Moyamoya Syndrome in a Child with HbEβ-Thalassemia
Zahra A1, Al-Abboh H1, and Habeeb
Y2, Adekile A1,3,
Hematology Unit1 and Neurology
Unit2, Department of Pediatrics, Mubarak Al-Kabeer
Hospital and Department of Pediatrics, Faculty of
Medicine3, Kuwait University, Kuwait
Address Correspondence to:
Professor Adekunle Adekile
Department of Pediatrics
Faculty of Medicine
Kuwait University
PO Box 24923
Safat 13110
Kuwait
Tel: +96525319486
Email: adekunle.adekile@ku.edu.kw
Word count
Abstract: 100
Text: 1170
No. of Figures: 2
Running Title: Moyamoya in Eβ-Thalassemia
Key Words: Moyamoya, cerebral infarcts, seizures, thalassemia
Abbreviations Key
ICA Internal carotid artery
Hb Hemoglobin
TDT Transfusion dependent thalassemia
NTDT Non-transfusion-dependent thalassemia
SCI Silent cerebral infarct
MMS Moyamoya syndrome
SCD Sickle cell disease
HU Hydroxyurea
OPD Outpatient department
MRI Magnetic resonance imaging
MRA Magnetic resonance angiography
EEG Electroencephalogram
ACA Anterior cerebral artery
MCA Middle cerebral artery
ICA Internal carotid artery
TIA Transient ischemic attack
Mg Milligram
Kg Kilogram
Abstract
Moyamoya is a progressive cerebrovascular disease associated with
stenosis or occlusion of the arteries of the Circle of Willis,
especially the supraclinoid internal carotid arteries (ICA), with
consequent multiple collaterals. While it is common in sickle cell
disease, it is rare in thalassemia. We present a 9-year-old, with
HbEβ-thalassemia, who presented with headache, vomiting and episodes of
transient hemiparesis. Initial imaging studies showed bilateral frontal
old lacunar infarcts and narrowing of the ICA, which progressed to
complete occlusion with compensatory dilatation of the basilar and
vertebral arteries. She is maintained on anti-platelet therapy and is
being evaluated for bypass surgery.
Introduction
Patients with transfusion- or non-transfusion-dependent thalassemia (TDT
or NTDT), suffer from a hypercoagulable state and often present with
thromboembolism 1-3. NTDT is more than 4 times likely
to be associated with thromboembolic events than TDT. In the former, the
events are mostly venous and relatively rare in the pediatric age group.
On the contrary, arterial strokes are more common in TDT than in NTDT
(28% vs 9% respectively). The risk factors in TDT are the higher rate
of iron overload-mediated morbidities like diabetes mellitus, cardiac
dysfunction and arrythmias 4-6. Silent cerebral
infarcts (SCI) are common in both groups3-7.
Moyamoya is an idiopathic, progressive cerebrovascular disease,
characterized by bilateral stenosis or occlusion of the arteries of the
circle of Willis, typically the supraclinoid internal carotid arteries,
followed by extensive collateralization. The patients are prone to
thrombosis, aneurysm, and hemorrhage. It presents an angiographic
appearance of tangled, tiny, collateral vasculature, that has been
compared to a puff of smoke8,9.
Moyamoya syndrome (MMS), occurs in a wide range of clinical conditions
including hemoglobinopathies, especially sickle cell disease
(SCD)10,11. Few reports of MMS have been reported in
TDT 12,13, but more commonly in NTDT14-16, and rarely in Eβ-thalassemia17,18.
Case Report
A.O., an Indian girl, first presented at the age of 15 months with
pallor, jaundice and dark urine. She was otherwise well and her
development was satisfactory. Apart from jaundice and pallor, the only
other positive findings were enlarged liver and spleen (2 cm below the
costal margin). There were no skeletal changes. Her initial CBC showed
WBC 5 x109/l, Hb 7gm/dl, MCV 59fl, platelets 414
x109/l and reticulocytes 5%. G6PD was normal; HPLC
showed HbA 36.3%, Hb A2 5.8%, HbF 27.5%, HbE 30.3%.
β-globin gene study revealed compound heterozygosity for Codon 41-42 del
CTTT and E 26 K (c.79 G > A), thus confirming the diagnosis
of Eβ-thalassemia. She was managed as NTDT and maintained on folic acid,
with transfusion only for severe anemia. Over the next one year, her Hb
was ~7.5 g/dl and she required transfusion only once. At
age 3 years, she was commenced on 20 mg/kg of hydroxyurea (HU) daily, to
which she showed modest response. However, after about one year on HU,
she started to develop skeletal changes. She was therefore commenced on
transfusion every 2 months.
