Stroke

CVA. 1

Risk Factors. 1

Classification. 1

Investigations. 2

Treatment of Ischaemic CVA. 2

Secondary prevention. 4

Young stroke. 5

Stroke Syndromes. 5

Studies. 5

References. 6

CADASIL. 6

Pathology. 6

Clinical manifestations. 6

Diagnosis. 7

Treatment 7

 

Classification and Risk factors

Classification – by cause

·       The TOAST classification of aetiology is currently most used (devised 1991)

 

 

Aust*

Ischaemic

85%

72.5

Large artery (thrombus or embolism)

      50%

 

Small artery

25%

 

Cardioembolic

20%

 

Other (rarities)

      5%

 

 

 

 

Haemorrhagic

15%

14.5

Hypertensice ICH

50%

 

SAH

25%

4.3

Other

25%

 

Unknown

 

8.7

*NEMESIS study

Full list of causes

Atheroembolism

·       Embolism

·       Thrombus – occlusive

·       Low flow with non-occlusive thrombus

·       Dolichoectasia

Small vessel disease

·       Standard

·       Cerebral amyloid angiopathy

·       CADASIL

 

Rarities

Autoimmune

·       Vasculitis

o   GCA

o   Takayasu’s

o   Other – PAN, Wegener’s

o   Kawasaki

o   Susac’s syndrome

o   Cogan syndrome

o   Primary cerebral vasculitis

·       SLE

·       Antiphospholipid syndrome (APLS)

·       Behcet’s disease

·       HSP

·       Essential cryoglobulinaemia

·       Sarcoidosis

·       Buerger’s disease

Secondary inflammatory vascular disease

·       Drugs

·       Radiation

·       Infections

Non-inflammatroy vasculopathies

·       RCVS

·       PRES

·       Moyamoya

·       Fibromuscular dysplasia

·       Connective tissue disorders (Marfan, Ehlers Danlos)

Congenital

·       Fibromuscular dysplasia

·       Hypoplastic carotid and vertebral arteries

·       Internal carotid artery loops

Dissection

·       Trauma

·       Cystic medial necrosis

·       Fibromuscular dysplasia

·       Syndromes – Marfan, Ehlers-Danlos, Osteogensisis imperfecta

·       Inflammation

·       Infection (syphilis)

·       ADPKD

Haematological

·       Hereditary coagulation/thrombophilia

·       Sickle cell disease

·       PNH

·       Essential thrombocytosis

·       Polycythaemia

·       Paraproteinaemia (hyperviscosity)

·       Haematological malignancy

Malignancy

·       Malignancy related hyperviscosity

·       Direct tumour effects

·       Marantic endocarditis

·       Chemotherapy treatment

Genetic

·       Fabry disease 

·       AR -CADASIL, CARASAL, RVCL, COL4A1

·       AD - Tangier disease, CARASIL, homocystinuria, Sneddon syndrome

·       Mitochondrial disease (MELAS)

Misc

·       Air, fat or cholesterol embolism

·       Migraine

·       OCP

·       Post angiography

·       Toxic effect so venom

·       HHT

Risk Factors

Non-Modifiable

·       Age

·       Sex (M>F)

·       Family history

·       Race

Modifiable - definite

·       HTN

·       DM

·       Smoking

·       Alcohol – U shaped, high consumption shows increased risk

·       OCP

·       Herpes Zoster (especially prior to age 40)

·       Other vascular disease

o   IHD

o   CCF/LVH

o   AF

o   PVD

Modifiable – possible

·       Hyperhomocysteinaemia  - association exists however causality and reversibility unknown

·       Plasma fibrinogen - association exists however causality and reversibility unknown

·       Haemoglobin level and hyperviscosity

·       Exercise – causality unknown

·       Obesity - causality  unknown

·       Dental procedures – risk increased after recent procedure

Previous Cerebrovascular disease

·       A big risk factor for stroke 14% of strokes will have prior stroke (~1/8)

