Medicine

®

Clinical Case Report

OPEN

Computed tomography-negative symptomatic
intracerebral hemorrhage in a patient with
cerebral small vessel disease
A case report
Jinhee Han, MD, Harin Yang, MD, Jeong Hoon Bae, MD, Hyun Young Kim, MD, PhD,
∗
Young Seo Kim, MD, PhD
Abstract
Rationale: Computed tomography plays a key role in the initial evaluation of suspected acute stroke by ruling out the possibility of

hemorrhage before thrombolysis. Recently, many reports have described cases of symptomatic microbleeds, and there may also
have been a case of computed tomography- negative intracerebral hemorrhage.
Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKbH4TTImqenVBZZxeh5YHRLeFcHv6Lr36rPQZZu6eCtz2ycD7raz9dyP/dJGl6AOUE= on 07/24/2020

Patient concerns: A 70-year-old female patient who had a history of lacunar infarction and severe small vessel disease developed
dysarthria. On brain non-contrast computed tomography there was no evidence of intracerebral hemorrhage. However, brain
magnetic resonance imaging performed at 3 hours after the initial computed tomography showed cerebral hemorrhage.
Diagnoses: The diagnosis was computed tomography-negative intracerebral hemorrhage.
Interventions: The patient was treated with cilostazole 100 mg twice a day with blood pressure management.
Outcomes: The dysarthria was fully recovered within 5 days and the patient did not suffer recurrent stroke symptoms over the
following 2 years.
Lessons: In patients with underlying severe small vessel disease and microbleeds, there could be computed tomography-negative
hemorrhage and susceptibility weighted magnetic resonance image could be needed. More attention is required before applying
thrombolysis therapy because there is a possibility of cerebral hemorrhage in those patients.
Abbreviations: DWI = diffusion weighted image, FLAIR = fluid attenuated inversion recovery, ICH = intracerebral hemorrhage,
MRI = magnetic resonance imaging, NCCT = non-contrast computed tomography, SWI = susceptibility weighted image, tPA =
tissue plasminogen activator.
Keywords: cerebral hemorrhage, computed tomography, microbleed, small vessel disease

treatment such as intravenous thrombolysis and endovascular
thrombectomy. Thus, prompt diagnosis and treatment are
necessary to minimize stroke-induced disability, and brain imaging
plays a major role in determining treatment strategy. Non-contrast
brain computed tomography (NCCT) is commonly used to
differentiate hemorrhage from ischemia because it takes a
short time and has high sensitivity for detecting cerebral
hemorrhage.[1]
Intravenous thrombolysis with tissue plasminogen activator
(tPA) is first line treatment in ischemic stroke patients who
present within 4.5 hours. However, hemorrhagic complications
were found to develop in 21.3% of patients and symptomatic
hemorrhage in 5.6%.[2] Once hemorrhagic complications occur,
neurologic symptom may deteriorate and patients may have poor
outcomes. Thus, intravenous thrombolysis should only be
undertaken after careful examination of early brain images for
signs of potential hemorrhagic. The authors encountered a case of
a patient with acute cerebral hemorrhage in whom early brain
NCCT gave no evidence of bleeding but magnetic resonance
imaging (MRI) indicated hemorrhage. Ruling out cerebral
hemorrhage by brain CT may be insufficient, especially in
patients with a history of severe small vessel disease and lacunar
infarction. We describe this case with emphasis on the need
for caution in employing intravenous thrombolysis in such
patients.

1. Introduction
Stroke is an emergent disease which results in death and severe
disability. However, in many cases it can be reversed by timely

Editor: Maya Saranathan.
Written informed consent was obtained from the patient for publication of this
case report and accompanying images.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are
available from the corresponding author on reasonable request.
Department of Neurology, College of Medicine, Hanyang University, Seoul,
Republic of Korea.
∗

Correspondence: Young Seo Kim, Department of Neurology, College of
Medicine, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133792, Republic of Korea (e-mail: aescula@hanmail.net).

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
How to cite this article: Han J, Yang H, Bae JH, Kim HY, Kim YS. Computed
tomography-negative symptomatic intracerebral hemorrhage in a patient with
cerebral small vessel disease: a case report. Medicine 2020;99:29(e21382).
Received: 20 November 2019 / Received in final form: 28 May 2020 / Accepted:
18 June 2020
http://dx.doi.org/10.1097/MD.0000000000021382

1

Han et al. Medicine (2020) 99:29

Medicine

Figure 1. Brain magnetic resonance image obtained 8 months previously. Diffusion-weighted imaging (A) shows increased signal intensity in left corona radiata
consistent with acute ischemic stroke. Susceptibility-weighted imaging(B) did not showed any hemorrhage in the ischemic stroke lesion. Susceptibility-weighted
imaging reveals multiple micro-bleedings in the temporo-parietal cortex, thalamus and basal ganglia (C), and confluent white matter changes with multiple silent
infarctions can be seen in the fluid-attenuated inversion recovery image (D), which implies underlying small vessel disease.

