des critères
d'exclusion neuroradiologiques peuvent optimiser les bénéfices
du traitement par le tPA.
J. Neurol. Sci. 2001; 28: 113-119
1995, a two-part National Institute of Neurological Disorders
(NINDS) study demonstrated the three-month efficacy of intravenous
tissue plasminogen activator (tPA) when administered to patients
within three hours of acute ischemic stroke onset.
Despite the positive trial result and subsequent reports of
tPA in clinical practice suggesting similar results, there
has been reluctance to use this medication because of the
risk of symptomatic intracranial hemorrhage (SICH) demonstrated
in multiple clinical trials and in real-world experiences.[1-7]
The literature suggests that deviation from the strict protocol
guidelines outlined in the NINDS study results in higher rates
of hemorrhage.[2,4,7] The concern over hemorrhage
delayed approval of this medication in Canada until February
only role of CT scanning in the NINDS study was to exclude
hemorrhage as a cause of stroke symptoms. Early ischemic changes
were noted but were not incorporated into decision-making.
Post hoc analysis of a large European study 
suggested that patients who had ischemic changes that involved
more than one-third of the middle cerebral artery (MCA) territory
on initial CT scan were more likely to suffer SICH.[2,8]
Excluding such patients might lower the rate of SICH without
protocol was devised in London, Ontario which prespecified
the exclusion of patients with greater than approximately
one-third involvement of the MCA territory on imaging who
were otherwise eligible for tPA according to the NINDS guidelines.
Outcomes and complications of the first 30 treated patients
were then prospectively collected and analyzed.
patients in this cohort are part of a larger Canadian study
(Canadian Activase in Stroke Effectiveness Study).
The use of follow-up data for research purposes, while protecting
the identity of patients, was approved by the local internal
December 1998, patients presenting within three hours of ischemic
stroke onset in London, Ontario were treated according to
the guidelines of the NINDS study with one major exception:
those with greater than one-third involvement of the MCA territory
on imaging were excluded from treatment. For patients with
acute symptoms, a central stroke pager was activated to notify
a member of the stroke team. The treating physician was one
of six stroke fellows and one attending level physician who
were experienced in CT interpretation for acute ischemic stroke.
Whenever possible, films were reviewed with one of four neuroradiologists
on call or another stroke physician. Treatment was initiated
at one of the three London adult emergency departments (London
Health Sciences Centre - University Campus, St. Joseph's
Hospital, and London Health Sciences Centre - South
Street Campus). Because many surrounding community hospitals
do not have CT scanners, patients presenting to a community
hospital were transferred to London Health Sciences Centre
- University Campus for further assessment, imaging
and possible treatment. tPA was delivered primarily in the
emergency room and, on occasion, in the CT scanner room. Following
treatment, patients were transferred to a neurological observation
unit for 24 hours post-tPA treatment.
consisted of a CT scan or MRI. An MRI was done when CT was
not immediately available. Treatment decision was based on
CT in 26 patients and on MRI in four patients. CT was performed
on a GE HiSpeed Advantage slip ring third generation scanner.
Scanning parameters were: space between slices 7 mm, DFOV
23.0 cm, matrix size 512 x 512. Average door-to-CT time was
51 minutes. MRI was performed on a GE 1.5T Signa Horizon scanner
with echoplanar capability and ultra-high speed gradients.
Scanning parameters were: space between slices 5 mm, FOV 30
x 19, matrix size 128 x 128. Sequences obtained were scout
images, axial diffusion-weighted images (B values of 0 and
1000), and axial gradient echo images (for the detection of
parenchymal blood). Patients with evidence of bleeding on
gradient-echo sequences were excluded from treatment. Average
door-to-MRI time was 71 minutes. Factors presumed related
to the increased door-to-imaging time for MRI included: 1)
screening for metallic objects on the patient's body which
are incompatible with MRI scanning, 2) transfer of the patient
to an MRI-compatible stretcher, 3) adjustment of cardiovascular
monitoring devices for the MRI, and 4) removal of MRI-incompatible
objects from persons assisting in the transfer of the patient
in the MRI suite. No screening for ferro-magnetic objects
was required in patients undergoing CT. Patients who had CT
were eligible for treatment in the scanning room.
no specific criteria to estimate greater than one-third involvement
of the MCA territory on the initial CT scan has been published,
we devised a method which bears the acronym "ICE". Briefly,
the ICE method is a three-step process (Figure
1). In step 1, a mentally formed geometric figure approximating
a trapezoid is superimposed on the CT scan image to idealize
(I) the MCA territory. In step 2, areas of presumed early
infarction are identified and another mentally formed geographic
figure which closes (C) around these areas is formed. In step
3, the area in step 2 is mentally superimposed on the area
in step 1 (I) and an estimate (E) of the proportion of these
two geometric areas is made. If the estimate is greater than
one-third, then the patient is deemed ineligible for treatment.
