925
whereas no inhibition with native LDL. When
was seen
cardiolipin liposomes were used as inhibitors, binding of
IgG to native or MDA-LDL was not decreased
significantly. The ability of oxidised LDL to inhibit the
binding of IgG to solid-phase single-stranded DNA was
tested in 10 sera from SLE patients. No inhibition was seen
in this assay.
LDL is a hydrophilic complex of lipids and
apolipoprotein B. The surface structure of LDL comprises
apolipoprotein B and a mixed phospholipid cholesterol
monolayer. LDL resembles the target antigen for aPL
antibodies in SLE, which consists of apolipoprotein H and
anionic phospholipids.6 In view of this structural similarity,
a crossreaction between aPL antibodies and antibodies to
oxidised LDL was not unexpected. Concentrations of
antibodies binding to native LDL were low (data not
shown) and native LDL did not inhibit cardiolipin activity.
Thus, MDA-LDL-binding antibodies in SLE patients are
presumably directed against epitopes generated during the
oxidative modification of LDL. These epitopes may,
however, differ from those recognised by antibodies in
elderly patients with atherosclerosis. Circumstantial
evidence suggests that certain moieties of aPL antibodies are
involved in mediating thromboembolic complications.5
Antibodies to phospholipids may interefere with blood
coagulation and thus increase the risk of developing
thrombosis. One the other hand, oxidised LDL is believed
to have a key role in the progression of atherosclerosis.l It
has been proposed that oxidative modification of LDL is a
prerequisite for the rapid accumulation of LDL in
macrophages and the formation of foam cells in
atherosclerotic lesions. One pathogenetic pathway in
atherogenesis may be mediated by autoantibodies directed
to oxidised LDL.1
We have demonstrated frequent occurrence, of high
concentrations, of antibodies against oxidised LDL in sera
from unselected patients with SLE. It is well recognised that
patients with SLE have a high incidence of atherosclerosis,
which is often associted with inflammatory changes.
Histologically similar changes are seen in aortocoronary vein
grafts, and graft occlusion has been associated with raised
concentrations of aPL." In this regard, oxidation of LDL
and immune response to oxidised LDL may have a role in
the pathogenesis of vascular complications in SLE.
Furthermore, on the basis of the reported crossreactivity
between aPL antibodies and antibodies to oxidised LDL, it
is possible that there is an immunological link between
thrombotic and atherosclerotic processes.
REFERENCES
1. Witztum
JL, Steinberg D. Role of oxidized low density lipoprotein in
atherogenesis. J Clin Invest 1991; 88: 1785-92.
2. Palinski W, Rosenfeld ME, Ylä-Herttuala S, et al. Low density
lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad
Sci USA 1989; 86: 1372-76.
3. Parums DV, Brown DL, Mitchinson MJ. Serum antibodies to oxidised
low-density lipoprotein and ceroid in chronic periaortitis. Arch Pathol
Lab Med 1990; 114: 383-87.
4. Salonen JT, Ylä-Herttuala S, Yamamoto R, et al. Autoantibody against
oxidised LDL and progression of carotid atherosclerosis. Lancet 1992;
339: 883-87.
5. McNeil HP, Chesterman CN, Krilis SA. Immunology and clinical
importance of antiphospholipid antibodies. Adv Immunol 1991; 49:
193-280.
6. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid
antibodies directed against a complex antigen that includes a lipid-
binding inhibitor of coagulation &bgr;2-glycoprotein I (apolipoprotein H).
Proc Natl Acad Sci USA 1990; 87: 4120-24.
7. Vaarala O. Binding profiles of cardiolipin-binding antibodies in SLE and
infectious diseases. J Autoimmunity 1991; 4: 819-30.
8. Palinski W, Ylä-Herttuala S, Rosenfeld ME, et al. Antisera and
monoclonal antibodies specific for epitopes generated oxidative
modification of low density lipoprotein. Arteriosclerosis 1990; 10:
325-35.
9. Harris EN, Gharavi AE, Patel SPR, Hughes GRV. Evaluation of the
anti-cardiolipin antibody test: report of an international workshop held
4 April 1986. Clin Exp Immunol 1987; 68: 215-22.
10. Morton KE, Gavaghan TP, Krilis SA, et al. Coronary artery bypass graft
failure—an autoimmune phenomenon? Lancet 1986; ii: 1353-57.
ADDRESSES: Departments of Immunobiology (O. Vaarala, MD, Prof
K. Aho, MD, T. Palosuo, MD), Nutrition (G. Alfthan, PhD), and
Biochemistry (M. Jauhiainen, PhD), National Public Health
Institute, Mannerheimintie 166, 00300 Helsinki, Finland; and
Second Department of Medicine, Helsinki University Central
Hospital, Helsinki, (M. Leirisalo-Repo, MD). Correspondence to
Dr Timo Palosuo
PET imaging of cerebral perfusion
and oxygen consumption in acute
ischaemic stroke: relation to
outcome
We used positron emission tomography (PET) to
assess the relation between combined imaging of
cerebral blood flow and oxygen consumption 5-18 h
after first middle cerebral artery (MCA) stroke and
neurological outcome at 2 months. All 18 patients
could be classified into three visually defined PET
patterns of perfusion and oxygen consumption
changes. Pattern I (7 patients) suggested extensive
irreversible damage and was consistently associated
with poor outcome. Pattern II (5) suggested
continuing ischaemia and was associated with
variable outcome. Pattern III (6), with
hyperperfusion and little or no metabolic alteration,
was associated with excellent recovery, which
suggests that early reperfusion is beneficial. This
relation between PET and outcome was highly
significant (p<0&middot;0005). The results suggest that
within 5-18 h of stroke onset, PET is a good predictor
of outcome in patterns I and III, for which therapy
seems limited. The absence of predictive value for
pattern II suggests that it is due to a reversible
ischaemic state that is possibly amenable to therapy.
These findings may have important implications for
acute MCA stroke management and for patients’
selection for therapeutic trials.
Neurological outcome is difficult to predict in the acute
phase of middle cerebral artery (MCA) ischaemic stroke.1
This situation, which hinders therapeutic trials, might be
926

