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Cerebral infarction in
haemoglobinopathies
Fenella Kirkham
Neurosciences Unit, UCL Institute Of Child Health, London
Southampton General Hospital, Southampton
Anaemias and stroke
• Thalassaemias especially intermediate
• Fanconi
• Blackfan-Diamond
• Sickle cell disease
• Hereditary spherocytosis
• Pyruvate kinase deficiency
• Evans’ syndrome
Zafeiriou et al in Ganesan and Kirkham 2011
Cerebrovascular complications of congenital and acquired anaemias
Dimitrios Zafeiriou, Steven Pavlakis and Fenella Kirkham
Underlying
cause
PXE Thro
mbu
s
Embo
lus
Haemorr
age
Aneur-
ysm
AVM TIAs Stenosis Moya moya
VST PT PL Cortical laminar
necrosis
Covert
SAH ICH A P EC IC
Haemoglobin SS + + ? + + + + + + + + + + + + ++
Haemoglobin SC
Haemoglobin Sβ-
thalassaemia
++
Haemoglobin AS
Thalassaemia
major
+ + + + + + ++
Thalassaemia
intermedia
+ +
Thalassaemia
minor (trait)
Pyruvate kinase
deficiency
+ +
Hereditary
spherocytosis
? ? + ?
Paroxysmal
nocturnal
haemoglobinuria
+
Fanconi + + +
Blackfan-Diamond + Multiple ? +
Acquired aplastic +
Acquired
haemolytic
+ +
Childhood Stroke and Cerebrovascular
Disease Birmingham Children’s Hospital
1993 – 1998 Andrew Williams, Paul Davies, Paul Eunson, Fenella Kirkham, Stuart Green
Haemorrhage Infarct Normal
BCH past medical history (n=120) n %
Previously well (cryptogenic) 48 40
Congenital heart disease 28 23
Cancer (leukaemia) 8 7
Meningitis 6 5
Chronic anaemia (sickle, thal) 6 5
Renal disease (nephrotic, HUS) 4 3
Liver disease 3 3
SLE 2 2
Alternating hemiplegia 2 2
Miscellaneous single cases 13 11
MRI Vascular:
MRA/MRV
Clinical and pathological findings Treatment
Sudden onset stroke with arterial territory infarct:
stenosis, occlusion, dissection ICA, MCA.
Exclude shunting
Transfuse, O2, Intensive care
Stroke Unit -TL
Silent cerebral infarction: no stroke but may
have had seizures. Stenosis, occlusion,
moyamoya ICA,MCA. Shunt
?Transfuse; ?Hydroxyurea
PRES: Posterior reversible encephalopathy
syndrome after rapid transfusion, acute chest,
hypertension
Treat seizures, hypertension, hypoxia
Venous sinus thrombosis: presents c
hemiplegia, seizures, coma. CT : empty delta,
thrombus, CTV /MRV
?Transfuse; rehydrate, anticoagulate
Abscess: seizures, headaches, coma, raised
intracranial pressure, fever
Antibiotics
Neurosurgeon
Intensive care
Intracerebral haemorrhage: sudden onset very
severe headache, coma. Venous , hypertension,
aneurysm
Neurosurgeon
Intensive care
Subarachnoid haemorrhage: sudden onset very
severe headache, coma . Aneurysm, venous ,
hypertension
Neurosurgeon
Intensive care
Subdural haemorrhage: headache, coma, raised
intracranial pressure, skull infarction. Exclude
trauma /NAI
Neurosurgeon
Intensive care
Extradural haemorrhage: headache, coma,
raised intracranial pressure, skull infarction.
Exclude trauma /NAI
Neurosurgeon
Intensive care
What clinical neurological
syndromes do we recognise?
Arterial ischaemic events
Acute stroke
TIAs, Stroke, Coma 9y girl HbSS, previously well, ‘Top of class’
Transient events e.g. Limp, Ataxia
TG aged 16 ICA occlusion
• Ataxia aged 5 yrs
• Low TCD
• Settled, not Tx
• Progressive
cognitive difficulties
• L hemiparesis
aged 16
• ICA occluded in
neck Telfer et al 2011
D
E
A B C
H E F G
Telfer et al 2011 Neck vessel disease
Headache
L R
Subdural Intracerebral Subarachnoid
Posterior
Cerebral
aneurysm
Haemorrhagic stroke
L R
a
b
c
d
Headaches post chest crisis
Seizures
Right MCA
220 cm/sec
Left MCA
130 cm/sec
SG Seizures
& TCD Prengler 2005
Other stroke syndromes
1. Venous sinus thrombosis
2. PRES: Posterior reversible
encephalopathy syndrome
3. Borderzone ischaemia
Sagittal sinus thrombosis Pneumococcal meningitis, longstanding epilepsy
Straight sinus thrombosis HbSC, unexplained hydrocephalus in infancy, headache, seizures, coma
Sébire 2005
Straight sinus thrombosis
‘Reversible posterior leukencephalopathy’ Henderson 2003
Chronic epilepsy
Chest crisis
Seizures
Coma
Bilateral borderzone infarction
Facial infection, seizures
What about ‘silent’ (covert)
infarction
Covert (‘silent’) CNS pathology in
sickle cell disease
‘Silent’ cerebral infarcts
(a) (b)
(c)
Haemorrhage on gradient ECHO
Prevalence of silent cerebral infarction in SCD with 95%
confidence intervals plotted against age
Thalassaemia?