·       1/8 people with TIA will go on to have CVA within 1 year

 

 

 

RR

RRR with treatment

NNT PP

NNT SP

NON-Modifiable

Age (80yrs vs 40yrs)

30

Modifiable

HTN

2-5

28-38%

100-300

50-100

AF

2-3 (?6)

68% warfarin

21% aspirin

20-83

13

DM

2-6

No proven effect

 

 

Smoking

2

50% at 1 year

Baseline risk after 5y

 

 

Hyperlipidaemia

(esp if <45yo)

<2

10-29%

 

 

Asymptomatic carotid stenosis

2.0

53%

85

 

Symptomatic carotid stenosis (70-99%)

65% at 2yrs

12

Symptomatic carotid stenosis (50-69%)

29% at 5yrs

77

Renal Impairment (eGFR <40)

( BMJ 2010)

1.43

 

Herpes zoster

(esp. age <40)

~1.7

 

 

 

PP primary prevention SP secondary prevention

 

 

 

 

Clinical

 

Stroke Syndromes

Lacunar

25%

Anterior circulation

51%

    Partial anterior

    34%

    Total

    17%

Posterior circulation

24%

 

 

 

Total Anterior Circulation Infarction (TACI)

·       Hemiparesis

o   With/without hemisensory loss

·       Homonymous hemianopia

·       Cortical deficit – neglect or aphasia

 

Partial Anterior Circulation Infarction (PACI)

·       Two out of the three from TACI

·       OR isolated cortical deficit

o   Aphasia

o   Predominantly proprioceptive deficit in one limb

o   Motor/sensory deficit restricted to one part of body

Lacunar Infarction

  • Pure motor or sensory stroke

 

Posterior Circulation Infarction (POCI)

Clinical

 

Symptoms

·       Headache – occurs in ~25% of strokes, more common in posterior circulation infarcts, may be correlated with site of injury.

·       Seizure – rare (~5%) at time of stroke, more common with haemorrhage,

o   Presence of seizure in stroke should prompt consideration of underlying tumour or encephalitis etc.

·        

Gerstmann Syndrome

·       Clinical features

o   Agraphia

o   Acalculia

o   Finger agnosia

o   Left-Right disorientation

·       Existence of the conditions seems controversial

·       (Don’t confuse with another Gerstmann Syndrome related to prions)

·       Caused by lesions in the dominant parietal lobe (usually left)

·       In particular the angular gyrus (junction of the temporal and parietal lobes)

·        

Investigations

Investigations - Acute

  • CT
    1. Signs
      1. Hyperdense MCA – occur in ~50% with proven MCA occlusion
      2. Basal ganglia changes
        1. – loss of definition of the grey matter best seen at the edge of the caudate capsule
      3. Cortical changes
        1. Loss of definition of the insular ribbon
    2. CT perfusion imaging
      1. Standard images show damaged region.
      2. Perfusion shows area of decreased blood flow – identifies ischaemic penumbra
  • MRI
    1. Better identification of posterior fossa, small white matter lesions and vasculitis etc
    2. Haemorrhage not as clear.
    3. DWI
      1. Very sensitive
      2. ~90% accurate
        1. False positives – Transient global amnesia, status, hypoglycaemia, TIA
        2. False negatives – 2-12%, especially if very early, more in posterior fossa
  • ECG
    1. AF or evidence of cardiomyopathy
  • Bloods – (as per 2010 guidelines)
    1. FBC
    2. Electrolytes
    3. CRP, ESR – inflammatory cause – infective endocarditis or giant cell arteritis
    4. LFTs – to diagnose liver disease and potential coagulopathy, baseline prior to starting statin
    5. Coagulation profile
    6. BSL – in case hypoglycaemia is contributing to the symptoms
  • CXR – as a baseline given risk of aspiration, evidence of cardiomegaly, dissection or malignancy. 

