TIA & Stroke

“How & why, do’s & don’ts”

Cerebrovascular Disease

Dr Ajay Kumar (Stroke Physician)

Dr Kalpa Jayanatha (Advanced Trainee, Nephrology)
April 2016
 Cerebrovascular Disease


• Wide disease spectrum

• Heterogeneous
- pathophysiology
- presentation
- treatment
• Many biologic targets
• Varied response to treatment & rehab
1 Louis R Caplan et al, UpToDate:Feb26,2014
2 Steven C Cramer, “Brain repair after stroke” ESC conf, London, June 2013
 Stroke


• Why the importance???

• Time is brain!!!
• Every min delay = 2 million neurons lost3,4
• Most devastating acquired adult neurological
disease!!!
• 2nd/3rd leading cause of death5
• For every stroke (at least) 5 significant others
affected5

• Maximise gain & minimise disability

• Needs holistic team effort, synchronised and co-
ordinated

3. Hacke et al NEJM 2008;359:1317

4. NINDS Study Group NEJM 1995; 333: 1581
 “Less stroke, better cognition”

Acute Phase Treatment

- Thrombolysis
- Clot retrieval
- Aspirin
- Stroke Unit, Neurosurgery

Residual
Risk
Factors XX TIA XX Stroke XX Deficit

Primary Secondary
Prevention Prevention
 CVS

Spectrum
Funny turns TIA Stroke Stroke/
Fatality/Palliation
Low / High risk Minor/moderate Severe
Isolated symptoms
Dizziness
Light headedness
ABCD2 score
Blurry vision <3 / >46
Gen weakness

7 Day 2% -10% 30 Day mortality 20-30%

Stroke risk <2%

Front loaded - 50% events occur in 1st 48hrs post TIA7

6. Johnston SC et al Lancet 2007;369:283

7. Rothwell PM et al Neurology 2005; 64:817
 Transient Ischemic attack (TIA) 


Classical: Time based “A TIA is defined as stroke symptoms and signs

that resolve within 24 hours”9

Problematic:
1. Most TIA symptoms very short lived9
2. If longer symptoms, minimal resolve10,11
3. Half with TIA have evidence of recent infarction on MRI (DWI)12

Hence:
AHA/ASA: Tissue based, focal neurological dysfunction, brain, spinal
cord, retinal ischemia without infarction8

8.Easton JD et al Stroke 2009;40:2276

9. Caplan LR et al Curr Atheroscler Rep 2006;8:276
10 Albers GW et al NEJM 2002;347:1713
11 Caplan LR et al Arch Neuo 2007;64:1080
12 Redgrave JN et al Stroke 2007;38:1482
 TIA Symptoms
Characteristic History Features: Typical Symptoms

• Sudden Unilateral Motor

- weakness
• maximum deficit - Face
- Arms
• focal symptoms - Legs

• loss of function Unilateral Sensory

- altered sensation
• rapid recovery - Dysphasia
- Hemianopia
- Monocular blindness

Outline Patient Definition Symptoms ABCD2 Investigations Management EXPRESS

 TIA/Stroke Mimics 13-15

• Dx: problematic, dodging, shifting target

• Accuracy: TIA 50% vs 85% Strokes

• Mimics:
A) Neurologic
1. Migraine with neurological symptoms
2. Seizure with Todd’s paralysis
3. Sensory march of amyloid angiopathy
B) Metabolic
4. Hypoglycaemia or Hyperglycaemia
5. Hyponatremia
C) Functional
 ABCD2 Score 7

Parameter Criteria Points

Age >60 yrs 1

BP >140/90 1

Clinical symptoms

Face, arm, leg weakness

2

(max 2 pts)

Speech 1
Duration >60 mins
2

(max 2 pts)

10-59 mins 1
Diabetes 1

Total 7

7. Rothwell PM et al Neurology 2005; 64:817

 ABCD2 Score
Risk Category 7 Stroke Risk at 7 Days
High Risk 11.7%
6

5
Moderate Risk 5.9%
4

3
Low Risk 2 1.2%
1
0

Outline Patient Definition Symptoms ABCD2 Investigations Management EXPRESS

 Investigations
• ABCD2 score <3 outpatient
>4 inpatient16

• Laboratory17 - FBC
- U&E’s
- Glucose

• ECG
• Brain Imaging: CT Head, MRI Brain
• Carotid Duplex
• Case-by-case investigations (i.e: young stroke)
16. Nguyen Hhuynh et al Neurology 2005; 65:1799
17. Rothwell PM et al Lancet 2007;370:1432
 Laboratory
FBC 1. Hb High
Polycythemia, 65g, 200g/L