CLINICAL DATA AND PET PATTERNS

D60, DO= neurological scores at day 60 and 0. ED = early death, EI = evolutionindex

(%), T=time (h) since stroke onset

related to the "ischaemic penumbra", whereby

hypoperfused, non-functional areas may or may not become
infarcted depending on whether (and, if so, when)
reperfusion occurs;2 thus a patient’s neurological deficit may
be stable, despite expanding infarction. Single photon
emission computed tomography (SPECT)3,4 does not easily
differentiate irreversibly compromised from ischaemic but
viable tissue, because uptake of radiotracers is not linearly
related to perfusion and it does not directly assess neuronal
function. The assessment of cerebral perfusion and oxygen
consumption by PET after a recent stroke has revealed
distinctive patterns,2,5 but clinical outcome was not
quantified. Preliminary results suggest that cerebral artery
thrombolysis is of benefit. It is done soon after stroke onset Three PET patterns.
(eg, within 6 h) on the basis of clinical computed
tomography (CT) and occasionally doppler ultrasound or Typical changes in perfusion (left) and oxygen consumption (right)
indicated by short arrows. Top: pattern I. extensive area of greatly reduced
angiographic data. We used PET to study prospectively perfusion and oxygen consumption; middle: pattern N, extensive area of
patients with acute MCA territory stroke to see whether moderate perfusion reduction and only focally large oxygen consumption
cerebral perfusion and oxygen consumption patterns (and perfusion) reductions (long arrows); bottom- pattern II increased
predict neurological course, and to see whether early perfusion with only focally reduced oxygen consumption (long arrows).
spontaneous reperfusion is beneficial.
We included patients with a first MCA stroke (< 18 h duration) undetermined in 6. PET was done 5"18 h (mean 11[6]) after
and no serious obtundation, haemorrhagic infarct on CT, or organ stroke onset (table). 5 patients died within 10 days. The 13
failure. The neurological deficit was quantified at day 0 and day 60 survivors’ courses were poor (3), intermediate (2), and good
by use of Mathew and MCA scales2 (with which near-maximum (8), according to the Mathew scale, and 4, 1, and 8,
recovery is expected at D60). Martinez-Vila’s evolution indices (EI) respectively, by the MCA scale. The DO value overlapped
were used to estimate the relative change in neurological deficit: between the three outcome categories although the 3
El [D60-DO] x l00j[IO&uuml;-DO] for improvement, El [D60-
= =