Secondary prevention – Investigations

Imaging

·       Carotid USS

·       MRI

o   Can use either MRA or Contrast enhanced MRI

o   Cost-effectiveness studies do not support routine use at current costs

o   Useful if delayed presentation and doubt about true degree of stenosis if in 50-79% range.

·       Echocardiogram

o   Cost effectiveness data do not support its routine use

o   Targeted use in patients with abnormal ECG or other evidence of thromboembolism etc.

 

Other

·       In addition to acute bloods listed above

·       Fasting lipids and BSL

 

Rare causes/young stroke bloods

·       Autoimmune screen

o   ANA

o   ENA

o   APLS

o   Anti-dsDNA

o   ANCA

·       Infection screen

o   Syphilis

o   HIV

o   HCV

·       Thrombophilia screen

o   APLS

o   Factor V leiden

o   Prothrombin gene mutation

o   Protein C+ S

o   AT III deficiency

·       Other

o   SPEP

·       Consider CSF (vasculitis etc)

·       Genetic/metabolic testing in selected cases

o   Fabry testing

 

Treatment - acute

Thrombolysis

    • Up to 4.5 hours beneficial
    • Up to 3 hours well proven (NINDS, ECAS II)
    • 3-4.5 hours shown to be effective (ECASS III trial)
      1. US guidelines suggest some exclusions from extended period – age >80, any warfarin use, baseline stroke score >25, hx of both DM and CVA.
    • However the earlier the better the outcomes.
    • Increases symptomatic haemorrhage 0.6% to 6.4% but does not alter mortality
    • Increases the number of patients with a favorable outcome (mRS 0-1)
    • Cochrane review showed 14% reduction in death or disability (if given within 3 hours)

Aspirin (within 48hours)

    • Trials looked at outcomes at 2-4 weeks and then again at 6 months – IST and CAST trials (1997).

At 14 days:

    • Reduces death at 14 days (5.0% vs 5.4% - NNT 200, 5/1000)
    • Recurrent ischaemic stroke (2.3% vs 1.6% - NNT 142, 7/1000)
    • Further stroke or death (9.1% vs 8.2% - NNT 111, 9/1000)
    • ICH – 2 extra per 1000 treated

At 6 months:

    • 13/1000 more people alive and independent at 6months.

 

Prevention of aspiration – speech therapy

DVT prophylaxis

    • Conflicting results – some studies show no benefit of heparin, LMWH seems to have consitently positive effect
    • No increase in haemorrhage with LMWH (high dose heparin/LMWH decreases DVT more but increases haemorrhage)
    • Enoxaparin better than heparin in one study:
    • RR 0.57 (10% vs 18%) PREVAIL study (The Lancet 2007; 369:1347-1355) (No difference in haemorrhage b/n groups)

Blood pressure

    • No conclusive evidence of any benefit from blood pressure lowering in the first 48hours
    • Arbitrary target of less than 220/110 set in guidelines
    • Above this level reduction of 10-20% per day may be attempted with agent of choice
    • Usual anti-hypertenstives should be given if no contra-indication

Manage cerebral oedema (peaks day 2-3 but can persist ~10days)

    • Raise bed head 20-30 degrees
    • Mannitol – insufficient evidence to recommend
    • Glycerol – evidence of short term benefit with no long term benefit – may be considered while awaiting surgery
    • Hyperventilation is temporary measure but may also cause vasoconstriction and extend CVA
    • Steroids – have not shown benefit and may cause harm, therefore avoid.
    • Decompression
      1. DECIMAL, DESTINY, HAMLET trials (and meta-analysis of all three: Lancet Neurol 2007; 6: 215–22)
      2. Significant overall increased survival (75% vs 24%, ARR 50%, NNT 2)
      3. Increases the number of people who survived with mRS </=3 (NNT 4)
      4. However the proportion of survivors with bad score increased – i.e. if survival, more likely to have poor outcome. 
      5. Note that average age was ~45yrs in these studies and patients <60years maximum.
      6. Decompression of cerebellar strokes more beneficial. 