Low Anaemia - clotting

2. WCC High
Infection, malignancy

Low Infection
3. Platelets High
Thrombocytosis (x106)

Low Penia, bleeding <10,000

U&E’s 1. Sodium Low Hyponatremia <120 mmol

Seizures

2. Glucose High
Ketotic coma

Low Hypoglycaemic coma

 Other Investigations 8

• ECG - 1. Arrhythmia (AF)

- 2. MI

Imaging 1. Brain CT/CTA, MRI/MRA

2. Carotids Duplex USS
3. Heart, aortic arch ECHO - TTE/TOE

• *Young patients*18 - Stroke screen

- Connective tissue
- Bubble study
8. Easton JD et al Stroke 2009 ;40:2276
18. Flemming KD et al Mayo Clin Proc 2004;79:1071
 EXPRESS Study 76

Early use of EXisting PREventive Strategies for Stroke

Study Setting Oxfordshire, UK

91,000 individuals registered with the

Eligible Population
63 primary-care physicians in 9
primary-care practices in Oxfordshire,
UK who are referred to the study
clinic by GP on suspected TIA or
stroke

591 Patients
Participant Population

Outline Patient Definition Symptoms ABCD2 Investigations Management EXPRESS

 EXPRESS Study 88

Phase 1 Phase 2
Between April 1, 2002 – Sept 30, 2004 Between Oct 1, 2004 – March 31,
Phase of delayed assessment and treatment 2007 delay of assessment and treatment
Reduced

Fax Immediate assessment

GP Study Clinic

Phone
310 281
Report and Assessed and treated
recommendations

Appointment Patient

Outline Patient Definition Symptoms ABCD2 Investigations Management EXPRESS

 Cerebrovascular Disease

Risk factors 19

Modifiable: Non-modifiable:
Hypertension Age
Diabetes Gender
Smoking Family history
Dyslipidemia
AF
Other lifestyle
factors19
• Note: Different risk factors in young vs older Patients
 Hypertension
• Single biggest risk factor!!
- (~1/5 in NZ>15yrs)5
- 50% CAD, Heart failure
- 62% Strokes20

• Target range: <140/80 if T2DM <130/8020

• BP reduction 12/5 mmHg: 30-40% RRR in both secondary and

primary event rate 5yrs22

• NNT: 11 patients for 5 yrs 1 for fatal or non-fatal major vascular

event23
20anic G et al,Oct 2013,vol31,Journal of Hypertention,ESH/ESC, 2013 Practice Guidelines.
21. Aburto Net al BMJ,2013 346
22 PROGRESS Collaborative Group,Lancet 2001;358:13;1033
23.INERACT II,SAMPARIS
 Diabetes
• Risk x2 vascular events
• Associated: dyslipidemia, endothelial dysfunction,
platelet & coagulation abnormalities24
• IGT May be a risk factor25
• Metabolic syndrome: insulin resistance + 3 or more: high
FBS,HT, low HDL, & obesity (may confer increased risk)26
• Strict glycemic control reduces retinopathy,
nephropathy, neuropathy19
• Macrovascular**: RCTs no consistent evidence for acute
coronary syndromes, strokes
• Evidence: UKPDS( 22yrs f/u)27,DCCT/EDIC28,29
• Life style changes: Benefits19

19. AHA/ASA 2011 Guidelines

24. Arvanitakis Z et al,Neurology 2006;67:1960
25. Vermeer SE et al Stroke 2006;37:1413
26. Koren—Morag et al Stroke 2005;36:1366
27. Holmes RR et al NEJM 2008;359:1577
 Smoking
• Risk increased for all stroke subtypes, dose dependant30-33

• Evidence from observational studies:

- Nurses Health Study: smokers RR 2.58, disappears 2 to 4yrs31
- Framingham Heart Study: OR 1.08 for moderate carotid
stenosis for every 5 pack yrs32
- Prospective Swedish cohort study (11,000 pts): ~40% strokes
attributable to smoking33

• Cessation – Medicine + therapy34,35

30. Ockene IS et al AHA Task force on risk reduction.Circulation 1997;96:3243

31. Kawachi I et al JAMA1993;269:232
32. Wison PW et al NEJM 1997;337:516
33. Li C et al Stroke 2005;36:234
34. Stead LF et al. Cochrane Database Syst Rev 2012;10 CD008286
35. Suls JM et al Am J prev Med 2012;42:655
 Dyslipidemia

• Major risk coronary artery disease

• Atherosclerotic disease & stroke: complex, but appears weak risk factor36

• Epidemiological evidence: ischaemic stroke attributable to cholesterol is

inconsistent & conflicting, BUT there are PITFALLS**

• Weak positive association with ischaemic strokes with high levels (>7mmol)37,38

• Association with haemorrhagic strokes: 4.14 mmol38

• Dyslipidemia, statin therapy & haemorrhage**39

• Other lipid lowering therapy has no significant impact on stroke incidence

36. Piechowski-J et al Stroke 2004;35:1523

37. Iso H et al NEJM 1989;320:904
38. Lindenstrom E et al BMJ 1994;309:11
39 Amarenco P et al NEJM 2006; 355:549
 Atrial Fibrillation
• Prevalence increases with age
• Evidence: BAATAF, SPINAF, AFASAK, CAFA, SPAF40
– Primary prevention: risk stratification CHA2DS2VASc
– Secondary prevention therapy 2011 ASA/AHA19
• Agents: Warfarin or NOACS (Dabigatran, Rivaroxaban,
Apixaban)
• Benefits: reduce baseline risk by two-thirds45
• Risk: CNS bleeding risk <1% per annum46
• Associated with larger/severe stroke 41,42

• Silent cerebral infarcts TIAs lead to cognitive

impairment 43,44
CHA2DS2VASc Score 47
 Other Risk Factors
• Age, risk of CVS increases with age
• Gender
• Family history
• Life style, ETOH, weight, diet50
• Connective tissue disease
• Others – APOE,51,52,53,
• Hyper homocysteinemia, inc levels ass with inc risk of CAD,
CVS, Isch, lacunar 54
• Rx with homocysteine reducing vitamins not beneficial for sec prevention19

50 . Furie KL et al Stroke 2011;42:227

51 McCarron MO et al Neurology 1999;53:1308
52. Schneider JA et al Stroke 2005 ;36:954
53. Sturgeon JD et alStroke 2005;36:2484
54. Eikelboom JW et al Stroke 2000;31:1069
 Risk factors

Young vs Older
Young (45 yrs) Older (Traditional RF)
• Connective tissue disease • HT
– SLE • DM
– Anti Phospholipid • Smoking
– Other vasculitis • AF
• Dissection • others
• PFO
• Moyamoya disease
• Familial - CADASIL
 STROKE

Ischaemic Haemorrhage
10-30%
70-90%
- HTN
- Thrombus - Amyloid
- Embolus
- Hypoperfusion
Many Sources of variance affecting stoke
outcome - Heterogeniety

• Pre-Stoke Disability • Effects on brain function

• Genetics • Acute stroke interventions
• Age • Time post-stroke
• Handedness • Post-stroke depression
• Medical co- • Medication(+ and -)
morbidities • Caregiver, social factors
• Initial and final • Quantity, quality, and timing
deficits • Of post –stroke therapy
• Injury mechanism,
side topography,
volume
 Intracranial Haemorrhage
• Causes

]
– Hypertension
– Ruptured saccular aneurysm MAJORITY
– Amyloid angiopathy
– Vascular Malformations

