Diagnostic
Strategies in Young Patients with Ischemic Stroke in Canada
Michael
T.Y. Chan, Zurab G. Nadareishvili, John W. Norris for the
Canadian Stroke Consortium
Abstract:
Background: A preliminary national survey of ischemic
stroke in the young (15-45 years) undertaken by the Canadian
Stroke Consortium indicated that in 44% of 356 patients, no
cause was found. Objective: To determine the
reason for this high incidence of diagnostic uncertainty in
young patients with ischemic stroke. Methods:
Neurologists in the ten Canadian stroke centers completed
a detailed questionnaire for patients aged 15-45 years admitted
to hospital between January 1993 and December 1997. Using
a step-wise diagnostic algorithm incorporating clinical, neuroimaging,
neurovascular and laboratory data, we divided patients into
three groups: (1) those with established cause for the ischemic
stroke, (2) those who remained unexplained despite adequate
investigation, (3) those who remained unexplained but were,
in our opinion, under-investigated. Results:
In 197 patients (56%), an identified cause was established
including cardioembolic sources (14%), extracranial arterial
dissection (13%), lacunar infarcts (8%) atherosclerosis (6%).
A miscellaneous group of 15%, included cerebral venous thrombosis,
coagulopathies, vasculitis and others. In 159 patients (44%)
with no apparent cause for their stroke, we considered only
81 (23%) adequately investigated, and 78 (21%) inadequately
investigated. Conclusion: About one in five
young patients was inadequately investigated by a stroke-oriented
group of neurologists. The major problem appears to be restriction
of investigations to neuroimaging alone (usually computerized
cerebral tomography), without further tests such as cerebral
angiography and cardiac imaging.
Résumé:
Stratégies diagnostiques chez des patients jeunes qui
ont subi un accident vasculaire cérébral ischémique
au Canada. Introduction: Une enquête
nationale préliminaire sur l'accident vasculaire cérébral
(AVC) ischémique chez les jeunes (15 à 45 ans)
sous l'égide du Canadian Stroke Consortium indique
qu'aucune cause n'a été mise en évidence
chez 44% des 356 patients étudiés. Objectif:
Déterminer la raison de ce haut taux d'incertitude
diagnostique chez des patients jeunes qui ont subi un AVC
ischémique. Méthodes: Les neurologues
des dix centres canadiens de l'AVC ont complété
un questionnaire détaillé sur leurs patients
âgés de 15 à 45 ans qui avaient été
hospitalisés entre janvier 1993 et décembre
1997. Nous avons séparé les patients en trois
groupes selon un algorithme diagnostique pas à pas
incorporant les données cliniques, neuroradiologiques,
neurovasculaires et biochimiques: (1) les patients dont la
cause de l'AVC ischémique était établie;
(2) ceux dont l'étiologie de l'AVC demeurait inexpliquée
malgré une investigation adéquate; (3) ceux
dont l'étiologie de l'AVC demeurait inexpliquée
mais dont l'investigation était inadéquate à
notre avis. Résultats: Chez 197 patients
(56%), la cause a été identifiée: une
source d'embolie chez 14%; une dissection artérielle
extracrânienne chez 13%; un infarctus lacunaire chez
8%; l'athérosclérose chez 6%. Un groupe hétérogène
composé de 15% des patients comprenait des patients
ayant subi une thrombose veineuse, des patients atteints de
coagulopathies, de vasculite ou d'autres pathologies. Des
159 patients (44%) n'ayant aucune cause apparente de leur
AVC, nous avons considéré que seulement 81 patients
(23%), avaient été investigués adéquatement
et 78 (21%) ne l'avaient pas été. Conclusion:
Environ un jeune patient sur cinq avait été
mal investigué par un groupe de neurologues travaillant
dans le domaine de l'AVC. Le problème majeur semble
être une investigation limitée à la neuroimagerie
(habituellement une tomographie cérébrale assistée
par ordinateur), sans autre test comme une angiographie et
une imagerie cardiaque.
Can.
J. Neurol. Sci. 2000; 27: 120-124
Although
stroke is a leading cause of death and disability in developed
countries, ischemic stroke below the age of 50 years is relatively
infrequent. In Canada in 1991, the incidence of cerebral infarction
in persons below 54 years was about 13/100,000, compared to
180/100,000 in those aged 55-65.(1) Consequently there are
few studies with sufficiently large populations of young stroke
patients on which to base adequate epidemiological data. The
etiological spectrum is different in older patients where
atherosclerosis is a major cause, while cardioembolism and
arterial dissection are the main documented causes in the
young.(2-5) In up to one third of these young patients no
cause was found, yet etiological attributions were often made,
for which little or no evidence-based data were available.
In
a preliminary national registry of young stroke patients undertaken
by the Canadian Stroke Consortium (CSC), we were surprised
by the large number of patients who, on hospital discharge,
had no established cause for their cerebral infarction. This
study was undertaken to evaluate the reason for high incidence
of diagnostic uncertainty in young patients with ischemic
stroke.