2. Case report

Emergency brain CT, which was done in the emergency room,
did not give evidence of cerebral hemorrhage (Fig. 2A). Since she
had only mild symptoms and 5 hours had passed from symptom
onset, she did not receive recombinant tissue plasminogen
activator (rtPA), and antiplatelet agent was continued with
conservative treatment. Brain MRI which was performed 3 hours
after the CT showed a low signal intensity in the left corona
radiata with a high signal rim on diffusion weighted image
(DWI). T1 weighted image showed isointensity without
enhancement, and T2 weighted image and susceptibility weighted
image (SWI) showed low signal intensity compatible with acute
stage cerebral hemorrhage (Fig. 2B-F). This was a new
hemorrhage not evident on brain MRI taken 8 months before.

A 70-year-old woman visited the emergency room with dysarthria
that had started 5 hours earlier. She had been diagnosed with
hypertension 11 years previously and took regular medication. She
had also been diagnosed with corona radiata infarction, severe white
matter change and multiple microbleeds 8 months earlier and was
taking 100 mg of cilostazole twice a day (Fig. 1). On physical
examination, temperature was 36.8°C, heart rate 108/min and
blood pressure 130/80 mm Hg. Laboratory findings such as
complete blood count, electrolytes, liver function test, renal function
test, and coagulation profiles were unremarkable. On neurologic
examination she complained only of dysarthria, without hemiparesis or sensory change.
2

Han et al. Medicine (2020) 99:29

www.md-journal.com

Figure 2. Brain computed tomography image obtained on the day of admission does not show any acute hemorrhage (A). Brain magnetic resonance image with
contrast enhancement obtained 3 hours after the initial CT. The diffusion-weighted image shows decreased signal intensity in the left corona radiata and a
perilesional high signal intensity towards the motor cortex (arrow) (B). T1 weighted image shows isointensity without enhancement (C, D). T2 weighted image (E) and
Susceptibility-weighted imaging (F) show low signal intensity compatible with acute hemorrhage. The subcortical white matter changes seen in fluid-attenuated
inversion recovery images were unchanged from the previous images (G). Brain magnetic resonance angiography shows no significant stenotic lesions in
intracranial arteries (H).

performed 3 hours after CT did not reveal any restricted diffusion.
In contrast, a relatively large low signal intensity was observed on
SWI. If the patient had reached the emergency room within the time
indicated for thrombolysis and had had more prominent
neurologic symptoms, thrombolysis might have been carried out
based on the results of NCCT and this might have caused a
thrombolysis-associated hemorrhage. Although a recent metaanalysis concluded that cerebral microbleeds were not associated
with symptomatic intracerebral hemorrhage (ICH) after intravenous thrombolysis, they were associated with poor functional
outcome and various types of ICH.[3] Thus, patients with ICH
without a prominent high density on NCCT, as in this case, should
be treated with great care.
There are 2 case reports of CT negative intracranial
hemorrhage. In 1 case, a hypertensive thalamic hemorrhage
was not detected by NCCT, but was observed by brain MRI
taken 12 hours later.[4] However, in that case there is a possibility
of hemorrhagic transformation after acute cerebral infarction. In
the other case, initial CT did not reveal a high density focus, but
cerebral hemorrhage was observed by MRI taken 3 hours later.[5]
However, there was some disagreement about whether bleeding
was really not evident on the CT scan, and it was suggested that
bleeding can only be ruled out by close observation by NCCT.
Although in our case cerebral hemorrhage occurred close to the
previous cerebral infarction, the lesion had not been visible by
MRI 8 months previously, and was consistent with the neurologic
symptoms. Thus, we believe that it may be regarded as a newly
developed cerebral hemorrhage. Recent reports emphasize that
acute microbleeds which are not detected by brain CT may cause
stroke symptoms.[6–8] However, the bleeding area in our patient

Besides this, white matter changes and multiple silent brain
infarctions were observed on fluid attenuated inversion recovery
images that were unchanged from 8 months before (Fig. 2G).
There was no stenotic lesion on brain magnetic resonance
angiography (Fig. 2H). All this evidence together led us to suggest
that the patient’s dysarthria was caused by corona radiata
hemorrhage.
The patient’s symptoms gradually improved over 5 days of
treatment, and cilostazole was maintained without change of
medication. To determine the cause of the repeated stroke events,
vasculitis-related factors, antiphospholipid syndrome screening,
cerebral autosomal dominant arteriopathy with subcortical
infarction genetic test and Fabry disease screening were
performed with negative results. The patient was followed-up
for 2 years in the outpatient clinic without recurrence of stroke
symptoms.