– Others; vasculitis, haemorrhagic infarction (Venous Sinus

Thrombosis), septic emboli (SBE), brain tumour, bleeding
disorders, anticoagulants, thrombolytic therapy, CNS
infection (HSV encephalitis), moyamoya, drugs (cocaine
and amphetamines), phenylpropanolamine (appetite
suppressants)
 Intracranial Haemorrhage
• Haemorrhage sites
– Putamen and Caudate (35%)
• Vessels: Lenticulostriate Penetrators of M1 segment
of MCA
– Subcortical Bleed (30%)
– Cerebellar (16%)
• Vessels: Off Posterior Cerebral Artery
– Thalamus (15%)
• Vessels: Thalamostriate Penetrators of P1 & P2
segment of Posterior Cerebral Artery
– Pons and Mid-brain (5-12%)
• Vessels: Penetrators of Basilar Artery
 Intracranial Haemorrhage
• Putamen Haemorrhage
– Spread of haemorrhage
along white matter
fibre tracts
– Symptoms and Signs;
hemiplegia,
hemisensory loss,
homonymous
hemianopsia, gaze
palsy, stupor, coma.
 Intracranial Haemorrhage
• Pontine Haemorrhage
– Medial hematoma extending to
base of pons
– Leads to deep coma within a
few minutes
– Probably secondary to
disruption of RAS.
– Examination: total paralysis,
pupils pinpoint, horizontal eye
movements missing, maybe
occular bobbing, facial palsy,
deafness, dysarthria when
patient awake
– Poor prognosis
 ICH Expansion & Mortality

Volume (60ml = 60% mortality)

GCS <8 (+ 30% mortality)
RISK OF HAEMATOMA EXPANSION

40% Site

10%
5%
1%

0-5 hours 6-24 hours 2 weeks 1 year

TIME FROM ONSET

55 J Neurosurg 1994 Jan;80(1):51-7 .
56 Cerebrovasc Dis 1999 Mar-Apr;9(2):102-8 .
 Ischaemic Stroke
Ischaemic Penumbra Infarcted Tissue

MABP Collateral Blood Flow

 FEB 2007

Ischaemic Stroke

Classification 58

Oxfordshire (OSCP, 1 yr mortality

Bamford) Classification
– TACI – total anterior 60%
circulation infarct
– PACI – partial anterior 19%
circulation infarct
– POCI – posterior 16%
cerebral infarct
– LACI – lacunar infarct 11%

58.BamfordJ et al Lancet22;337(8756):1521-6,1991
 Lacunar Infarct (LACI)

Classification
• LACI – 5 Major syndromes 89

- Pure motor
- Pure Sensory
- Mixed
- Dysarthria clumsy hand
- Ataxic hemiparesis
• Small discrete infarcted area - penetrating artery occlusion.
• Lipohyalanosis – HT,?DM, embolism
• Due to location normally don’t affect higher cortical cognitive
function.
89 Jamary OF et al Lacunar infarcts UpToDate Aug20,2013
 Regional Brain Syndrome
•Frontal lobe Parietal Lobe

Broca’s
area

Occipital
Temporal Lobe Wernicke’s area
Lobe
 How to test?
• History
• Examination
– Cranial Nerves, Limbs, Gait
– Suspected higher centres
• Speech
• Memory
• Reading, comprehension
• Writing, calculation, drawing
• Gnosia, graphaesthesia, praxia
• Primitive reflexes
 Diagnosis

MCA Strokes
• Left Parietal (Dominant) • Right (Non dominant)
• Aphasia/Speech + • Aparaxia
– Receptive /Fluent
(temporal lobe)
• Plus contralateral
- motor
– Expressive/Non fluent
(frontal lobe) - sensory
• Left right disorientation
• Finger Agnosia
• Plus contralateral
- motor
- sensory Astreognosis
Agraphesthesia
2 point discrimination
 Dominant parietal lobe signs

• Gerstmann’s syndrome (AALF)

–
Acalculia 25+14 = 42
– Agraphia

– Left right disorientation

– Finger agnosia
 Non-dominant parietal lobe signs

• Agraphaesthesia

• Sensory inattention
 Other parietal lobe signs
• Tactile agnosia
• Apraxia
– Dressing
– Constructional
• Spatial neglect
• Inferior homonymous quadrantanopia
 Other parietal lobe signs
• Tactile agnosia
• Apraxia
– Dressing
– Constructional
• Spatial neglect
• Inferior homonymous quadrantanopia
 Temporal lobe signs
• Memory
– Short-term
– Long-term
• Superior homonymous quadrantanopia
 Diagnosis

ACA Strokes

• Frontal lobe phenomenon :