 

 

 

BSLs – can be disturbed by CVA,

    • Should be monitored in all patients regardless of DM status
    • Studies have shown that high BSL correlated with worse outcome (TOAST study)
    • Interventional studies to prove that tight control improves outcome have negative so far (but small) GIST-UK
    • Recommend reducing very high BSLs but very tight control unproven

Stroke units

    • Large systematic review (Cochrane 2009)
    • Decreased mortality (ARR 3%)
    • NH care requirement decreased (ARR 2%)
    • Independence increased (ARR 5%)
    • Death or dependency OR 0.82

Cooling

    • No evidence that physical cooling helps
    • Some low grade evidence that paracetamol in patients with fever has beneficial effects on outcome.

Seizures

    • Occur early (<7days) in probably ~3% of patients
    • No evidence for prophylactic anticonvulsant use
    • No particular agent proven superior for recurrent seizures

 

 

Secondary Prevention - Interventions

·       Risk of recurrence:

o   43% at 10 years (4%/year)

Anti-platelet agents

Aspirin

o   RRR ~13-20%

Clopidogrel

•   CAPRIE – clopidogrel vs aspirin in a group of mixed vasculopaths found non-significant benefit in CVA

Clopidogrel and Aspirin

•   MATCH – combination of aspirin and clopidogrel post stroke – combination worse (Risk of life-threatening bleed - 2.6% vs 1.3%)

•   SPS3 (2012) – aspirin and clopidogrel post lacunar stroke – no significant reduction in stroke, more bleeding.

•   SPS3 subgroup – the addition of clopidogrel to patients who were already taking aspirin when they had stroke – no benefit

•   CHANCE trial (NEJM 2013)

o   China, 5170pts with minor stroke (NIHSS </=3 at time of recruitment) or high risk TIA (ABCD >/=4).

o   RCT to Aspirin vs Aspirin/Clopidogrel (300mg loading dose +75mg daily starting with 24hours of event)

o   Dual agent continued for 21 days

o   Stroke 8.2% vs 11.7% (HR 0.68, ARR 3.5% (NNT 29))

o   Haemorrhage similar in both groups (0.3%)

 

 

•   POINT Trial (NEJM 2018)

o   USA/Europe/Aust/NZ

o   Similar to CHANCE, similar outcomes

o   Aspirin vs Aspirin/Clopidogrel (600mg loading dose +75mg daily)

o   Primary outcome - Stroke/MI/vascular death – 5% vs 6.5%

-   ARR1.5%

-   RRR 23%

o   Stroke/MI/vascular death/major haemorrhage 5.8% vs 6.8%

o   Ischaemic Stroke – 4.6% vs 6.3%

 

 

Aspirin and dipyridamole

•   ESPS-2, Esprit 06

•   RRR ~ 37%

•   PROFESS – compared clopidogrel and asasantin

•   no difference in outcomes

•   greater proportion of asasantin dropped out due to SE – headache in particular

Warfarin – NOT USEFUL ULESS AF

•   ESPIRIT trial (post TIA or ‘small CVA’) – no benefit, more SE.

•   Treat AF – as per usual guidelines

Hyperlipidaemia

•   Statins of proven benefit

•   Overall OR 0.88 (Risk of ischaemic stroke 0.8, Haemorrhagic OR 1.73, thus partially offsetting benefit)

•   SPARCL trial – Atorvastatin 80mg

o   Given to patients who would not otherwise get  statin

o   HR for stroke 0.84

o   ARR at 5yrs 2.2%

o   No mortality difference

o   Increase in ICH

Blood pressure

•   Recommended for most – benefit regardless of baseline BP

•   All agents have shown some benefit except Beta blockers

•   AHA Guideline 2014

o   Target <140/90 for all patients

o   Target <130 systolic for lacunar patients

 

•   PROGRESS study

o   Stroke within 5 yrs (median 8mths), high or high normal BP, given perindopril or placebo

o   Indapamide added if necessary

o   Overall – RRR 28%, ARR 4%

o   Perindopril/indapamide – bigger decrease in BP - RRR 43%

o   Benefit regardless of baseline BP

•   PRoFESS

o   Telmisartan vs placebo with no effect

o   However BP reduction was only 4/2mmHg

Carotid disease

    • Surgery if appropriate

Smoking

    • Increased risk of stroke essentially disappears 5 years after cessation.