S/ β-thalassaemia
• Silent infarct 38%
• Vasculopathy on MRA
15%
β-thal/Hb E disease
• Silent infarct 24-28%
– 60% if splenectomy
• Vasculopathy on MRA
– 25% if splenectomy
Stroke syndromes in
thalassaemia • Cardioembolic
• Arteriopathy
– Intracranial
– Carotid
– Moyamoya
• Venous sinus thrombosis
• Silent cerebral infarction
A B 15.13
Clinical risk factors for stroke
• For all stroke: low haemoglobin
• Overt infarct
– Previous transient ischemic attack
– Hypertension
– Chest crisis
• Silent infarct
– Seizures, few painful episodes Kinney 1999
– Male gender, systolic hypertension DeBaun 2012
• Haemorrhage
– High white cell count
Risk factors for ischaemic stroke in SCA
O2 availability, O2 demand
- Sleep-disordered breathing
- Acute chest syndrome
- Acute polymerisation
- Infection
CNS Vasculopathy
•Intracranial/extracranial
•Stenosis
•Occlusion
•Dissection
•Moyamoya
CBF, Cerebrovascular reserve
- Low baseline hemoglobin
-High % HbS increases
CBFindependent of hemoglobin,
especially at HbS levels >40%.
Relative and
acute anemia
-Low baseline hemoglobin
-Relative acute drop in
hemoglobin (< 5.5 g/dl)
-Parvovirus B19
Ischemic Injury to the Brain
- Hypertension
- Diabetes mellitus
- Hyperlipidemia
- Atrial fibrillation
- Renal disease
Conventional
risk factors
Cerebral blood flow and
haemoglobin Prohovnik et al 2009
CO2 reactivity and baseline CBF Prohovnik et al 2009
?Borderzone hypoperfusion/?PFO
11 y.o. with SS presented with severe headache
following transfusion for aplastic crisis.
Day 1 Day 3 PFO identified
Dowling, et al., 2016
PFAST
Acute SI after Acute Anemic
Events
5 yo boy SCD 11 yo girl SCD 9 yo boy SCD 4 yo girl SCD 3 yo boy w/o SCD
Aplastic Crisis Aplastic Crisis Vert laceration Aplastic Crisis Aplastic Anemia
Hbg= 3.4 g/dl Hgb= 2.7 g/dl Hgb=2.4 g/dl Hgb=2.2 g/dl Hgb=1.9 g/dl
5/10 cases (8 with SCD) had acute SI during Acute Anemic Event
Acute SI led to Permanent Brain Injury in 4/4 pts who had f/u MRI
Only previously reported case of Acute SI in SCD was also in setting of AAE
Dowling, et al., 2010 Zimmerman, 2005
Prevention stroke and progressive SCI
in children with sickle cell disease?
Blood transfusion
• STOP
• SITT
Hydroxyurea
• SWiTCH – secondary stroke
• TWiTCH – secondary high TCD
• SPIN /SPRING – primary stroke
T2 ratio L posterior thalamus:CSF Evidence for iron deposition in stroke
East
London
Cohort
2000-2002
ICNC 2012
Brisbane
Kirkham,
Collinson
et al
Neuropsychological functioning
• Meta-analysis from all studies using
Wechsler full-scale IQ and MRI to
distinguish SCI- and SCI+
CNS event free survival in SCD
patients with mean overnight oxygen
saturation > or < 96%
Years after sleep study
76543210
Pro
port
ion
CN
S fr
ee
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Mean Sa02 < 96%
Yes
No
n=25 HbSS (SCI-)
n=14 sibling controls
Conclusions
• Several stroke syndromes
– Sickle cell disease
– Thalassaemia
• Blood transfusion essential for thalassaemia
– Attention better after transfusion (Raz 2012)
• Primary and secondary prevention of stroke
and SCI in SCD c blood transfusion for life!
– But no evidence of improvement in cognition
• Long term effects of transfusion on brain?