Methods
Members
of the CSC reviewed the records of all patients aged 15-45
years, using ICD-9 codes (433, 434, 436, 437) with a diagnosis
of ischemic stroke, who were admitted between January 1993
and December 1997 to Canadian hospitals. After completing
a special case record form, data were stored centrally by
computer at the coordinating centre in Toronto. All identified
arterial and venous strokes were included. We excluded transient
ischemic attack (in view of the uncertainty of diagnosis),
strokes secondary to surgical procedures, and patients with
subarachnoid hemorrhage. In those who had more than one stroke
during the study period, we included only the first episode.
Data
included demographic factors, putative risk factors, clinical
features, final hospital diagnosis, and all diagnostic and
laboratory procedures such as computed cranial tomography
(CCT) or magnetic resonance imaging (MRI), 24 hour monitoring
of cardiac rhythm (Holter), hematological testing, transthoracic
echocardiogram (TTE), transesophageal echocardiogram (TEE),
carotid ultrasound, and all forms of cerebral angiography.
We
studied the frequency and types of CCT, MRI, carotid doppler,
TTE, and TEE, and determined how frequently specific hematological
work-up were performed when these other tests proved negative.
We
considered patients adequately investigated according to a
step-wise, progressive, diagnostic algorithm if they had brain,
neurovascular and cardiac imaging, as well as specific hematological
testing including lupus anticoagulant (LA) and antiphospholipid
antibodies (APLA), antithrombin III, protein C, protein S,
activated protein C resistance (factor V Leiden), hyperhomocystinemia,
cholesterol and sickle cell factor. We considered them inadequately
investigated if the cause remained unexplained and only some
of these investigations had been performed.
Risk
factors were deemed present in patients already receiving
treatment for hypertension, diabetes, hypercholesterolemia,
ischemic heart disease and migraine and all drugs were documented
including current use of contraceptive pills. Migrainous stroke
was only diagnosed when the stroke occurred during or immediately
after a migraine attack as defined by the International Headache
Society (IHS) criteria.(6) The diagnosis of arterial dissection
was accepted only in the presence of angiographic imaging
(catheter or MRI), in view of the limited value of Doppler.(7)
Strokes
were classified into modified TOAST classification:(8) 1.
Large artery atherosclerosis; 2. Cardioembolic; 3. Small vessel
disease; 4. Dissection; 5. Miscellaneous (migraine, vasculitis,
venous thrombosis, coagulopathies etc.); and 6. Unknown causes
(Cryptogenic). In patients with more than one potential cause,
we chose the most potent etiological factor and ascribed only
one cause.
We
divided the patients into two groups, 15-30 years of age,
and 30-45 years of age, since the putative etiologies change
during the three decades of age used in this study. Atherosclerosis,
for example, is rare below age 30.(9)
Statistical
evaluations were made by means of t test to determine significant
differences between means (P < 0.05), and the X2
test was used to determine significant differences between
proportions. Data were stored on SPSS (version 7.5 for windows)
software.
Results
Records
from a total of 356 patients in 10 centres were examined:
58% (207) were men, mean age 36 ± 8 years, and 42% (149)
were women, mean age 35 ± 7 years.
Hypertension
was present in 29%, hypercholesterolemia in 10%, cardiac disease
in 14%, diabetes in 12%, migraine in 29% of women and in 12%
of men. Eighteen percent of women were taking oral contraceptives
and 12% were pregnant or within six weeks post-partum.
Patients
with established cause of stroke
A
cause for the patients stroke was found in 197 cases (56%),
the largest identified group being cardioembolic (14%) [Table
1]. Arterial dissection was the second major cause
(13%) and in 25% of these cases, a recent history of cervical
trauma was present, but since this is a retrospective study,
the incidence of minor trauma may be underestimated. In patients
31-45 years, dissection was the commonest identified cause
of ischemic stroke.
Lacunes
and carotid stenosis, were almost absent in the younger age
group (<30 years) (Table
1).
Twenty-seven
patients had acquired cardiac lesions and 24 had congenital
cardiac lesions as the presumed cause of stroke (Table
2). In this group ischemic heart disease accounted for
33% (17/51) of the cases, followed by rheumatic heart disease
(8%), bacterial endocarditis (6%), atrial fibrillation (4%)
and atrial myxoma (2%). Patent foramen ovale (PFO) was the
leading congenital cause of cardioembolic stroke (29%, 15/51).
In the absence of proof of a concomitant venous source, such
as deep venous thrombosis (DVT), this cause must remain speculative,
and we found no evidence of clinical and laboratory testing
to confirm either a diagnosis of DVT or a concomitant coagulopathy.
Atrial or ventricular septal defect and mitral valve prolapse
were other congenital cardiac causes of stroke, each representing
6% (3/51).