The same method applied to diffusion-weighted imaging. Interobserver
reliability of this method was tested among five fellows who
were blinded to any clinical information. With 20 test scans,
the median kappa was 0.80.
neuroradiologist (AJF) on the CT advisory panel for the ATLANTIS
rt-PA study  reviewed all but two missing films
of the 30 treated patients, approximately nine months after
the last patient received treatment. Two of the reviewed CT
studies were thought to show more than one-third MCA territory
involvement (ie. treatment not recommended). Follow-up imaging
of these patients, however, did not confirm the presence of
infarction with more than one-third MCA territory involvement
suggesting that either 1) more than one-third MCA territory
involvement was not present on initial imaging, or, more remotely,
2) petechial hemorrhage had occurred on follow-up scans with
pseudonormalization of these scans. Films of patients
excluded from treatment were also reviewed and were all corroborated
as showing more than one-third MCA territory involvement.
all patients, a modified Rankin score was assigned for premorbid
status, at discharge, and at three months. An NIH Stroke Scale
score (NIHSSS) was measured at baseline, 24 hours, and three
months. A follow-up imaging study was obtained on all patients
within 24-72 hours. Intracranial hemorrhage was defined as
an ovoid area of hyperdensity on CT scan or hypointensity
on gradient-echo (blood sensitive) MRI sequences. Symptomatic
intracranial hemorrhage was defined as an intracranial hemorrhage
accompanied by a 1-point decrease in level of consciousness
or a 4-point or greater increase in the total NIHSSS, in accordance
with the Prolyse in Acute Cerebral Thromboembolism (PROACT)
data collected included medical history, time of symptom onset,
city of symptom onset, transfer times from peripheral hospitals,
door-to-imaging time, imaging-to-treatment time, and door-to-treatment
time. The driving distance from the city of onset to London
was calculated using an Internet-based program.
were made between local patients and patients in the NINDS
study. When comparing baseline patient characteristics,
comparisons were only made for age and time to treatment,
factors that are known to be associated with increased risk
for hemorrhage. A chi square test for associations was used.
For cell values less than five, a two-tailed Fisher's exact
test was used. Calculations were performed with Epi Info,
version 6.04b. Student's t-test was used to compare
differences between means.
intervals (95%) were computed for hemorrhage rates. For 0
values, the "rule of threes" (3/n) was used to calculate the
theoretical maximum risk (with 95% certainty).
December 1, 1998 and February 1, 2000, 30 patients were treated
in London, Ontario with intravenous tPA for acute ischemic
stroke. Based on our prespecified imaging criteria, one patient
who would have otherwise qualified for tPA was excluded. Her
initial scan (Figure 1) showed
apparent involvement of the majority of the MCA territory
as well as anterior cerebral artery territory. Follow-up imaging
corroborated these findings and the patient died of cerebral
herniation. Baseline characteristics in comparison to the
published information on part II of the NINDS rt-PA study
are presented in Table
1. Patients in the London group were, on average, older
(13% of patients were greater than age 80) and treated significantly
later (97% beyond 90 minutes). Three patients had an initial
NIHSSS greater than 20, two had a violation of the traditional
NINDS protocol (both with treatment greater than 180 minutes),
two received tPA in the setting of recent catheterization,
and one received tPA in the setting of a concomitant myocardial
percent of patients had symptom onset between 6:00 and 18:00
(Figure 2). Twenty-seven percent
of patients treated in London were transferred from hospitals
outside the city (Figure 3).
The average time between arrival at the community hospital
to arrival at the London hospital was 78 minutes (range 46-110
minutes). The average driving distance was 48 kilometers (range
29-98 kilometers). The average door-to-treatment time was
92 minutes for all patients (range 26-174 minutes).
at 24 hours and three months in patients treated in London
compared to patients in part II of the NINDS study are presented
in Table 2. Follow-up
imaging showed a new infarction in 80% of patients. There
was no statistically significant difference between the London
group and the treated arm of the NINDS tPA study in 24-hour
4-point improvements or three-month normal outcomes. A statistically
significant reduction in death or severe disability was observed.