• History -Apathy, avolitional, personality changes,
emotional liability
• Examination - signs, Motor weakness - Leg weaker than
arm
• Primitive release reflexes, grasp, palmo mental, pout,
snout, rooting etc
• Higher mental function tests - Language problems,
Judgment, Cognitive issues insight, comprehension,
executive tasking
 Frontal lobe signs
• Primitive reflexes
– Grasp
– Palmomental
– Snout
 Occipital lobe signs
• Homonymous hemianopia
• Alexia
 Treatment/Rehab
• Immediate - Hyper acute / acute -Urgency
• ‘Sub acute / chronic phases’
• Setting - appropriate
• Team effort…. medical, patient, family,
community
• Rehab/follow up
• **Longitudinal monitoring and follow up
• Long haul dynamic process
 Antiplatelet therapy 48

• Secondary prevention
• Aspirin (A) RRR 18% NNT 83 (IST, CAST trials)
• Clopidogrel (C)
• Dipyridamole (D) RRR 17%
• Dual (A + C) RRR ~33%, MATCH, CAPRIE
• Dual (A + D) RRR 33%, ESPSII, ESPIRIT

• ACCP recommend: Anti-platelet secondary prevention (level I

evidence)

• Combination A + C 3 months (MATCH trial)

A + C 21 days dual, then mono therapy agent (CHAN
 Stroke thrombolysis

The Evidence
NINDS (1995) ECASS III (2008)
• Window - <3hrs • Window – 3-4.5hrs
• NNT 6 • NNT 14
• 33% functional recovery at • 34% functional recovery at
90 days 90 days
• ICH rates - 6% • ICH rate - 2.4%

No mortality difference between treatment groups

and placebo in both, NNH – 16 ,SAME
 Recommend carotid endarterectomy

• If symptomatic carotid stenosis of 49

– >80% NNT 5
– 70-80% NNT 8
– *50-69% NNT 15 (men)
– on same side as stroke
– patient otherwise well
– low surgical risk

• Early intervention!!, after 3 mths NNT 125 to prevent 1

disabling stroke/death – NASCET, Swedish Stroke Registry

49. Rothwell PM et al Lancet 2004; 363:915

 Stroke rehab

Main Points
• Many post-stroke biological targets exist
in relation to recovery
• Many therapies are under evaluation to
improve recovery
• How to match the right patient with the
right therapy?
 Post Stroke 

Issues
• Psychological perspective
– Depression
– Cognitive impairment/Dementia
– Behavioral issues/disinhibition, sexuality
– Delirium, Fatigue
• Physical
• Patients – deficits, communication, mobility, self cares,
fear of recurrence, nutrition
• Livelihood – work, driving, advanced directives, etc
• Others….
• Whanau/Family/spouse-needs, caregiver burnout,
financial, caregiver burnout
• Community - networking, support
 Post Stroke

Depression
• Common - quantification difficult – methodological issues -16%-61%.
• Prevalence post stroke 29%60
• Screening - Depression scales vs single question “Do you often feel sad or
depressed?” 86% sensitivity,78% specificity41
• Predictors – stroke severity, disability, pre-stroke depression, cognitive
impairment, anxiety60
• Myths - hemisphere &location61,62
• Prognosis- depression at 3mo correlation with poor outcome 1yr –no
causation inferred63
• Remission ass with better functional outcomes63
• Treatment - effectiveness, Pharmocotherapy, Psychotherapy, combination not
established
• - but mounting evidence that interventions beneficial65-67
• - No definite evidence to guide specific choice of therapy45-51
• - Treatable illness –structured, monitoring F/U43,45-51
 Many Sources of Variance affecting
Stoke outcome – Heterogeniety 84

• Pre-Stoke Disability • Effects on brain function

• Genetics • Acute stroke interventions
• Age • Time post-stroke
• Handedness • Post-stroke depression
• Medical co- • Medication(+ and -)
morbidities • Caregiver, social factors
• Initial and final • Quantity, quality, and timing
deficits • Of post –stroke therapy
• Injury mechanism,
side topography,
volume
HPA axis
Stroke and depression
Antidepressive therapy and 

long-term survival
 Post stroke cognitive assessment/
rehab
• Evidence based, evidence generated?
• Assessment tools, MMSE, MoCA, ACER, RUDAS
• Longitudinal assessment
• Risk of Cognitive impairment/Dementia 62,63