In May 2016, at the age of 5 years, she had haploidentical bone marrow
transplantation, with the mother as the donor. However, there was no
engraftment and her Hb rapidly dropped to the baseline value. Since
September 2016, she has been on regular transfusion every 5-6 weeks and
30 mg/kg/day deferasirox.
She was admitted to the hospital in December 2019 with acute liver
injury: elevated transaminases and direct bilirubin, along with
abdominal pain and vomiting. Blood-borne virology and hepatitis screen
were negative. Deferasirox was discontinued; she gradually improved with
supportive therapy and was discharged after 1 week.
At the OPD visit in March 2020, she complained of repeated attacks of
early morning headache and non-projectile vomiting of recent onset. She
reported two episodes of transient right-sided weakness and numbness
that lasted for a few minutes. There was no neurologic deficit, the
sensorium was unaffected and cranial nerves were normal. The weakness
was not progressive. There was no prior history of focal neurological
deficit, seizures, cognitive or psychiatric manifestations and no
pertinent family history.
MRI showed multiple old lacunar infarcts in both cerebral hemispheres,
while MRA revealed normal intracranial arteries. The distal segments of
both ICAs were small in caliber. MRA of the neck showed small calibers
of both ICAs, with compensatory dilatation of both vertebral arteries.
EEG showed no specific abnormalities and echocardiography was normal.
Serum ferritin was not elevated and there was no evidence of iron
accumulation in the liver or heart. Thrombophilia screening,
inflammatory markers and antibody studies were all normal.
She was on regular transfusion, low-dose deferasirox (10 mg/kg/day) and
prophylactic aspirin. Despite this, 4 months later, she complained of
more frequent and more prolonged episodes of weakness in both hands and
feet, with associated dysarthria but no loss of consciousness or spatial
perception. These were suspected to be partial seizures and she was
treated with carbamazepine, after which the episodes ceased. She was
neurologically normal in-between attacks.
Repeat MRI showed no evidence of new ischemic or inflammatory changes;
the previously seen cerebral infarcts were evident. However, MRA now
showed complete occlusion of both ICAs as they enter the intracranial
cavity (Fig 1). The ACA and MCA showed good flow, being supplied from
posterior cerebral arteries through communicating arteries bilaterally.
The calibers of the vertebral and basilar arteries and communicating
arteries were more than double to compensate for the ICA occlusion (Fig.
2).
Three weeks after the imaging studies, the patient had no more morning
headache or vomiting, there was reduced frequency of TIAs and no
weakness.
Discussion
Eβ-thalassemia spans the spectrum of NTDT to TDT and our patient was
initially managed as NTDT, but eventually became transfusion dependent.
She could therefore, present with complications associated with the 2
phenotypes. Indeed, she presented with TIA and was eventually found to
have several old lacunar infarcts. Therefore, an initial impression of
SCI was made but, because of extension of her symptoms, repeat imaging
confirmed complete occlusion of both ICAs, with increased collaterals,
consistent with MMS8 . She had also shown evidence of
deferasirox hepatotoxicity.
MMS may be asymptomatic but could present with TIA, ischemic or
hemorrhagic stroke, and epilepsy. Rarely, patients may develop dystonia,
chorea, or dyskinesia19,20. Our patient presented with
morning headache and transient brief unilateral weakness, which became
more frequent and lasted for longer periods of time. She later developed
focal seizures, accompanied by dysarthria. Other common causes of
abnormal movements such as drug side effects, Sydenham’s chorea, and
neurodegenerative conditions, vasculitis, autoimmune conditions,
infections, thrombophilias, and connective tissue disorders were all
ruled out.
She had been on regular transfusion for at least 5 years before her
neurological symptoms. This supports the premise that, while transfusion
dependency reduces the effect of chronic tissue hypoxia, patients are
still at risk of arterial thrombosis 4,13,21 .
Moreover, MMS is not uncommon among patients with HbE-β-thalassemia. In
one study, three of four beta thalassemia patients with MMS were NTDT
and one of them was HbE-β-thalassemia 22. In another
recent study among 13 patients of MMS with thalassemia, 6 were TDT and 3
had HbE-β-thalassemia 13. Our patient is, however,
much younger than those in the literature.
The complete occlusion of both ICAs in our patient probably prevented
the appearance of new vessel formation and the appearance of the classic
puff of smoke, especially given the good compensation by communicating
vertebral and basilar arteries. This is consistent with stage II of the
Suzuki MMS staging system 8.
There is no curative treatment for MMS; it is therefore imperative to
search for and treat any underlying condition. The vascular occlusion
tends to continue despite any known medical management13 as in our patient, who was on aspirin therapy and
regular transfusions. She is currently being considered for bypass
surgery 23.
Conflict of Interest
The authors have no conflict of interest to declare.
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