In comparison to the placebo arm, statistically significant
improvements in the 24 hour NIHSSS, and reduction in death
or severe disability were observed.
rates in comparison to patients in parts I and II of the NINDS
tPA study are presented in Table
3. One patient treated locally developed a vitreous hemorrhage
which resolved spontaneously. Because the number of patients
treated in London is small at this time, a statistically significant
reduction in symptomatic intracranial hemorrhage in comparison
to the treatment arm could not be achieved (p=0.24 with two-tailed
Fisher's Exact Test). Given that no SICH were observed in
the London group, the maximum possible rate (with 95% certainty)
is 10%, using the rule of threes. There was no statistically
significant difference in overall intracranial hemorrhage
rate (symptomatic and asymptomatic) between the London group
and the NINDS placebo arm.
outcomes of patients in this series are similar to, and in
some respects better than, patients in the NINDS study. These
data provide further support to growing evidence from other
centers around the world that tPA can be given outside of
the NINDS trial with similar rates of normal or near-normal
function in those treated.[3-6,6-18]
the beneficial effects of tPA in acute ischemic stroke, there
has been a marginal increase in the use of this medication
for this purpose. Most likely, the biggest fear is the risk
of symptomatic and fatal intracranial hemorrhage.
Therefore, the decision to treat, or, in this case, not to
treat, lies mainly in the fear of side effects despite overall
the NINDS study, the risk of symptomatic intracranial hemorrhage
with tPA was 6.4%. Post hoc analysis suggested
that several factors including advanced age and NIHSSS greater
than 20 were associated with this increased risk. In The European
Cooperative Acute Stroke Study-I, an additional risk factor
was identified for the first time, namely greater than one-third
involvement of the MCA territory on CT, as identified by experts.[2,8]
Subsequent nonrandomized studies have supported this observation.
Despite their retrospective nature, so suggestive were these
findings that they were implemented as part of the exlusion
criteria in a six-hour intra-arterial thrombolytic trial,
 a 3-5-hour intravenous tPA trial, 
and a 0-6-hour intravenous tPA trial. The rates
of SICH in these trials were 7.0%, 10.2%, and 8.8% respectively.
These rates of hemorrhage are less than comparable trials
with similar time windows and without prespecified CT exclusion
criteria ie. 21.2% in 0-6 hours  and 12.6% in
0-4 hours. Further, some animal studies have suggested
that tPA may actually enlarge infarct volume after permanent
brain injury has already occurred, [23,24] though
others have failed to reproduce these findings.[25,26]
The precise definition and method for one-third estimation
has not been published. Nevertheless, the gestalt observation
is important because it suggests a potential area of nonintervention.
A recent study has shown only fair inter-rater reliability
for the estimation. In that study, participants
did not employ a systematic method of estimation.
these data are based on a small number of patients, it appears
that the prespecified use of CT exclusion criteria by treating
physicians may reduce the rate of symptomatic intracranial
hemorrhage and increase the rate of good outcomes at 24 hours
despite recruitment of older patients at later treatment times.
In addition, there was no increase in the risk of symptomatic
intracranial hemorrhage in patients with relative contraindications
(NIHSSS > 20 or age >80), or in patients with direct
violations of the traditional protocol. We suppose that the
lower rates of symptomatic intracranial hemorrhage are explained
by the smaller volume of initial tissue infarction present
for subsequent hemorrhage. Previous studies have suggested
that those who have symptomatic hemorrhage are those who likely
would have had poor outcomes despite thrombolytic therapy.
Further, the finding of a trend towards an increased rate
of good outcomes at 24 hours suggests that the patient population
selected were those most likely to benefit (ie. those who
had not already gone on to tissue infarction).
implementation of a measure to reduce the occurrence of a
suspected precipitant to an undesirable outcome has occurred
in other settings. The New Zealand Cot Death study group suggested,
through a case control study, that infants who slept in a
prone position had an increased risk of sudden infant death
syndrome. In February 1991, a national campaign
was launched to have babies sleep in the supine position.