patients with a Mathew value of less than 25 died, and all 4

DO] x 100/[DO], where DO and D60 were the Mathew or the MCA
values on days 0 and 60, respectively.’ Neurological course was
defined as poor (death or EI<25%), intermediate (26-74%), or
good (>75%). We used the 150 equilibrium method,8 which
produces parametric images of perfusion and oxygen consumption.
PET data that were marred by head movements were not used. The
sets of images (14 for each patient), produced by use of a
pseudocolour scale (which was adjusted in each case for easy
identification of low pixel values), were searched by sight for
consistent patterns. Abnormalities were defined as: a serious
reduction in perfusion (tissue viability threshold <12
mL/100
mL.min), moderate perfusion reduction (12-20 mL/100 mL.min),
perfusion increased relative to contralateral side (spontaneous
reperfusion), serious reduction in oxygen consumption (< 1 4
mL/100 mL.min), and moderately reduced oxygen consumption
(1-4-20 mL/100 mL.min).-’ The probability of the PET x
neurological course distribution was calculated with Fisher’s exact
test.
18 patients were included (mean age 74[SD 82] years).
The cause of the stroke was an embolism in 12 patients and
with values greater than 70 recovered completely (155 and 85
for MCA scale, respectively). The PET images could be
separated into three patterns (figure). Pattern I images (7
patients) showed greatly reduced perfusion and oxygen
consumption over a large cortical-subcortical area; pattern
II images (5 patients) showed moderate to large perfusion
reduction (irrespective of extent), and a reduction in oxygen
consumption that was either moderate (irrespective of
extent) or large (but not over a large area), or both; pattern
III images (6 patients) showed an increase in perfusion,
irrespective of extent but without associated areas of
reduced perfusion, and oxygen consumption that was
unchanged or decreased in a small area. In 2 pattern I
patients, the affected area exceeded the MCA territory with,
in 1, hyperperfusion over part of the hypometabolic area. All
pattern I patients had a poor neurological course and all
pattern III patients had a good recovery; in pattern II, 1
patient died and 2 had an intermediate and 2 a good recovery