The
miscellaneous group (Table
3) consisted of cerebral venous thrombosis as the most
common cause (24%), followed by APLA syndrome (15%), and 13%
with an ischemic cerebral lesion accompanied by a migraine
attack. One patient, presenting initially with stroke but
both negative CT and cerebral angiography, was readmitted
three months later with another "transient ischemic attack
(TIA)" when MR scanning immediately identified the typical
plaques of multiple sclerosis.
Patients
with unknown cause
Among
159 patients (44%) where no cause for their stroke was found,
81 (23%) were adequately investigated according to our predefined
criteria, but 78 (21%) were inadequately investigated. There
was no significant difference in the frequency when carotid
duplex was used, or in cardiac imaging studies (Table
4), but inadequately investigated patients had significantly
less angiography (p < 0.001), TEE and TTE than patients
with established causes of stroke. There was no significant
difference in the frequency of investigations between patients
with established causes of stroke and those who remained unexplained
even after adequate investigation, so there still remains
a group of unexplained cause in spite of complete neurological,
vascular and hematological investigations (81/159 = 55% of
the cryptogenic group) (Table
4).
Discussion
In
published studies of young stroke patients, the etiology remains
completely unexplained in 23-50% of the cases.(2-5) Some of
these etiological discrepancies between published series of
ischemic stroke in the young may represent regional differences,
such as the relative high occurrence of stroke induced by
drug abuse in large cities in the USA(10) or by alcohol in
Finland.(2) However, we believe a major reason so many remain
unexplained is either the lack of adequate neurovascular investigation
or the incorrect perception of the weighting of risk factors.
For instance, in a pooling of data in three German data banks,
of 1564 patients with stroke or TIA, 17% were attributed to
cardiogenic causes. Patients investigated by TEE compared
to those without this investigation had much higher rates
of cardiac thrombus (11% vs 2.4%), mitral valve prolapse (22%
vs 0.6%) and PFO (7.4% vs 0%), yet the authors concluded that
this investigation did not appreciably aid in determining
the cause of the stroke.11
Cardiac
lesions previously considered benign, such as asymptomatic
chronic atrial fibrillation, are now recognized as powerful
sources of cardioembolic stroke, with an annual frequency
of about 4% of ischemic strokes.(12) Although one in five
otherwise normal people have detectable PFO this is increasingly
recognized as an established cause of paradoxical embolism.(13)
Although the presence of PFO alone (or associated abnormalities
such as atrial septal aneurysm) does not justify a causal
relationship, recent data indicate that the majority of patients
with stroke have evidence of deep vein thrombosis (evident
on imaging but not necessarily clinically).(14) Therefore,
when a PFO is considered as a possible cause of cerebral embolism,
besides a clinical search for DVT venography, radionucleide
or ultrasound imaging are also mandatory,(15) and failing
that, hematological testing for coagulopathy defects should
be performed.
Arterial
dissection, previously believed a rare phenomenon, has been
increasingly recognized due to safer neurovascular imaging,
both by catheter or MR angiography, and in one series was
the most frequent determined etiology.(2) Though sometimes
visualized by ultrasound methods, the specificity of the Doppler
technique alone is often inadequate for a reliable diagnosis.(7)
Abnormalities
of blood coagulation were rare in this study, APLA elevations
were present in only 4%, and homocystinemia in 1% of patients,
in keeping with previous published figures.(16) Coagulopathy
studies can be deferred until after the initial diagnostic
imaging has proven negative.
In
older stroke populations (>45 years) the major cause of
ischemic stroke is atherosclerosis of large arteries, lacunar
infarction due to small artery disease, and cardioembolic
stroke predominantly due to atrial fibrillation. Together,
these comprise 40-50% of all cases.(17) In young patients
there should be a different approach to prevention of recurrence,
since the common causes are congenital cardiac lesions and
extracranial arterial dissection, with less frequent involvement
of small and large cerebral or extracranial arterial disease.
In the Baltimore-Washington study of traditional risk factors
for ischemic stroke, in 296 young patients compared with controls,
an increased prevalence of hypertension, diabetes and cigarette
smoking were found significant, but unfortunately no data
regarding stroke types are available, so the relevance of
the relationship remains uncertain.(4)
The
routine use of aspirin as the ubiquitous stroke prophylaxis
is rarely indicated in young patients with ischemic stroke
when there is no evident cause after complete investigation.
In young patients with ischemic stroke, when all investigations
have been proven negative, there is a tendency to prescribe
aspirin nonspecifically. This is not evidence-based and raises
the question of how long the medication should be administered?
Aspirin is not devoid of adverse effects and should not be
prescribed without pharmacological justification. No patient
should be abandoned diagnostically until the full range of
cerebral, neurovascular and cardiac imaging, in conjunction
with hematological testing is utilized. We believe that if
these steps had been undertaken in our patients, the cause
of stroke may have been identified in up to 21% more cases,
leading to improved treatment and prevention of further episodes.
Appendix
