Ischemic infarction following an intra-cerebral hemorrhagein an adult sickle cell disease with angiographic Moyamoya

Praveen Kumar Gupta Æ Krishnan Pudukode Ramnath ÆPrabha Ramadorai Æ Abdulla Alajmi ÆJanaki Sudhakar Praharaju

Published online: 1 June 2007

� Springer Science+Business Media, LLC 2007

Abstract A 43-year-old lady, known case of sickle cell

disease (SCD) was admitted in sickle cell crises and

developed a left frontal intracerebral hematoma. She

worsened further neurologically and was found to have

developed a large left middle cerebral artery (MCA)

infarct. Angiogram showed Moyamoya pattern. The patient

was managed conservatively with exchange transfusions

and made good recovery. She is being maintained on

monthly exchange transfusions and hydroxyurea. Such a

presentation has been described infrequently, that too

mostly in children. Only once, it has been reported with

adult SCD. Diagnostic and management controversies are

discussed in the light of available literature.

Keywords Adult � Angiographic � Intracerebral �Ischemia � Hematoma � Moyamoya stroke � Sickle cell

disease

Introduction

Ischemic stroke with Moyamoya changes is often seen in

pediatric and intracerebral hemorrhages in adult sickle cell

disease (SCD) [1]. Simultaneous presentation of both,

hemorrhage and ischemic infarction in a patient has not

often been reported. Here, we discuss a middle-aged lady

with SCD who was admitted for sickle cell crisis and found

to have an intracerebral hemorrhage at presentation and

subsequently developed an arterial infarct. She was found

to have Moyamoya on angiography. Development of both

the conditions in a patient was difficult to explain and the

treatment was debatable. The case is discussed to explain

the possible pathogenesis of both the condition in the given

patient and treatment options in the light of presumed

pathogenesis.

Case report

A 43-year-old Bahraini lady, known case of homozygous

SCD with persistent high HbF, was admitted with backache

and epigastric pain. She had been treated infrequently in

the past for vaso-occlusive crises and anemia requiring

blood transfusion occasionally. Initial hemoglobin elec-

trophoresis was of SF pattern with HbS, 66.1%; HbF,

26.7% and HbA2, 3.2%. She denied using oral contra-

ceptives and her last delivery was 7 years back. She was

afebrile with a pulse 90/min regular and blood pressure

130/80 mmHg. Her systemic examination was unremark-

able. Blood investigations revealed hemoglobin 140 g/l,

TLC 9.1 · 109/l, platelets 185 · 109/l, reticulocyte count

4.99% and LDH 431 u/l (normal range 135–214 u/l). She

was treated symptomatically for vaso-occlusive crises.

P. K. Gupta (&) � K. Pudukode Ramnath

Department of Clinical Neurosciences, Salmaniya Medical

Complex, Ministry of Health, P.O. Box 12, Manama 311,

Kingdom of Bahrain

e-mail: pkguptaram@hotmail.com

P. Ramadorai � A. Alajmi

Department of Hematology and Oncology, Salmaniya Medical

Complex, Ministry of Health, P.O. Box 12, Manama 311,

Kingdom of Bahrain

J. S. Praharaju

Department of Imaging and Radio-diagnosis, Salmaniya Medical

Complex, Ministry of Health, P.O. Box 12, Manama 311,

Kingdom of Bahrain

123

J Thromb Thrombolysis (2008) 25:227–230

DOI 10.1007/s11239-007-0050-8

Within a few days, she became drowsy, developed

expressive aphasia and right hemiparesis. CT scan of the

brain showed 33 · 21 · 24 mm left frontal intracerebral

hemorrhage with surrounding edema and sub-arachnoid

hemorrhage in left sylvian fissure and frontal sulci

(Fig. 1(1.1, 1.2)). She was treated with dexamethasone.