3. Discussion
Non-contrast brain CT (NCCT) is the most useful mode of brain
imaging for differentiating ischemic stroke from hemorrhagic
stroke before deciding for or against thrombolysis. Hence,
guidelines recommend NCCT for initial brain imaging for stroke
patients.[1] However, the occurrence of acute symptomatic cerebral
hemorrhage not revealed by NCCT, as in this case, suggests that
thrombolytic treatment based on NCCT alone may not be safe.
Although this patient was not indicated for thrombolysis because
of her mild symptoms and the delayed presentation, she was
initially diagnosed as acute cerebral infarction and treatment was
performed based on that diagnosis. However, DWI MRI
3

Han et al. Medicine (2020) 99:29

Medicine

Conceptualization: Young Seo Kim.
Data curation: Harin Yang, Jeong Hoon Bae, Young Seo Kim.
Writing – original draft: Jinhee Han.
Writing – review & editing: Young Seo Kim.

exceeded 5 mm, which is not within the range of microbleeds (2–
5 mm), and so it may be regarded as a macrobleed or cerebral
hemorrhage rather than a microbleed. One observational study
has suggested that microbleeds are more likely to be symptoms of
stroke when DWI shows a high signal rim around the low signal
intensity.[9] Our patient did have a high signal rim around the low
signal lesion on DWI, and it was present in the motor cortex
direction. Therefore, our patient’s cerebral hemorrhage, which
was invisible on NCCT, may have caused the stroke symptom.
Cerebral small vessel disease is produced by damaged brain
arteries, arterioles, capillaries, and veins. It may lead to silent
radiologic findings such as white matter changes, lacunar
infarction, microbleeds, and enlarged Virchow Robin spaces.
The pathologic changes include fibrinoid necrosis, lipohyalinosis,
and Charcot Bouchard aneurysm, and the pathologic findings are
the same as the findings of intracerebral hemorrhage.[10] Thus,
intracerebral hemorrhage is likely to occur in patients with severe
small vessel disease and a higher burden of microbleeds.[11] In
addition, endothelial dysfunction, inflammation and rupture of
microaneurysms can occur in small vessel disease patients, and may
be associated with thrombolysis-related hemorrhage and poor
functional outcome.[12,13] In the present case, severe small vessel
disease was confirmed by the past subcortical lacunar infarction,
severe white matter changes on fluid attenuated inversion recovery
images and multiple microbleeds on SWI. Although cerebral
infarction with minor symptoms is not a reason for being excluded
from thrombolysis and insisting on safety, careful consideration is
needed before carrying out thrombolysis therapy in patients with
severe small vessel disease because of the possibility of CT-negative
hemorrhage, as in our case.

References
[1] Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the
early management of patients with acute ischemic stroke: a guideline for
healthcare professionals from the American heart association/American
stroke association. Stroke 2018;49:e46–110.
[2] Kim BJ, Park JM, Kang K, et al. Case characteristics, hyperacute
treatment, and outcome information from the clinical research center for
stroke-fifth division registry in South Korea. J Stroke 2015;17:38–53.
[3] Wang S, Lv Y, Zheng X, et al. The impact of cerebral microbleeds on
intracerebral hemorrhage and poor functional outcome of acute ischemic
stroke patients treated with intravenous thrombolysis: a systematic
review and meta-analysis. J Neurol 2017;264:1309–19.
[4] Nakada T, Kwee IL. Computed tomography-negative acute thalamic
hematoma. J Neuroimaging 1996;6:119–21.
[5] Packard AS, Kase CS, Aly AS, et al. Computed tomography-negative”
intracerebral hemorrhage: case report and implications for management.
Arch Neurol 2003;60:1156–9.
[6] Cho BH, Kim JT, Heo SH, et al. Lobar cerebral microbleeds associated
with transient focal neurological symptoms followed by symptomatic
intracerebral hemorrhage. J Neurol 2012;259:1991–3.
[7] Choi PK, Chung JY, Lee SJ, et al. Recurrent cerebral microbleeds with
acute stroke symptoms: a case report. Medicine (Baltimore) 2018;97:
e12480.
[8] Heo SH, Lee D, Lee D, et al. Differentiation of a symptomatic cerebral
microbleed from silent microbleeds. Int J Stroke 2014;9:E2.
[9] Heo SH, Lee D, Kwon YC, et al. Cerebral microbleeds in the patients
with acute stroke symptoms. Front Neurol 2018;9:988.
[10] Ter Telgte A, van Leijsen EMC, Wiegertjes K, et al. Cerebral small vessel
disease: from a focal to a global perspective. Nat Rev Neurol
2018;14:387–98.
[11] Charidimou A, Imaizumi T, Moulin S, et al. Brain hemorrhage
recurrence, small vessel disease type, and cerebral microbleeds: a
meta-analysis. Neurology 2017;89:820–9.
[12] Kongbunkiat K, Wilson D, Kasemsap N, et al. Leukoaraiosis,
intracerebral hemorrhage, and functional outcome after acute stroke
thrombolysis. Neurology 2017;88:638–45.
[13] Zand R, Tsivgoulis G, Singh M, et al. Cerebral microbleeds and risk of
intracerebral hemorrhage post intravenous thrombolysis. J Stroke
Cerebrovasc Dis 2017;26:538–44.

Author contributions
JH drafted the manuscript. HY, JHB, HYK contributed to the
intellectual discussion of the patient. YSK conceived to report the
patient and drafted manuscript together. Each author has
participated sufficiently in the work to take public responsibility
for appropriate portions of the content.

4