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?