MRI done 3 days later showed an evolving left middle

cerebral artery (MCA) infarct and previously noted left

frontal hematoma (Fig. 1(1.3, 1.4)). MR angiogram

showed marked irregularity of intracranial vessels, non-

visualization of internal carotid arteries (ICA) bilaterally

with absent left A1, paucity of left MCA branches, and

prominent right posterior communicating artery. She was

continued on dexamethasone and other supportive treat-

ment, however she suddenly worsened further neurologi-

cally, became unconscious, opening eyes only to deep

painful stimulus and developed dense right-sided hemi-

plegia. Pupils remained equal and reacting. She was noted

to be not taking adequate feeds for almost 24 h prior to this

deterioration. Repeat CT scan of the brain showed

resolving hematoma and left MCA infarct. Ipsilateral lat-

eral ventricle was compressed but there was no midline

shift. She was ventilated, started on IV fluids, 20% mannitol

and given exchange transfusion to reduce her HbS below

30%. There was good improvement in the next 24 h. She

was weaned off the ventilator within 24 h and underwent

four vessel angiography that showed narrowing and

occlusion of distal ICA and hypertrophied lenticulostriate

vessels bilaterally at the origin of carotid bulb, more on the

right and poor visualization of left MCA branches

(Fig. 2(2.1–2.4)). Her vasculitic and prothrombotic

screening (ANA, VDRL, homocysteine, Protein C and S,

antithrombin III activity, activated protein C resistance,

lupus anticoagulant, anticardiolipin antibody IgG and IgM)

Fig. 1 (1.1, 1.2) Noncontrast CT scan of brain showing left frontal

intracerebral hematoma with surrounding edema and sub-arachnoid

hemorrhage in left sylvian fissure (black arrow) and frontal sulci.

(1.3, 1.4) FLAIR and T2 weighted sequences of brain, 3 days later,

showing an evolving left middle cerebral artery (MCA) infarct with

an existing left frontal hematoma

Fig. 2 (2.1, 2.2) AP view of bilateral carotid angiogram showing

diffuse small caliber of ICA, tapering and occlusion beyond

bifurcation of ICA and hypertrophied lenticulostriate vessels (white

arrows). (2.3, 2.4) Lateral angiogram of carotids showing narrowing

of bilateral ICA beyond carotid bulb (black arrows). (2.5) Close up

view of Moyamoya vessels (white arrow). (2.6) Lateral angiogram of

the posterior circulation showing filling of anterior circulation vessels

through posterior communicating artery

228 P. K. Gupta et al.

123

was normal. The patient was started on hydroxyurea 1 g

daily and regular exchange transfusions on a monthly basis.

She gradually improved and on last follow up 7 months

later, she is able to walk independently, has right facio-

brachial weakness and motor aphasia. The MRI and MRA

repeated nine months after initial presentation showed no

progression in Moyamoya vessels and findings similar to

the previous study.

Discussion

Sickle cell disease is a recessive autosomal genetic disorder

that manifests with microvascular occlusion and can pres-

ent with infarctions in various organs including the central

nervous system. Arterial ischemia results from vascular

changes due to sickle cell adherence, intimal damage,

hyperplasia and endoluminal narrowing which increases

flow and turbulence, perpetuating endothelial damage,

slowing RBC mobility and sludging. Reduced cerebral

blood flow due to occlusion or stenosis of the distal internal

carotid artery may result in the development of fine col-

laterals usually from the thalamo-perforate and lenticu-

lostriate arteries. This produces an appearance of puff of

smoke on angiography called Moyamoya in Japanese [2].

Ischemic infarction is seen commonly in children to an

extent of 90.6% whereas hemorrhage is observed in 88.2%

of adults as a complication of Moyamoya [3].

Moyamoya disease is an idiopathic cerebrovascular

disease mostly found in Japan, characterized by sponta-

neous and progressive occlusion of the terminal portion of

the bilateral ICA, proximal parts of anterior cerebral artery

and the MCA with a spontaneous developed collateral

vascular network. The criteria for cerebro-vascular Moya-

moya disease is defined by characteristic angiographic

findings—narrowing or obstruction of internal carotid

siphon bilaterally; ‘‘Moyamoya vessels’’ at the base of the

brain or basal ganglionic regions; poorly or often not

visualized main trunks of the cerebral arteries e.g. anterior,

middle, and/or posterior cerebral arteries and unknown

etiology [4]. Similar vascular changes in the cerebral

circulation may be seen in many systemic conditions e.g.

Sickle cell anemia, thalassemia, Aplastic anemia, Neuro-

fibromatosis, Down’s syndrome, Turner’s syndrome,

tuberculous meningitis, Wilm’s tumor, polycystic kidney,

pulmonary sarcoidosis, oral contraceptives, connective

tissue disorder, post-radiation vasculopathy and trauma

[5, 6]. It has been suggested that patients with systemic

disorders with angiographic features similar to Moyamoya

disease be described with the term angiographic Moya-

moya following the associated clinical condition [7]. In a

retrospective study of children with SCD suffering acute

stroke, 43% were found to have angiographic features of

Moyamoya and no cases with intracerebral hemorrhage

were found. Patients with Moyamoya collaterals were

found to be at higher risk for recurrent ischemic strokes and

transient ischemic attacks compared with patients without

these collaterals. The presence of Moyamoya indicates

severe disease [8].