• Incidence - 6-32%62
• Recurrent strokes worse impact64
• Silent cerebral infarcts,AF,HT
• Rehab –difficult, ?what,?how Safety net
62. Ivan CS et al Stroke 2004;35:1264
63. Desmond DW et al Stroke 2002;33:2254
64. Srikanth VK et al Stroke 2006; 37:2479
 Take home message 1
1. PSD is a clinical, not strictly
pathophysiological, definition (emphasis on
stroke)
2. PSD is heterogeneous in terms of mechanisms
(SVD, large vessel, strategic sites, multiple
lesions)
3. PSD is frequent (a major consequence of
stroke)
4. A history of stroke doubles the risk of incident
dementia
 Take home message 2
1. A number of risk factors for PSD exists
2. Dementia is only part of the spectrum of
the cognitive consequences of stroke
(consider also mild cognitive impairment
– MCI)
3. Need of identifying and harmonizing
instruments for detecting post-stroke
MCI as early as possible in the disease
course
 Cerebrovascular disease

Future exciting!!
Therapies:
A) Medical/surgical
– Acute stroke therapies, Thrombolysis, Thrombolysis plus (ultrasound)86,
clot retrival85, Stents87 - extracranial, intracranial, hemicranectomy79,
shunt80
B) Technology
- Telemedicine65, Facebook, robotic assisted82
C) MDT
- Circuit training83, Targeted therapy81, utilising assistants/equivalents
• Research
• - Laboratory
• - Collaborative multicenter trials- Psychiatric, Stroke physicians /
Rehabilitation / Neurologists
65. Johansson et al Telemed Telecare 2011;17:1-6
66. Vahedi K et al Lancet Neurol 2007;6:215
67. Broderick J et al Stroke 2007;38:2001
 Remember!!!
• Time is Brain, Action is salvation
• Move - talk field – work field !!
• Treat immediately, aggressively
• Holistic team effort - maximize Gain
- minimize disability
- insync,
coordinated
• Thank you
 Acknowledgements
• Steven C. Cramer, MD. Professor, Depts.
Neurology, Anatomy & Neurobiology, and
Physical Medicine & Rehabilitation. Vice Chair
for Research, Dept. Neurology Clinical Director,
Sue & Bill Gross Stem Cell Research Centre.
Director, Neuroimaging Core, Inst for Clinical
Translational Science. University of California,
Irvine
 Acknowledgements cont
• Prof. Gert Kwakkel Chair Neuro-rehabilitation VU
University Medical Centre, Amsterdam & UMC Utrecht,
ESC conference, London May 2013
• Dr Alex Leff, Clinical senior lecturer & consultant
neurologist. Institute of Neurology & Institute of
Cognitive Neuroscience. National Hospital for
Neurology & Neurosurgery, ESC conference May 2013
 References
1. Louis R Caplan et al UpToDate:Feb26,2014
2. Steven C Cramer ,”Brain repair after stroke” ESC conf,London , June 2013
3. Hacke et al NEJM 2008;359:1317
4. NINDS Study Group NEJM 1995;333:1581
5. 5 www.stroke.org,nz/preventing-stroke
6. Johnston SC et al Lancet 2007;369:283
7. Rothwell PM et al Neurology 2005; 64:817
8. Easton JD et al Stroke 2009;40:2276
9. Caplan LR et al Curr Atheroscler Rep 2006;8:276
10.Albers GW et al NEJM 2002;347:1713
11.Caplan LR et al Arch Neuo 2007;64:1080
12.12 Redgrave JN et al Stroke 2007;38:1482.
13. Montgomery BM et al Arch Intern Med 1964 ;114:680
14. Bos MJ et al JAMA 2007 ;298:2877
15. Cochrane T et al Neurology 2005;65:1140
16. Nguyen Hhuynh et al Neurology 2005; 65:1799
17.Rothwell PM et al Lancet 2007;370:1432
18. Flemings KD et al Mayo Clin Proc 2004;79:1071
 References cont
19.Furie KL et al Stroke 2011; 42:227 ,AHA/ASA 2011 Guidelines