Concomitant with a major decline in the percentage of babies
sleeping in the prone position, the rate of sudden infant
death syndrome in New Zealand dropped sharply from 4.2/1000
live births before the intervention to 2.5/1000 afterwards.
Despite the lack of a randomized study comparing prone sleeping
to supine sleeping, many accept the above observations as
powerful evidence for the need of such an intervention.
respect to positive outcomes, similar three-month cure rates
were observed compared to the treated arm of the NINDS study.
Some might argue, therefore, that benefits gained at 24 hours
have somehow been lost in subsequent follow-up. However, there
are significantly less severely disabled or deceased patients
at three months; these findings are potentially important
given that 13% of the patients in this series were over the
age of 80.
percent of treated patients were transferred from outside
hospitals without CT scanner availability. We feel that emergency
bypass protocols may further increase the percentage of patients
eligible for this treatment by reducing the critical amount
of time spent in transit to non-CT hospitals. The observation
that 83% of treated patients had symptom onset between the
12 hours from 06:00 to 18:00 suggests that hospitals which
can only operate CT scans during certain hours, a situation
which is not uncommon in the Canadian setting, may still be
able to treat the vast majority of patients. In addition,
the observation that 80% of patients had a new infarction
on follow-up imaging suggests that the vast majority of patients
who are treated can correctly be identified as suffering from
ischemic strokes, as opposed to other diagnoses, despite the
paucity of time for diagnosis.
this time, it would be difficult to suggest that these results
might be generalizable to other groups of physicians because
the treating physicians in this series were specifically trained
in acute stroke treatment and CT interpretation. Nevertheless,
these findings suggest that a well designed "stroke team"
has the capacity to safely and effectively administer acute
authors thank Mary McTaggart, Connie Frank, Cheryl Mayer (nurse
coordinators) and Rose Freitas (secretary) for their assistance
in arranging patient follow-up and data acquisition and Santosh
Deshpande (pharmacist) for his help in drafting the thrombolysis
protocol. In addition, the authors thank the ambulance, emergency
room, neuroradiology, laboratory, pharmacy, critical care,
and neuroscience personnel at London Health Sciences Centre
and St. Joseph's Hospital for their assistance in coordinating
the London stroke thrombolysis program.
National Institute of Neurological Disorders and Stroke
rt-PA Stroke Study Group. Tissue plasminogen activator
for acute ischemic stroke. N Engl J Med 1995; 333: 1581-1587.
W, Kaste M, Fieschi C, et al. Intravenous thrombolysis
with recombinant tissue plasminogen activator for acute
hemispheric stroke. The European Cooperative Acute Stroke
Study (ECASS). JAMA 1995; 274: 1017-1025.
GW, Bates VE, Clark WM, et al. Intravenous tissue-type
plasminogen activator for treatment of acute stroke:
the Standard Treatment with Alteplase to Reverse Stroke
(STARS) study. JAMA 2000; 283: 1145-1150.
AM, Barber PA, Newcommon N, et al. Effectiveness of
t-PA in acute ischemic stroke: outcome relates to appropriateness.
Neurology 2000; 54: 679-684.
D, Krieger D, Villar-Cordova C, et al. Intravenous tissue
plasminogen activator for acute ischemic stroke: feasibility,
safety, and efficacy in the first year of clinical practice.
Stroke 1998; 29: 18-22.
M, Stenzel C, Schmulling S, et al. Early intravenous
thrombolysis for acute ischemic stroke in a community-based
approach. Stroke 1998; 29: 1544-1549.
IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen
activator for acute ischemic stroke: the Cleveland area
experience. JAMA 2000; 283: 1151-1158.
Kummer R, Allen KL, Holle R, et al. Acute stroke: usefulness
of early CT findings before thrombolytic therapy. Radiology
1997; 205: 327-333.
MD, Barber PA, Buchan AM, for the CASES Investigators.
The Canadian Activase for Stroke Effectiveness Study
(CASES). Stroke 2000; 31: 315. (Abstract)
WM, Wissman S, Albers GW, et al. Recombinant tissue-type
plasminogen activator (Alteplase) for ischemic stroke
3 to 5 hours after symptom onset. The ATLANTIS Study:
a randomized controlled trial. Alteplase Thrombolysis
for Acute Noninterventional Therapy in Ischemic Stroke.
JAMA 1999; 282: 2019-2026.