(table). This PET x outcome distribution was highly
significant (p < 0-0005, with either scale).
Thus, pattern I was consistently associated with poor
outcome and pattern III with good recovery, whereas
recovery was unpredictable for pattern II patients. Our
sample, although small, was representative with respect to
age, outcome, and stroke mechanism; neither age nor sex
influenced outcome. Computed PET image analysis9
showed three distinct perfusion-oxygen consumption
clusters congruent with the three visually defined patterns.
The PET x clinical relation was maintained if only two
categories of either EI ( < 50% and > 50%) or outcome
(poor, < 50, or good, > 50) were used (p < 0-0005 and 001,
respectively). Although outcome could have been predicted
retrospectively by extreme DO values, PET images
predicted outcome in patients with intermediate DO values
(p = 0-07 for both scales). Within 5-18 h after stroke onset,
PET seems more reliable than initial neurological values,
especially for patients in patterns I and III.
Pattern I reflects extensive, irreversible ischaemia, and
accordingly, these deaths were due to transtentorial
herniation and late CT showed large infarcts in the 3
survivors; it could be due to persistent MCA trunk occlusion
with ineffective collaterals, or "no re-flow" (no reperfusion
despite recanalisation). Pattern III suggests early complete
reperfusion from spontaneous recanalisation; good
collaterals presumably limited damage during ocdusion10
and late CT showed small infarcts in all patients. Pattern II
was associated with widely variable outcome, which suggests
that deteriorating or non-recovering strokes may be partly
due to continuing necrosis and rapidly recovering strokes to
reperfusion of penumbral tissue after PET.
This study accords with the reported benefit from
therapeutic thrombolysis within 6 h of stroke onset.6
Presently, however, most patients are seen later. In pattern
I, thrombolysis would be too late or may even lead to
oedema or haemorrhage, while it would be ineffective with
pattern III. Delayed thrombolysis may benefit patients in
pattern II, although even limited infarction could be
hazardous. Our results may be important for prognosis,
especially in therapeutic trials in which exclusion of patients
with pattern I or III, who are unlikely to benefit, would give
more opportunity to assess drug effects. For a practical
application, SPECT perfusion imaging would be preferable
but needs to be assessed.
This work was supported by CNAM-INSERM grant 82/90. We thank the
physicians of the Emergency and Neurology Departments, and Dr A. Zipfel
(Synthelabo, Bagneux, France) for statistical assistance.
REFERENCES
1. Wade DT, Hewer RL. Rehabilitation after stroke. In: J F Toole, ed.
Handbook of clinical neurology. Amsterdam: Elsevier, 1989; 11:
233-54.
2. Bogousslavsky J, Guez D, Biller J, eds. Cerebral ischemia: from
pathophysiology to treatment. Cerebrovasc Dis 1991;1 (suppl 1): 1-138.
3. Giubilei F, Lenzi GL, Di Piero V, et al. Predictive value of brain
perfusion single-photon emission computed tomography in acute
ischemic stroke. Stroke 1990; 21: 895-900.
4. Limburg M, van Royen EA, Hijdra A, Verbeeten B. rCBF-SPECT in
brain infarction: when does it predict outcome? J Nucl Med 1991; 32:
382-87.
5. Wise RJS, Bernardi S, Frackowiak RSJ, Legg NJ, Jones T. Serial
observations the
on pathophysiology of acute stroke. Brain 1983; 106:
197-222.
6. Wardlaw JM, Warlow CP. Thrombolysis in acute ischaemic stroke: does
it work? Stroke 1992; 23: 1826-39.
927
7. Martinez-Vila E, Guill&eacute;n F, Villanueva JA, et al. Placebo-controlled trial
of nimodipine in the treatment of acute ischemic cerebral infarction.
Stroke 1990; 21: 1023-28.
8. Marchal G, Rioux P, Petit MC, et al. Regional cerebral oxygen
consumption, blood flow and blood volume in healthy human aging.
Arch Neurol 1992; 49: 1013-20.
9. Marchal G, Beaudouin V, Serrati C, Rioux P, Viader F, Baron JC. New
automated analysis of metabolic PET images: application to acute
ischemic stroke. Cerebrovasc Dis 1992; 2: 235.
10. Ringelstein EB, Biniek R, Weiller C, Ammeling B, Nolte PN, Thron A.
Type and extent of hemispheric brain infarctions and clinical outcome
in early and delayed middle cerebral artery recanalization. Neurology
1992; 42: 289-98.
ADDRESSES: INSERM U320, Cyceron, Caen, France (G. Marchal,
MD, P. Rioux, MD, PhD, M. C. Petit-Tabou&eacute;, MD, J. M. Derlon, MD, J. C.
Baron, MD); Clinica Neurologica Dell’Universita di Genova, Italy
(C. Serrati, MD); CHRU C&ocirc;te de Nacre, Caen (F. Viader, MD, V. de la
Sayette, MD, F. Le Doze, MD); CEA DSV/DPTE, Caen (P. Lochon);
CAC F. Baclesse, Caen (M. C. Petit-Tabou&eacute;); and CHU Pellegrin,
Bordeaux, France (J. M. Orgogozo, MD). Correspondence to Dr Jean
Claude Baron, INSERM U320, Cyceron, BI Becquerel, BP 5027, 14021
Caen, France.
Insulin prophylaxis in individuals at
high risk of type 1 diabetes
Prevention of type I diabetes is now a practical
goal thanks to the ability to define confidently a
high-risk group and the success of preventive
strategies in animal models. We describe here a pilot
trial of low-dose insulin to prevent diabetes in
relatives of patients with type I diabetes.
In a screening programme at the Joslin Diabetes Center,
Boston, first-degree relatives of patients with type I diabetes
are monitored by measurement of islet cell (ICA) and
insulin (IAA) autoantibodies, and by metabolic tests,
including first-phase insulin release in an intravenous
glucose-tolerance test (IVGTT).1,2 Our modelbased on
ICA, IAA, and IVGTT insulin, can identify a group of
relatives in whom the risk of diabetes is 72 % at three years of
follow-up and over 90% at four years. Those at the high risk
and aged 7-40 years were eligible for the prevention
protocol. They were required to have a normal oral
glucose-tolerance test (fasting plasma glucose < 6-4, 2 h
< 7 -8, and all intervening values < 11 1 mmol/L).
Subcutaneous insulin has been effective in preventing diabetes
and insulitis in two animal models of spontaneous type I diabetes.45
In man, Shah et al have shown that two weeks of intravenous insulin
at the onset of clinical type I diabetes seems to preserve endogenous
C-peptide release for up to a year, and that this effect may be
prolonged by repeating the therapy every 12 months. We used a
combination of these two approaches in our pilot trial, giving
low-dose subcutaneous insulin daily with 5-day courses of
intravenous insulin every 9 months. The intravenous infusions
were given to patients admitted to the Clinical Research Center,
Children’s Hospital, Boston. During these 5 days the infusion was
adjusted to maintain fasting and non-mealtime plasma glucose
between 33 and 4-2 mmol/L and postprandial (2 h period starting
at the beginning of each meal) plasma glucose below 5-0 mmol/L.
Plasma glucose was measured every 10-30 min with a bedside
analyser. Outpatient daily insulin was divided into two