20. Manic G et al, Oct 2013,vol31,Journal of Hypertension, ESH/ESC, 2013 Practice Guidelines.
21. Aburto Net al BMJ,2013 346
22. PROGRESS Collaborative Group, Lancet 2001;358:13;1033
23.INERACT II,SAMPARIS
24. Arvanitakis Z et al, Neurology 2006;67:1960
25. Vermeer SE et al Stroke 2006;37:1413
26.Koren—Morag et al Stroke 2005;36:1366
27.Holmes RR et al NEJM 2008;359:1577
28.DCCT Research group. NEJM 1993;329:977
29.Nathan DM et al NEJM 2005;353:2643
30. Ockene IS et al AHA Task force on risk reduction. Circulation 1997;96:3243
31. Kawachi I et al JAMA1993;269:232
32.Wison PW et al NEJM 1997;337:51633
33.Li C et al Stroke 2005;36:234
34.Stead LF et al. Cochrane Database Syst Rev 2012;10 CD008286
35.Suls JM et al Am J prev Med 2012;42:655
36. Piechowski-J et al Stroke 2004;35:1523
37. Iso H et al NEJM 1989;320:904
38. Lindenstrom E et al BMJ 1994;309:11
 References cont
39 Amarenco P et al NEJM 2006; 355:549
40 Atrial Fibrillation Investigators (AFI) Group Arch Intern Med 1994;154:1449
41. Anderson DC et al Stroke 2002;33:1963
42. Harrison MJ et al Stroke 1984 ;15:441
43. Ezekowitz MD et al Circulation 1995;92:2178
44. Cullinane M et al Stroke 1998 ;29:1810
45.Hylek EM et al NEJM 2003;349:1019
46.Rosand J et al Arch Intern Med 2004;164:880
47.Van Staa et al J Thromb Haemost 2011;9:39
48.Jamary O et al UpToDate Oct 16;2013
49. Rothwell PM et al Lancet 2004; 363:915
50. Furie KL et al Stroke 2011;42:227
51. McCarron MO et al Neurology 1999;53:1308
52. Schneider JA et al Stroke 2005 ;36:954
53. Sturgeon JD et alStroke 2005;36:2484
54. Eikelboom JW et al Stroke 2000;31:1069
55. J Neurosurg 1994 Jan;80(1):51-7
56. Cerebrovasc Dis 1999 Mar-Apr;9(2):102-8
57. Caplan LR Caplan’s Stroke 4th ed 2009.p22
58. BamfordJ et al Lancet22;337(8756):1521-6,1991
59. NEJM 333:1581-7
 References cont


60. Ayerbe L et al Br J Psychiatry 2013;202:14

61. Robinson RG et al Stroke 1982;13;635
62. Herrmann et al N Stroke 1998;29:618
63. Chemerinski E et al Stroke 2001;32:113
64. Watkins C BMJ 2001:323:1159
65. Hackett ML et al Cochrane Database Syst Rev 2008; CD003437
66. William LS et al Stroke 2007;38:998
67. Mitchell PH et al Stroke 2009; 40:3073
68. Wiart L et al Stroke 2000; 31:1829
69. Robinson RG et al Am J psychiatry 2000; 157:351
70. Kimura et al M Stroke 2000;31:1482
.71 Gainotti G et al J Nuerol Neurosurg Psychiatry 2001;71:258
 References cont
59. Jorge RE et al Am J Psychiatry 2003;160:1823
60. Schmid AA et al Neurology 2011 ;76:1000
61. Robinson RG et al JAMA 2008;299:2391
62. Ivan CS et al Stroke 2004;35:1264
63. Desmond DW et al Stroke 2002;33:2254
64. Srikanth VK et al Stroke 2006; 37:2479
65. Johansson et al Telemed Telecare 2011;17:1-6
66. Vahedi K et al Lancet Neurol 2007;6:215
67. Broderick J et al Stroke 2007;38:2001
68. Kwakkel et al Disabil & Rehab 2006;28:823-830
69. Lo et al NEJM 2010;10:1056
83. Van de Port et al BMJ 2012;344:e2672
84. Steven C Cramer ,”Brain repair after stroke” ESC conf,London , June 2013
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