JP, Fox AJ, Pelz DM, Brothers M, Drake CG. "Disappearing
infarcts": signs of apparently reversible ischemic changes
on serial CT and MR scans. AJNR Am J Neuroradiol 1988;
9: 1041. (Abstr)
A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase
for acute ischemic stroke. The PROACT II study: a randomized
controlled trial. Prolyse in Acute Cerebral Thromboembolism.
JAMA 1999; 282: 2003-2011.
accessed on May 15, 2000
Info, version 6.04b. Freeware downloaded from www.cdc.gov/epo/epi/downepi6.htm
on January 15, 2000
JA, Lippman-Hand A. If nothing goes wrong, is everything
all right? Interpreting zero numerators. JAMA 1983;
D, Bates VE, Verro P, et al. Initial clinical experience
with IV tissue plasminogen activator for acute ischemic
stroke: a multicenter survey. The t-PA Stroke Survey
Group. Neurology 1999; 53: 424-427.
KM, Woolfenden AR, Graeb D, et al. Intravenous tissue
plasminogen activator for acute ischemic stroke: a Canadian
hospital's experience. Stroke 2000; 31: 2920-2924.
DZ, Rose JA, Honings DS, Garwacki DJ, Milbrandt JC.
Treating acute stroke patients with intravenous tPA.
The OSF stroke network experience. Stroke 2000; 31:
C, Morgenstern LB, Barnholtz JS, Frankowski RF, Grotta
JC. Neurologists' attitudes regarding rt-PA for acute
ischemic stroke. Neurology 1998; 50: 1491-1494.
W, Kaste M, Fieschi C, et al. Randomised double-blind
placebo-controlled trial of thrombolytic therapy with
intravenous alteplase in acute ischaemic stroke (ECASS
II). Second European-Australasian Acute Stroke Study
Investigators. Lancet 1998; 352: 1245-1251.
therapy with streptokinase in acute ischemic stroke.
The Multicenter Acute Stroke Trial - Europe Study
Group. N Engl J Med 1996; 335: 145-150.
GA, Davis SM, Chambers BR, et al. Streptokinase for
acute ischemic stroke with relationship to time of administration:
Australian Streptokinase (ASK) Trial Study Group. JAMA
1996; 276: 961-966.
YF, Tsirka SE, Strickland S, et al. Tissue plasminogen
activator (tPA) increases neuronal damage after focal
cerebral ischemia in wild-type and tPA-deficient mice.
Nat Med 1998; 4: 228-231.
SE, Rogove AD, Bugge TH, Degen JL, Strickland S. An
extracellular proteolytic cascade promotes neuronal
degeneration in the mouse hippocampus. J Neurosci 1997;
GM, Li H, Sun P, Buchan AM. Tissue plasminogen activator
does not increase neuronal damage in rat models of global
and focal ischemia. Neurology 1999; 52: 1381-1384.
W, Wang X, Asahi M, et al. Effects of tissue type plasminogen
activator in embolic versus mechanical models of focal
cerebral ischemia in rats. J Cereb Blood Flow Metab
1999; 19: 1316-1321.
JC, Chiu D, Lu M, et al. Agreement and variability in
the interpretation of early CT changes in stroke patients
qualifying for intravenous rtPA therapy. Stroke 1999;
EA, Scragg R, Stewart AW, et al. Results from the first
year of the New Zealand cot death study. N Z Med J 1991;
J, Caldis S, Tonkin SL. New Zealand's SIDS prevention
program and reduction in infant mortality. Health Educ
Q 1995; 22: 162-171.
paper was presented at the 35th Canadian Congress of
Neurological Sciences meeting in Ottawa, Ontario on
June 14, 2000 as the Bayer Prize in Neurocritical Care.
the Department of Clinical Neurological Sciences (BS,
BD, JGM, EW, AT, CO, GBY, AJF, JDS, VH); Department
of Neuroradiology (AJF); Department of Neurocritical
Care (GBY); Department of Neurology, St. Joseph's Hospital
(BD, AK); London Health Sciences Centre, London, ON;
Department of Neurology (AD), Penn State University/Geisinger
Health System, PA, USA.
June 28, 2000. Accepted in final form January 24, 2001.
requests to: Brian Silver, London Health Sciences Centre,Department
of Clinical Neurological Sciences, 339 Windermere Road,
Room 7GE-5, London, Ontario N6A 5A5 Canada
J. Neurol. Sci. 2001; 28: 113-119