Clinical Neurology and Neurosurgery 115 (2013) 802–804

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Clinical Neurology and Neurosurgery
journal homepage: www.elsevier.com/locate/clineuro

Case report

Thrombolytic therapy in total mismatch with severe stroke after acute
MCA-occlusion and negative DWI
Lars Neeb a,b,∗, Frederik Geisler b, Matthias Wendt b, Andrea Rocco b, Jochen B. Fiebach a, Kersten Villringer a
a
b

Center of Stroke Research Berlin, Charite Universitaetsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany
Department of Neurology, Charite Universitaetsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany

a r t i c l e

i n f o

Article history:
Received 5 June 2012
Received in revised form 9 July 2012
Accepted 16 July 2012
Available online 4 August 2012
Keywords:
Stroke
Magnetic resonance imaging
Total mismatch
Thrombolytic therapy
Diffusion weighted imaging

1. Introduction

2. Case report

Total mismatch is a recently described magnetic resonance
imaging (MRI) pattern in acute stroke patients with no signal
changes in diffusion weighted images (DWI) and extensive hypoperfusion on perfusion weighted images (PWI). The prognostic value
and importance for treatment decision based on this finding in
MRI have recently been controversially discussed in patients with
minor stroke [1,2]. Here we report a case of a 98-year-old woman
that presented with severe stroke and total mismatch in the left
middle cerebral artery (MCA) territory in MRI scan and an occlusion of the proximal MCA (M1) in time-of flight MR angiography
(TOF-MRA). The patient was treated with systemic thrombolysis
followed by complete remission of neurological symptoms and
remaining negative DWI in post treatment MRI. We discuss the
possible pathophysiological background of this phenomena and its
impact on tailoring therapeutic strategies in patients with relative
contraindications to thrombolytic therapy.

A 98-year-old woman was admitted to our hospital 50 min
after sudden onset of global aphasia and right-sided sensomotoric hemisyndrome (National Institutes of Health Stroke Scale
(NIHSS) = 13; modified Rankin Scale (mRS) before incident = 0).
63 min after symptom onset a 3 T MRI was performed. Despite the
serious neurological deficit, DWI images showed no restrictions.
However, PWI displayed an extensive hypoperfusion in the left
middle cerebral artery territory with corresponding M1 occlusion
in the TOF-MRA (Fig. 1A).
Acute intracranial haemorrhage or microbleeds could be
excluded in T2*. Despite the great age of 98 years a systemic thrombolysis as an individual treatment attempt was performed due to
the severe neurological deficit and pre-stroke mRS of 0 in combination with a total mismatch and M1-occlusion in MRI and MRA. After
exclusion of other contraindications recombinant tissue plasminogen activator (rt-PA) was administered with a dose of 0.9 mg/kg
intravenously 85 min after stoke onset. Concurrent lessening of
neurological symptoms could be observed. During thrombolysis
a transcranial duplex examination was performed which yielded
a recanalization of left M1. 2 h after therapy onset neurological
symptoms were completely resolved (NIHSS = 0). An additional MRI
scan at that time still showed no restrictions on DWI images, but
a clear decline of perfusion deficits with small persistent hypoperfusion in the left central MCA territory. MRA showed a complete

∗ Corresponding author at: Center of Stroke Research Berlin, Charite Universitaetsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
Tel.: +49 30 8445 4102.
E-mail address: lars.neeb@charite.de (L. Neeb).
0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.clineuro.2012.07.018

L. Neeb et al. / Clinical Neurology and Neurosurgery 115 (2013) 802–804

803

Fig. 1. (A) Baseline MRI (DWI, MTT, TOF-MRA) showing left MCA M1 occlusion and extensive perfusion deficit with negative DWI. (B) MRI 2 h after systemic thrombolytic
therapy (DWI, PWI-MTT, TOF-MRA) reveals recanalization of left MCA M1 with nearly complete reperfusion and still no signal changes in DWI.

recanalization of M1 (Fig. 1B). No signs of haemorrhagic transformation were noted on T2* images.
Despite the good neurological outcome the patient suffered a
heart attack and had to be resuscitated one day later. The patient
was transferred to the intensive care unit and died 12 days later
due to cardiac failure. Hence no further follow up MRI could be
performed.
3. Discussion
We report a case of a 98-year-old woman with a severe stroke
and total mismatch in MRI (no signal changes in DWI but extensive PWI deficit of nearly the whole left MCA-territory) who was
treated with systemic thrombolytic therapy. Follow-up MRI 2 h
after thrombolytic therapy (3 and a half hours after symptom onset)
revealed persistent negative DWI but diminishing hypoperfusion
and consecutive recanalization of preceding MCA occlusion. Correspondingly all neurological symptoms had resolved at that time.
DWI is a sensitive and early marker of cytotoxic edema in
cerebral ischaemia. Negative DWI is mostly found in brain stem
infarction or lacunar syndromes in patients with mild stroke symptoms [3]. Territorial stroke caused by occlusion of M1 with severe
neurological deficits and initial negative DWI is rare. According to
the severe neurological symptoms, M1 occlusion and extensive perfusion deficit in the presented case we would have expected a signal
change in DWI 50 min after stroke onset.
Recently three patients with fluctuating symptoms (varying
NIHSS from 0 to 10) and a total mismatch in MRI who had a
favourable outcome after intravenous thrombolytic therapy were
reported. The authors concluded that PWI can facilitate treatment
decisions in unstable cases with negative DWI.
They hypothesized that negative DWI in these patients could be
explained through a moderate hypoperfusion not severe enough to
produce a diffusion lesion [2]. At least two of the reported patients