Our patient had homozygous SCD and suffered an

intracerebral hemorrhage. The hemorrhage was peripheral,

frontal cortical in location, very similar to venous infarcts.

Moyamoya was probably not the cause for the hemorrhage

in this case as has often been suggested in the literature

because the hemorrhage in Moyamoya occurs in and

around the basal ganglia in relation to proliferating

Moyamoya vessels or in relation to engorged and dilated

artery (anterior choriodal or posterior communicating ar-

tery) as a result of occlusion of a major arterial trunk. It

could have been a hemorrhage as a result of capillary and

venous occlusion due to SCD but no abnormality was

noted in the venous phase of angiography. Subsequent to

the hemorrhage, she worsened neurologically and was

noted to have a large left MCA infarct. The infarction is

likely to be due to vasospasm produced by the subarach-

noid hemorrhage that was present with the frontal hema-

toma. Alternatively, limited vascular reserve due to

impaired vascular reactivity in Moyamoya reduces the

capacity for blood flow compensation. Any cause increas-

ing the intracranial pressure puts the brain region supplied

by these vessels at the risk of ischemia [9]. In our patient,

the frontal hematoma probably could have increased the

intra-cerebral pressure locally worsening the ischemia and

contributed to the evolution of MCA infarct, which was not

seen in the initial CT scan. Dehydration causing her dete-

rioration is also a possibility as her intake was less prior to

deterioration due to her slowly worsening drowsiness but

no osmotic agents were started prior to her second deteri-

oration. The infarction was localized to the hemorrhagic

region and dehydration alone can not be the cause for this

localized infarction. Combined effect of hemorrhage and

dehydration looks very likely possibility. SCD status is yet

another known predisposing factor for cerebral infarction.

She had raised LDH, which has been found to predict

endothelial dysfunction associated with the syndrome of

hemolysis and also identifies a subgroup of SCD at risk for

complications [10].

Infarction following intracerebral hemorrhage has been

reported earlier in two publications only, mostly in children

and once only in adults [9, 11]. Our patient a known case of

SCD since early age presented with neurological compli-

cation only in adult age and is the second in the world

literature to do so. The patient improved well on conser-

vative medical management of hyperventilation, dexa-

methasone and 20% Mannitol but hydration was well

maintained at this stage of management and remains the

Ischemic infarction and intracerebral hemorrhage in adult sickle cell disease with Moyamoya 229

123

cornerstone of treatment and to prevent further complica-

tions. Adequate hydration is mandatory in the management

of this condition irrespective of cause of neurological

deterioration—hemorrhagic or ischemic. HbS was also

reduced to <30% by exchange transfusion. Role of ex-

change transfusion is debatable in acute hemorrhagic

conditions but if the cause of bleeding is not due to

regenerating Moyamoya vessels (in and around basal

ganglion) or leaking blood vessels (intraventricu-

lar—Anterior Choroidal or suprasellar, basal cis-

terns—Posterior Communication artery) and is likely due

to sickle cell process, one can consider this modality to

lower HbS <30% and prevent progression of this complex

clinical course to ischemia. She continues to do well on

hydroxyurea and regular transfusions.

It is yet unknown whether regular blood transfusions

reverse or halt the vascular abnormalities in patients with

SCD. In one study, 24 of 44 patients had progressive

large vessel disease on MRA even after several years on

a regular transfusion protocol. Progressive vessel changes

were more common among patients with Moyamoya [8].

Chronic transfusion therapy programs that have the goal

of maintaining HbS levels below 30% in children with

SCD is known to reduce the risk of recurrent stroke, but

does not reduce the recurrence of other transient neuro-

logic events or hemorrhagic strokes [12]. Large studies

of adult SCD with hemorrhagic strokes are lacking.

There is more than 60% risk of recurrence of hemor-

rhagic strokes in hemorrhagic Moyamoya [13], however

the cause of bleeding in hemorrhagic Moyamoya is yet

unknown [14].

Revascularization surgery has not been found to prevent

rebleeding but helps in reducing ischemic symptoms and

formation of Moyamoya vessels in about a fourth of the

patients [15]. The best treatment modality for these patients

will be clear only when large series of adult SCD with

intracerebral hemorrhage and angiographic Moyamoya are

published. It is important that adult patients with SCD

presenting with acute stroke be investigated for the

presence of Moyamoya, as this is associated with higher

risk of recurrent stroke.

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