Physical activity

    • Proven in primary prevention but no studies in secondary prevention – recommended as likely beneficial

Weight reduction

    • No proven benefit

Alcohol

    • No specific recommendations for secondary prevention – see primary prevention
  •  

Young stroke

·       >65 (>45 in ATSI)

·       Still largely due to atheroembolic disease however a higher proportion are due to other causes

·       Procoagulant screen

o   Protein c/s, ATIII, Factor V Leiden, Lupus anti-coagulant, homocysteine

·       TOE – patent foamen ovale

·       MRI – AVM

·       CT Angio/ MRA – carotid dissection

 

Studies

SPARCL

  • Atorvastatin after CVA

ESPS-II

 

EXPRESS study

  • Lancet Neurology 2009
  • Patients presenting with TIA
  • Effect of either direct referral (from ED) to speciality clinic vs returning pt to GP for subsequent referral to speciality clinic. 
  • Decreased admission for stroke at 90 days (2% vs 8%), decreased CVA at 6months, decreased overall hospital costs. 

 

Thrombolysis

NINDS

  • NEJM 2005
  • 624 patients within 3 hours
  • Reduced deatha and disability by 6.6%

 

SITS-MOST

  • Thrombolysis in practice
  • 6500 patients
  • ICH 7.3% (3x risk)
  • Confirmed benefits – as per NINDS trial

 

ECASS III trial

  • NEJM Sept 25 2008
  • Alteplase vs Placebo in 3 to 4.5hour time period
  • Improvement in ‘favourable outcomes’, no difference in mortality.

SITS-ISTR

  • Lancet 2008 372
  • Compared outcomes between (3 to 4.5hours) and <3hours – similar safety

 

 

References

Series from the Lancet Vol 369 (2007)

 

 

CADASIL

·       (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)

·       Onset <50years, median first stroke ~50

·       All patients with mutation will have MRI lesions by age 35

·       Variable course – age of onset does not predict rapid course and survival can be long.

Pathology

·       NOTCH3 gene mutations

·       Involved in smooth muscle cell function

·       Abnormal protein accumulates within cells in blood vessel walls and has an adverse effect on their development and response to injury (exact action not clear)

·       Affects all blood vessels but clinical manifestations limited largely to the brain

·       Rare – several hundred families worldwide

Clinical manifestations

·       Four

o   Ischaemic episodes (85%)

o   Cognitive deficits (60%)

o   Migraine with aura (30%)

o   Psychiatric disturbances (25%)

·       Ischaemic stroke

o    Median onset ~50

o   Classic lacunar syndromes

o   Unusual brainstem ‘lacunars’

1.     Pseudobulbar palsy

·       Cognitive deficits

o   Essentially a vascular dementia

·       Migraine

o   Often an early sign

o   Reduces in frequency as disease progresses

·       Psychiatric

o   Depression is major issue

o   Bipolar, panic and rarely psychosis can occur

o   Apathy is common

Diagnosis

·       MRI

o   Well defined typical lacunar infarcts

o   Less well defined T2 hyperintensities in subcortical white matter – less discrete, frequently symmetrical

1.     Anterior temporal lobe lesions in 90%

o   Cerebral microbleeds also common

o   Brain atrophy

·       Genetic testing

·       Biopsy – skin

o   Characteristic changes in blood vessel walls (granular osmiophilic material)

Treatment

·       None

·       Treat other vascular risk factors

·       Triptans should be avoided in migraine because of increased risk of stroke.

·