showed an extensive hypoperfusion in more than 2/3 of the MCA
territory, which does not necessarily correspond to a moderate
hypoperfusion. Unfortunately the authors did only state that time
between symptom onset and MRI was less than 6 h and did not give
the exact time. Total mismatch could be explained by a reduction
in cortical blood flow that is caused in our case by MCA-occlusion
and possibly in part compensated by increase of collateral blood
flow. The reduction of cortical blood flow could be severe enough
to reach the threshold for causing neural dysfunction and signal
changes in PWI but too slight to cause major energy failure with
consequent DWI changes especially in sequences obtained close
by symptom onset.
Another case series reported four patients with minor stroke,
middle cerebral artery occlusion and total mismatch who had
a spontaneous recovery of ischaemic symptoms without thrombolytic therapy. Follow-up imaging 96 h later revealed new lesions
in DWI and recanalization in all patients. In contrary to Cho et al.
the authors assumed that total mismatch represents a surrogate
marker for favourable outcome without the necessity of thrombolytic therapy [1].
Although unproven, it is widely assumed that the area of
PWI–DWI mismatch, characterized by a larger region of hypoperfusion than the region of diffusion abnormality, represents, at
least in part, remaining salvageable tissue (the so called penumbra) that could be saved by recanalizing therapy. The mismatch
concept might help for selection of patients for delayed treatment
who may benefit from thrombolytic therapy beyond 3 or 4.5 h.
As unthresholded visual PWI/DWI mismatch overestimates tissue at risk, it is a major challenge to define which single or combined
perfusion parameter threshold allows best to distinguish between
benign oligemia and penumbra to give a reliable estimate of tissue fate. Using the perfusion parameter Tmax , a threshold between
4 and 6 s appeared in a retrospective analysis optimal for early
identification of critically hypoperfused tissue [4]. Fig. 2 shows the

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L. Neeb et al. / Clinical Neurology and Neurosurgery 115 (2013) 802–804

Fig. 2. Illustration of PWI deficits according to initial Tmax maps obtained 63 min after stroke onset. Different Tmax delays (>2 s, >4 s, >6 s, >8 s) were generated by thresholding
the respective images. The amount of critical hypoperfused tissue decreases with prolonged delay but is still present even at a threshold >8 s.

Tmax perfusion maps of the presented patient with still extended
PWI deficits at Tmax thresholds between 4 and 6 s emphasizing the
urgency of recanalizing therapy.
Based on the presented data by Kim et al. [1] it is not possible to conclude that the reported four patients would have had a
favourable outcome in case of no recanalization. Due to the low
number of patients it remains unclear if spontaneous recanalization is associated with total mismatch or occurred incidentally in
these four cases.
As chances of recanalization are improved through treatment
with rt-PA the clinical course of these patients argues rather for an
early thrombolytic therapy in patients with total mismatch with
a high fraction of tissue at risk and clinical symptoms of (minor)
stroke. Not treating these patients with a dramatic perfusion defect
and verified vessel occlusion would leave them at risk for permanent severe neurological deficits. The good neurological outcome
in the presented patient with a short delay from symptom onset to
treatment underlines the importance of rapid procedures in acute
stroke patients.
As prevailing license criteria for thrombolytic therapy with rtPA are restricted to patients under the age of 80 the advanced
age of the presented patient could have argued against thrombolytic therapy. Until recently no randomized controlled trial
assessed the benefit/risk ratio for thrombolytic therapy in stroke
patients at a great age. However, the just published IST-3 trial
could show that treatment with rt-PA within 6 h after stroke
onset also improves functional outcome in elderly patients and
may extent the use of thrombolytic therapy in this population
[5].
Our case shows that total mismatch might also be a positive
predictor for successful thrombolysis in patients who are more
severely affected than reported before (NIHSS 13). Unfortunately
the patient suffered of cardiac complications that were most likely
not associated with stroke treatment, which made additional
evaluation of her further neurological and functional outcome
impossible. It cannot be excluded that the myocardial infarction was a consequence of a detached pre-existing intracardiac

thrombus or a prothrombotic state following rt-PA treatment.
However, in contrast to rt-PA treated coronary patients the use
of antiplatelet strategies or anticoagulation as adjunctive therapy
should be avoided in rt-PA treated stroke patients during the
first 24 h after thrombolysis due to the extra risk of intracerebral
haemorrhage.
4. Conclusion
Total DWI–PWI mismatch is an interesting imaging phenomenon, whose impact and underlying pathophysiology are not
completely understood. The finding of total mismatch in MRI might
help planning therapeutic strategies especially in patients with relative contraindication to thrombolysis such as high age as in the
presented case.
Acknowledgment
The authors would like to thank Ivana Galinovic for helping to
create the perfusion maps.
References
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MCA occlusion. Journal of Neuroimaging: Official Journal of the American Society
of Neuroimaging 2011;21:399–402.
[2] Cho TH, Hermier M, Alawneh JA, Ritzenthaler T, Desestret V, Ostergaard L,
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